Conditions

Question 1

Carney Complex (gene & inheritance)

Answer 1

PRKAR1A

Dominant

Question 2

Carney Complex(tumors)

Answer 2

Tumors:

• Myxomas (breast myxomatosis, osteochdromyoxma, cardiac myxoma)
• Thyroid carcinoma
• Skin tags, lipomas
• Psammomatous melanotic schwannomas
• Sertoli cell tumors
• Pituitary & Breast adenomas

**Must always histologically confirm myxoma (connective tissue tumor)

Question 3

Carney Complex(non-tumor features)

Answer 3

Pale brown to black lentigines; increase in number and appear anywhere on the body including the face, the lips, and mucosa around puberty

Epithelioid-type blue nevi (small bluish domed papules with a smooth surface), combined nevi, café au lait macules, and depigmented lesions

Question 4

HBOC(genes & inheritance)

Answer 4

BRCA1 (17q21) & BRCA2 (13q21.3)

Dominant

Tumor suppressor genes

Question 5

HBOC (tumors)

Answer 5

• Breast (40-80% lifetime risk, higher in BRCA1)
• Ovarian (11-40% lifetime risk, higher in BRCA1)
• Male Breast Cancer
• Prostate cancer (higher in BRCA2)
• Pancreatic cancer (higher in BRCA2)
• Melanoma (BRCA2 only)

Question 6

HBOC (management)

Answer 6

• Breast awareness @ 18
• Clinical breast exam every 6-12 mos @ 25 (female) OR @ 35 (male)
• Annual MRI @ 25-Annual Mammogram @ 30
• Option of prophylactic mastectomy
• Recommend BSO @ 35-40
• Prostate exams starting @ 40

**Gail=Tamoxifen (5 yr risk >1.6%)

**Claus=MR

Question 7

FAP(gene & inheritance)

Answer 7

Familial Adenomatous Polyposis

APC gene (5q21-22)

Dominant

15-30% de novo rate

Question 8

FAP(major features (excluding tumors) & testing criteria)

Answer 8

Major features:

• 100+ adenomatous colon polyps
• Average age of onset for 1st polyps : 16yrs

Testing criteria:

• 10+ polyps
• Fam hx FAP
• Fam hx adenomas & FAP-related extra-colonic findings

Question 9

FAP(associated tumors & clinical features)

Answer 9

• Colon (~100% lifetime risk)
• Small bowel
• Pancreatic
• Bile duct
• Stomach
• Thyroid (papillary)
• CNS
• Liver (rarely hepatoblastoma in children)
• Jaw osteoma
• Abdominal desmoid tumors

Clinical Features:

• absent/supernumerary/malformed teeth
• CHRPE

Question 10

FAP(treatment)

Answer 10

Colectomy is recommended after adenomas emerge

in approximately one third of individuals the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient

Question 11

AFAP

Answer 11

Attenuated Familial Adenomatous Polyposis

10-99 adenomatous colon polypsTumors typicaly more proximal in colon

**I130K polymorphism found in 6-7% of affected individuals

Question 12

Gardner Syndrome (FAP Variant)

Answer 12

FAP with osteomas and soft tissue tumors (fibromas, desmoid, epidermoid)

Question 13

Turcot Syndrome(FAP/HNPCC Variant)

Answer 13

FAP with CNS tumors, specifically medulloblastoma

**Caused by monoallelic MMR (1/3) or APC (2/3) mutation

Question 14

HNPCC/Lynch Syndrome(genes & inheritance)

Answer 14

• Hereditary Non-Polyposis Colorectal Cancer
• MLH1, PMS2, MSH2, MSH6, EPCAM
• MLH1 & MSH2 most common | MSH6 rare
• Most commonly caused by MLH1 SOMATIC mutations

***BRAF (V600E) somatic mutation =sporadic, causes MLH1 hypermethylation

-Dominant-Base pair su

Question 15

HNPCC(associated tumors)

Answer 15

Major associated tumors:

• Colorectal (R ascending)
• 80% lifetime risk

***Adenomatous tumors

• Uterine-Small bowel
• Ureter
• Renal pelvis
• Ovarian

Other associated tumors:

• Stomach**
• Gallbladder
• Brain

Question 16

Amsterdam I Criteria

Answer 16

• 3 individuals with CRC (1 must be FDR of other 2)
• 2 generations
• 1 diagnosed <50yrs

**FAP excluded

Question 17

Amsterdam II Criteria

Answer 17

**Includes Lynch-related tumors (CRC, uterine, small bowel, ureter & renal pelvis)

• 3 individuals with Lynch-related tumors(1 must be FDR of other 2)
• 2 generations
• 1 diagnosed <50yrs**FAP excluded

**50% of true Lynch families meet criteria

Question 18

MLH1 & PMS2(tumor testing)

Answer 18

MMR genes

• HNPCC/Lynch

**Most tumors are MSI-high (must rule out BRAF mutation)

• Absence of both: MLH1 mutation OR MLH1 promotor hypermethylation (R/O through BRAF testing)
• Absence of PMS2: PMS2 mutation or MLH1 mutation

Question 19

MSH2 & MSH6(tumor testing)

Answer 19

MMR genes

• HNPCC/Lynch
• Absence of both: MSH2 mutation OR EPCAM mutation
• Absence of MSH6: MSH6 mutation

Question 20

HNPCC (treatment)

Answer 20

• If CRC present, full colectomy with ileorectal anastomosis indicated
• Colonoscopy every 1-2 years starting @ 25-Consider annual pap smear, transvaginal US, endometrial biopsy, and CA-125 level

Question 21

Bethesda Criteria

Answer 21

• CRC diagnosed <50yrs-Personal history of 2 Lynch-related cancer diagnoses
• CRC that is MSI-high dx <60yrs
• Personal history of CRC & Fam hx (FDR) with Lynch cancer dx <50yrs
• Personal history CRC with 2 FDR or SDR wit Lynch cancer at any age

**Has a 75%

Question 22

HNPCC(testing criteria)

Answer 22

• Meets Amsterdam II criteria
• Meets Bethesda criteria
• Diagnosed with Uterine cancer <50yrs
• Known Lynch syndrome in family
• >=5% risk of Lynch on prediction model

Question 23

MUTYH-associated polyposis(gene & inheritance)

Answer 23

MUTYH Recessive

-Base excision repair genes

**Mutations lead to G:C or T:A transversions can lead to Lynch-like features/cancer risks

Question 24

MUTYH(associated features)

Answer 24

• Characterized by an increased risk for adenomatous colon polyps and CRC (80%)
• High amount of phenotypic heterogeneity (10-100 adenomas, 100+ adenomas, APC normal)

Question 25

MUTYH(referral indication)

Answer 25

Any individual with a personal history of OR FDR with: - 10+ cumulative adenomatous colon polyps with or without CRC - MMR proficient CRC diagnosed

Question 26

Li-Fraumeni(gene & inheritance)

Answer 26

TP53 (17p13) & CHEK2 (22q12.1) Dominant - TP53 protects against cancer but causes premature aging; policing of cells is too strict - too many cells enter apoptosis; Upregulation occurs when mutation present - ~20% de novo - Multiple primary tumors with the first primary often occurring before age 30. ~100% lifetime risk for cancer. \*\*TP53 mutation analysis for female breast cancer \<35 years

Question 27

Li-Fraumeni(associated tumors)

Answer 27

Sarcomas Breast cancer Brain tumpors (astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas) Adrenocortical carcinomas Other: GI cancers, GU cancers, leukemias and lymphomas, lung cancer, neuroblastoma, skin cancers, thyroid cancers

Question 28

Li-Fraumeni(diagnostic criteria)

Answer 28

All of the following: - Proband with sarcoma \<45yrs - FDR with cancer \<45 - AND FDR/SDR with any cancer \<45 or sarcoma at any age \*\*Most important to screen for childhood brain cancers & breast cancer screening

Question 29

Chompret Criteria(Li-Fraumeni)

Answer 29

- Proband with tumor in LFS-spectum \<46yrs AND at least 1 FDR/SDR with LFS tumor (except breast if proband also has breast) before age 56 or with multiple tumors; OR - Proband with multiple tumors (except multiple breast tumors) two of which belong to LFS tu

Question 30

MEN1(gene & inheritance)

Answer 30

MEN1 (11q13)Dominant \*\*Sequencing detects most cases \*\*MEN1 - tumor suppressor gene

Question 31

MEN1(associated tumors)

Answer 31

Parathyroid (100% by age 50) Anterior pituitary (30-40%) Well-differentiated endocrine (gastrinoma, insulinoma, glucagonoma, VIPoma) Carcinoid Adrenocortical (pheos are rare)

Question 32

MEN1(growths)

Answer 32

Facial angiofibromas Collagenomas Lipomas Cafe a lait macules

Question 33

MEN1(diagnostic criteria)

Answer 33

Tumor in 2 of: -parathyroid, enteropancreatic endocrine tissue, OR anterior pituitary; ORTumor in one and FDR with MEN1

Question 34

MEN1(treatment)

Answer 34

- Head MRI @ 5yrs - Abdominal CT or MRI @ 20yrs - Calcium serum concentrations @ 8yrs - Gastrin @ 20yrs - Pancreatic polypeptide @ 10yrs - Prolactin @ 5yrs

Question 35

MEN2(gene & inheritance)

Answer 35

RET (10q11.2)Dominant \*\*PROTO-ONCOGENE Sequencing detects majority of MEN2 cases (MEN2A exon 10&11; MEN2B exon 16)

Question 36

MEN2A(clinical features)

Answer 36

- Medullary thyroid cancer (\<35 yrs) - Pheochromocytoma (50%) - Hyperparathyroidism - Parathyroid adenomas - May present with cutaneous lichen amyloidosis \*\*Prophylactic thyroidectomy \*\*GoF mutations

Question 37

MEN2B(clinical features)

Answer 37

- Medullary thyroid cancer in childhood (prophylactic thyroidectomy BEFORE age 1) - Pheochromocytoma (50%) - Marfanoid habitus, kyphoscoliosis - Hooded eyes, prominent lips - Growths: mucosal neuromas, diffuse ganglioneuromatosis of the digestive tract

Question 38

Familial Medullary Thyroid Cancer

Answer 38

Medullary thyroid cancer without other symptoms of MEN2A/MEN2B \*No pheo or parathyroid adenoma/hyperplasia \*\*GoF mutations

Question 39

Hirschprung's disease

Answer 39

\*\*LoF mutations (chromosome 10) Megacolon Constipation

Question 40

Neurofibromatosis Type 2(gene & inheritance)

Answer 40

NF2 (22q12.2) - tumor suppressor Dominant 50% de novo rate; can have somatic mosaicism \*\*sequencing detects 75%; del/dup detects 10-15% Diagnostic criteria: - bilateral vestibular schwannomas - first degree relative - unilateral 8 nerve mass OR two of the following: +++meningioma, glioma, schwannoma, juvenile posterior subcapsular lens opacity-unilateral vestibular schwannoma AND 2 of the following: +++meningioma, schwannoma, glioma, NF, posterior subcapsular lens opacity-multiple meningiomas AND unilateral vestibular schwannoma OR two of the following: +++schwannoma, glioma, NF, cataract

Question 41

NF2(features)

Answer 41

-Bilateral vestibular schwannomas by 30yrs +conductive hearing loss +tinnitus +balance dysfunction (death by drowning key finding) +decreased visual acuity -Schwannomas elsewhere in body +nerve sheath tumors - Ependymomas - Meningiomas - Cafe-au-lait macule

Question 42

Tuberous Sclerosis Complex(gene & inheritance)

Answer 42

TSC1, TSC2 Dominant \*\*Lots of funky growths \*\*TSC2/PCKD contiguous gene deletion, features of TSC and AD PKD \*\*sequencing

Question 43

TSC(major features)

Answer 43

Angiofibromas (\>3) or fibrous cephalic plaqu Cardiac rhabdomyoma Cortical dysplasias, including tubers and cerebral white matter migration lines Hypomelanotic macules Lymphangioleiomyomatosis Multiple retinal nodular hamartomas Renal angiomyolipomas Shagreen patch Subependymal nodules Ungual fibromas

Question 44

TSC (minor features)

Answer 44

- "Confetti" hypopigmented skin lesions - Dental enamel pits - Intraoral fibromas - Multiple renal cysts - Nonrenal hamartomas - Retinal achromic patch

Question 45

Von Hippel-Lindau Disease(gene & inheritance)

Answer 45

VHL (3p25)Dominant \*\*sequencing followed by deletion analysis (by southern blot) gives very high detection rate

Question 46

Von Hippel-Lindau Disease (associated tumors)

Answer 46

Hemangioblastomas (brain,spinal, retinal) Multiple and bilateral renal cysts Renal cell carcinoma Pheochromocytomas Paraganglioma Pancreatic lesions (cysts, neuroendocrine tumors) Endolymphatic sac tumors Epididymal and broad ligament cystadenomas

Question 47

PTEN Hamartoma Tumor Syndrome(gene & associated syndromes)

Answer 47

PTEN \*\*start with sequencing Variant syndromes: - Cowden - Bannayan-Riley-Ruvalcaba - Proteus - Proteus-like

Question 48

PTEN(associated tumors)

Answer 48

- 2 or more hamartomas in the colon - Breast cancer - Uterine cancer - FOLLICULAR thyroid cancer - Colon cancer - Renal cell carcinoma - Uterine leiomyomas (fibroids) - Mucocutaneous lesions +trichilemmomas +acral keratoses +papillomatous lesions +lipomas +fibromas

Question 49

PTEN (other features)

Answer 49

Macrocephaly, trichilemmomas, lipomas, pigmented macules of the glans penis,

Question 50

Lhermitte-Duclos(PTEN variant)

Answer 50

PTEN with dysplastic gangliocytoma of the cerebellum

Question 51

Cowden(PTEN variant)

Answer 51

- Presents in 2nd or 3rd decade - Macrocephaly & autism - Mucocutaneous facial & oral Papules - Gingival cobblestoning - Acral keratosis - Benign hamartomas of breast, thyroid, uterus, GI - Dystrophic and adenomatous multinodular goiter, GI polyps, adenosis

Question 52

Bannayan-Riley-Ruvalcaba(PTEN variant)

Answer 52

Macrocephaly Hamartomatous polyposis Lipomas Pigmented macules of the glans penis

Question 53

Proteus Syndrome(PTEN variant)

Answer 53

- CT nevi - Disproportionate overgrowth - Dysregulated adipose tissue - Vascular malformation - Risk of ovarian or parotid tumor in 2nd decade

Question 54

Xeroderma Pigmentosum(gene & inheritance)

Answer 54

XPA, XPC, ERCC2, POLH RecessiveDNA -repair protein (NER pathway); UV induced DNA damage

Question 55

Xeroderma Pigmentosum(features)

Answer 55

- Severe sun sensitivity - UV exposure to conjunctiva, cornea, and lids-\> severe keratitis - Progressive neurologic deterioration +acquired microcephaly +decreased/absent DTRs +progressive SNHL +cognitive impairment -\>1000x increased risk of skin and eye neoplasms

Question 56

Birt-Hogg-Dube (gene & inheritance)

Answer 56

FLCN Dominant

Question 57

Birt-Hogg-Dube(clinical features)

Answer 57

-Skin lesions: +Fibrofolliculomas +Perifollicular fibromas +Trichodiscomas +Angiofibromas +Acrochordons -Bilateral and multifocal renal tumors (CHROMOPHOBE CLEAR CELL renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, clear cell renal carcinom

Question 58

Constitutional Mismatch Repair Deficiency

Answer 58

-Characterized by: +high risk of childhood cancers (including LS-associated cancers, hematologic malignancies, and embryonic tumors) +NF1 type features with cafe-au-lait spots and skinfold freckling +Lisch nodules, neurofibromas, & tibial pseudoart

Question 59

Familial Gastrointestinal Stromal Tumor (GIST)

Answer 59

Genes: KIT, PDGFRA, SDHB, SDHC +Germline mutations in KIT: hyperpigmentation, mast cell tumors, dysphagia +PDGFRA mutations: large hands - NF1 can develop GISTs - Wild type GISTs are defied as GISTs that do not have mutations in KIT, PDGFRA, or BRAF

Question 60

Familial Pancreatic Cancer

Answer 60

At least two FDR with pancreatic ductal adenocarcinoma Hereditary syndromes: BRCA2 and CDKN2A

Question 61

Familial Prostate Cancer

Answer 61

AR, AD, and X-linked inheritance patterns

Question 62

Hereditary Diffuse Gastric Cancer

Answer 62

- Gene: CDH1 (occurs in 25-50% who meet criteria) - Increased risk for: +Diffuse gastric cancer +Lobular breast cancer +Signet ring CRC

Question 63

Hereditary Leiomyomatosis and Renal Cell Cancer

Answer 63

- Gene: FH - Renal cancer (papillary type 2 "fried egg") - Cutaneous leiomyoma - Uterine fibroids - Pheos/Paras

Question 64

Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)

Answer 64

- Genes: CDKN2A, ARF - Multiple melanotic nevi (usually \>50) and fam hx melanoma - Individuals have a 17% risk for pancreatic cancer by age 75

Question 65

Hereditary Mixed Polyposis Syndrome

Answer 65

Atypical juvenile polyps Colonic adenomas Colorectal carcinomas Inflammatory and metaplastic polyps Duplication on chromosome 15q13-q14

Question 66

Hereditary Papillary Renal Cell Carcinoma

Answer 66

- Gene: MET - Risk of developing papillary type 1 RCC

Question 67

Hereditary Paraganglioma-Pheochromocytoma Syndrome(genes)

Answer 67

-SDHB, SDHD, SDHC, SDHAF2, MAX, TEME127 +SDHB "Bad" - increased risk for malignancy, fewer tumors, renal cancer +SDHD "Dad" - more tumors, decreased malignancy risk, IMPRINTED-Increased risk for Paras/Pheos

Question 68

Hereditary Retinoblastoma

Answer 68

- RB1 (chr 13) - Malignant tumor of the retina, usually occurring before 5yrs +~40% of all retinoblastomas are hereditary -Osteosarcoma

Question 69

Juvenile Polyposis Syndrome(gene & inheritance)

Answer 69

SMAD4, BMPR1A Autosomal dominant 25% de novo

Question 70

Juvenile Polyposis Syndrome(features)

Answer 70

- 3-5 polyps with juvenile pathology (HAMARTOMAS) - Increased risk for CRC, stomach, upper GI tract, and pancreatic cancer - Extraintestinal features: +valvular heart diesease (11%) +telangiectasia or vascular anomalies (9%, all in SMAD4) +Macrocephaly

Question 71

Nevoid Basal Cell Carcinoma Syndrome

Answer 71

- Gene: PTCH1 - Multiple jaw keratocysts beginning in teens - Multiple basal cell carcinomas beginning in 20s - Physical features: +Macrocephaly, frontal bossing, coarse facial features, facial milia, skeletal anomalies, palmar plantar pits +Cardiac fibromas, ovarian fibromas

Question 72

Peutz-Jeghers Syndrome

Answer 72

- Gene: STK11 - Mucocutaneous hyperpigmentation of the mouth, nose, lips, eyes, genitalia, or fingers - Multiple hamartomatous polyps in the GI tract - Increased risk for: +CRC, pancreatic, gastric, small intestinal, breast cancers +ovarian sex cord tumors

Question 73

Serrated Polyposis Syndrome(formerly hyperplastic)

Answer 73

- Unknown genetic causeReferral reasons: - \>=5 serrated polyps near sigmoid (2 must be \>10mm) - 20+ serrated polyps anywhere - Any number of serrated polyps near sigmoid if FDR with SPS

Question 74

Familial Colorectal Cancer, Type X(FCCTX)

Answer 74

- Meets Amsterdam criteria (clinical dx Lynch) - MSI stable - IHC normal - Left sided tumors - CRC risk is 2-fold increase, later onset - CRC only (NO enometrial) - More polyps than lynch - Management: +c/scope every 5y starting 5-10yrs before earliest dx

Question 75

BRCA Carrier Rate(AJ population vs. General Population)

Answer 75

AJ population: 1/40 General population: 1/800

Question 76

BRCA VUS rate (African American vs. European Population)

Answer 76

African American: 20% \*\*AA cancers are more commonly triple negative European Ancestry: 7%

Question 77

What factors cause an increased risk for breast cancerProtective factors for breast cancer

Answer 77

Increased risk factors (prolonged estrogen exposure): - Menarche \<12yrs-Nulliparity - Menopause \>52yrs - Consuming \>2-3 EtOH drinks per week Protective factors: - 4 hours exercise per week-Breastfeeding - Maintaining ideal weight - Kids before 30

Question 78

BRCA facts 1. Can BRCA1 tumors be treated with drugs that target the estrogen receptor? 2. Is BRCA1 more likely to be invasive lobular? 3. Is BRCA1 or BRCA2 more likely to be triple negative? 4. Is BRCA1 or BRCA2 more likely to be estrogen receptor positive?

Answer 78

1. No 2. No 3. BRCA1 4. BRCA2

Question 79

MUTYH-associated polyposis

Answer 79

MUTYH\*\*Mutations lead to G:C or T:A transversions can lead to Lynch-like features/cancer risks -Characterized by an increased risk for adenomatous colon polyps and CRC (80%)-High amount of phenotypic heterogeneity (10-100 adenomas, 100+ adenomas, APC normal)

Question 80

HNPCC/Lynch Syndrome

Answer 80

-MLH1, PMS2, MSH2, MSH6, EPCAM- MLH1 & MSH2 most common | MSH6 rareMajor associated tumors:-Colorectal (R ascending) - 80% lifetime risk, Uterine, Small bowel, Ureter, Renal pelvisOther associated tumors:-Ovarian, Stomach\*\*, Gallbladder, Brain Treatme

Question 81

Amsterdam I & II Criteria

Answer 81

-3 individuals with CRC (1 must be FDR of other 2)-2 generations-1 diagnosed \<50yrs\*\*FAP excluded

Question 82

Bethesda Criteria

Answer 82

-CRC diagnosed \<50yrs-Personal history of 2 Lynch-related cancer diagnoses-CRC that is MSI-high dx \<60yrs-Personal history of CRC & Fam hx (FDR) with Lynch cancer dx \<50yrs-Personal history CRC with 2 FDR or SDR wit Lynch cancer at any age\*\*Has a 75%

Question 83

MLH1 & PMS2(tumor testing)

Answer 83

MMR genes - HNPCC/Lynch\*\*Most tumors are MSI-high (must rule out BRAF mutation)-Absence of both: MLH1 mutation OR MLH1 promotor hypermethylation (R/O through BRAF testing)-Absence of PMS2: PMS2 mutation or MLH1 mutation

Question 84

MSH2 & MSH6(tumor testing)

Answer 84

MMR genes - HNPCC/Lynch- Absence of both: MSH2 mutation OR EPCAM mutation-Absence of MSH6: MSH6 mutation

Question 85

Li-Fraumeni(gene, inheritance & diagnostic criteria)

Answer 85

TP53 (17p13) & CHEK2 (22q12.1)Dominant-TP53 protects against cancer but causes premature aging; policing of cells is too strict - too many cells enter apoptosis; Upregulation occurs when mutation present-~20% de novo-Multiple primary tumors with the first primary often occurring before age 30. ~100% lifetime risk for cancer.\*\*TP53 mutation analysis for female breast cancer \<35 years -Proband with sarcoma \<45yrs, FDR with cancer \<45 AND FDR/SDR with any cancer \<45 or sarcoma at any age

Question 86

Li-Fraumeni(associated tumors)

Answer 86

#NAME?

Question 87

Chompret Criteria(Li-Fraumeni)

Answer 87

-Proband with tumor in LFS-spectum \<46yrs AND at least 1 FDR/SDR with LFS tumor (except breast if proband also has breast) before age 56 or with multiple tumors; OR-Proband with multiple tumors (except multiple breast tumors) two of which belong to LFS tu

Question 88

MEN1

Answer 88

MEN1\*\*Sequencing detects most cases\*\*MEN1 - tumor suppressor gene Associated tumors:-Parathyroid (hyperparathyroidism, hypercalcemia)-Pituitary (prolactinoma)-Pancreatic neuroendocrine (gastrinoma, insulinoma, glucagonoma)-Carcinoid tumors-Adrenocortical tumors Growths:-Angiofibromas, Collagenomas, Lipomas, Meningiomas, Ependymomas, Leiomyomas

Question 89

MEN1(treatment)

Answer 89

-Head MRI @ 5yrs-Abdominal CT or MRI @ 20yrs-Calcium serum concentrations @ 8yrs-Gastrin @ 20yrs-Pancreatic polypeptide @ 10yrs-Prolactin @ 5yrs

Question 90

MEN2A

Answer 90

-Medullary thyroid cancer (\<35 yrs)-Pheochromocytoma (50%)-Hyperparathyroidism-Parathyroid adenomas-May present with cutaneous lichen amyloidosis\*\*Prophylactic thyroidectomy \*\*GoF mutations

Question 91

MEN2B

Answer 91

-Medullary thyroid cancer in childhood (prophylactic thyroidectomy BEFORE age 1)-Pheochromocytoma (50%)-Marfanoid habitus, kyphoscoliosis-Hooded eyes, prominent lips-Growths: mucosal neuromas, diffuse ganglioneuromatosis of the digestive tract\*\*ABSENCE OF

Question 92

Familial Medullary Thyroid Cancer

Answer 92

Medullary thyroid cancer without other symptoms of MEN2A/MEN2B\*\*GoF mutations

Question 93

Hirschprung's disease

Answer 93

\*\*LoF mutations (chromosome 10)MegacolonConstipation

Question 94

Neurofibromatosis Type 2

Answer 94

NF2 (50% de novo rate) - tumor suppressor-Bilateral vestibular schwannomas by 30yrs +conductive hearing loss +tinnitus +balance dysfunction (death by drowning key finding) +decreased visual acuity-Schwannomas elsewhere in body +nerve sheath tumors-Ependymomas-Meningiomas-Cafe-au-lait macules-Cataracts

Question 95

Tuberous Sclerosis Complex

Answer 95

TSC1, TSC2\*\*TSC2/PCKD contiguous gene deletion, features of TSC and PKD\*\*sequencing -SEIZURES (hypsarrhythmia noted on EEG)-CARDIAC RHABDOMYOMA-Angiofibroma-Cortical dysplasia-Hypomelanotic macules-LAMs (lymphangioleiomyomatosis)-Multiple retinal nodular hamartomas-SHAGREEN PATCH-Renal angiomyolipoma-SEGAs (subependymal giant cell astrocytoma)-Subependymal nodules-Ungual fibromas-Neuroendocrine tumors+pituitary adenoma, parathyroid adenoma, pancreatid adenoma, gastrinoma, pheochromocytoma, carcinoids Minor features:-"Confetti" hypopigmented skin lesions, Dental pits, Intraoral fibromas, Multiple renal cysts, Retinal achromic patch

Question 96

Von Hippel-Lindau Disease

Answer 96

VHL\*\*sequencing followed by deletion analysis (by southern blot) -CLEAR CELL renal carcinoma-Spinal or cerebellar hemangioblastoma-Pancreatic neuroendocrine tumors-Endolymphatic sac tumors-Pheochromocytoma (secrete Norepi only)-Paraganglioma-Retinal angioma-Multiple renal and pancreatic cysts

Question 97

PTEN

Answer 97

-2 or more hamartomas in the colon-Breast cancer-Uterine cancer-FOLLICULAR thyroid cancer-Colon cancer-Renal cell carcinoma-Uterine leiomyomas (fibroids)-Mucocutaneous lesions +trichilemmomas +acral keratoses +papillomatous lesions +lipomas +fibromas Othe

Question 98

Lhermitte-Duclos(PTEN variant)

Answer 98

PTEN with dysplastic gangliocytoma of the cerebellum

Question 99

Cowden(PTEN variant)

Answer 99

-Presents in 2nd or 3rd decade- Macrocephaly & autism-Mucocutaneous facial & oral Papules-Gingival cobblestoning-Acral keratosis-Benign hamartomas of breast, thyroid, uterus, GI-Dystrophic and adenomatous multinodular goiter, GI polyps, adenosis a

Question 100

Bannayan-Riley-Ruvalcaba(PTEN variant)

Answer 100

#NAME?

Question 101

Proteus Syndrome(PTEN variant)

Answer 101

-CT nevi-Disproportionate overgrowth-Dysregulated adipose tissue-Vascular malformation-Risk of ovarian or parotid tumor in 2nd decade

Question 102

Xeroderma Pigmentosum

Answer 102

XPA, XPC, ERCC2, POLHRecessive; DNA-repair protein (NER pathway); UV induced DNA damage-Severe sun sensitivity-UV exposure to conjunctiva, cornea, and lids-\> severe keratitis-Progressive neurologic deterioration +acquired microcephaly +decreased/absent DTRs +progressive SNHL +cognitive impairment-\>1000x increased risk of skin and eye neoplasms

Question 103

Birt-Hogg-Dube

Answer 103

FLCN-Skin lesions: +Fibrofolliculomas +Perifollicular fibromas +Trichodiscomas +Angiofibromas +Acrochordons-Bilateral and multifocal renal tumors (CHROMOPHOBE CLEAR CELL renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, clear cell renal carcinoma)-Multiple bilateral lung cysts (lung blebs) often associated with spontaneous pneumothorax

Question 104

Constitutional Mismatch Repair Deficiency

Answer 104

-Characterized by: +high risk of childhood cancers (including LS-associated cancers, hematologic malignancies, and embryonic tumors) +NF1 type features with cafe-au-lait spots and skinfold freckling +Lisch nodules, neurofibromas, & tibial pseudoarthos

Question 105

Familial Gastrointestinal Stromal Tumor (GIST)

Answer 105

Genes: KIT, PDGFRA, SDHB, SDHC +Germline mutations in KIT: hyperpigmentation, mast cell tumors, dysphagia +PDGFRA mutations: large hands- NF1 can develop GISTs-Wild type GISTs are defied as GISTs that do not have mutations in KIT, PDGFRA, or BRAF

Question 106

Familial Pancreatic Cancer

Answer 106

#NAME?

Question 107

Hereditary Diffuse Gastric Cancer

Answer 107

-Gene: CDH1 (occurs in 25-50% who meet criteria)-Increased risk for: +Diffuse gastric cancer +Lobular breast cancer +Signet ring CRC

Question 108

Hereditary Leiomyomatosis and Renal Cell Cancer

Answer 108

-Gene: FH-Renal cancer (papillary type 2 "fried egg")-Cutaneous leiomyoma-Uterine fibroids-Pheos/Paras

Question 109

Hereditary Melanoma (aka Familial atypical mole and malignant melanoma - FAMMM)

Answer 109

-Genes: CDKN2A, ARF-Multiple melanotic nevi (usually \>50) and fam hx melanoma-Individuals have a 17% risk for pancreatic cancer by age 75

Question 110

Hereditary Mixed Polyposis Syndrome

Answer 110

#NAME?

Question 111

Hereditary Papillary Renal Cell Carcinoma

Answer 111

-Gene: MET-Risk of developing papillary type 1 RCC

Question 112

Hereditary Paraganglioma-Pheochromocytoma Syndrome

Answer 112

-SDHB, SDHD, SDHC, SDHAF2, MAX, TEME127 +SDHB "Bad" - increased risk for malignancy, fewer tumors, renal cancer +SDHD "Dad" - more tumors, decreased malignancy risk, imprinted-Increased risk for Paras/Pheos

Question 113

Hereditary Retinoblastoma

Answer 113

-RB1 (chr 13)-Malignant tumor of the retina, usually occurring before 5yrs +~40% of all retinoblastomas are hereditary

Question 114

Juvenile Polyposis Syndrome

Answer 114

SMAD4, BMPR1A -3-5 polyps with juvenile pathology-Increased risk for CRC, stomach, upper GI tract, and pancreatic cancer-Extraintestinal features: +valvular heart diesease (11%) +telangiectasia or vascular anomalies (9%, all in SMAD4) +Macrocephaly (11%)-SMAD4 may also show symptosm of hereditary hemorrhagic telangiectasia

Question 115

Nevoid Basal Cell Carcinoma Syndrome

Answer 115

-Gene: PTCH1-Multiple jaw keratocysts beginning in teens-Multiple basal cell carcinomas beginning in 20s-Physical features: +Macrocephaly, frontal bossing, coarse facial features, facial milia, skeletal anomalies +Cardiac fibromas, ovarian fibromas, medul

Question 116

Peutz-Jeghers Syndrome

Answer 116

-Gene: STK11-Mucocutaneous hyperpigmentation of the mouth, nose, lips, eyes, genitalia, or fingers-Multiple hamartomatous polyps in the GI tract-Increased risk for: +CRC, pancreatic, gastric, small intestinal, breast cancers +ovarian sex cord tumors with

Question 117

Serrated Polyposis Syndrome(formerly hyperplastic)

Answer 117

-Unknown genetic causeReferral reasons:-\>=5 serrated polyps near sigmoid (2 must be \>10mm)-20+ serrated polyps anywhere-Any number of serrated polyps near sigmoid if FDR with SPS

Question 118

Familial Colorectal Cancer, Type X(FCCTX)

Answer 118

-Meets Amsterdam criteria (clinical dx Lynch)-MSI stable-IHC normal-Left sided tumors-CRC risk is 2-fold increase, later onset-CRC only (NO enometrial)-More polyps than lynch-Management: +c/scope every 5y starting 5-10yrs before earliest dx

Question 119

Major Malformation

Answer 119

#NAME?

Question 120

Minor Anomaly

Answer 120

#NAME?

Question 121

Syndrome

Answer 121

#NAME?

Question 122

Association

Answer 122

#NAME?

Question 123

VACTERL

Answer 123

Vertebral anomaliesAnal atresiaCardiac defectsTracheoesophageal fistulaEsophageal atresiaRenal and radial anomaliesLimb defects

Question 124

Malformation

Answer 124

#NAME?

Question 125

Sequence

Answer 125

#NAME?

Question 126

Potter Sequence

Answer 126

Renal agenesis/renal malformation leading to oligohydramnios which causes distinct physical appearance

Question 127

Pierre-Robin Sequence

Answer 127

Micrognathia leads to cleft palate and glossoptosis and subsequent respiratory distress

Question 128

Deformation

Answer 128

#NAME?

Question 129

Disruption

Answer 129

#NAME?

Question 130

Dysplasia

Answer 130

#NAME?

Question 131

CHARGE

Answer 131

ColobomaHeartchoanal Atresiagrowth RetardationGenital abnormalitiesEar abnormalities

Question 132

Locus Heterogeneity

Answer 132

Mutations in DIFFERENT GENES can cause the SAME DISORDER/phenotypic presentation +ie. Noonan syndrome, Autism

Question 133

Allelic Heterogeneity

Answer 133

DIFFERENT MUTATIONS/alleles on the SAME GENE can cause the SAME DISORDER +ie. Cystic Fibrosis

Question 134

Phenotypic Heterogeneity

Answer 134

DIFFERENT MUTATIONS on the SAME GENE can cause DIFFERENT PHENOTYPES +ie. FBN1, FGFR3

Question 135

Pleiotropy

Answer 135

One gene mutation influences many unrelated phenotypic traits +ie. PKU, Sickle-cell

Question 136

Variable Expressivity

Answer 136

#NAME?

Question 137

Penetrance

Answer 137

#NAME?

Question 138

Arthrogryposis

Answer 138

Congenital joint contracture in two or more areas of the body

Question 139

Amyoplasia

Answer 139

-Literally "no muscle growth"-Replacement of skeletal muscle by dense fibrous tissue and fat-May also include vascular compromise-Form of arthrogryposis\*\*Occurs sporadically due to lack of fetal movement which may be due to an external/environmental facto

Question 140

Ectrodactyly

Answer 140

Deficiency or absence of one or more CENTRAL digits of the hand or foot

Question 141

Klippel-Feil Anomaly

Answer 141

-Congenital fusion of any two of the seven cervical vertebrae-May be caused by mutations in GDF3 and GDF6-AD form at 8q22.2 also associated with laryngeal malformation

Question 142

Mesomelic shortening

Answer 142

Shortening of the DISTAL long bones

Question 143

Rhizomelic shortening

Answer 143

Shortening of the PROXIMAL long bones

Question 144

Micromelic shortening

Answer 144

Shortening of the DISTAL and PROXIMAL long bones

Question 145

Talipes Equinovalgus/Equinovarus

Answer 145

Club foot-Valgus: feet turned outward-Varus: feet turned inward

Question 146

Triploidy

Answer 146

Entire extra set of chromosomes69, XXX / 69, XXY-Present in 1-2% of conceptions, 10% of miscarriages-Typically results in miscarriage in the FIRST TRIMESTER

Question 147

Digyny

Answer 147

#NAME?

Question 148

Diandry

Answer 148

-Extra set of paternal chromosomes-Large cystic/partial molar placenta-Normal growth or limited fetal growth restriction-Maternal serum screening 10x higher hCG -Maternal risk for pre-eclampsia and choriocarcinoma

Question 149

Common features of triploidy

Answer 149

3,4 syndactylyCystic placenta

Question 150

Can Triploidy be detected on NIPT?

Answer 150

Yes, only via SNP-method (ie. Natera)

Question 151

Trisomy 13(Patau Syndrome)

Answer 151

-Maternal Meiosis I-Holoprosencephaly-Cleft lip-VSD, Double outlet right ventricle-Echogenic kidneys-Omphalocele\*\*MSS does not adjust risk for this disorder-Few survive to term, most die within first year of life

Question 152

Trisomy 18(Edward Syndrome)

Answer 152

-Maternal Meiosis II-Clenched fists-Choroid Plexus cysts-Rocker bottom feet-IUGR-Polyhydramnios-Omphalocele\*\*MSS: all markers low-Few survive to term, most die within first year of life

Question 153

Trisomy 21 - Prenatal findings(Down Syndrome)

Answer 153

-Maternal OR Paternal Meiosis I-Increased nuchal translucency in first trimester-Increased nuchal fold in second trimester (\>6.0mm)-Structural heart defect (50%)-Hypoplastic nasal bone-Echogenic bowel-Echogenic intracardiac focus (weak association)\*\*MSS:

Question 154

Trisomy 21 - Postnatal findings(Down Syndrome)

Answer 154

-Mild to moderate ID-Good social skills-CHD (~50% - VSD, ASD, ToF)-Increased risk for leukemia-Decreased risk for solid tumors-BRUSHFIELD SPOTS-GI problems-Hearing loss-Hypothyroidis-Upslanted palpebral fissures-Epicanthal folds-Sandal gap-Short stature

Question 155

Cat Eye Syndrome

Answer 155

-Partial trisomy or tetrasomy of Chromosome 22 +Associated with marker chromosome 22-Usually de novo but parents may be unaffected mosaic- Features +Coloboma +Preauricular pits/tags +Cardiac defects +Missing or underdeveloped kidneys +Short st

Question 156

Turner Syndrome

Answer 156

45, X-Due to paternal meiosis I-Features +Coarctation/Aortic stenosis +Obesity +Amenorrhea +STREAKED OVARIES +Learning difficulties +Horseshoe kidney +Short stature +Webbed neck +Cystic hygroma

Question 157

Klinefelter Syndrome

Answer 157

47, XXY-Maternal or Paternal Meiosis I-Tall stature-Normal intelligence (may have reading/speech difficulties)-Feminization at puberty +Gynecomastia, broad hips, reduced/absent facial hair-Reduced fertility-Hypogonadism-Increased risk for Breast cancer and Thromboembolism

Question 158

XYY Syndrome

Answer 158

47, XYY-Tall stature-DD-Learning difficulties-Behavior problems-No like to increased aggression-NORMAL sexual development

Question 159

TRUE OR FALSE. The karyotype of a spontaneous abortion is more likely to be abnormal than that of a stillborn infant.

Answer 159

TRUE

Question 160

Chromsomes where imprinting should be considered

Answer 160

6, 7, 11, 14, 15, 16

Question 161

Russell-Silver Syndrome(mode of imprinting)

Answer 161

-11p15.5 (30-50% of cases) +Hypomethylation on paternal chromosomes at IC1 leads to H19 expression and IGF2 silencing -Typically, IC1 is methylated with IGF2 expression +Duplication of maternal 11p15.5 (unknown prevalence)-Maternal UPD 7 (7-10

Question 162

Russell-Silver Syndrome(clinical features)

Answer 162

-Triangular face shape with delicate features-Head sparing IUGR --\> SGA/low birth weight-Normal Head Circumference-Hypoglycemia --\> sweating at night-Developmental delay, Learning Disabilities-BLUE SCLERA IN CHILDHOOD-Body asymmetry (small, arm span const

Question 163

Beckwith-Wiedemann Syndrome(mode of imprinting)

Answer 163

11p15 +Maternal loss of methylation IC2 (50%) (causes expression of IGF2 and silencing of H19 - BAD) +Paternal UPD (20% of cases) +Maternal gain of methylation at IC1 (5%) (causes expression of IGF2 and silencing of H19 - BAD) +Maternal CDKN1C mutation (40% familial; 5-10% sporadic) - CDKN1C stops cells from entering cell cycle, mutations allows for overgrowth/overproliferation\*\*IGF2=overgrowth\*\*\*Need mom expressed (H19)

Question 164

Beckwith-Wiedemann Syndrome(Major features)

Answer 164

-Overgrowth-Macrosomia-Earlobe creases, helical ear pits-Macroglossia (enlarged tongue)-OMPHALOCELE-Visceromegaly-Increased risk for embryonic tumors (wilms, hepatoblastoma, neuroblastoma) +Test AFP, discontinue at age 4-Renal abnormalities-Cytomegaly o

Question 165

Beckwith-Wiedemann Syndrome(Minor features)

Answer 165

#NAME?

Question 166

Angelman Syndrome(mode of imprinting)

Answer 166

15q11.2q13 +Maternal 15q11.2q13 deletion including UBE3A (65-75%) +Paternal UPD (3-7%) +Maternal UBE3A mutation (5-11%) +Maternal imprinting defect of 15q11.2q13 (maintains methylation improperly)\*\*\*Need Mom expressed

Question 167

Angelman Syndrome(major features)

Answer 167

-"Happy puppet syndrome"-Severe DD beginning at 6-12 months-Limited or absent speech-Ataxia-Hand Flapping-Seizures-PROGRESSIVE MICROCEPHALY (born normocephalic, microcephaly by age 2)-Laughter, smiling, excitability

Question 168

Angelman Syndrome(minor features)

Answer 168

#NAME?

Question 169

Prader-Willi Syndrome(mode of imprinting)

Answer 169

15q11.2q13 +Maternal UPD (20-30%) +Paternal deletion 15q11.2q13 (65-75%) +Paternal gene deletion of region responsible for methylation/imprinting (de novo OR inherited) +Unbalanced chromosomal rearrangement\*\*\*Need Dad expressed

Question 170

Prader-Willi Syndrome(features)

Answer 170

-Hypotonia & FTT in neonatal/early development-GDD-Excessive eating (pica)-Obesity-Mild ID-Hypogonadism-Hypothyroidism-Sleep Abnormalities-Behavioral problems (Autistic beh., controlling/manipulative, tantrums, hyperactivity, psychosis, compulsive beh

Question 171

Birt-Hogg-Dube

Answer 171

Individual with a person OR FDR with 5 or more BHD associated facial or truncal papules

Question 172

Constitutional Mismatch Repair Deficiency

Answer 172

Any individual with a personal for FDR with:-LS-associated cancer in childhood-Another type of childhood cancer AND one or more of the following: +Cafe-au-lait macules, skinfold freckling, lisch nodules, neurofibromas, tibial pseudoarthrosis or hypopigmented skin lesions +Family history of LS-associated cancer +A second primary cancer +A sibling with a childhood cancer +Consanguineous parents

Question 173

Cowden Syndrome

Answer 173

Any individual with a personal history or FDR with:-Lhermitte-Duclose diagnosed after 18yrs-Any 3 criteria from the major or minor diagnostic criteria list in the same person

Question 174

FAP

Answer 174

Any individual with personal or FDR with:-10+ adenomatous colon polyps with or without a CRC or other FAP-assoc cancer-A cribriform morular variant of papillary thyroid cancer-A desmoid tumor-Hepatoblastoma diagnosed before age 5

Question 175

Familial GIST

Answer 175

Any individual with a personal history or FDR with:-3+ close relatives with GIST-Wild-type GIST-Individuals with 3+ GISTs

Question 176

Familial Pancreatic Cancer

Answer 176

Any individual with a personal or FDR with:-AJ ancestry and pancreatic cancer at any age-Pancreatic cancer and a close relative with pancreatic cancer-3+ cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer-3+ cases of pancreatic cancer and/or melanoma

Question 177

Familial Prostate Cancer

Answer 177

Any individual with a personal or FDR with:-3 or more FDR with prostate cancer-2 or more cases of prostate cancer diagnosed \<55-Aggressive prostate cancer (Gleason score 7+) and 2+ cases of breast, ovarian, or pancreatic cancer

Question 178

Hereditary Diffuse Gastric Cancer

Answer 178

Any individual with a personal or FDR with diffuse gastric cancer

Question 179

Hereditary Leiomyomatosis and Renal Cell Cancer

Answer 179

Any individual with a personal or FDR with:-Cutaneous leiomyomas-RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer

Question 180

Familial Atypical Mole and Malignant Melanoma(Hereditary Melanoma)

Answer 180

Any individual with a personal or FDR with:-3 or more melanomas in the same person-3 or more cases of melanoma and/or pancreatic cancer

Question 181

Hereditary Mixed Polyposis Syndrome

Answer 181

Any individual with a personal or FDR with 10+ colorectal polyps with mixed histology

Question 182

Hereditary Papillary Renal Cell Carcinoma

Answer 182

Any individual with a personal or FDR with papillary type 1 RCC

Question 183

Hereditary Paraganglioma-Pheochromocytoma Syndrome

Answer 183

Any individual with a personal or FDR with a paraganglioma or pheochromocytoma

Question 184

Hereditary Retinoblastoma

Answer 184

Any individual with a personal or FDR with a retinoblastoma

Question 185

Juvenile Polyposis Syndrome

Answer 185

Any individual with a personal or FDR with:-3-5 cumulative histologically proven juvenile GI polyps-Any number of juvenile GI polyps with a positive family history of JPS-Multiple juvenile polyps located throughout the GI tract

Question 186

Lynch Syndrome

Answer 186

Any individual with a personal or FDR with:-CRC or endometrial cancer before 50-CRC or endometrial cancer diagnosed after 50 with a FDR with CRC or endometrial cancer at any age-Synchronous or metachronous CRC or endometrial cancer-Sebaceous adenoma or carcinoma and one or more additional case of any LS-associated cancer in the same person or relatives-A tumor exhibiting MMR deficiency-Fam hx of 3+ LS-associated cancers

Question 187

Melanoma Astrocytoma Syndrome

Answer 187

Any individual with a personal or FDR with:-Melanoma and astrocytoma in the same person-One case of melanoma and one case of astrocytoma in 2 FDR

Question 188

MEN1

Answer 188

Any individual with a personal or FDR with:-2+ different MEN1-associated tumors in the same person-Gastrinoma-Multiple different pancreatic neuroendocrine tumors in the same person-Parathyroid adenoma diagnosed before 30-Parathyroid adenomas involving multiple glands-Parathyroid adenoma with a fam hx of hyperparathyroidism or MEN1-associated tumors

Question 189

MEN2

Answer 189

Any individual with a personal or FDR with:-MTC-Pheochromocytomas-Oral or ocular neuromas (lips, tongue, sclera, or eyelids)-Diffuse ganglioneuromatosis of the GI tract

Question 190

MUTYH-associated polyposis

Answer 190

Any individual with a personal or FDR with:-10+ cumulative adenomatous colon polyps with or without CRC-MMR proficient CRC diagnosed

Question 191

Nevoid Basal Cell Carcinoma Syndrome

Answer 191

Any individual with a personal or FDR with any 2 criteria-Multiple jaw keratocysts beginning in teens and multiple basal-cell carcinomas beginning in 20s-Macrocephaly-Frontal bossing-Coarse facial features-Facial milia-Skeletal anomalies-Cardiac fibromas, Ovarian fibromas, Medulloblastoma

Question 192

Peutz-Jeghers Syndrome

Answer 192

Any individual with a personal or FDR with:-2+ histologically confirmed PJ GI polyps-One or more PJ GI polyp with mucocutaneous hyperpigmentation-Ovarian sex cord tumor with annular tubules-Adenoma malignum of the cervix-Sertoli cell tumor-Pancreatic cacner and one or more PJ GI polyp-Breast cancer and one or more PJ GI polyp-One ore more PH polyp and a positive family history of PJS

Question 193

Rhabdoid tumor predisposition types 1 & 2

Answer 193

Any individual with a personal or FDR with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type

Question 194

Serrated Polyposis Syndrome

Answer 194

Any individual with a personal or FDR with:-At least 5 serrated polyps proximal to the sigmoid colon, 2 of which are \>1 cm (10mm) in diameter-\>20 serrated polyps throughout the large bowel-Any number of serrated polyps proximal to the sigmoid colon and a positive family history of SPS

Question 195

Tuberous Sclerosis Complex

Answer 195

Any individual with a personal or FDR with any two criteria-Brain tumors-Kidney tumors-Heart tumors-Skin and neurological abnormalities-Skin lesions

Question 196

Von-Hippel-Lindau Syndrome

Answer 196

Any individual with a personal or FDR with:-Clear cell RCC if he/she: +has bilateral or multifocal tumors +is diagnosed before age 50 +has a close relative with clear cell RCC-CNS hemangioblastoma-Pheochromocytoma-Endolymphatic sac tumor-Retinal capillary hemangioma

Question 197

Monosomy 1p36

Answer 197

-Aggression/self-injurious behavior-Mild to severe ID-Microcephaly-Scoliosis/kyphosis-Brain MRI abnormalities (cerebral atrophy, ventricular asymmetry and/or enlargement, hydrocephalus)-Visual problems (cataracts, nystagmus, strabismus, hypermetropia)-Hea

Question 198

Wolf-Hirschhorn Syndrome

Answer 198

4p16.3-"greek warrior helmet" (microcephaly, ocular hypertelorism)-Preauricular tags-Growth restriction-Mild-to-profound ID-Coloboma-CHDs-Sleep disturbances-Seizures-Cleft lip/palate-Visceral problems-Antibody deficiency-Hand stereotypies

Question 199

Cri Du Chat Syndrome(chromosome location)

Answer 199

5p- syndromeDominant5p15.2 (critical region)5p15.3 (cat-cry region)Typically de novo (85-90%); PATERNAL de novo (80%)

Question 200

Cri Du Chat Syndrome(major features)

Answer 200

#NAME?

Question 201

Cri Du Chat Syndrome(minor features)

Answer 201

#NAME?

Question 202

Williams Syndrome

Answer 202

7q11.23Dominant, typically de novoContains ELN gene-Cardiovascular disease: SUPRAVALVULAR AORTIC STENOSIS, pulmonic stenosis-Hoarse voice-Connective tissue anomalies: inguinal/umbilical hernia, rectal prolapse, joint limitation or laxity, soft/lax skin-Mild to severe ID-Strong verbal/language skills (poor visuospatial skills)-Friendly/talkative/empathetic/ANXIOUS personality-Endocrine dysfunction: hypothyroid, hypercalcuria, IDDM-STELLATE IRIS-Progressive SNHL-Coarse facies with coarsening over time

Question 203

WAGR Syndrome

Answer 203

11p13-Wilm's tumor (50%)-Aniridia, may also have ptosis and/or cataracts-Genitourinary anomalies +more common in males +women may have streaked ovaries/increased risk for gonadoblastoma-Retardation-Subset have obesity\*\*WT1 - wilms tumor gene\*\*PAX6 - aniridia

Question 204

Smith-Magenis Syndrome

Answer 204

17p11.2 deletion-Inverted circadian rhythm-Aggression, anxiety, impulsiveness, ADHD-REDUCED pain sensitivity-Strabismus-Ear abnormalities-CONDUCTIVE hearing loss-Dysmorphic features-"page turning" motion

Question 205

Miller-Dieker Lissencephaly Syndrome

Answer 205

17p13.3 deletion-Lissencephaly (smooth brain)-ID-Epilepsy-Death in infancy or early childhood-Dysmorphic features: upturned nares, thickened upper lip, frontal bossing, small jaw, low-set posteriorly rotated ears, midface hypoplasia, hypertelorism

Question 206

DiGeorge Syndrome(VeloCardioFacial syndrome)CATCH

Answer 206

22q11.2 deletion-Cardiac anomalies (interrupted aortic arch, ToF)-Abnormal facies-Thymic aplasia (recurrent infection)-Cleft palate-Hypocalcemia/Hypoparathyroidism

Question 207

DiGeorge Syndrome(other features)

Answer 207

-ID/LD-Growth hormone deficiency-Skeletal anomalies-Renal anomalies-CONDUCTIVE & SENSORINEURAL hearing loss-Feeding and swallowing problems-Preauricular tags or pits-Ophthalmologic anomalies-Increased risk for embryonal tumors

Question 208

Smith Magenis Syndrome (inheritance)

Answer 208

-FISH for deletion (90-95%)-Sequencing only (5-10%)-Del/Dup analysis (90-95%); ~90% have 17p11.2 deletion that includes RAI1 gene

Question 209

Alpha-1 Antitrypsin Deficiency

Answer 209

Recessive; SERPINA1\*\*PI\*Z is most common pathogenic mutation (PI\*M is normal)-deficient enzyme: alpha-1 antitrypsin (A1AT)-excess metabolite: decreased A1AT in the lungs, increased abnormal A1AT in the liver-metabolic testing: low serum A1AT-COPD with otherwise unknown etiology-liver disease at any age-C-ANCA positive vasculitis-necrotizing panniculitis (inflammation of the fatty fibrous tissue directly beneath the skin)

Question 210

Canavan Disease

Answer 210

Recessive; ASPA-deficient enzyme: aminoacylase 2-excess metabolite: n-acetylaspartic acid-metabolic testing: elevated urine NAA-symptoms onset in infancy and progress rapidly-TRIAD: hypotonia, had lag, macrocephaly-leukodystrophy-ID-motor skill regression-feeding difficulties-hypo/hypertonia-poor head control-macrocephaly-paralysis-blindness-seizures-shortened lifespan (teens)\*\*milder form exists with mild DDNO treatment

Question 211

Glucose-6-phosphate dehydrogenase deficiency

Answer 211

X-LINKED recessive; G6PD\*\*most common human enzymatic disorder-prolonged neonatal jaundice (can lead to kernicterus if untreated)-hemolytic crisis in response to tirggers:+illness+antimalarial drugs, sulfonamides, analgesics (aspirin)+FAVA BEANS+certain chemicals-diabetic ketoacidosis-severe crisis can lead to kidney failure-common in people of African, middle-eastern, and SE Asian descent

Question 212

Hemochromatosis

Answer 212

Recessive; HFEExcess metabolite: ironMetabolic testing: elevated serum ferritin-hepatomegaly-cirrhosis-hepatocellular carcinoma-diabetes-cardiomyopathy-hypogonadism-arthritis-progressive increase ins skin pigmentationTreatment:-low iron diet-therapeutic phlebotomy-liver transplant may be required if substantial damage

Question 213

Smith-Lemli-Opitz (SLOS)

Answer 213

Recessive; DHCR7-deficient enzyme: 7-dehydrocholesterol reductase-excess metabolite: 7-dehydrocholesterol (7DHC)-metabolic testing: elevated serum 7DHC-mod to severe ID-microcephaly-aggression, self-injury, autism-sensory hypersensitivity-strabismus, cataracts, functional eye abnormalities-congenital heart defects-GI issues-pyloric stenosis-feeding difficulties-renal anomalies-dysmorphic features:+2,3 toe syndactyly, postaxial polydactyly of hands or feet, ambiguous genitalia, hypospadias, bitemporal narrowing, short, upturned nose, ptosis, micrognathia, epicanthal folds, capillary hemangioma of the nose

Question 214

Smith-Lemli-Opitz (SLOS)Dysmorphic features

Answer 214

-2,3 toe syndactyly, -postaxial polydactyly of hands or feet-ambiguous genitalia-hypospadias-bitemporal narrowing-short, upturned nose-ptosis-micrognathia-epicanthal folds-capillary hemangioma of the nose

Question 215

Wilson Disease

Answer 215

Recessive; ATP7B-deficient enzyme: ceruloplasmin-excess metabolite: copper-metabolic testing: high urinary/hepatic/serum copper, low serum ceruloplasmin-liver disease (recurrent jaundice, hepatitis, fatty liver, hemolytic anemia)-neurologic disease (tremors, poor coordination, loos of fine motor control, chorea, spastic dystonia)-psychiatric manifestations (depression, aggression, phobias, antisocial behavior, poor memory, shortened attention span)KAYSER-FLEISCHER rings - visible on eye-renal problems-arthritis-pancreatitis-cardiomyopathy-SUNFLOWER cataracts

Question 216

General stats of Metabolic conditions in the Neonatal period

Answer 216

Metabolic conditions in Neonatal period:-Usually happen in term babies-Babies have good APGARS b/c the placenta will filter out built up metabolites-Are normal from birth to the first 24-48 hours. Takes time for metabolites to build up

Question 217

Glutaric acidemia type I

Answer 217

GCDH; most common OA-macrocephaly-unusual fluid collections pre-frontal and temporal lobes-“metabolic stroke-like features” causing severe dystonia and motor impairment

Question 218

Late onset Tay Sachs symptoms

Answer 218

psychiatric symptoms (e.g., psychosis)dystonia, ataxiamuscle weaknessno “cherry red spot”cognitive sparing

Question 219

Metabolic conditions with psychiatric findings

Answer 219

MCADD, PKU, Galactosemia, Citrulinnemia (ASD), Homocystinuria

Question 220

Batten Disease

Answer 220

RecessivePT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, KCTD7Excess metabolite: Lipofuscins-symptom onset in childhood; disabling neurodegeneration leading to death between ages 6-teenage years-neurodegeneration-vision problems-seizures-personality/behavioral changes-echolalia-clumsiness-poor growth-poor circulation in lower extremities-decreased body mass-breath-holding spells-bruxism

Question 221

Danon Disease

Answer 221

X-linked Dominant; LAMP2-hypertrophic cardiomyopathy-Wolff-Parkinson-White conduction-skeletal muscle myopathy-visual/retinal pigment disturbances-ID (usually absent in females)

Question 222

Fabry Disease

Answer 222

X-linked; GLADeficient enzyme: alpha-galactosidase (GL-3)-acroparathesias (pain & tingling in limbs)-fabry pain crises-angiokeratomas-anhidrosis/hypohidrosis-corneal whorl-left ventricular hypertrophy-GI problems-renal insufficiency (proteinuria)-depression secondary to chronic painTreatment: Fabrazyme (ERT)

Question 223

Fabry Disease(diagnosis)

Answer 223

X-linked; GLADeficient enzyme: alpha-galactosidase (GL-3)-Enzyme analysis is only useful for diagnosis in males

Question 224

Gaucher DiseaseType 1

Answer 224

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: GlucocerebrosideN370S mutation responds very well to ERT-LEAST SEVERE-hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-gaucher cells/bone crises-erlenmeye flask deformity-NO CNS INVOLVEMENT

Question 225

Gaucher DiseaseType 2

Answer 225

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: Glucocerebroside-MOST SEVERE-bulbar and pyramidal signs-ID-convulsions-hypertonia-apnea-NO BONE DISEASE/CRISES-hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-dermatologic abnormalities-lifespan: 2-4 years

Question 226

Gaucher DiseaseType 3

Answer 226

Recessive; GBADeficient enzyme: GlucocerebrosidaseExcess metabolite: Glucocerebroside-intermediate phenotype-chronic neuropathic-progressive myoclonic epilepsy-oculomotor apraxia -hepatosplenomegaly-thrombocytopenia-pulmonary hypertension-gaucher cells/bone crises-Erlenmeyer flask deformities-survival into teens and adulthood

Question 227

Gaucher Disease(treatment)

Answer 227

\*\*MOST COMMON DISEASE IN AJ POPULATIONERT-cerezyme, VPRIV, elelyso-most effective for individuals with type 1-not effective for individuals with type 2 (ERT cannot cross blood-brain barrier)-improves some symptoms with type 3Substrate reduction therapy-miglustate, eliglustat-for individuals with type 1, some type 3 who cannot do ERT due to allergic reaction/hypersensitivity/poor venous access

Question 228

Krabbe Disease

Answer 228

Recessive; GALCDeficient enzyme: GalactosylceramidaseExcess metabolite: psychosine-normal appearance at birth, symptom onset at 3-6 months-Psychosine can become stored in the brain-irritability (cry a lot more than most babies)-fevers-stiffening of limbs with sissoring of legs-opisthotonic posturing (arched back, head back)-seizures-feeding difficulties/vomiting-mental and motor delay-muscle weakness-spasticity-deafness (startled by loud noises)-optic atrophy and blindness-paralysis-no organomegaly present-death by age 2

Question 229

Mucopolysaccharidoses

Answer 229

GLYCOSAMINOGLYCANSMPSI - Hurler syndromeMPSII - Hunter syndrome (\*\*X-LINKED)MPSIII - San-Filippo syndromeMPSIV - Morquio syndromeMPSVI - Maroteaux-Lamy syndromeMPSVII - Sly syndrome

Question 230

MPSI - Hurler/Hurler-Sheie

Answer 230

RecessiveHurler-Scheie is milder form-DD/ID-REGRESSION-Hepatosplenomegaly-Skeletal anomalies-Short stature-Cardiac anomalies-Corneal clouding-Coarse facial features-Hearing loss

Question 231

MPSII - Hunter

Answer 231

X-LINKED-DD/ID-REGRESSION-skeletal anomalies-short stature-cardiac anomalies-CLEAR corneas-Coarse facial features-hearing loss

Question 232

MPSIII - San-Filippos

Answer 232

Recessive-MILDER skeletal phenotype-MILDER hepatosplenomegaly-Coarse facial features-Progressive sleep and behavioral problems-Developmental Delays-NO cardiac anomalies-CLEAR corneas-Neuro involvement may be more prominent-Pulmonology problems

Question 233

MPSIV - Morquio

Answer 233

Recessive-SEVERE skeletal phenotype (short trunked dwarfism)-NORMAL intellect-chest deformities-cardiac anomalies-bone malformation -macrocephaly

Question 234

MPSVI - Maroteaux-Lamy

Answer 234

Recessive-coarse facial features-skeletal anomalies-short stature-cardiac anomalies-corneal clouding-NORMAL intellect-Very similar to MPSI/II, X-Ray findings help tell apart

Question 235

MPSVII - Sly

Answer 235

Recessive-DD-REGRESSION-cardiac anomalies-SEVERE hepatosplenomegaly-coarse facial features-recurrent ENT problems-distinct skeletal dysplasia

Question 236

Niemann-Pick DiseaseType A

Answer 236

Recessive; SMPD1Deficient enzyme: Acid sphingomyelinaseExcess metabolite: SphingomyelinMost common in the Ashkenazi Jewish population-development stops at 12 months and regresses-death by age 3-CHERRY RED spot on eye exam-hepatosplenomegaly (SEVERE)-failure to thrive-progressive nervous system deterioration-profound brain damage-pulmonary insufficiency-recurrent lung infections

Question 237

Niemann-Pick DiseaseType B

Answer 237

Recessive; SMPD1Deficient enzyme: Acid sphingomyelinaseExcess metabolite: SphingomyelinSame genes as Type A but Type B has more enzyme activity-similar symptoms, but later onset and milder-cognitive function may be spared

Question 238

Niemann-Pick DiseaseType C

Answer 238

Recessive; NPC1, NPC2Deficient enzyme: Defect in intracellular cholesterol trafficking Excess metabolite: Abnormal intracellular cholesterol homeostasis in cultured fibroblasts showing reduced ability to esterify cholesterol -onset from infantile to adult-hepatosplenomegaly (SEVERE)-dystonia-dysphagia-progressive neurological deterioration-cerebellar ataxia-dysarthria-vertical supranuclear gaze palsy-psychosis-progressive hearing loss

Question 239

Tay-Sachs disease

Answer 239

Recessive; HEXADeficient enzyme: Hexosaminidase A-normal development up to ~6 months of age followed by progressive neurodegeneration-average lifespan is ~2 years-failure to achieve motor milestones/motor regression-loss of responsiveness-visual deterioration-seizures-progressive head enlargement due to cerebral gliosis-recurrent infections-difficulties swallowing-CHERRY RED SPOT on eye exam

Question 240

Tay-Sachs disease Adult-Onset

Answer 240

Recessive; HEXADeficient enzyme: Hexosaminidase A-NO cherry red spot-slowly progressive neurodegeneration-progressive muscle wasting-dysarthria-fasciculations-cognitive dysfunction-dementia-psychiatric problems-psychosis-can be indistinguishable from progressive adolescent onset SMA or ALS

Question 241

Skeletal MPS features

Answer 241

-Coarse Facies-Joint stiffness-Claw hand deformity-Spindle shaped hands-Spinal Gibbus (Kink in spine)-Unable to raise arms above shoulders-Hip stiffness (cannot stand up straight)-Broad ribs-Dystosis multiplex (multiple X-Ray findings)

Question 242

Name the lysosomal storage disease caused by defects in the degradation of Glycoaminoglycans (GAGs).

Answer 242

MPS GAGs are not broken down and accumulate throughout the body-Skeletal, liver/spleen, brain, pulmonary system, eyes (corneal clouding)

Question 243

Name the feature of Gaucher disease that is most often the presenting feature.

Answer 243

Enlarged spleen

Question 244

What is the cause of anemia/low white cell counts in Gaucher disease?

Answer 244

Entrapment of RBCs and platelets within the bone marrow. This can lead to thrombocytopenia.

Question 245

This mutation causing Gaucher Disease Type III has the distinct finding of disturbance of the upward gaze where patients cannot move their eyes up an must move their head to look up.

Answer 245

L44PIn general, onset tends to be earlier with this mutation

Question 246

Gaucher Type\_\_\_\_ does not respond to ERT

Answer 246

Gaucher Type II

Question 247

Treatment for Krabbe disease

Answer 247

#NAME?

Question 248

General symptoms

Answer 248

#NAME?

Question 249

Why order citrulline?

Answer 249

Plasma concentration of citrulline helps to distinguish between proximal (CPS1, NAGS, OTC) and distal (ASS, ASL, ARG) disorders\*\*Absent or LOW = proximal\*\*ELEVATED = distal

Question 250

Labs to order

Answer 250

Plasma concentration of citrullineArginine is often reduced in all except Arginase deficiency (ARG)

Question 251

Treatment

Answer 251

#NAME?

Question 252

PROXIMAL urea cycle disorders

Answer 252

CPS1NAGSOTC\*\*functions in the mitochondria

Question 253

CPS1

Answer 253

-deficient enzyme: carbamoyl phosphate synthetase 1-severe lethal neonatal onset or less severe later onset-elevated ammonia levels

Question 254

NAGS

Answer 254

#NAME?

Question 255

OTC

Answer 255

X-LINKED-deficient enzyme: ornithine transcarbamylase-elevated ornithine, uracil, and orotic acid-females can be affected-may present neonatally or in childhood after illness or high protein intake\*\*most common urea cycle disorder

Question 256

DISTAL urea cycle disorders

Answer 256

ASSASLARG\*\*functions in the cytosol

Question 257

ASS

Answer 257

ASS1-deficient enzyme: arginosuccinic acid synthetase-elevated citrulline

Question 258

ASL

Answer 258

ASL-deficient enzyme: arginosuccinic acid lyase-elevated citrulline and arginosuccinic acid

Question 259

ARG

Answer 259

ARG1-deficient enzyme: arginase-elevated arginine-hyperammonemia is RARELY present-different metabolic presentation - slower onset, muscle weakness often present

Question 260

Brugada

Answer 260

Dominant; SCN5A, KCNE#, SCN#, CACN# (23 genes total)\*\*Channelopathy-sudden death (mean age 40 yrs)-abnormal EKG : negative T wave, coved type ST segment-ventricular fibrillation-self-terminating polymorphic ventricular tachycardia-episodes of syncope-nocturnal agonal respiration (gasping)\*CACNA1C also associated with timothy syndrome (LQTS)Management: ICD, avoid agents that induce arrhythmias

Question 261

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Answer 261

Dominant:RYR2 (50%-55%), TRDN, CALM1Recessive: CASQ2-type of arrhythmia (ventricular tachycardia)-sudden death or syncope (80%) with exercise/excitement-hard to distinguish from LQTS when sudden death is presenting symptom, however CPVT is associated with normal baseline/resting EKG and abnormal EKG only after andrenergic event--QRS complexes with frequent and rapid changes inmorphology-major cause of sudden death in childhood with mean age onset 7-9yrs

Question 262

CADASIL

Answer 262

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathyDominant; NOTCH3-onset between 35-55 yrs-migraines with aura-strokes-mood disturbances-progression to subcortical dementia-pseudobulbar palsy-leukoencephalopathy\*\*most common form of hereditary stroke disorder

Question 263

Familial Hypercholesterolemia

Answer 263

Dominant/Recessive; LDLR, APOB, PCSK9, LDLRAP1-Xanthomas (chol rich fat depostis beneath skin around the eyes and tendons)-elevated cholesterol-premature atherosclerosis-coronary artery disease-increased risk for MI-homozygotes have more severe features and may require liver transplant/suffer MI much earlier+liver transplant is only for severe cases, but the major source of the problem/defective enzymes are in the liver, so this effectively treats the disease (however, risks for organ transplantation)

Question 264

Hereditary Hemorrhagic Telangiectasia (HHT)

Answer 264

Dominant; ACVRL (ALK1), ENG, SMAD4, GDF2-telangiectasias - mucosal lining of the nose, lips/tongue, GI tract-epistaxis (nose bleeds)-arteriovenous malformations (AVMs) - occur in large organs in lung, brain, heart, GI/liver may all cause lethal stroke/MI/cardiac failure-JUVENILE POLYPS (in SMAD4 only)

Question 265

Long QT Syndrome

Answer 265

Dominant & Recessive; 15 genesType 1: KCNQ1 - exercise/burst Type 2: KCNH2 - loud noisesType 3: SCN5A - sleep-prolonged QTc interval on EKG\*\*Torsades de pointes are characteristic finding (generates from left ventricle)-Sudden death-Syncope

Question 266

Jervell and Lange-Nielsen syndrome

Answer 266

Recessive; KCNE1, KCNQ1-Long QT -congenital DEAFNESS

Question 267

Timothy Syndrome

Answer 267

Dominant; CACNA1C - usually de novo-Long QT syndrome-Syndactyly-Autism-Structural cardiac malformation-ID-Dental anomalies

Question 268

Hypertrophic Cardiomyopathy (HCM)

Answer 268

Dominant; sarcomeric genes - MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3...-unexplained left ventricular hypertrophy causing decreased cardiac output-Seen in Noonan/Costello, Fabry, Timothy, GSDIII...PRKAG2 and LAMP2-Result in metabolic storage disease of myocardium-PRKAG2 associated with Wolf Parkinson-White syndrome-LAMP2 causes Danon disease, X-linked with cardiomyopathy, muscle weakness, and ID

Question 269

Dilated Cardiomyopathy (DCM)

Answer 269

Dominant, Recessive, X-linked Cytoskeletal genes - TTN, LMNA, MYH7, MYH6, SCN5A, MYBPC3, TNNT2...(lots more!)-stretching of muscle fibers (often in left ventricle) leads to dilation of the chamber and reduced cardiac output-Seen in DMD, mitochondrial diseases, dystorphinopathies, Alstrom, Barth, Emery-Dreifuss...-Mutations in TTN are most common known cause of DCM-TNNT2 mutations may be associated with early onset & aggressive disease

Question 270

Anderson-Tawil Syndrome

Answer 270

Dominant: KCNJ2-Skeletal abnormalities (dental anomalies, short stature and scoliosis)-Periodic paralysis and LQTS that is exacerbated by hypokalemia (low potassium)-Dysmorphic features (low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly,

Question 271

Schwartz LQTS score

Answer 271

Schwartz LQTS score• ≤1.0 point: low probability of LQTS• 1.5-3.0 points: intermediate probability of LQTS• ≥3.5 points: high probability of LQTS

Question 272

2011 Schwartz LQTS Diagnostic Criteria

Answer 272

Based on points with total giving LQTS score-represents probability of LQTS3 Domains: 1. EKG findings: LQTS score, Torsade pointes\*, Twave alternans, Notched T wave in 3 leads, Resting heart rate below 2nd %tile for age2. Clinical history: Syncope (w/or w/o stress), Congenital deafness3. Family history: Family member with definite LQTS, Unexplained SCD \<30 in immediate family member\*\*\*In absence of medication/disorders effect EKG\*\* Cannot count same person 2x

Question 273

Pulmonary Arterial Hypertension (PAH)

Answer 273

Wide spread obstruction and obliteration of the smallest pulm arteries causes resistance to blood flow through lungs. Leads to heart failure.Dominant: BMPR2 (75%) ACVRL1 (1%) ENG(1%)20% Pentrance when BMPR2Female:Male ratio is 2.5Initial symptomsDyspnea (60%)Fatigue (19%)Reynaud's Phenomenon (10%) Mostly femalesSyncope (8%)Chest pain (7%)Mean survival is 2.8yrs after Dx

Question 274

PAH and HHT

Answer 274

Note: Both can occur together when ACVRIL1 mutation present. ENG or SMAD8 rarely

Question 275

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Answer 275

Dominant: DSP (6-16%), PKP2(11%-43%), DSG2(12-40%)Reduced penetrance, variable expressivityProgressive fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and SCDCharacterized by 4 stagesSymptoms: Heart palpitations, Ventricular tachycardia +fibrillation, syncope, dyspnea, heart failureDiagnostic criteris has 6 Domains with major/minor criteria: Fhx, arrhythmias, Depolar/Conduction abnormalities, Repolarization abnormalities, Tissue biopsy, dysfunction/structural alterations

Question 276

Cardiac Amyloidosis

Answer 276

Deposits of abnormal protein (amyloid) in heart tissue. Deposits will begin to take place of normal heart tissue and can affect signaling.

Question 277

Transthyretin Amyloidosis

Answer 277

Dominant: TTRDe novo rate: 66%Group of diseases caused by the accumulationof abnormal protein in the body, Onset 3rd-7th decade of life-žSlowly progressive peripheral + autonomic sensorimotor neuropathy,-Cardiomyopathy, -Vitreous opacities-CNS amyloidosisMost mutations reported are singe bp substitution=AA substitutionTwo common mutations– V30M –Portuguese (1/538), Swedish and Japanese– V122I - African-American population (3.0-3.9%)

Question 278

Hemophilia A(coagulopathy)

Answer 278

Factor VIII deficiencyX-linked recessive; F8\*\*30% de novointron 22 inversion\>seq\>del/dup-Diagnosis based on clotting factor assay-excessive bleeding-renewed bleeding after initial bleeding stops-deep-muscle, intracranial, GI tract bleeds without obvious trauma-poor wound healing-menorrhagia in symptomatic females-excessive bruising, deep-muscle hematomas-chronic joint disease from frequent bleeds which can lead to disability\*heterozygous females may be affected, important to assess coagulation factor levels in bloodTreatment: regular factor VIII intravenous infusions, acute treatment with DDAVP

Question 279

Hemophilia B(coagulopathy)

Answer 279

Factor IX deficiencyX-linked recessive; F9Seq\>Del/dup-Diagnosis based on clotting factor assay-excessive bleeding-renewed bleeding after initial bleeding stops-deep-muscle, intracranial, GI tract bleeds without obvious trauma-poor wound healing-menorrhagia in symptomatic females-excessive bruising, deep-muscle hematomas-chronic joint disease from frequent bleeds which can lead to disability\*heterozygous females may be affected, important to assess coagulation factor levels in bloodTreatment: regular factor IX intravenous infusions, acute treatment with DDAVP

Question 280

Factor V Leiden thrombophilia(coagulopathy)

Answer 280

Dominant, Recessive; F5\*\*Leiden refers to common allele c.1691G\>A (p.R506Q)-increased risk for venous thromboembolism++slight increased risk in heterozygoes++significantly increased/likelihood for multiple VTE events in homozygotes-increased risk for pregnancy loss (2-3x risk in heterozygotes)Treatment: long-term oral anticoagulants is necessary, particularly in homozygotes\*\*it is possible to be heterozygous for multiple coagulopathies which increases risk cumulatively

Question 281

von Willebrand Disease(coagulopathy)

Answer 281

Dominant (most), Recessive; VWF-mild to moderate mucocutaneous bleeding++easy bruising, nosebleeds, heavy periods-Types 2B and 2N may have thrombocytopenia-Type 2N has more severe bleeding and mimics hemophilia

Question 282

Alpha-Thalassemia - types(hemoglobinopathy)

Answer 282

di-genic; HBA1, HBA2Hb Bart's Hydrops fetalis - del 4Hemoglobin H disease (HbH) - del 3Alpha Thal minor - del 2Silent Carrier - del 1\*\*DEL/DUP ANALYSIS

Question 283

Alpha-Thalassemia - Hb Bart's Hydrops Fetalis(hemoglobinopathy)

Answer 283

di-genic; HBA1, HBA2-deletion of all 4 alpha-globin alleles-complete absence of alpha globin-fatal in utero (30-36 weeks)-splenomegaly-pleural/pericardial effusions-generalized edema\*\*DEL/DUP ANALYSIS

Question 284

Alpha-Thalassemia - HbH disease(hemoglobinopathy)

Answer 284

di-genic; HBA1, HBA2-deletion of 3 alpha-globin alleles-MICROCYTIC HYPOCHROMIC ANEMIA-hepatosplenomegaly-may have skeletal changes affecting facial features-those severely affected require regular blood transfusions\*\*DEL/DUP ANALYSIS

Question 285

Alpha-Thalassemia - Alpha Thal Minor(hemoglobinopathy)

Answer 285

di-genic; HBA1, HBA2-deletion of 2 alpha-globin alleles-mild microcytic hypochromic anemia ++can be clinically mistaken for iron deficient anemia-Alpha-thal CIS (aa/--)++seen in SE and E Asian populations (1:20)-Alpha-thal TRANS (a-/a-)++seen in African Middle East and Mediterranean populations\*\*DEL/DUP ANALYSIS

Question 286

Alpha-Thalassemia - Silent Carrier(hemoglobinopathy)

Answer 286

di-genic; HBA1, HBA2-deletion of 1 alpha-globin allele-typically asymptomatic-may have low mean corpuscular volume (MCV)\*\*DEL/DUP ANALYSIS

Question 287

Beta Thalassemia - types(hemoglobinopathy)

Answer 287

Recessive; HBBThalassemia Major - Hb SB-/SB-Thalassemia Intermedia - Hb SB+/SB+ OR SB-/SB+Thalassemia Minor - Hb SB-/SB or SB+/SB\*\*SEQ ANALYSIS

Question 288

Beta Thalassemia - Major(hemoglobinopathy)

Answer 288

Recessive; HBB-SB-/SB--severe microcytic hypochromic anemia-splenomegaly-severe bone deformities-death before 20 if untreatedTreatment: periodic blood transfusions, splenectomy, chelation of transfusion-induced iron overload\*\*SEQ ANALYSIS

Question 289

Beta Thalassemia - Intermedia(hemoglobinopathy)

Answer 289

Recessive; HBB-SB+/SB+ or SB-/SB+-anemia-may need transfusions during illness or pregnancy depending on severity of anemia\*\*SEQ ANALYSIS

Question 290

Beta Thalassemia - Minor(hemoglobinopathy)

Answer 290

Recessive; HBB-SB-/SB or SB+/SB-Microcytic anemia-lower than normal mean corpuscular volume (MCV)\*\*SEQ ANALYSIS

Question 291

Sickle Cell Anemia(hemoglobinopathy)

Answer 291

HBB-Hb SS genotype (normal is Hb AA)-Hb S results from HBB p.E6V-Sickle-shaped red blood cells-chronic hemolysis-vaso-occlusive events ("sickle cell crises") - damage to tissues, pain, acute or chronic injury++often affects bones, spleen, liver, brain, lungs, kidney, and joints-splenic dysfunction-acute chest syndrome - chest pain, fever, pulmonary infiltrate, respiratory problems, hypoxia++major cause of mortality-dactylitis - inflammation of an entire digit-stroke-pulmonary hypertension\*\*SEQ ANALYSIS

Question 292

Sickle Cell Trait(hemoglobinopathy)

Answer 292

Hb AS genotype-usually non-symptomatic-extreme exertion, high altitude, or dehydration may cause vaso-occlusive events ("sickle cell crises") - damage to tissues, pain, acute or chronic injury++often affects bones, spleen, liver, brain, lungs, kidney, and joints-may have higher risk for venous thromboembolism-protective advantage against malaria\*\*SEQ ANALYSIS

Question 293

Which models give breast cancer risk only?

Answer 293

GailClaus

Question 294

Which models give breast cancer AND mutation risk?

Answer 294

Tyrer-CuzickBRCAProBOADICEACouch2/Penn2 & Myriad give BRCA mutation risk only

Question 295

Which models can be used on an unaffected proband?

Answer 295

Gail (unaffected proband only)Claus (unaffected proband only)Tyrer-Cuzick (unaffected proband only)MyriadBRCAProBOADICEA

Question 296

Which models can be used on both an affected & unaffected proband?

Answer 296

MyriadCouch2/Penn2BRCAProBOADICEA

Question 297

In what models can only a female proband be used?

Answer 297

GailClausTyrer-Cuzick

Question 298

Which models consider paternal family history?

Answer 298

ClausTyrer-CuzickMyriadBRCAProBOADICEA

Question 299

Which models consider Breast Cancer?

Answer 299

GailClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

Question 300

Which models consider Ovarian Cancer?

Answer 300

Tyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

Question 301

Which models consider other BRCA related cancers?

Answer 301

Tyrer-CuzickBRCAProBOADICEA

Question 302

Which models consider bilateral BC?

Answer 302

Tyrer-CuzickCouch2/Penn2BRCAProBOADICEA

Question 303

Which models consider contralateral BC?

Answer 303

BOADICEA

Question 304

Which models consider male BC?

Answer 304

Couch2/Penn2MyriadBRCAProBOADICEA

Question 305

Which models consider ONLY BC \<50y

Answer 305

Couch2/Penn2Myriad

Question 306

Which models consider FDR?

Answer 306

Gail (FDR only)ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

Question 307

Which models consider FDR & SDR?

Answer 307

ClausTyrer-CuzickCouch2/Penn2MyriadBRCAProBOADICEA

Question 308

Which models are not degree of relation specific, only cases with cancer?

Answer 308

Couch2/Penn2Myriad - must use one FDR or SDR, then can consider other cases

Question 309

Which models consider TDR?

Answer 309

Tyrer-Cuzick (BC only)BRCAPro

Question 310

Which models allow the use of only 2 relatives?

Answer 310

GailClaus

Question 311

Which models allow input for age of unaffected relatives?

Answer 311

Myriad (gives age ranges)BRCAPro

Question 312

Which models allow input for age of onset for family members?

Answer 312

ClausTyrer-CuzickMyriad (gives age ranges)BRCAPro

Question 313

Which models consider Ashkenazi Jewish ancestry?

Answer 313

Couch2/Penn2MyriadBRCAPro

Question 314

Which models consider the probands current age?

Answer 314

Gail ClausTyrer-CuzickBRCAPro

Question 315

Which models consider age of onset (if proband affected)?

Answer 315

BRCAPro

Question 316

Which model considers personal features including weight, height, and BMI?

Answer 316

Tyrer-Cuzick

Question 317

Which models consider the number of biopsies and biopsy outcome?

Answer 317

Gail Tyrer-Cuzick

Question 318

Which models consider tumor hormone status (f proband affected)?

Answer 318

BRCAPro

Question 319

Which models take into account BSO?

Answer 319

BRCAPro

Question 320

Which models take into account age at menarche?

Answer 320

GailTyrer-Cuzick

Question 321

Which models take into account age at first live birth?

Answer 321

Gail

Question 322

Which models take into account parity, age at menopause and HRT use?

Answer 322

Tyrer-Cuzick

Question 323

Which models take into account previous genetic testing or carrier status?

Answer 323

BRCAPro

Question 324

Which models consider genes other than BRCA or polygenic inheritance?

Answer 324

Tyrer-CuzickBOADICEA

Question 325

Gail Model

Answer 325

-Gives 5 year risk and lifetime risk-used for consideration of tamoxifen (5 yr risk \>1.6%)-Breast cancer risk ONLY in UNAFFECTED FEMALE proband 35 or older-Family history (FDR only, BC only, max 2 relatives)-considers:++current age++#biopsies and outcome+

Question 326

Claus Model

Answer 326

-gives lifetime risk-used for consideration of annual breast MRI (lifetime risk \>20%)-Breast cancer risk ONLY in UNAFFECTED FEMALE proband-Family history (FDR/SDR, BC only, max 2 relatives)-Considers:++age of onset in relatives (affected & unaffected)

Question 327

Tyrer-Cuzick Model

Answer 327

-estimates breast cancer risk AND mutation risk-used in unaffected FEMALE probandConsiders:-paternal family history-breast & ovarian cancer-FDR, SDR & TDR (breast only in TDR)-age of onset in affected relatives-proband factors (age, weight, height

Question 328

Couch2/Penn2 Model

Answer 328

-pre-test BRCA probabilityConsiders:-women with breast cancer \<50-bilateral breast cancer-Ovarian cancer +/- breast cancer-MALE breast cancer-Prostate & pancreatic cancer-AJ ancestry

Question 329

Myriad Tables

Answer 329

-BRCA probability-proband options: ++no breast cancer, ++BC\<50, ++BC \>50, ++male BC, ++OV, ++BC & OC-Considers AJ ancestryLimitations: -biased population toward high risk/penetrant families-no exact ages of diagnosis or exact # of relatives-Breast &am

Question 330

BRCAPro

Answer 330

-estimates breast cancer risk AND mutation risk-proband can be affected or unaffectedConsiders:-paternal fam hx-family history of Breast AND Ovarian-Bilateral breast cancer-MALE breast cancer-FDR, SDR, TDR-age of unaffected AND affected relatives-Ashkenaz

Question 331

BOADICEA

Answer 331

-estimates breast cancer risk AND mutation risk-proband can be affected or unaffectedConsiders:-paternal fam hx-family history of Breast AND Ovarian AND other related cancers-Bilateral breast cancer-Contralateral breast cancer-MALE breast cancer-FDR, SDR-

Question 332

What are the typical symptoms of Neonatal onset?

Answer 332

#NAME?

Question 333

What categories of metabolic syndromes present with vomitting, lethargy, and coma?(Symptom complexes)

Answer 333

#NAME?

Question 334

What categories of metabolic syndromes present with Acidosis (Typically severe)?(Symptom complexes)

Answer 334

Organic Acidemias -Blood pH (Blood gases) of \<7.1-Blood bicarbonate of \<10

Question 335

What categories of metabolic syndromes present with Respiratory Distress?(Symptom complexes)

Answer 335

#NAME?

Question 336

What categories of metabolic syndromes present with Hypoglycemia?(Symptom complexes)

Answer 336

#NAME?

Question 337

What categories of metabolic syndromes present with Organomegaly?(Symptom complexes)

Answer 337

#NAME?

Question 338

What categories of metabolic syndromes present with Seizure?(Symptom complexes)

Answer 338

-Urea Cycle Disorders (due to hyperammonemia)-Organic Acidemias (due to hyperammonemia/hypoglycemia)-Gluconeogenesis Defects-Lysosomal-usually later

Question 339

Metabolic conditions that are due to primary neuromuscular dysfunction

Answer 339

Tay Sachs, Krabbe-Metabolites accumulate leading to storage in the Brain/CNS/Eye tissue-Muscular weakness is result of CNS involvement

Question 340

Metabolic conditions that are due to primary muscular dysfunction

Answer 340

Pompe, VLCAD, Muscle GSD (Type V)-Metabolites may be stored in muscle (Pompe, GSD Type V)-Affect energy source used by cardiac muscle (VLCAD)-No CNS involvement, DD is due to muscle weakness influencing attainment of milestones

Question 341

Disorders with Organomegaly

Answer 341

#NAME?

Question 342

Disorders with Fasting Intolerance

Answer 342

#NAME?

Question 343

Which GSD is X linked?

Answer 343

GSD Type IX -Fasting hypoglycemia-Mild lactic acidosis-Mild hyperlipidemia

Question 344

Hypertrophic Cardiomyopathy can occur in this type of GSD.

Answer 344

GSD Type III or Cori Disease or Forbes DiseaseCaused by defects in the Debrancher enzyme the breaks chains of glycogen. Enzyme present in heart.

Question 345

FAO: Lab trends

Answer 345

UOA to make diagnosis-Dicarboxylic aciduria with acyl-gylcines-Hypoketotic hyppglycemia is keyLow Total carnitine levels High Esterified Carnitine RatioAcyl-Carnitine Profile: May or may not be normalNo lactic acidosisNo ketones detected in blood/urine with hypoglycemia suggest FAO

Question 346

Which FAO has muscle involvement?

Answer 346

VLCADCardiac muscle depends on long chain FA for fuel Skeletal muscle also use LC FA as energy source Lipid myopathy-Lipids will accumulate in skeletal muscle causing weaknessLCHAD:cardiomyopathy

Question 347

What time after a meal will metabolic disorders with fasting intolerance/hypoglycemia present?

Answer 347

Hepatic GSD: 4-8 hours after meal, body has used up blood glucose but cannot utilize glycogenFAO: 8-12-Energy after this time is made by FAO processHypoglycemia 2-4 hours after a meal are caused by intolerance to a food/component of the food-Ex Galactosemia Note: Timing can vary

Question 348

Disorders of gluconeogenesis (Carbohydrate Metabolism defect)

Answer 348

Pyruvate Carboxylase DeficiencyHereditary Fructose IntoleranceInhibition of Gluconeogenesis -FTT w/ persistent fructose-Seizures-Hepatomegaly-Vomiting-HypoglycemiaNormal UOA except lactic acid w/c is elevated

Question 349

Recommended labs when child presents with fasting intolerance/hypoglycemia

Answer 349

Anion Gap: Will be significantly highLactate: Tends to be highUric AcidTriglyceride levelsUrine/blood ketonesUOACarnitine profileAcyl-carnitine profile

Question 350

Recommended labs when child presents with neuromuscular symptoms

Answer 350

Lactate (mito)Creatinine KinaseMyoglobinBrain MRI---Leukodystrophy (Tay Sachs, Krabbe)Muscle biopsyEnzyme assayGenetic testingNote: Expect labs to be normal or non-specific (Think about reliability of CK)

Question 351

Recommended labs when child presents with organomegaly symptoms

Answer 351

Anion Gap; will be highLactateBlood glucoseBlood counts: LSDsUrine GAGs: MPSSkeletal SurveyLiver/Bone marrow biopsy-Histology provides clues: "Gaucher" cells in BM, glycogen granules in liver (GSD)

Question 352

True or FalseAll cases of abnormal glycogen storage are caused by GSD.

Answer 352

False.All GSDs have glycogen storage, but not all cases of abnormal glycogen storage are due to defects of GSD.

Question 353

True or FalseGSDs exist on a spectrum based on severity

Answer 353

TrueGSD Type I; most severe formGSD Type III: moderate, but have severe progressive cardiomyopathyGSD Type IV-IX: Least severe

Question 354

Metabolic conditions with predisposition to infection

Answer 354

Galactosemia --gram-negative sepsisPropionic acidemia, methylmalonic acidemia--neutropeniaMitochondrial disease (e.g., Pearson syndrome --pancytopeniaGaucher disease --neutropenia, splenomegalyGlycogen storage disease type Ib --neutropeniaLysosomal storage diseases --otitis media, respiratory infections, splenomegaly

Question 355

Disorders with diminished exercise intolerance

Answer 355

-Glycogen storage disease (type V)-Carnitine transport disorders (carnitine palmitoyltransferase [CPT] II deficiency)-Fatty acid oxidation defects (very long chain acyl CoA dehydrogenase [VLCAD] deficiency)-Mitochondrial diseases

Question 356

Metabolic disorders with X-linked inheritance:

Answer 356

#NAME?

Question 357

Metabolic disorders with Autosomal dominant:

Answer 357

#NAME?

Question 358

What is the cause of hyperammonemia in Organic Acidemias?

Answer 358

High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal organic acid metabolites.

Question 359

What is the cause of hyperammonemia in Urea Cyle Disorders?

Answer 359

High ammonia levels occur because defects in that pathway block the ability of the body to convert ammonia to a less toxic form

Question 360

What is the cause of hyperammonemia in Mitochondrial Disorders?

Answer 360

The first part of the urea cycle is located in the mitochondrion. In certain mitochondrial diseases, the dysfunctional environment can compromise urea cycle function and produce high ammonia levels

Question 361

What is the cause of hyperammonemia in FAO Disorders?

Answer 361

High ammonia levels can occur due to secondary inhibition of the urea cycle by the abnormal fatty acid metabolites

Question 362

Metabolic disorders with prenatal onset of disease can occur when the defect is severe and integral to cellular metabolism. May see dysmorphy features or malformations. Name these disorders.

Answer 362

Peroxisomal disease--Zellweger syndromeFatty acid oxidation defects--glutaric acidemia IIMitochondrial disease--pyruvate dehydrogenase complex deficiencyDisorders of glycosylation--carbohydrate-deficient glycoprotein syndromesDefects in cholesterol synthesis --Smith-Lemli-Opitz syndrome

Question 363

Which brain areas in particular are at risk in metabolic disease?

Answer 363

Basal ganglia (stroke-like episodes):--Organic acidemias: glutaric acidemia type I, propionic and methylmalonic acidemia--Mitochondrial diseaseBrain stem --Leigh diseaseWhite matter--LeukodystrophiesMore randomly –Stroke-like episodes--Infarction from hyperammonemia--Mitochondrial disease

Question 364

Leukodustrophies

Answer 364

Globoid cell (Krabbe) leukodystrophyMetachromatic leukodystrophyX-linked adrenoleukodystrophyCanavan diseaseMitochondrial disease

Question 365

\_\_\_\_\_\_\_\_\_ ketone production is found in \_\_\_\_\_chain and \_\_\_\_\_\_chain defects and _____ transport disorders.\_\_\_\_\_\_ chain defects are associated with significant ketosis.

Answer 365

Low ketone production is found in the medium chain and longer chain defects and the carnitine transport disorders.Short chain defects are associated with significant ketosis.

Question 366

Presencce of glutarylcarnitine is seen in the FAO disorder

Answer 366

Glutaryic Acidemia Typs I and II

Question 367

What are the metabolic differentials if patient has Isolated Developmental Delay?

Answer 367

Carbohydrate-deficient transferrinCreatine and guanidinoacetate

Question 368

If diagnostic urine specimen is _____ for glucose (using a regular dipstick) but ____ for reducing substances, what disorders should be considered?

Answer 368

NEGATIVE for glucose POSITIVE for reducing substances. Consider galatosemia or fructose intolerance.

Question 369

Alkaptonuria - features(Amino Acid Disorder)

Answer 369

Recessive; HGD-Black urine-Bone/cartilage necrosis (Ochronosis)-Height loss secondary to spinal changes-Aortic/mitral valve calcification

Question 370

Alkaptonuria - labs to order & treatment(Amino Acid Disorder)

Answer 370

Recessive; HGDLabs: 24hr urinalysis for homogentisic acid (elevation)Treatment: -Dietary Phe and Tyr restriction-Nitisone can inhibit enzyme responsible for buildup of homogentisic acid

Question 371

Homocystinuria - features(Amino Acid Disorder)

Answer 371

Recessive; CBS-Hypopigmentation-Seizures-Risk for MI-MVP-Psychiatric problems-Marfanoid habitus (pectus deformities, ectopia lentis)-Distinguishable from Marfan by:+present of intellectual disability+thromboembolitic events (strokes; vs vessel/aortic dilation seen in marfan)+joint contractures

Question 372

Homocystinuria - labs to order & treatment(Amino Acid Disorder)

Answer 372

Recessive; CBSLabs: PAA, also on NBSTreatment:-Vitamin B6 (pyridoxine)-Protein restricted diet-Betaine provides alternate pathway for breakdown of homocysteine (\*\*risk for excess methionine with this treatment)-If residual enzyme activity is present, folate and vit B12 can optimize enzyme activity

Question 373

Maple Syrup Urine Disease - features(Amino Acid Disorder)

Answer 373

Recessive; BCKDHA, BCKDHB, DBT\*isoleucine, leucine, valineDeficient enzyme: Branched Chain Ketoacid Dehydrogenase-Urine smells like maple syrup-Developmental delay-Poor feeding-Extreme Lethargy-Opisthotonic posturing-Respiratory failure-Encephalopathy with illness

Question 374

Maple Syrup Urine Disease - labs to order & treatment(Amino Acid Disorder)

Answer 374

Labs: PAA, also on NBS, UOA :elevated ketoacids Treatment:-AVOID leucine-Dietary leucine restriction/high calorie leucine free formulas

Question 375

Phenylketonuria - features if untreated(Amino Acid Disorder)

Answer 375

\*Recessive; PAH\*Inability to convert Phe to Tyr-Features if untreated:+severe ID+microcephaly+"musty odor"+seizures+behavioral problems+exaggerated neurologic reflexes

Question 376

Phenylketonuria - features if treated(Amino Acid Disorder)

Answer 376

\*Recessive; PAH\*Inability to convert Phe to Tyr-Features if treated:+dependent on how well treatment is maintained+psychiatric problems+learning difficulties/lower IQ

Question 377

Phenylketonuria - labs to order & treatment(Amino Acid Disorder)

Answer 377

Labs: PAA, NBS, Biopterin (BH4) is a cofactor for phe hydroxylase - need to rule out biopterin deficiencyTreatment: -Dietary restriction of Phe-Special low Phe foods/formulas-If an individual has residual enzyme activity, biopterin supplementation may help improve enzyme activity

Question 378

Maternal PKU

Answer 378

-High Phe levels are a teratogen-Mother's with PKU who do not maintain treatment will expose their fetuses to high Phe levels-Fetal features:+microcephaly+IUGR+ID+increased risk for CHDs

Question 379

Tyrosinemia - type 1(Amino Acid Disorder)

Answer 379

Recessive; FAH-Most severe-Hepatosplenomegaly-Acute liver failure/jaundice-Renal failure-RICKETS-Failure to thrive-Chronic weaknessTreatment: Orfadin (prevents buildup of toxic metabolite)

Question 380

Tyrosinemia - type 2(Amino Acid Disorder)

Answer 380

Recessive-Keratosis palmoplantaris (hyperkeratosis of hands and feet)-ID (~50%)-Ocular and cutaneous findings-Growth retardationTreatment: Dietary restriction of Phe and Tyr

Question 381

Tyrosinemia - type 3(Amino Acid Disorder)

Answer 381

Recessive\*\*Rarest form-Normal liver function-Mild ID-SeizuresTreatment: Dietary restriction of Phe, Tyr, and Met

Question 382

Amino Acidopathies

Answer 382

-chronic & progressive-usually no neonatal crisis (except MSUD)-symptoms develop slowly

Question 383

Fatty Acid Oxidation Disorders(signs and symptoms)

Answer 383

#NAME?

Question 384

Fatty Acid Oxidation Disorders(types)

Answer 384

VLCAD - exhibit cardiomyopathy & generalize myopathy; ^C14LCHAD - exhibit cardiomyopathy & generalize myopathy; female carriers at risk for HELLP; ^C14-18MCAD (most common); ^C6-10SCAD - does not present with hypoketotic hypoglycemia

Question 385

Fatty Acid Oxidation Disorders(labs to order)

Answer 385

UOA, Acylcarnitine profile, acylglycines\*\*labs may only be abnormal during crisesMolecular genetic confirmation

Question 386

Fatty Acid Oxidation Disorders(treatments)

Answer 386

#NAME?

Question 387

X-linked Adrenoleukodystrophy - forms(FAO disorder)

Answer 387

\*X-linked recessive; ABCD1 gene-Childhood Cerebral Form-Adrenomyeloneuropathy-Addison's Disease

Question 388

X-linked ALD - Childhood Cerebral Form(FAO disorder)

Answer 388

\*X-linked recessive; ABCD1 gene-Onset between 4-8 years of age-Progressive neurodegenerative decline-Behavioral and learning deficits-Seizures-Adrenocortical dysfunction-Total disability and early death 6 months-2 years after onset

Question 389

X-linked ALD - Adrenomyeloneuropathy(FAO disorder)

Answer 389

\*X-linked recessive; ABCD1 gene-Onset in 20s-Progressive stiffness and weakness in the legs0Abnormal sphincter control-Sexual dysfunction-Adrenocortical dysfunction-Neuropathy-40-50% have brain MRI abnormalities (leukodystrophy)-10-20% of those with leukodystrophy have severely progressive cognitive decline and early death

Question 390

X-linked ALD - Addison's Disease(FAO disorder)

Answer 390

\*X-linked recessive; ABCD1 gene-Adrenal insufficiency in the absence of MRI/brain anomalies-Increased skin pigmentation from excess ACTH

Question 391

X-linked ALD - Affected females(FAO disorder)

Answer 391

#NAME?

Question 392

X-linked ALD - Treatment(FAO disorder)

Answer 392

#NAME?

Question 393

CPT2

Answer 393

CPT2-lethal neonatal form: liver failure, CM, death in days/months-severe infantile form: liver failure, CM, onset in 1st year, sudden death-myopathic form: most common, myalgia attacks, variable age of onset

Question 394

General features of Galactosemias

Answer 394

#NAME?

Question 395

GALT/Gal-1-P deficiency(features)

Answer 395

-Features:+neonatal onset+NO AVERSION to galactose containing foods+hyperbilirubinemia+liver dysfunction+renal tubular acidosis+ID+DD+cataracts+sepsis+POF

Question 396

GALT/Gal-1-P deficiency(genetics & treatment)

Answer 396

-Recessive; FOXO3 gene (Duarte allele p.N314D)\*\*Duarte allele is a much milder manifestation, attenuation of Gal-1-P rather than depletionTreatment:-dietary lactose restriction-calorie supplementation-non-dairy protein supplementation\*\*AVOID LEGUMES

Question 397

GALK deficiency

Answer 397

#NAME?

Question 398

GALE deficiency

Answer 398

-Deficient enzyme is Galactokinase empirase-Treatment: dietary LACTOSE & GALACTOSE restriction-SEVERE onset-psychomotor retardation-hyperbilirubinemia-liver dysfunction-renal tubular acidosis-ID/ DD-cataracts-sepsis

Question 399

Von-Gierke Disease/GSD1 - features(glycogen storage disorder)

Answer 399

Recessive; G6PCGSD Type1a: Primary enzyme defect GSD Type 1b: Transporter defect, more difficult to treat-hypoglycemia-hyperlipidemia-hyperuricemia-lactic acidosis-liver dysfunction/hepatomegaly-DD-GI problems-growth retardation-renal problems/kidney stones-muscle weakness is uncommon

Question 400

Von-Gierke Disease/GSD1 - treatment(glycogen storage disorder)

Answer 400

Recessive; G6PC-Avoid fasting/maintain normal glucose to avoid hypoglycemia++body cannot release glycogen, so when it is made it builds up in the liver and kidneys, blood sugar levels are therefore dependent on diet-Nighttime glucose infusions to avoid-Cornstarch between meals-Complex carbs-High protein/fat diet-Liver transplant for severe cases

Question 401

Pompe Disease/GSD2 - Infantile onset(glycogen storage disorder & lysosomal storage disorder)

Answer 401

Recessive; GAAAlpha-glucosidase is deficient enzyme-cardiomegaly-hypotonia-cardiomyopathy-respiratory distress-recurrent respiratory infections-enlarged tongue-death in 1st year of life if untreatedTreatment: Myozyme (ERT)

Question 402

Pompe Disease/GSD2 - Late onset(glycogen storage disorder & lysosomal storage disorder)

Answer 402

Recessive; GAAAlpha-glucosidase is deficient enzyme-slowly progressive proximal muscle weakness++can mimic limb-girdle muscular dystrophy-hypotonia-impaired cough-delayed motor milestones-dysphagiaTreatment: Lumizyme

Question 403

McArdle Disease/GSD5(glycogen storage disorder)

Answer 403

Recessive; PYGMMyophosphorylase is deficient enzymeLabs: Enzyme assay/muscle biopsy-myoglobinuria-myopathy-skeletal muscle weakness-exercise intolerance-rhabdomyolysisTreatment:-B6 supplementation-Sucrose supplementation before exercise-High protein/fat diet

Question 404

Isovaleric Acidemia(organic acidemia)

Answer 404

Recessive; IVDPrevents breakdown of leucineDeficient enzyme: isovaleric acid CoA dehydrogenase deficiency-SMELLY FEET-metabolic acidosis-protein aversion-thrombocytopenia-vomiting, poor feeding, coma-seizures-DD-50% severe acute neonatal with rapid death-50% chronic, episodic with asymptomatic intervals\*\*Biotin deficiency can mimic this disorder

Question 405

Isovaleric Acidemia - labs & treatment(organic academia)

Answer 405

Recessive; IVDPrevents breakdown of leucineDeficient enzyme: isovaleric acid CoA dehydrogenase deficiencyLabs to order: UOA: Isovaleric Acid, Acylglycines, Acylcarnitine profile: elevated C5, detected on NBS Treatment:-Dietary leucine restriction-Glycine supplementation during acute episodes\*\*Biotin deficiency can mimic this disorder

Question 406

Lesch-Nyhan syndrome(organic academia)

Answer 406

X-LINKEDDeficient enzyme: hypoxanthine-guanine phosphoribosyltransferase-ID/DD-Growth retardation-Opisthotonic posturing-Dysphagia-Self-injuring behavior-Hyperuricemia-Renal failure-Treatment is based on management of symptoms-Affected females typically only present with hyperuricemia-Severe cases result in death, typically from renal failure, by 1st or 2nd decade of life-Phenotype is highly variable

Question 407

Proprionic Acidemia- PA(Organic Acidemia)

Answer 407

AR; PCCA, PCCB-Deficient enzyme: Proprionyl CoA carboxylase-Cofactor: Biotin-Excess Metabolite: Propionyl CoA-Metabolic testing: Acyl-carnitine profile (elevated C3), UOA\*: Methyl Citrate, High Glycine, High Anion Gap-Severe ketoacidosis after 24 hours-Neutropenia -Thrombocytopenia-Hyperammonemia -Acute crisis-Hypotonia-Lethargy-Coma-Seizures -Poor appetite -Vomiting\*UOA to distinguish PA from MMA

Question 408

Methylmalonic Acidemia-MMA(Organic Acidemia)

Answer 408

Recessive; MUT, MMAA, MMABDeficient Enzyme: methylmalonyl-CoA mutaseExcess metabolite: MMA CoACofactor: B12 (Synthesis defects may mimic MMA)Metabolic testing: Acyl-carnitine: elevated C3, UOA: methymalonic acid, Normal B12/methionine Neonatal symptoms-lethargy-vomiting-hypotonia-hypothermia-respiratory distress-severe ketoacidosis-hyperammonemia-neutropenia & thrombocytopenia

Question 409

Amino acid restrictions for organic acidemia

Answer 409

VOMITV: ValineO: Odd chain FAM: Methionine I: IsoleucineT: Threonine

Question 410

Organic Acidurias

Answer 410

-high risk of decompensation within 24-72 hours-acute presentation: toxic encephalopathy, decreased feeding, poor tone, seizures, irritability, lethargy -\> coma-Treat with carnitine supplementation

Question 411

Sinus node

Answer 411

Specialized group of cells in the right atrium that generates impulses that coordinate the pumping of blood

Question 412

What is an Arrhythmia? Name 2 common types

Answer 412

Abnormal heart beatBradycardia: Excessively slow heart beatTachycardia: Excessiverly rapid heart beat

Question 413

Ventricular Fibrillation

Answer 413

Ventricules quiver rather than pumping blood

Question 414

Electrocardiogram

Answer 414

A study used to record the electrical activity of the heart using electrodes attached to the skin

Question 415

What does each wave/interval on an EKG represent?P wave, St-T wavePR intervalQT interval

Answer 415

P wave- Represents atrial activationST-T wave- Represents ventricular repolartizationPR interval- Represents the time from onset of arterial activation to onset of ventricular activationQT interval: Duration of ventricular activation and recovery (End of the PR interval to the end of the T wave)

Question 416

What is the QRS complex?

Answer 416

Represents ventricular activation

Question 417

Echocardiogram

Answer 417

A test that uses ultrasound to visualize the heart

Question 418

What is the difference between a Transthoracic Echo (TTE) and a Transesophageal Echo (TEE)?

Answer 418

TTE is non-invasive and most common echoTEE is invasive, comes down through the esophagus to look down at the heart--Gives a clearer image

Question 419

Ejection Fraction

Answer 419

Measurement of the blood ejected from the left ventricle with each heart beatNormal is 50% or higher

Question 420

Why might a heart catherization be performed?

Answer 420

Pulmonary arterial pressureMyocardial biopsy

Question 421

SyncopePalpatations

Answer 421

Fainting, bried loss of consciousness caused by temporary lack of oxygenated bloodFeelings or sensations that the heart is pounding/racing or skipped/stopped a beat

Question 422

Sudden cardiac death

Answer 422

Death from abrupt loss of heart function-Occurs within 1 hr of cardiac symptom onset-Natural, rapid, and unexpected-25%-50% have no prior heart medical history

Question 423

Pre symptomatic testingPredisposition testingPharmacogenetic testing

Answer 423

Presymptomatic: Asymptomatic individual Predisposition applies to multifactorial disordersPharmaco applies to analysis of genes responsible for drug response

Question 424

Traditional approaches to genetic testing are limited by these factors:

Answer 424

Low penetranceAge related penetrancePremature death\*Negative family history does not exclude a genetic basis

Question 425

Cardiomyopathy

Answer 425

Disease of heart muscleCan lead to heart failure:---Swelling of lower extremities ---DyspneaIncreases risk for arrhythmias, stroke and SCD

Question 426

Types of cardiomyopathy

Answer 426

Dilated: Most common, mostly happens in adultsHypertrophy: Affects all agesRestrictive: Mostly in older adults, scar tissue replaces normal muscleArrhythmogenic Right Ventricular Dysplasia (ARVD): Often teens and young adults, death of RV muscle replaced with scar tissue, palp&syncope after physical activity

Question 427

Describe DCM

Answer 427

-Muscle that makes up the left ventricle stretchesand becomes thinner, spreads to the rightventricle and atria-Dilated heart chambers cannot pump bloodefficiently (systolic dysfunction – ejectionfraction less than 50%)

Question 428

Describe HCM

Answer 428

#NAME?

Question 429

Name 2 X-linked DCM genes & their associated diseases

Answer 429

DMD: DuchenneTaz: Barth syndrome

Question 430

What percentage of HCM are caused by mutations in sarcomere genes

Answer 430

60%-70%: Most are AD inheritanceMHY7 AND MYPBC3 each make up to 40% HCMMHY7 mutations are associated with younger age of dx, more severe HCM,nearly complete penetrance but with variable survival

Question 431

What % of individuals with HCM have more than 1 mutation?

Answer 431

5% -compound het-double heterozygous-homozygousReally limits predicting of clinical course!

Question 432

True of false, over half of Left Ventricular Non Compaction Cardiomyopathy is inherited(Non-Compaction Cardiomyopathy)

Answer 432

True. Aprroximately 70% LVNC inheritedWide range of onet-Adult form: 40yrs-Congenital form: 6yrsNormal heart development includes compaction betwen weeks 5-8 of pregnancy. If this does not happen properly, NCCM/LVNC results

Question 433

What is the clinical presentation of NCCM?

Answer 433

#NAME?

Question 434

Screening guidelines for HCM

Answer 434

ž 12-18 years• ECG and echocardiography• Repeat evaluation every 12-18 monthsž \>18-21 years• ECG and echocardiography• Repeat evaluation approximately every 3-5 years orin response to any change in symptoms• Tailor evaluation if the family has late-onset LVH orHCM-related complicationsAvoid competitive endurance training, bursts of activity, weight lifting

Question 435

This gene is associated with the highest percentage of NCCM cases

Answer 435

MYH7~15%LDB3~3%TAZ~3

Question 436

Tissues with high energy demand

Answer 436

Nerve: cortex, basal ganglia, brain stem, special sense, autonomic nerveMuscle: skeletal, cardiac, smoothEndocrine tissueRenal tubuleGrowth

Question 437

POLG-related Disorders

Answer 437

Alpers-Huttenlocher syndrome (AHS)Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA)Ataxia Neuropathy Spectrum (ANS)Childhood Myocerebrohepatopathy Spectrum (MCHS)Progressive External Ophthalmoplegia (PEO)--Can be Autosomal Dominant or Recessive

Question 438

Neurologic Red Flags in Mito

Answer 438

Stroke-Non vascular distribution, MRI/ADC map shows mixture of hyper and hypo intensityBasal Ganglis Lesions-B/L symmetric (characteristic of Leigh's) Encephalopathy-Hepatopathy -Precipitated by Valproic Acid exposure, associated with liver failureEpilepsy-Epilepsia Partialis Continua (EPC), myoclonis, status epilepticusCognitive Decline: Regrssion with illnessAtaxia-Associated with epilepsy, neuroimaging may show cerebellar atrophy, white matter lesions, basal ganglis lesionOcular signs-Optic nerve atrophy, ophthalmoplegia, ptosis, retinopathySensorineural hearing loss-At early age, accompanied by other systemmic symptoms

Question 439

Evaluation of a patient with suspected mito disease

Answer 439

FhxPhysical examMetabolic screening--Lactate, pyruvate, Ammonia, PAA, UOA, Carnitine, AcylcarnitineMolecular testing--mtDNA, nDNA, NGS panels, exomeTissue biopsy--Skin, muscle, liver--Histopathology, EM, mtDNA, RC/PDH,mtCNV

Question 440

Leigh Syndrome

Answer 440

Inheritance: X-linked or autosomal recessive, can also be mitochondrialGenes: Over 50 nuclear genes, MT-ATP6, MT-CO3, MT-ND1 through MT-ND6, MT-TK, MT-TL1, MT-TV, MT-TWMajor features:●Rapid developmental regression●Onset in first months/years of life●Onset after an energetically taxing event●Failure to thrive●Diarrhea●Vomiting●Dysphagia●Seizures●Lactic acidosis●Muscular deterioration●Hyptoonia●Dystonia●Ataxia●Ophthalmoparesis●Nystagmus●Cardiac and respiratory failure●Pyruvate dehydrogenase deficiency●VSDs●Peripheral neuropathy●Lifespan is 6-7 years oUsually death is caused by respiratory failure

Question 441

Leigh Syndrome genetics

Answer 441

Nuclear encoded Complex I: NDUFS 1,2,4,7,8 and NDUFVI cause Leigh and Leukpdystrophy Nuclear encoded Complex II genes cause Leigh with paragangliomas and pheochromocytomasNuclear encoded Complex IV genes code for assembly proteins: SURF1 (common), SCO2, COX10, 15

Question 442

Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)nDNA

Answer 442

Inheritance: Autosomal Recessive Gene: TYMP (thymidine phosphorylase, abnormal function can lead to mtDNA abnormalities like depletions, deletions, duplicaitons) ●Progressive gastrointestinal dysmotility ---early satiety, nausea, dysphagia, GERD, postprandial emesis, abdominal pain and/or distention, and diarrhea●Cachexia●Ptosis/ophthalmoplegia or ophthalmoparesis●Leukoencephalopathy●Demyelinating peripheral neuropathy ---paresthesias (tingling, numbness, and pain)---symmetric & distal weakness more prominently affecting lower extremities60% will have symptoms before 20yrs

Question 443

Barth Syndrome

Answer 443

Inheritance: X-linked recessiveGene: TAZMajor features:●Cardiomyopathy oLeft ventricular non-compaction●Neutropenia●Underdeveloped muscles and muscle weakness●Growth delay●Exercise intolerance●Normal intelligence or Mild-to-moderate learning disabilities●Growth problems resolve after puberty●Major causes of death are CM and neutropenia

Question 444

POLG-related Disorders: Symptoms

Answer 444

Inheritance: Autosomal recessive, autosomal dominantGene: POLGDisorders caused by POLG exist on a spectrum with some overlap, features seen include:●Psychiatric illness oDepression, psychosis, dementia●Seizure disorders/epilepsy●Extrapyramidal movement disorders oParkinsonianism, chorea●Cerebrovascular involvement●Sensorineural deafness●Retinopathy●Myopathy●Exercise intolerance●Peripheral neuropathy●Endocrine/gonadal failure●GI problems●Liver failure●Cardiomyopathy●Cataracts●Early death may occur

Question 445

Pyruvate Dehydrogenase Deficiency

Answer 445

Inheritance: X-linkedMost common form is E1, Alpha Deficiency Metabolic form: ●Lactic acidosis/elevated blood lactate ●Hyperventilation secondary to metabolic acidosisNeurologic form: ●Onset in the first year of life ●Hypotonia ●Poor feeding ●Lethargy ●Brain MRI abnormalities ●Developmental delay ●Intellectual ●Seizures ●Microcephaly ●Blindness ●Spasticity ●Progressive disorderSevere infantile-onset cases have a lifespan of ~6 mosTreatment:●Sodium bicarbonate for acute metabolic episodes●Ketogenic diet

Question 446

Primary Coenzyme Q10 Deficiency

Answer 446

Inheritance: Recessive Genes: PDSS1, PDSS2, CoQ2,3,6,7,9, ADCK3, ETFDH, APTX. BRAF, CABC16 clinically distinct phenotypes●Encephalomyopathic form with seizures and ataxia●Multisystem infantile form with encephalomyopathy, cardiomyopathy, and renal failure●Predominantly carebellar form with ataxia and cerebellar atrophy●Leigh syndrome with growth retardation●Isolated myopathy ●Steriod resistant nephrotic syndromeTreatment: CoQ10 supplementation

Question 447

Common features of Mito Disorders

Answer 447

●Poor growth●Exercise intolerance●Muscle weakness●Vision/hearing loss●Learning disabilities●Seizures and strokes

Question 448

Three clinical categories of mtDNA depletion syndromes

Answer 448

nDNA mutations with downstream effects that cause the quantitative loss of mtDNA copiesMyopathic (TK2, RRM2B)Encephalomyopathic: (SUCLA2, SUCLG1, RRM2B, TYMP)Hepatocerebral: (DGUOK, MPV17, POLG, C10orf2)

Question 449

mtDNA Syndromes

Answer 449

MELAS: Mitochondrial Encephalopathy Lactic Acidosis Stroke-like episodesMERRF: Myoclonic Epilepsy with Ragged Red FibersNARP: Neuropathy Ataxia Retinitis Pigmentosa MILS: Maternally-Inherited Leigh Syndrome (same gene as NARP)LHON: Leber's Hereditary Optic Neuropathy KSS/Pearson: Kearne-Sayre Syndrome

Question 450

MELAS

Answer 450

Inheritance: MitochondrialCommon mutation: 3243A\>G point mutation in tRNA-leuMost common feature is diabetes w/ or w/o deafness●Generalized tonic-clonic seizures●Recurrent headaches●Anorexia●Recurrent vomiting● Exercise intolerance ●Proximal limb weakness ●Lactic Acidosis ●Seizures associated with stroke-like episodes of transient hemiparesis or cortical blindness. ● Stroke-like episodes associated with altered consciousness● Cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. ●Sensorineural hearing loss i

Question 451

LHON

Answer 451

Inheritance: MitochondrialLow penetranceMajor features:●Rapid central vision loss in 20's-30's●Dystonia (mostly males)

Question 452

LHON Genetics

Answer 452

Most cases caused by 3 homoplastic mtDNA mutations in Complex I genes--11778G\>A, 3460G\>A, 14484T\>CPossibly most common mitoSex bias: males are 4x more likely to go blind14484T\>C is associated with vision recovery

Question 453

MERRF

Answer 453

Inheritance: MitochondrialCommon mutation: 8344A\>GMajor features:●Myoclonic Epilepsy●Ragged Red Fibers – clumps of diseased mitochondria that accumulate in the muscle fibers●Symmetrical lipomatosis around neck●Hearing loss

Question 454

NARP

Answer 454

Inheritance: MitochondrialCommon mutation: 8993G\>T or 8993G\>C Major features:●Neuropathy●Ataxia●Retinitis Pigmentosa

Question 455

Kearne-Sayre Syndrome(mtDNA Deletion Syndrome)

Answer 455

Inheritance: MitochondrialGenes: Caused by large deletions of mtDNA that are present in all tissues in individuals with KSS●Chronic progressive external ophthalmoplegia (CPEO)●Pigmentary retinopathy- usually rod-cone dystrophy oFunduscopy reveals atypical "salt and pepper" retinopathy o Mild visual acuity loss●Cardiac conduction abnormalities oAV block●Onset before 20 years of age●Cerebellar ataxia may be seen●Some individuals with mtDNA deletions may present with CPEO without other symptoms of Kearns-Sayre

Question 456

Kearne-Sayre Syndrome: Genetics and recurrence risk (mtDNA Deletion Syndrome)

Answer 456

Single most common cause of heteroplasmy for 5kb mtDNA, "Common Deletion", contains a tRNAKSS can be due to other deletions, deletions-duplications, AD AR genes-Duplications have a high recurrence risk-Low recurrence risk for deletions (~4%)5kb deletion can cause other phenotypes, inclduing Pearson syndrome

Question 457

Pearson Syndrome(mtDNA Deletion Syndrome)

Answer 457

Inheritance: MitochondrialGenes: Caused by large deletions of mtDNA which are predominantly seen in hematopoietic cells ●Fatal in infancy●Failure to thrive●Sideroblastic anemia●Exocrine pancreas dysfunctionNote: Children initially dx with Pearson can progess to develop signs and symptoms of KSS

Question 458

Chronic progressive external ophthalmoplegia (CPEO)(mtDNA Deletion Syndrome)

Answer 458

Inheritance: mtDNA deletion, AR/AD (RRM2B)●Ptosis●Ophthalmoplegia●Oropharyngeal dysfunction (Variable severerity)● Proximal limb muscle weakness.

Question 459

Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s Disease)

Answer 459

Inheritance: Most cases are idiopathic/familial, some are autosomal dominant or autosomal recessiveGenes: ALS1-ALS14Major features: ●Caused by motor neuron death ●Muscle weakness/atrophy ●Stiffness/cramping of muscles ●Difficulty swallowing ●Foot drop ●Progressive bulbar palsy ●Diffculty talking ●Progressive motor deterioration/muscle atrophy ●Loss of ability to walk/use hands and arms ●Loss of ability to speak/swallow ●Ventilator dependence ●Average survival from onset of symptoms is 4yrs ●Disease usually starts between ages 50-60

Question 460

Charcot-Marie-Tooth Disease (CMT)

Answer 460

Inheritance: Autosomal dominant, autosomal recessive, X-linkedGenes: Many, Duplications of PMP22 are responsible for 70-80% of cases (AD)Major features: ●Onset of symptoms in early childhood or early adulthood ●Foot drop oForefoot drops due to muscle weakness oCan cause hammer toe ●Muscle wasting and weakness ●Neuropathy and loss of feeling in feet, ankles, legs, hands, and arms ●Painful, spasmodic muscular contractions ●Damage of sensory nerves while pain nerves are left intact ●Bruxism ●Scoliosis ●Pregnancy and emotional stress can exacerbate disease progression ●Vocal tremor from muscle wasting ●Neuropathic pain ●Eventual wheelchair dependence ●Milder forms exist

Question 461

Duchenne Muscular Dystrophy

Answer 461

Inheritance: X-linked recessiveGene: DMD ●Out of frame deletions typically lead to DMDDuchenne Muscular Dystrophy ●Symptom onset between the ages of 2-3 ●Progressive proximal muscle weakness of legs and pelvis oWeakness spreads to rest of body oProximal to distal progression: Trunk, pelvid girdle, and shoulder girdle are lost first ●Awkward gait and/or difficulty with stairs ●Toe walking ●Clumsiness ●Easy fatigue ●Motor delay ●Lumbar hyperlordosis ●Muscle contractures ●Pseudohypertrophy of the calf ●Increased risk for behavioral and learning disorders ●Trouble standing from a lying/sitting position oPositive Gower’s sign ●Elevated serum CPK ●EMG showing destruction of tissue (rather than damage to nerves) ●Cardiomyopathy ●Arrhythmia ●Skeletal deformities ●Wheelchair dependence by 13 ●Late stage respiratory difficulties/ventilator dependence o Increased risk for pneumonia o Dysphagia ●Late stage congestive heart failure ●Average lifespan 20-30

Question 462

Becker Muscular Dystrophy

Answer 462

In frame deletions typically lead to BMD ●Slightly milder phenotype than DMD ●Later onset progressive muscle weakness thanDMD ●Severe upper extremity weakness ●Toe-walking ●Positive Gower’s sign ●Skeletal deformities oScoliosis ●Pseudohypertrophy of the calves ●Activity induced muscle cramps ●Preservation of neck flexor muscle strength oDifferentiaties BMD from DMD ●Wheelchair dependency by ~16 ●CardiomyopathyAverage lifespan is mid 40s

Question 463

Emery-Dreifuss Muscular Dystrophy

Answer 463

Inheritance: X-linked, autosomal dominant, autosomal recessiveGenes: EMD, LMNA, SYNE1, SYNE2, FHL1Major features: ●Muscle wasting and weakness ●Toe walking ●Joint contractures ●Arrhythmia ●Wheelchair dependency/respiratory insufficiency ●May have intellectual disability (X-linked)

Question 464

Facio-Scapulo-Humeral Muscular Dystrophy

Answer 464

Inheritance: Autosomal DominantGenes: Due to deletions of 4q35 which cause deletions of the microsatellite repeat D4Z4. Normally 11-100 repeats units on wild-type alleles. Deletions leading to 10 or fewer repeats lead to FSHDMajor features: ●Normal lifespan ●Slowly progressive weakness of the facial muscles, scapular muscles, and humeral muscles ● CK elevated but not \>1500 ●No weakness in bulbar or ocular muscles ●Winged scapula ●Onset of symptoms by 20 years of age

Question 465

Limb-Girdle Muscular Dystrophy

Answer 465

Inheritance: Autosomal dominant, autosomal recessiveGene: Too manyMajor features: ●Symmetric proximal slowly progressive muscle weakness ●Elevated CK levels ●Difficulty walking and using stairs ●Difficulty bending over ●Frequent falls ●Difficulty holding arms above head ●Pseudohypertrophy ●Respiratory difficulties ●Lower back pain ●Heart palpitations ●Facial muscle weakness ●Distal muscle weakness ●Shoulder weakness ●Age of onset typically between 10-30 oFaster progression with earlier onset ●Not typically fatal, but can weaken heart or lungs and lead to death

Question 466

Nemaline Myopathy: General

Answer 466

Inheritance: Autosomal dominant, autosomal recessiveGenes: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3Major features: ● Long face ●Muscle weakness, most severe in the face, neck flexors, and proximal limbs ●Hypotonia ●Depressed/absent deep tendon reflexesMuscle biospy shows myopathic changes and Nemaline bodies

Question 467

Nemaline Myopathy: Severe congenital NM

Answer 467

Severe congenital NM ●Severe hypotonia and muscle weakness at birth ●Feeding difficulties ●GI reflux ●Respiratory insufficiency o Often leads to early mortality

Question 468

Spinal Muscular Atrophy (SMA) Types I & II

Answer 468

Inheritance: Autosomal recessiveGene: SMN1SMAI: ●Onset 0-6 months ●Hypotonia with muscle weakness ●Absence of motor development ●Involuntary twitching of the tongue ●Mild joint contractures ●Absent tendon reflexes ●Normal brain function and intellect ●Respiratory failure ●Lethal by age 2SMAII ●Onset after age 6 months ●Can sit independently once placed in a seated position ●Hypotonia ●Absent tendon reflexes ●Normal intellect ●May live past age 4

Question 469

Spinal Muscular Atrophy (SMA) Types III & IV

Answer 469

SMAIII●Onset after age 10 months●Most motor milestones achieved●Muscle weakness manifesting as frequent falls and trouble with stairs●Proximal limb weaknessoLegs worse than armsSMAIV●Adult onset muscle weaknessSeverity can be affected by number of SMN2 copies. SMN2 can compensate for absent SMN1, the more SMN2 copies, the less severe the phenotype

Question 470

Walker Warburg Syndrome

Answer 470

Inheritance: Autosomal recessiveGenes: POMT1, POMT2Major features: ●Hypotonia ●Muscle weakness ●Developmental delay ●Absence of motor skill development ●Severe Intellectual disability ●Seizures ●Brain defects oLissencephaly (Cobblestone Lis for type 2) oHydrocephalus oPronto-cerebellar malformation ●Encephalocele oGap in skull that won’t seal oMeninges of brain can protrude through this gap ●Microphthalmia ●Retinal abnormalitiesLifespan of 1-3 years

Question 471

Amish Nemalin Myopathy

Answer 471

Amish NM ●Neonatal onset with early childhood onset ●Hypotonia ●Contractures ●Muscle tremors ●Severe pectus carinatum ●Muscle atrophy ●Respiratory insufficiency

Question 472

Intermediate Nemalin Myopathy

Answer 472

Intermediate NM ●Early development of joint contractures ●Motor delay due to muscle weakness ●Wheelchair/respiratory deficiency by age 11Typical (mild) congenital NM ●Hypotonia, weakness, and feeding difficulties ●Spontaneous anti-gravity movements ●Respiratory involvement is limited (recurrent lower respiratory tract infections and/or nocturnal hypoventilation)

Question 473

Childhood-onset Nemaline Myopathy

Answer 473

Childhood-onset NM ●Slowly progressive symmetric weakness of ankle dorsiflexion with foot drop ●Onset in 1st or 2nd decade of life ●Motor milestones usually metAdult-onset NM ●Generalized muscle weakness onset between ages 20-50 without antecedent symptoms ●May have cardiomyopathy ●May present with “head drop”

Question 474

What does the Gower's maneuver/sign indicate?

Answer 474

●Sign of proximal weakness●Not indicative of a speficic diagnosis but is seen in DMD& BMD

Question 475

Trendelenburg Gait

Answer 475

Weakness of the abductor muscles of the lower extremity, gluteus medius and gluteus minimus

Question 476

DMD/BMD carriers

Answer 476

●Less than 5% of carriers also have weakness but not as severe●Dilated cardiomyopathy main concern and may be independent of X-inactivationDMD carriers: 5%-8% lifetime risk or DCM Up to 20% lifetime risk for LV dilationBMD carriers: \<1% risk of DCM Up to 15% lifetime risk of LV dilation

Question 477

Genetic testing for DMD/BMD

Answer 477

Done in 2 tiersTier 1: Test for exonic del/dupsTeir 2: Full dystrophin gene sequencing if no exonix del/dup

Question 478

Sarcoglyanopathies (LGMD 2C-F)

Answer 478

Sarcolycan genes: SGCA,SGCB,SGCG, SGCDInitial muscle involvement is similar to DMD/BMD-Similar age onset (3-15yr), Elevated CK,Differentiate from DMD/BMD-Intellectually normal development-All AR and affect males and femalesSGs account for ~70% of all childhood onset LGMD ~10% of all adult onset LGMD

Question 479

Ullrich CMD

Answer 479

Inheritance: Autosomal Recessive or de novo dominantGenes: COL6A1, COL6A2, COL6A3●Significant hypotonia and weakness, initial contractures not obligatory●No or temporary ambulation●CK: normal to high●Charachteristic coexistence of very significant distal hyperlaxity and proximal contractures●Kyphoscoliosis, torticollis, hip dislocation, talipes●Skin: palmar softness, proximal keratosis pilaris, abnormal scars● Early respiratory compromise

Question 480

Bethlem myopathy

Answer 480

Inheritance: Autosomal Dominant or de novo Genes: COL6A1, COL6A2, COL6A3●Congenitial joint contractures●Torticollis (50%) may be present, but often resolve●CK: normal to mildly elevated●After initial joint hypermobility, new development of contractures:●Achilles tendons, elbows, deep finger flexors, pectoralis, quadriceps●Very slowly progressive, contractures may become major of a problem, +/- late loss of ambulation●Restrictive lung disease, nighttime hypoventilation

Question 481

SMA Genetics

Answer 481

~95% have homzygous deletion of exon 7 of MSN1~5% have heterozygous deletion of exon 7 of SMN1 gene and a point mutation in the other SMN1 alleleRare for SMA patients to have a homozygous non deletion mutationSecond most common lethal recessive disease after cystic fibrosisCarrier frequency: Caucasian 1/47 AJ: 1/67 Pan ethnic: 1/54

Question 482

Ataxia Telangiectasia(gene, inheritance, disrupted repair)

Answer 482

ATMRecessiveDouble-stranded break repair (disrupted)\*\*Heterozygous carriers of ATM mutations are at an increased risk for breast cancer

Question 483

Ataxia Telangiectasia(features)

Answer 483

ATM; Recessive; Double-stranded break repair- Increased risk for cancer, especially lymphomas and leukemias- Ataxia- Telangiectasias in whites of eyes (may appear in other sun exposed areas)- Oculomotor apraxia- Involuntary movements- Recurrent ear/sinus/upper respiratory infections- Delayed puberty onset- Premature menopause- Growth delay- Drooling- Dysarthria (slurred speech)- Premature aging- Type 2 diabetes at young age- Neurologic symptoms typically stable in first 4-5 years and slowly progressive afterward- Shortened lifespan (25-50 years)

Question 484

Bloom syndrome(gene, inheritance, disrupted repair)

Answer 484

BLMRecessiveIncreased sister chromatid exchanges/double-stranded break repair\*\*Common in AJ population - 1:100

Question 485

Bloom syndrome (features)

Answer 485

BLM; Recessive; Increased sister chromatid exchanges/double-stranded break repair-IUGR-short stature-extreme growth deficiency-"butterfly shape" skin lesions/rashes after sun exposure-HIGH PITCH VOICE-feeding difficulties-immune deficiency-premature menopause-azoospermia/oligospermia-COPD-intellectually normal, some may have learning problems-little subcutaneous fat tissue during childhood-risk for cancer: COLON, breast, liver, respiratory tract, lymphatic, sarcoma, germ-cell, CNS, retinoblastoma, Leukemia

Question 486

Cockayne syndrome(gene, inheritance, disrupted repair, types)

Answer 486

ERCC6, ERCC8RecessiveNucleotide Excision Repair-Type 1: "classic" or "moderate" form - normal prenatal growth with onset of growth and developmental abnormalities in first 2 years-Type 2: severe/early-onset; overlaps with cerebrooculofacioskeletal syndrome or Pena-Shokeir syndrome type 2-Type 3: mild/late-onset - essentially normal growth and cognitive development or by late onset-Xeroderma pigmentosum-Cockayne syndrome: facial freckling and early skin cancers typical of XP and some features typical of CS; DOES NOT include skelatl involvement, facial phenotype of CS, or CNS dysmyelination and calcifications

Question 487

Cockayne syndrome(features)

Answer 487

ECCD6, ECCD8; Recessive; Nucleotide excision repairMajor features:-postnatal growth failure-Progressive microcephaly-Leukodystrophy-Neurologic dysfunction-Developmental delay-Behavioral problems-Intellectual deteriorationMinor features: photosensitivity, demyelinating peripheral neuropathy, pigmentary retinopathy, cataracts, SNHL, dental anomalies, characteristic physical appearance (CACHECTIC DWARFISM), premature aging\*\*Only XP-CS type has cancer/infection predisposition

Question 488

Fanconi Anemia(genes, inheritance, disrupted repair)

Answer 488

FANCA-FANCP, BRCA2, BRIP1, PALB2, RAD51C, SLX4Recessive, X-linked recessive (FANCB)Cross-link repair, homologous recombination repair\*\*treatment with androgens and hematopoietic growth factors may help/stem cell transplant

Question 489

Fanconi Anemia(features)

Answer 489

Cross-link repair, homologous recombination repair-short stature-skeletal anomalies (abnormal limbs & digits, dysplastic, hypoplastic, or absent)-microcephaly-skin lesions: hyper & hypopigmentation, cafe-au-lait-dysmorphic facial features-gentiourinary abnormalities-azoospermia-DD & ID-CONDUCTIVE hearing loss (middle ear skeletal anomalies)-CHDs-GI issues (atresia, malrotation)-kidney problems-pituitary/CNS hypoplasia-PANCYTOPENIA/BONE MARROW FAILURE-significantly increased risk for cancer: lymphatic/leukemia & head/neck tumors

Question 490

Nijmegen Breakage Syndrome(gene, inheritance, disrupted repair)

Answer 490

NBN (NBS1)RecessiveHomologous recombination repair

Question 491

Nijmegen Breakage syndrome(features)

Answer 491

NBN (NBS1); Recessive; Homologous recombination repair-microcephaly-growth delay-recurrent sinopulmonary infections-progressive decline in intellecutal ability leading to borderline-to-moderate ID-dysmorphic features-T and B-cell lymphomas are common