Hyperpigmentation

Question 1

Answer 1

Ashy dermatoses

A spectrum of cutaneous pigmentary disorders of uncertain aetiology characterised by the development of persistent grey-blue hypermelanotic cutaneous macules for which no specific
cause can be identified. It has been proposed that ashy dermatosis be used for all such cases but that erythema chronicum perstans be limited to those cases in which an inflammatory phase with redness has been observed.

Females more than males

The active border in cases of erythema chronicum perstans shows vacuolar degeneration of the basal cells. The epidermis contains much pigment and there is pigmentary incontinence; the dermal vessels are sleeved with an infiltrate of lymphocytes and histiocytes, and there are many melanophages

In a Mexican population, HLA-DR4 has been associated with erythema dyschromicum perstans.

Clinically, ashy dermatosis is characterised by numerous macules of varying shades of grey;there may initially be signs
of inflammation with a red, slightly raised and palpably infiltrated margin (erythema dyschromicum perstans).

The macules vary in size and tend to coalesce over
extensive areas of the trunk, limbs and face. Against the general greyish background are macules of hypomelanosis or hypermelanosis. The condition is persistent and slowly extends. The lesions are mostly asymptomatic, although some patients may experience mild pruritus. Mucous membranesare spared.

Differential diagnosis
* Lichenplanus pigmentosus.
* Postinflammatory hypermelanosis secondary to identifiable
cause.
* Late pinta, which should be excluded in endemic areas.

Disease course and prognosis
The initial erythematous phase tends to settle after several months.
The pigmentation is persistent with a tendency to extend gradually over years.

If there is a history of pruritus, and clinical features of
papules and plaques associated with the pigmented lesions,
the condition is unlikely to be AD

Acquired large (>5 cm) hyperpigmented macules are char-
acteristic in AD and EDP. In typical cases of AD and EDP,
the trunk is a common area of involvement.
Cases described as EDP without a history or current evi-
dence of erythematous border can be considered synony-
mous with AD.

Question 3

What is lichen planus pigmentosus?

Answer 3

Lichen planus pigmentosus. This is a pigmentary disorder seen in India or in the Middle East, which may or may not be associated with typical LP papules. The macular hyperpigmentation involves chiefly the face, neck and upper limbs, although it can be more widespread, and varies from slate grey to brownish black. It is mostly diffuse, but reticular, blotchy and perifollicular forms are seen. The duration at presentation ranged from 2 months to 21 years in one series. Occasionally, there is a striking predominance of lesions at intertriginous sites, especially the axillae. The mucous membranes, palms and soles are usually not involved, but involvement of mucous membranes has been observed. LP pigmentosus has been anecdotally reported in association with acrokeratosis of Bazex.

Lichen planus pigmentosus inversus has been described as a variant of lichen planus with mildly pruritic hyperpigmented macules and/or patches involving intertriginous and flexural skin folds in light skinned individuals.

Only a minority of cases of LPP have past or current evidence of typical lichen planus.

LPP involves the head and neck region in most cases.

In LPP, temple, forehead, preauricular region, ears, mental
and submental region, and neck are the more common
areas of involvement in the head and neck region.

In LPP, after the head and neck region, the next most com-
mon area of involvement is the flexures, particularly axillae.

LPP lesions are found on sun-exposed areas as well as
non-sun-exposed areas.

LPP-like pigmentation has been associated with lichen
planopilaris of the scalp in some cases

Question 4

What is idiopathic eruptive macular pigmentation?

Answer 4

IEMP is characterized by asymptomatic, nonconfluent brown macules involving the neck, proximal extremities, and trunk with no preceding inflammation or history of drug exposure.
Histology is characterized by hyperpigmentation of the basal layer of the epidermis and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate and normal mast cell counts.

Small macules (0.5–2 cm) of acquired pigmentation, occur-
ring predominantly in adolescents and young adults with or
without raised velvety pigmented lesions, which resolve
within a few months or a few years could be termed IEMP,
provided that the pigmented macules did not appear follow-
ing a known disease episode such as a viral exanthem, a
lichenoid drug eruption, or pityriasis rosea, etc.

Typically regresses over several months or a few years

Question 5

Define Rieh’s melanosis.

Answer 5

The term Riehl’s Melanosis should only be used to describe
numerous fine (i.e., few millimeters in size) or reticulate,
acquired macules of pigmentation of uncertain etiology
occurring on the face, neck, and upper chest.

If a diagnosis of a relevant contact dermatitis can be estab-
lished; numerous fine (e.g., few millimeters in size) acquired
macules of pigmentation of uncertain etiology occurring on
the face, neck, and upper chest, should be termed pig-
mented contact dermatitis

Question 6

Answer 6

Confluent and reticulated papillomatosis (CARP) is an uncommon disorder of epidermal keratinisation characterised by the development of hyperkeratotic papules which coalesce into confluent and, in places, reticulated plaques on truncal skin. An abnormal reaction to commensal microorganisms has been postulated to play an aetiological role.

It is predominantly a disease of young adults. In one series of
patients,the meanageat onsetwas 19 years.

A number of reports have demonstrated the presence of Malassezia organisms in CARP. This has led to speculation that CARP is due to an abnormal host reaction to Malassezia. Several studies have shown, however, that only about one-half of patients with CARP have significant yeast populations on affected skin.

Some patients with CARP appear to respond to tetracycline and macrolide antibiotics, which has led to the suggestion that skin bacteria may be responsible for this disease. It has been suggested, however, that the response to antibiotics may be due to their anti-inflammatory rather than their antibacterial properties.

The patient is usually a young, postpubertal individual. Plaques
of CARP are located mainly on the trunk, especially on the
presternal, interscapular and epigastric areas. They are generally asymptomatic.

Patients first notice pigmented, 1–2 mm diameter hyperkeratotic papules on the trunk. These coalesce to form greyish blue plaques which are confluent at the centre but become reticular towards the periphery of the plaques. Over weeks or months, the plaques spread to involve the lower abdomen and pubic areas. The face and limbs may be affected. Localised forms affecting only the face or pubic area have been reported.
Mucous membranes are not involved. A number of different
patternsofskin involvementhave been described.
Differential diagnosis
The most common differential diagnoses proposed in cases of CARP include:
* Acanthosis nigricans.
* Prurigo pigmentosa.
* Macular amyloid.
* Darier disease.
* Epidermal naevus.
* Plane warts.
* Pityriasis versicolor.
* Dermatitis neglecta (inadequate frictional cleansing).

Disease course and prognosis
It is a chronic disease with remissions and exacerbations. If CARP responds to treatment, it may relapse when treatment is withdrawn although persistent remission after tetracyclines is reported.

Management
It is a chronic disease and is purely cosmetic, so no treatment is an option if the condition does not bother the patient. Spontaneous improvement has been reported. In overweight patients, weight reduction may result in improvement. In some women, CARP may improve during pregnancy or with the use of the oral contraceptive.

A wide range oforal antibiotics have been found to be
effective in CARP: the most effective appears to be
minocycline; azithromycin is an alternative.

Question 7

Kwashiorkor

Answer 7

The classic phenotypic forms include kwashiorkor and maras-
mus. Kwashiorkor refers to the disease state that arises from the prolonged disproportionate intake of carbohydrate (energy or calories) in excess of other macronutrients, specifically protein. As a result of hypoproteinaemia, affected individuals manifest signs of growth retardation and most notably oedema.

In kwashiorkor, excess carbohydrate without significant protein intake suppresses insulin production, resulting in the inhibition of protein synthesis. Patients with this condition manifest clinically with signs of hypoproteinaemia, including oedema and fatty infiltration of the liver due to deficiencies in lipoproteins. Those chronically affected also demonstrate immune suppression due to decreased production of immune proteins such as immunoglobulins and are therefore at risk for opportunistic infections. Growth retardation is noted but typically falls between 60% and 80% of ideal bodyweight.

In kwashiorkor, affected individuals may also exhibit loss of
subcutaneous fat. Peripheral oedema is a consistent feature due to the associated hypoproteinaemia. Abdominal distention is a feature observed in children and has been attributed to hepatomegaly from increased fatty deposition due to lack of available apolipoproteins.

The skin findings are highly characteristic and include a dermatosis that has been likened to ‘cracked skin’,
‘peeling paint’, ‘enamel paint’, ‘flaky paint’ or ‘crazy paving’ due
to the typical scale and irregular fissuring noted on examination. Over time, more defined plaques may arise that may be more concentrated in areas of friction such as the intertriginous areas.

The CDC recommends inpatient care for children with evidence of severe oedema and malnutrition, as well as those with mild to moderate oedema and no appetite, or those with associated medical complications. Those without complications and who have an appetite should be managed in the outpatient setting.

Question 8

Answer 8

Dyschromatosis symmetrica hereditaria (DSH) – also called symmetrical dyschromatosis of the extremities and symmetrical or reticulate acropigmentation of Dohi [90] – is characterised by freckle-like pigmented macules on the face associated with small hyper-and hypopigmented macules affecting the back of the hands and feet. The condition usually begins in early childhood and has been predominantly reported in Japanese and Chinese individuals. The prevalence of DSH in the Japanese population is
estimated to be1.5 per 100000.

Dyschromatosis symmetrica hereditaria has a dominant pattern of inheritance and is caused by a heterozygous mutation in the ADAR1 gene (adenosine deaminase acting on RNA1) located on chromosome 1q2. ADAR1 mediates a post-transcriptional modification of the messenger RNA known as RNA editing. Miyamura et al. postulated that impaired RNA editing during melanoblast migration causes their differentiation into either hyper- or hypoactive melanocytes and that the most affected melanocytes are those that migrate farthest, to the extremities, i.e. the hands and feet.

Question 9

Answer 9

Dyschromatosis universalis hereditaria (DUH) is a rare auto-
somal genodermatosis characterised by hyper- and hypopig-
mented macules distributed over the entire surface of the skin. The lesions usually appear in infancy or early childhood. Involvement of the palms or soles is unusual. Abnor-
malities of the hair and nails have also been reported. Also, DUH has been associated with neurological, ophthalmological and haematological complications.

There is now evidence for genetic heterogeneity in DUH. Het-
erozygous mutations in SASH1 have associated with DUH,
DUH2 maps to chromosome 12q21q23a and DUH3 is caused by mutation in the ABCB6 gene on chromosome 2q35.

Question 10

What syndromes are associated with multiple CALM that are also NF like?

Answer 10

Question 11

What syndromes are associated with multiple CALM?

Answer 11

Question 12

What syndromes are associated with multiple CALM?

Answer 12

Question 13

which drugs can cause hyperpigmentation?

Answer 13

Question 14

which drugs can cause hyperpigmentation?

Answer 14

Question 15

What can cause linear hyperpigmentation in the lines of blashcko?

Answer 15

Question 16

What can cause linear hyperpigmentation but not follow the lines of blaschko?

Answer 16

Question 17

Answer 17

Linear and Whorled Nevoid Hypermelanosis

„ Hyperpigmentation in whorls and streaks following the lines of Blaschko
„ Usually becomes apparent within the first year of life
„ Associated systemic findings occur in a minority of affected
individuals
„ Increased melanin within the epidermis and few melanophage

LWNH is a genetically heterogeneous, mosaic skin condition charac-
terized by a clone of skin cells with increased pigment production29
.
A variety of underlying mosaic chromosomal anomalies have been reported. Mosaicism for a gain-of-function mutation in the KIT ligand gene (KITLG) was reported in a patient with extensive LWNH, thus representing a mosaic presentation of familial progressive hyperpigmentation.

Clinical features
Swirls and streaks of brown pigmentation usually appear early during the first year of life. The full extent of skin involvement is typically apparent by the time the child is 2–3 years of age 28. The linear hyperpigmentation tends to persist indefinitely. Occasionally, patients with “pigmentary mosaicism” will develop both hypo- and hyperpigmented streaks.

Approximately 10%–25% of patients with LWNH who present
to a pediatric dermatologist have extracutaneous findings, which typically become apparent during infancy and may be neurologic, musculoskeletal, or (less often) cardiac in nature.

Question 18

What is the gene, inheritence pattern and likely presentation on the skin of IP?

Answer 18

This X-linked dominant multisystem disorder is characterized by skin lesions distributed along the lines of Blaschko, including vesicles (stage 1), verrucous lesions (stage 2), hyperpigmentation (stage 3) and, eventually, hypopigmentation (stage 4). The third stage usually
presents within the first year of life and is characterized by gray to gray–brown streaks and whorls along the lines of Blaschko.
The trunk is a common area of involvement. The pigmentation
fades gradually during late childhood to adolescence, often persisting primarily in intertriginous sites. IP is due to mutations in the IKBKG (NEMO) gene.

The gradual fading of stage 3 lesions reflects increased
apoptosis within the affected streaks, followed by replacement with normal skin.

Answer 19

DYSKERATOSIS CONGENITA

Genetically heterogeneous disorder due to defective telomere
maintenance, with X-linked recessive inheritance in the most
common form
„ Triad of reticulated hyperpigmentation, nail dystrophy (e.g.
pterygium), and leukoplakia
„ Bone marrow failure resulting in thrombocytopenia, anemia, or pancytopenia
„ Continuous lacrimation (epiphora) due to lacrimal duct atresia, pulmonary fibrosis, and liver cirrhosis may develop
„ Predisposition to malignancy, especially mucosal squamous cell carcinoma (e.g. mouth, anus)

The most common form of DKC has an X-linked recessive pattern of inheritance, but autosomal dominant and autosomal recessive forms also exist.

The overall male : female ratio is ~3 : 1

A lacy reticulated pattern of hyperpigmentation generally develops during the first decade of life. This occurs primarily on the neck, upper chest, and upper arms and is sometimes admixed with macules of hypopigmentation. Telangiectasias and epidermal atrophy may also be seen, i.e. poikiloderma.

Additional cutaneous features include wrinkled skin on the extremities, dorsal aspects of the hands, and genitalia; palmoplantar hyperhidrosis and hyperkeratosis;
loss of dermatoglyphics; frictional bullae; acrocyanosis;
and premature graying of the hair.

Nail involvement is present in the vast majority of patients, typically appearing during early childhood. Initial changes include longitudinal ridging and splitting, followed by pterygia formation and occasionally complete nail loss. Leukoplakia occurs in most patients, usually manifesting during early adolescence. White plaques on the oral mucosa are observed most commonly, with a predilection for the lateral portions of the tongue. Involvement of the urethra, vagina, and
anus may also be seen. The teeth may be malformed, missing, or have aberrant spacing or extensive caries.

Epiphora (continuous lacrimation) due to lacrimal duct atresia is common. Bone marrow failure occurs in 50%–90% of patients and is a major cause of mortality. It presents during the second or third decade with anemia, thrombocytopenia, or pancytopenia. Malignancies tend to develop during the third or fourth decade, most notably squamous cell
carcinomas of the mouth, anus, cervix, vagina, esophagus, and skin.

There is also an increased risk of myelodysplastic syndrome, acute myeloid leukemia, and gastrointestinal carcinomas.
Other potential systemic manifestations include pulmonary fibrosis, liver cirrhosis, developmental delay, short stature, avascular necrosis of the femoral head, esophageal or urethral stenosis, cryptorchidism, male hypogonadism, and immunologic dysfunction leading to opportunistic
infections. Of note, increased severity in successive generations (anticipation) due to progressive telomere shortening has been observed in autosomal dominant forms of DKC.

Hoyeraal–Hreidarsson syndrome is a severe variant of DKC characterized by early bone marrow failure, immunodeficiency, cerebellar hypoplasia, microcephaly, enteropathy, and growth retardation (intrauterine and postnatal).

Caused by mutations in several DKC genes, it typically leads to death in early childhood. Revesz syndrome is another related disorder that features progressive neurologic deterioration, intracranial calcifications, and exudative retinopathy together with the manifestations of DKC; it is caused by heterozygous mutations in TINF2.