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A case of hypopigmentation disorder: hereditary or idiopathic genodermatoses?

Passanisi S1, Torrisi GG2, Morabito L1, Cutrupi MC1

1Pediatric Unit, University of Messina, Italy

2Unit of Dermatology, "Vittorio Emanulee" Hospital, University of Catania, Catania, Italy


Abnormal changes of skin colour are observed in a vast number of diverse disorders with different underlying mechanisms. Essentially, any change of the components that contribute to normal skin colour, resulting in their excess or deficiency within the skin will produce an altered cutaneous colouration. Some authors use the term ‘pigmentation’ disorders as synonymous to ‘melanotic’ disorders to include entities that are characterized by a pathological change in melanin or melanocytes and differentiate these from the ‘non-melanotic’ disorders which are due to alterations of other cutaneous chromophores (1). Melanotic disorders are broadly divided into hypermelanotic (due to excess melanin but normal melanocytic population) and hypermelanocytic (due to normal melanin and increased melanocytic proliferation) as well as hypomelanotic/amelanotic and hypomelanocytic/amelanocytic which are due to melanin deficiency and reduction or absence of melanocyte number respectively. (2). Further categorization distinguishes these groups into congenital and acquired, circumscribed, mixed and generalized, epidermal, dermal and mixed groups.
We present a patient who had hypopigmentation disorders likely secondary to hereditary disease, describing probable causes and its differential diagnosis.


Case report 

A.C., the  third child born of non consanguineous Caucasians parents, was born by cesarean section, at 33 weeks of gestational age. The pregnancy was complicated by placenta previa. The birth weight was 1750 g. At birth she was in good health, exept transitory hypotonia. Although prematurity she has not needed intensive cure during the first days of life. At the age of 7 years she was admitted to the emergency room of our hospital, AOU G. Martino of Messina, for traumatic head injury. She was submitted to cranial TC, which showed lesions typical of previous cerebral ischemia; therefore she was hospitalized in Pediatric Neurology Department for further investigations. During the hospitalization she was referred to our observation for multiple, rounded and ovalar, asymptomatic, well marginated, hypomelanotic skin macules on the trunk, upper and lower limbs, associated to skin xerosis (Fig. 1 a, b, c). These lesions had been present since she was 1 years. No other phenotic features were present. Familiar dermatological history was positive since mother, older brother, maternal uncle, two cousins (affected uncle’s sons) had presented, when they were children, the same skin lesions which were regressed at the pubertal age. On the suspicion of hereditary disease with autosomal dominant inheritance, genetic investigations as cromosome karyotyping, array comparative genomic hybridization were performed and they are still ongoing.




Fig. 1 Multiple, rounded and ovalar, asymptomatic, well marginated, hypomelanotic skin macules on the trunk (a), upper and lower limbs, associated to skin xerosis



Hypo- and hyper-pigmentation disorders are the most severe dermatological diseases observed in patients from all over the world. These disorders can be divided into melanoses connected with disorders of melanocyte function, which could be secondary to immunological, infectious or inflammatory causes, and hereditary melanocytoses connected with melanocyte development. Hereditary hypomelanocytoses are caused by abnormal melanoblast development, migration and proliferation as well as by abnormal melanocyte viability and proliferation. These disorders are represented by piebaldism, Waardenburg syndrome, and Tietz syndrome, and are caused by different mutations of various or the same genes. The types of mutations comprise missense and nonsense mutations, frameshifts (in-frame insertions or deletions), truncating variations, splice alterations and non-stop mutations (3).
Piebaldism is a rare autosomal-dominant disorder of melanocyte development characterized by congenital poliosis, and stable patches of leukoderma (4). Piebaldism is caused by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene, located on chromosome 4q12, which affects the differentiation and migration of melanoblasts from the neural crest during the embryonic life (5). Characteristically, lesions of leukoderma are well-circumscribed, irregular, white patches that are often accompanied by hyperpigmented macules noted on both depigmented and unaffected adjacent skin (6). Poliosis circumscripta, traditionally known as white forelock, may be the only manifestation in 80% to 90% of cases and is present at birth (7). The white forelock typically appears in a triangular shape and the underlying skin of the scalp also is amelanotic. Pigmentary anomalies in piebaldism are typically restricted to the hair and skin. Rare associations have been reported with piebaldism, in particular Hirschprung's disease or aganglionic megacolon, supporting evidence of a network of interacting genes and proteins for the regulation of melanocytes and enteric plexus neurons during their development at the time of embryogenesis (8). 
Waardenburg syndrome is a genetic syndrome consisting primarily of anomalies of the skin, hair, eyes, and ears and affects 1 in 40, 000 according to population studies (9). There are four major types of Waardenburg syndrome, generally involving the PAX3 (Paired box 3), MITF
(microophthalmia-associated transcription factor), SOX10 (Sry box 10), EDN3 (endothelin 3), and EDNRB (endothelin receptor type B) genes (10, 11). As established at the Waardenburg consortium, diagnosis requires fulfillment of either two major criteria or one major and two minor criteria. (12) Major criteria include the characteristic white forelock (hair depigmentation), pigmentary anomalies of the iris, congenital sensorineural deafness, dystopia canthorum, or an affected first degree relative. Minor criteria are depigmented macules or patches, synophrys, broad nasal root, nose hypoplasia, or early graying of the hair by age 35. The musculoskeletal system and gastrointestinal tract can also be affected in certain subtypes.
Tietz syndrome is a hypopigmentation-deafness syndrome resulting, like WS2, from mutations in the region of the MITF gene encoding the DNA-binding domain, resulting in early embryionic loss of all melanocyte precursors. Tietz syndrome individuals exhibit generalized cutaneous hypopigmentation similar to that found in albinism, rather than distinct depigmented patches (13). Affected individuals could also showed mild craniofacial anomalies and retention of some hearing function.
In the case we have described differential diagnosis include several form of acquired hypopigmentation disease enclosing:
- pityriasis alba, which is a localized hypopigmented disorder of childhood with many existing clinical variants. Poor cutaneous hydration appears to be a common theme for most risk factors and may help elucidate the pathogenesis of this disorder. Alleviation of the various risk factors, such as atopy, xerosis and mineral deficiencies, via patient education on proper skin care and hygiene, use of lubricants and emollients, topical corticosteroid therapy in the presence of inflammation, and the novel administration of topical anti-inflammatory drugs such as calcineurin inhibitors can play a crucial role in promoting remission or resolution (14). 
- iatrogenic causes of hypopigmentation disorders, such as those related to imiquimod, an immune response modifier used to treat certain types of skin growths (actinic keratoses) or skin cancer (superficial basal cell carcinoma) (15, 16). 
- exposure to toxic agents such as hydroquinone, aromatic organic compound, which represent the major component in most black and white photographic developers for film and paper  and which is contained in some cosmetics too (17). 
- cutaneous infectious disease such as pityriasis versicolor, a superficial fungal infection of the skin caused by Malassezia species that induces a characteristic rash of well demarcated, thin, scaly plaques that can be hypopigmented, hyperpigmented, or erythematous which need topical treatments including ketoconazole, selenium sulphide, or zinc pyrithione shampoo (18).
Due to the wide spectrum of causes of hypopigmentation disorders, the diagnosis is not always immediate. In our patient positive results of genetic investigations could lead to a resolution of the case. On the contrary, in the case of negativity we could consider, in addition of aforementioned causes of acquired hypopigmentation diseases, the diagnosis of a specific and endemic skin disease such as pityriasis rotunda sardoa, an idiopathic dyschromic-desquamative genodermatoses characterized by hypopigmented lesions which were resolved in the pubertal age, described in the last century in some Mediterrean areas, especially in Sardinia (19).

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