The dyschromatoses

INTRODUCTION — The dyschromatoses are a group of rare, inherited, pigmentary disorders characterized by the development during infancy or childhood of numerous, irregular, hyperpigmented and hypopigmented macules approximately 5 mm in diameter [1]. Dyschromatosis symmetrica hereditaria (DSH; MIM #127400) and dyschromatosis universalis hereditaria (DUH; DUH1 [MIM #127500], DUH2 [MIM #612715], DUH3 [MIM #615402]), which are the two most common dyschromatoses, were first reported and most commonly occur in Japan.

This topic will discuss the clinical manifestations, diagnosis, and treatment of DSH and DUH. Other congenital and inherited hyperpigmentation disorders and the acquired hyperpigmentation disorders are discussed separately. (See "Acquired hyperpigmentation disorders".)

EPIDEMIOLOGY — Epidemiologic data on the inherited dyschromatoses are limited. The prevalence of dyschromatosis symmetrica hereditaria (DSH) in Japan is estimated to be approximately 1.5 per 100,000 [2]. The prevalence of dyschromatosis universalis hereditaria (DUH) is probably much lower than DSH prevalence. One study reported that approximately 1.9 and 0.3 per 100,000 dermatology consultations in Japan are related to DSH and DUH, respectively [3].

DYSCHROMATOSIS SYMMETRICA HEREDITARIA — Dyschromatosis symmetrica hereditaria (DSH), also called reticulate acropigmentation of Dohi, is an autosomal dominant disorder characterized by a mixture of hypopigmented and hyperpigmented macules approximately 5 mm in diameter on the dorsa of the hands and feet (picture 1) and freckle-like macules on the face. First described by Toyama in 1910, DSH has been mainly reported in Japan and China [4,5]. However, DSH has also been reported in patients from Korea [6], Taiwan [7], Thailand [8], India [9,10], Turkey [11], Italy [12], and the United Kingdom [13].

Genetics — DSH (MIM #127400) is caused by variants in the adenosine deaminase acting on RNA1 gene (ADAR1) at 1q21.3, which encodes the RNA editing enzyme [2]. DSH is inherited in an autosomal dominant manner with nearly complete penetrance but variable expressivity. Both familial and sporadic cases have been reported. More than 180 different variants throughout ADAR1 have been described in patients with DSH [14]. These variants, including nonsense, missense, frameshift, and splice-site variants, are thought to lead to ADAR1 haploinsufficiency.

A variant in the 5' untranslated region of ADAR1 was described as pathogenic [15]. The reduced translation of ADAR1 was demonstrated to arise from this variant [15].

Biallelic variants in ADAR1 cause Aicardi-Goutières syndrome 6 (AGS6; MIM #615010), a severe childhood autoimmune disease characterized by encephalitis and interferonopathy that mimics viral infection [16]. However, DSH is generally not a feature of AGS.

There are several reports of children with DSH, neurologic symptoms, and brain abnormalities (eg, calcifications or bilateral striatal necrosis) associated with compound heterozygous ADAR1 variants [10,17,18].

Pathogenesis — Adenosine deaminase acting on RNA1 (ADAR1) is an RNA-editing enzyme that catalyzes the deamination of adenosine to inosine in double-stranded RNA substrates during post-transcription processing [19]. Inosine acts as guanine during translation, resulting in codon alterations or alternative splicing sites that lead to functional changes in proteins [20].

ADAR1 has two isoforms of different sizes, regulated by different promoters: constitutively expressed ADAR1-p110 (110 kDa) and interferon-inducible ADAR1-p150 (150 kDa) [21]. Regulated by different promoters, the two variants are thought to be involved in different cellular functions, including stem cell maintenance, protection against stress-induced apoptosis, and innate immune response [22-25]. Studies indicate that the interferon-inducible ADAR1-p150 promoter is involved in the modulation of the response to several viral infections, including measles, influenza, hepatitis C, hepatitis D, lymphocytic choriomeningitis, and polyoma virus infection [26,27].

Mutation analysis has shown mutations in the coding region only of the p150 isoform in DSH patients [28]. This finding supports the hypothesis that DSH is caused by the p150 isoform of ADAR1, although the substrate gene edited by ADAR1 in the skin is unknown. Further studies are needed to clarify the mechanisms underlying the degeneration and/or dysfunction of melanocytes in DSH and its localization to the distal extremities and face, despite the ubiquitous expression of ADAR1 [22,29].

Clinical features — DSH is characterized by a mixture of hypopigmented and hyperpigmented macules approximately 5 mm in diameter, distributed predominantly on the dorsal aspect of the hands and feet (picture 1), but sometimes extending to the dorsal aspect of the extremities (picture 2). In some patients, freckle-like macules or a mixture of hypopigmented and hyperpigmented macules develop on the face (picture 3). The presence of facial lesions appears to be associated with greater severity of lesions on the extremities [30]. Palms, soles, and mucosa are uninvolved.

DSH commonly develops during infancy or early childhood [31]. Lesions first appear before the age of six years in approximately 70 percent of cases [32]. Lesions extend progressively during childhood, become stable before adolescence, and then persist for life [31,33]. Skin findings are more pronounced after sun exposure, although patients do not show photosensitivity [32,34,35].

Lesions are asymptomatic and do not show telangiectasia, atrophy, or scale. Inter- and intrafamilial phenotypical variation has been reported [36]. It is the author's experience that some parents may have only faint hypopigmented macules on the dorsa of the fingers, whereas their children have widespread macules over the extremities.

DSH is, in most cases, an isolated disorder. However, there are rare reports of DSH in association with other disorders, including neurologic disorders [10,17,33,37], pernio/chilblain [38], psoriasis [39], acral hypertrophy [40], and depression [41]. Some patients with DSH and neurologic symptoms may in fact have a variant of AGS associated with mutation in ADAR1 [16,18,33,37]. (See 'Genetics' above.)

Histopathology — Histopathologic examination of lesional skin shows little melanin in hypopigmented macules and increased melanin pigmentation in the basal layer of hyperpigmented lesions along with pigmentary incontinence [7,36]. In the hypomelanotic areas, as well as in the surrounding normal skin, there is a decreased number of melanocytes; in the hyperchromic areas, melanocytes appear increased in size, with elongated and numerous dendrites, indicating active melanosome transfer to the keratinocytes [7]. Electron microscopy studies have shown abnormalities in melanocytes in the hypomelanotic skin, including a decrease in number, fatty degeneration, vacuolization of cytoplasm, swollen mitochondria, and condensed, irregularly shaped nucleus [7,36].

DYSCHROMATOSIS UNIVERSALIS HEREDITARIA — Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis characterized by hypopigmented and hyperpigmented macules involving the entire body surface. First described in 1933 by Ichikawa and Hiraga [42], it predominantly occurs in patients from Japan [43] but has also been reported in patients from India [44,45], Bangladesh [46], Saudi Arabia [47,48], Nigeria [49], and Tunisia [50].

Genetics — DUH shows genetic heterogeneity. It is inherited in an autosomal dominant fashion with variable penetrance, but there are reports of autosomal recessive transmission [47,51]. Cases due to de novo variants have also been described [52]:

●DUH1 – The locus for the autosomal dominant form (DUH1; MIM #127500) was initially mapped at chromosome 6q24-q25.2 in two Chinese families [53]. Subsequently, heterozygous variants in the SASH1 gene on chromosome 6q24 were detected in affected individuals from Chinese families with DUH1 [54,55]. Other groups have reported that some cases with the lentiginous phenotype, but without hypopigmented, macular skin lesions, are associated with heterozygous SASH1 variants [56-58].

Homozygous mutations in SASH1 have been associated with CAPOK (cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma) syndrome (MIM #618373) in one Moroccan family cell [59].

●DUH2 – The locus for the autosomal recessive form DUH2 was mapped at chromosome 12q21-q23 in a consanguineous family from Saudi Arabia [47,51]. However, a pathogenic gene variant for this subtype has not been identified.

●DUH3 – Genome-wide linkage analysis studies in two large, Chinese kindreds with multiple members affected over five generations indicated that DUH3 (MIM #615402) is caused by mutations in the adenosine triphosphate (ATP)-binding cassette subfamily B, member 6 gene (ABCB6) at 2q35, encoding a transporter protein that regulates de novo porphyrin synthesis [60,61].

Pathogenesis — DUH is thought to be caused by a deficiency of melanin synthesis and/or melanosome sorting [46,62,63]. The ABCB6 gene is widely expressed in many tissues. In the skin, the ABCB6 protein is expressed in keratinocytes and melanocytes and has a diffuse cytoplasmic distribution, including the outer mitochondrial membrane, endoplasmic reticulum, Golgi apparatus, plasma membrane, and exosomes [60].

In a study of mouse melanoma B16 cell line, the wild-type ABCB6 protein was distributed in an endosome-like pattern and was abundant in the dendrites, whereas the ABCB6 protein with the mutations found in DUH was retained in the Golgi body [60]. These preliminary findings suggest that ABCB6 may be involved in the transfer of melanosome to keratinocytes.

The function of SASH1 is unknown. It has been suggested that SASH1 may be a tumor suppressor gene involved in maintenance of cell and tissue homeostasis through a variety of cellular signaling pathways. In DUH, it may be involved in altered melanocyte migration and melanin synthesis [64,65].

Histopathology — Histologic examination of a skin biopsy shows, in DUH, a focal increase or decrease in the melanin content of the basal layer in hyper- and hypopigmented macules, respectively. Pigment incontinence is occasionally observed. An ultrastructural study demonstrated normal numbers of active melanocytes but different amounts of fully melanized melanosomes in hyperpigmented and hypopigmented macules [46].

Clinical features — DUH usually presents in the first year of life with asymptomatic, hyperpigmented and hypopigmented, irregular macules, similar to those seen in DSH, located mainly on the trunk but also on the face and extremities [1]. Lesions on the face may resemble ephelides or lentigines. The palms, soles, and mucosal surfaces are usually spared but may be involved [44,66]. Some patients may present with multiple lentigines in the absence of hypopigmented, macular skin lesions [56-58].

DUH usually occurs in isolation. However, there are reports of DUH associated with systemic complications, including short stature, deafness, epilepsy, and erythrocyte, platelet, and tryptophan metabolism abnormalities [1,44,45,67].

DIAGNOSIS — The diagnosis of inherited dyschromatosis is usually clinical. Histology is nonspecific and shows focal increase or decrease in melanin content of the basal layer in the hyperpigmented and hypopigmented macules, respectively.

Although the individual macular lesions of dyschromatosis symmetrica hereditaria (DSH) and dyschromatosis universalis hereditaria (DUH) are indistinguishable on typical cases, differentiating DSH from DUH is usually not difficult based upon clinical findings, including lesion distribution and time of onset:

●In DSH, lesions manifest during childhood and are typically limited to the distal extremities.

●In DUH, lesions appear in the first year of life on the trunk and then extend to the entire body surface.

Genetic testing is not routinely performed; however, it may be helpful in difficult cases to differentiate DSH and DUH from each other and from other inherited disorders of pigmentation.

DIFFERENTIAL DIAGNOSIS — Inherited and acquired pigmentary disorders that may be confused with DSH or DUH include:

●Reticulate acropigmentation of Kitamura – Reticulate acropigmentation of Kitamura (RAK; MIM #615537) is a rare genodermatosis caused by mutations in the ADAM10 gene, encoding A disintegrin and metalloproteinase domain-containing protein 10 [68]. RAK is characterized by dot-like or reticulate, slightly depressed, sharply demarcated, hyperpigmented macules affecting the dorsa of the hands (picture 4) and feet and palmoplantar pits [69]. In contrast to DSH, hypopigmented macules are absent in RAK. (See "Congenital and inherited hyperpigmentation disorders", section on 'Reticulate acropigmentation of Kitamura'.)

●Dowling-Degos disease – Dowling-Degos disease (DDD; MIM #179850, #607491, #615618) is a rare genodermatosis caused by mutations in the KRT5 gene [70], the POFUT1 gene [71], and the POGLUT1 gene [72]. DDD is characterized by dot-like or reticulate, hyperpigmented macules mainly affecting the flexures and major skin folds. However, a single report described a patient with DDD due to a heterozygous POGLUT1 mutation who showed sharply demarcated, hyperpigmented macules mainly affecting the dorsa of the hands and feet (picture 5) and sparing the flexor areas of the extremities [73].

●Xeroderma pigmentosum – Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in genes involved in nucleotide excision repair of carcinogen adducts induced by ultraviolet (UV) irradiation [74]. XP is characterized by extreme sensitivity of the skin to sunlight, abnormal pigmentation, xerosis, telangiectasia, atrophy, and a high tendency to develop skin cancers at a very early age. Mild cases of XP or the early stage of XP in a child may be sometimes difficult to differentiate from DSH [35]. Photosensitivity tests, cellular hypersensitivity to UV radiation, complementation studies and chromosomal breakage studies using the patient's fibroblasts, and genetic analyses can be performed for definite diagnosis [35]. (See "The genodermatoses: An overview", section on 'Xeroderma pigmentosum'.)

●Amyloidosis cutis dyschromica – Amyloidosis cutis dyschromica is an exceedingly rare type of primary cutaneous amyloidosis characterized by reticular hyperpigmentation with hypopigmented macules distributed over nearly all of the body (picture 6). Histologic examination of a skin biopsy shows hyperkeratosis, necrotic keratinocytes in the basal layer, and melanophages as well as amorphous eosinophilic material (amyloid) deposits in the upper dermis. (See "Acquired hyperpigmentation disorders", section on 'Primary cutaneous amyloidosis'.)

Exposure to chemicals that are toxic to melanocytes, such as diphenylcyclopropenone and monobenzyl ether of hydroquinone, may cause patchy depigmentation that may mimic the dyschromatoses [75]. History of exposure to these agents usually clarifies the diagnosis. Histologic examination of a skin biopsy shows absence of melanocytes in the hypopigmented areas.

TREATMENT — There are no effective treatments for the hereditary dyschromatoses. Because tanning emphasizes the contrast between hyperpigmented and hypopigmented spots, patients with dyschromatosis should adopt photoprotection measures, including sun avoidance and use of protective clothing and broad-spectrum sunscreens with a sun protection factor (SPF) of at least 30. There is a single case report of dyschromatosis symmetrica hereditaria (DSH) lesions successfully controlled by topical sunscreen [76].

There is a single case report of treatment of DSH lesions using miniature punch grafting followed by excimer light therapy [77]. The Q-switched alexandrite laser has been successfully used to remove facial and labial lentigines in a single patient with DUH [78].

SUMMARY AND RECOMMENDATIONS

●Definition – The dyschromatoses are a group of rare, inherited, pigmentary disorders mainly reported in Japan and China and characterized by the presence of numerous, irregular, hyperpigmented and hypopigmented macules approximately 5 mm in diameter. (See 'Introduction' above.)

●Dyschromatosis symmetrica hereditaria – Dyschromatosis symmetrica hereditaria (DSH), also called reticulate acropigmentation of Dohi, is an autosomal dominant disorder caused by mutations in ADAR1 gene, encoding the RNA editing enzyme adenosine deaminases acting on RNA1 (ADAR1). DSH develops during infancy or early childhood and is characterized by a mixture of hypopigmented and hyperpigmented macules approximately 5 mm in diameter on the dorsa of the hands and feet and freckle-like macules on the face (picture 7). (See 'Dyschromatosis symmetrica hereditaria' above.)

●Dyschromatosis universalis hereditaria – Dyschromatosis universalis hereditaria (DUH) is a rare pigmentary genodermatosis characterized by hypopigmented and hyperpigmented macules, which is the same as the lesion of DSH, involving the entire body surface. DUH is inherited in an autosomal dominant or recessive manner and shows genetic heterogeneity. DUH has been reported in association with short stature, deafness, epilepsy, and erythrocyte, platelet, and tryptophan metabolism abnormalities. (See 'Dyschromatosis universalis hereditaria' above.)

●Diagnosis and differential diagnosis – The diagnosis of inherited dyschromatosis is usually clinical. Histology is nonspecific and shows focal increase or decrease in melanin content of the basal layer. Genetic testing is not routinely performed; however, it may be helpful in difficult cases to differentiate DSH and DUH from each other and from other inherited or acquired disorders presenting with dyspigmentation, such as reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), xeroderma pigmentosum (XP), and amyloidosis cutis dyschromica. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Management – There are no effective treatments for the inherited dyschromatoses. Photoprotection measures, including sun avoidance and use of protective clothing and broad-spectrum sunscreens with a sun protection factor (SPF) of at least 30 may be helpful to avoid contrast enhancement between hyperpigmented and hypopigmented macules. (See 'Treatment' above.)