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Linear and whorled nevoid hypermelanosis: Past reflections and future directions

DII small banner By Warren R. Heymann, MD
July 4, 2017

Whorled Nevoid Hypermelanosis
Linear or circular arrangement of pigmented macules along the lines of Blaschko.
Credit: JAAD
I recall meeting Debra Chester Kalter as a young, remarkable dermatologist, chatting annually with her at the AAD meeting. She was my wife’s classmate at the Baylor College of Medicine (class of 1981). Dr. Kalter was the first to accurately detail Linear and Whorled Nevoid Hypermelanosis (LWNH) nearly 30 years ago (1). In 1994, I was shocked and saddened to learn of her death from cancer at age 40. When brilliance leaves us prematurely (think Mozart, Gershwin, Van Gogh, et cetera) one can only ponder, with regret, what potential future accomplishments went unfulfilled.

The following is the abstract from Dr. Kalter’s article describing LWNH:
Two cases are presented of congenital linear and whorled hypermelanosis. Hyperpigmented macules in streaky configurations along Blaschko’s lines appeared gradually after birth. Histologic examination revealed prominent epidermal melanocytes and irregular basal layer hyperpigmentation with normal melanosomes. This condition must be differentiated from incontinentia pigmenti, early systematized epidermal nevus, extensive hypomelanosis of Ito, and chimerism. Other similar case reports from the literature suggest that incidence is sporadic and may be associated with more serious congenital anomalies. The patterning is the inverse to that found in hypomelanosis of Ito. Developmental somatic mosaicism may be responsible for this patterned hypermelanosis.

Familial progressive hyper- and hypopigmentation (FPHH) is an autosomal dominant disorder with reduced penetrance. Clinical features include progressive diffuse, partly blotchy hyperpigmented lesions, multiple café-au-lait spots, admixed with scattered hypopigmented macules, and lentigines. FPHH is distinct from familial progressive hyperpigmentation (FPH), in which no hypopigmented lesions are present, and which is phenotypically and histologically closer to Dyschromatosis Universalis Hereditaria 2 (DUH2). It also differs from the Legius syndrome, characterized by familial café-au-lait spots and skin fold freckling, caused by mutations in SPRED1. Amyere et al performed a genome-wide linkage analysis in seven families with FPHH, and identified linkage on 12q21.12-q22, which overlaps with the DUH2 locus. They investigated whether KITLG in the locus is mutated in FPHH. They discovered three different mutations in four families. A reported FPH substitution was observed in two FPHH families, and two, to their knowledge, previously unreported substitutions cosegregated with FPHH in two separate families. All three mutations were in a conserved beta-strand in KITLG, suggesting its important role in the activation of the KITLG receptor c-Kit. In aggregate, mutations in a single gene cause various pigmentation disorders: FPH, FPHH, and likely DUH2. The authors concluded that KITLG is an important modulator of skin pigmentation. (2)
In the editorial that accompanies Amyere et al, Picardo and Cardinali state that the control of skin pigmentation is exerted by a complex melanogenic paracrine network. This occurs between mesenchymal and epithelial cells, which regulates melanocyte survival, proliferation, and melanogenesis. (3) In addition to melanogenesis, the KITLG/C-Kit/RAS/MAPK signaling pathways also have an important role in the regulation of hematopoiesis, stem cell survival, gametogenesis, and mast cell biology (development, migration and function). KITLG influences melanocyte proliferation and melanin distribution, and activates keratinocytes to produce promelanogenic factors. Other genetic disorders characterized by patchy dyspigmentation, including neurofibromatosis type 1, piebaldism and Legius syndrome, are caused by loss of function mutations in other genes in this pathway, respectively NF1, KIT and SPRED1. Advances in genetics have also enabled the molecular identification and differentiation of other syndromes of hyperpigmentation such as Dowling-Degos disease (KRT5), reticulate acropigmentation of Kitamura (ADAM10), reticulate acropigmentation of Dohi (ADAR) and dyschomatosis universalis hereditaria 3 (ABCB6). (4) Despite these advances, vagaries exist. A recent genetic analysis of a kindred with FPHH failed to reveal any KITLG mutation in two affected individuals, suggesting that other genes are responsible for FPHH in that family. (5)

Sorlin et al have reported the molecular basis for LWNH as a mosaic presentation in a 6-year-old FPHH due to KITLG mutations, by performing whole-exome sequencing from the patient and his unaffected parents. The authors identified a de novo postzygotic KITLG variant. Additionally, c-KIT staining showed increased epidermal expression in basal keratinocytes, and HMB45 staining revealed increased melanocytes in the basal epidermal layer. Because they have not yet studied additional patients with LWNH, involvement of other genes in this pigmentary phenotype could not be excluded. (6)
Defining the molecular mechanism(s) of these disorders opens potential therapeutic horizons. For example, an experimental topical formulation of imatinib, delivered by iontophoresis, has been studied in murine melanoma cells. (7) Can a topical formulation that affects the KITLG/C-Kit/RAS/MAPK pathway be far behind? I surmise that if she was still with us, Dr. Kalter, would not only be excited by this prospect, she probably would have already figured it out.

1. Kalter DC, et al. Linear and whorled nevoid hypermelanosis. J Am Acad Dermatol 1988; 19: 1037-44.
2. Amyere M, et al. KITG mutations cause familial progressive hyper- and hypopigmentation. J Invest Dermatol 2011 ; 131 : 1234-9.
3. Picardo M, Cardinali G. The genetic determination of skin pigmentation: KITLG and KITLG/c-Kit pathway as key players in the onset of human pigmentary diseases. J Invest Dermatol 2011; 131: 1182-5.
4. Cuell A, et al. Familial progressive hyper-and hypopigmentation and malignancy in tow families with new mutations in KITLG. Clin Exp Dermatol 2015; 40:860-4.
5. Zeng L, et al. Familial progressive hyperpigmentation and hypopigmentation without KITLG mutation. Clin Exp Dermatol 2016; 41: 927-9.
6. Sorlin A, et al. Mosaicism for a KITLG mutations in linear and whorled nevoid hypermelanosis. J Invest Dermatol 2017; 137: 1575-78.
7. Labala S, et al. Layer-by-layer polymer coated gold nanoparticles for topical delivery of imatinib mesylate to treat melanoma. Mol Pharm 2015; 12: 878-88.

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