Alternative titles; symbols
SNOMEDCT: 715630006; ORPHA: 280628, 79146; DO: 0111373;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q21.32 | Hyperpigmentation with or without hypopigmentation | 145250 | Autosomal dominant | 3 | KITLG | 184745 |
A number sign (#) is used with this entry because of evidence that familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is caused by heterozygous mutation in the KIT ligand gene (KITLG; 184745) on chromosome 12q21.
Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation of variable intensity sometimes associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. These features, which involve the face, neck, trunk, and limbs, are seen at birth or develop early in infancy (summary by Wang et al., 2009 and Amyere et al., 2011).
Also see familial progressive hyperpigmentation (FPH1; 614233).
Familial progressive hyperpigmentation was observed by Chernosky et al. (1971) in 4 individuals in 2 generations of a black family. It was characterized by patches of cutaneous hyperpigmentation that were present at birth and increased in size and number with age. Eventually large areas of skin became hyperpigmented. A mother had 2 affected children by different husbands.
Westerhof et al. (1978) reported a family of Hindustani origin in which 14 affected individuals over 3 generations exhibited congenital hypomelanotic and hypermelanotic cutaneous macules. No instance of male-to-male transmission was found. Some family members with macules also had retarded growth and mental deficiency. Light microscopic findings of hyper- and hypopigmented skin were similar to those of normal skin, except that background staining of keratinocytes in dark and light macules was higher and lower, respectively, than in control skin. Ultrastructurally, hypomelanotic skin showed small melanosomes within melanosome complexes in keratinocytes, whereas hypermelanotic skin showed large melanosomes distributed singly in keratinocytes.
Rebora and Parodi (1989) reported a 4-generation Italian family with what they designated 'melanosis universalis hereditaria.' The 37-year-old male proband exhibited diffuse hyperpigmentation that was particularly intense on the face and neck. There were darker spots on a brownish background on his trunk, palms, and soles, and pigmented areas were also present on the oral mucosa. A few small hypopigmented macules were present on his trunk. The pigmentation reportedly began 1 to 2 months after birth, starting from the external genitalia, which were completely dark brown by adulthood; white spots were also observed on his trunk in infancy. Histopathology showed an increase of melanin in the basal layer; the dermis was normal, and no melanophages were seen. Electron microscopy showed keratinocytes with a larger number of melanin granules than normal, some of which displayed free melanosomes, whereas others within the phagosomes showed a caucasoid pattern.
Debao and Ting (1991) examined 15 affected persons in 6 generations of a kindred of Han nationality living in China. The onset of the pigmentation was either at birth or in early infancy and consisted of irregular patches which increased with age in size, number, and confluence. Progression was rapid during childhood and slower during adolescence and resulted in extensive hyperpigmentation of the conjunctiva, face, neck, trunk, limbs, lips, oral mucosa, palms, and soles. Biopsies from hyperpigmented areas showed hyperkeratosis with marked increase in the amount of melanin in the epidermis, especially in the basal cell layer and at the tips of the rete ridges. The dermis appeared normal. In all, 21 persons in 6 generations were affected. The hyperpigmentation showed no whorls or streaks.
Zanardo et al. (2004) studied 3 unrelated families from southeastern Germany in which affected individuals exhibited a progressive, diffuse, partly blotchy hyperpigmentation of variable intensity, intermixed with scattered small hypopigmented macules, a few large hypopigmented areas, and occasional cafe-au-lait spots, as well as a generalized lentiginosis that covered the entire skin surface, including the mucous membranes and conjunctivae. Light microscopy of hyperpigmented areas showed strong basal layer hyperpigmentation of the epidermis and a few melanophages around the superficial blood vessels, but there was no increase in the number of melanocytes within the epidermis. Sections from a hypopigmented macule also showed slight basal hyperpigmentation of the epidermis, but there were virtually no melanophages around the upper dermal vessels. Ultrastructural analysis revealed a normal mode of Caucasian-like melanogenesis with varying amounts of regular mature melanosomes and complexes within keratinocytes. Two of the families had multiple affected individuals over 3 generations, whereas in the third family, 3 sisters were affected, 2 of whom had only a few large cafe-au-lait spots. None of the patients had additional symptoms.
Hoo and Shrimpton (2005) reported a 3-generation family of French Canadian ancestry with concurrent cafe-au-lait spots and hypopigmented macules. There were several instances of father-to-son transmission, suggesting autosomal dominant inheritance. The pattern of pigmentation changed with increasing age, from circumscribed, large cafe-au-lait and hypopigmented macules to hyper- and hypopigmented freckling. Other than multiple cafe-au-lait spots, no other symptoms of neurofibromatosis I (NF1; 162200) were noted in the family.
Wang et al. (2009) followed up on a 6-generation Chinese family from Shandong province originally described by Debao and Ting (1991). All affected individuals manifested a pigmentation disorder without association of any other system disease. Hyperpigmentation was reported on the conjunctiva, face, neck, trunk, limbs, hands, palms, and soles. Skin biopsy of hyperpigmented skin showed a significant increase in the number of melanocytes and of the melanin content in basal keratinocytes, as well as a slight increase in the size of the melanocytes. No affected member had skin cancer.
The transmission pattern of FPHH in the family reported by Wang et al. (2009) was consistent with autosomal dominant inheritance.
Wang et al. (2009) performed a genomewide scan for linkage analysis in the 6-generation Chinese family originally described by Debao and Ting (1991). Two-point linkage analysis mapped the locus to chromosome 12q21.31-q23.1 with a maximum 2-point lod score of 4.35 (theta = 0.00) at D12S81. Haplotype analysis confined the locus within an interval of 9.09 cM, flanked by markers D12S1667 and D12S2081.
Amyere et al. (2011) performed linkage analysis in 2 families with FPHH, a family of French Canadian ancestry previously reported by Hoo and Shrimpton (2005) and a Danish family. Multipoint analysis revealed significant linkage at chromosome 12q, and analysis of 2 additional FPHH families from Germany (Zanardo et al., 2004) also showed linkage to this locus.
Wang et al. (2009) identified a missense mutation in the KITLG gene (N36S; 184745.0003) in a 6-generation family segregating familial progressive hyperpigmentation. The mutation cosegregated with affected individuals and was not present in any unaffected members. Functional analysis revealed that this is a gain-of-function mutation and that the presence of the mutant allele increased the content of melanin by 109% compared to wildtype KIT ligand in human melanoma cells. Tyrosinase (606933) activity was significantly increased in mutant compared to wildtype controls as well.
In affected individuals from 7 families with cutaneous hyper- and hypopigmentation, Amyere et al. (2011) analyzed the KITLG gene and identified heterozygosity for 3 different missense mutations in 4 families: the N36S substitution was detected in 2 German families originally reported by Zanardo et al. (2004) (cases 1 and 2); a V33A substitution (184745.0004) was identified in the family of French Canadian origin reported by Hoo and Shrimpton (2005); and a T34P substitution (184745.0005) was identified in a Danish family. The 2 mutation-positive German families shared a common haplotype and came from the same area of Germany, suggesting common ancestry; however, the 3 remaining families without a mutation, who were also German, did not share that haplotype.
Scheidt (1926) described 14 affected in 4 successive generations. Orth (1929) described 2 families, each with 4 affected generations. Pegum (1955) and Wende and Bauckus (1919) each described generalized hyperpigmentation beginning in infancy in 2 sibs. Tvaroh and Kares (1968) described 5 affected in 3 generations.
Amyere, M., Vogt, T., Hoo, J., Brandrup, F., Bygum, A., Boon, L., Vikkula, M. KITLG mutations cause familial progressive hyper- and hypopigmentation. J. Invest. Derm. 131: 1234-1239, 2011. [PubMed: 21368769] [Full Text: https://doi.org/10.1038/jid.2011.29]
Chernosky, M. E., Anderson, D. E., Chang, J. P., Shaw, M. W., Romsdahl, M. M. Familial progressive hyperpigmentation. Arch. Derm. 103: 581-591, 1971. [PubMed: 4326548]
Debao, L., Ting, L. Familial progressive hyperpigmentation: a family study in China. (Letter) Brit. J. Derm. 125: 607 only, 1991. [PubMed: 1760373] [Full Text: https://doi.org/10.1111/j.1365-2133.1991.tb14812.x]
Hoo, J. J., Shrimpton, A. E. Familial hyper- and hypopigmentation with age-related pattern change. (Letter) Am. J. Med. Genet. 132A: 215-218, 2005. [PubMed: 15551335] [Full Text: https://doi.org/10.1002/ajmg.a.30381]
Leber, R. Ueber eine Familie mit erblichem universellem Melanismus. Z. Kinderheilkd. 58: 142-147, 1936.
Orth, H. Ueber zwei Faelle von erblichem Melanismus. Arch. Derm. Syph. 158: 95-97, 1929.
Pegum, J. S. Diffuse pigmentation in brothers. Proc. Roy. Soc. Med. 48: 179-180, 1955. [PubMed: 14371572]
Rebora, A., Parodi, A. Universal inherited melanodyschromatosis: a case of melanosis universalis hereditaria? (Letter) Arch. Derm. 125: 1442-1443, 1989. [PubMed: 2802660]
Scheidt, W. Einige Ergebnisse biologischer Familienerhebungen. Arch. Rass. Ges. Biol. 17: 135-139, 1926.
Tvaroh, F., Kares, B. Familial occurrence of diffuse melanosis. Plzen. Lek. Sborn. 22 (suppl.): 35-38, 1968.
Wang, Z.-Q., Si, L., Tang, Q., Lin, D., Fu, Z., Zhang, J., Cui, B., Zhu, Y., Kong, X., Deng, M., Xia, Y., Xu, H., Le, W., Hu, L., Kong, X. Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. Am. J. Hum. Genet. 84: 672-677, 2009. [PubMed: 19375057] [Full Text: https://doi.org/10.1016/j.ajhg.2009.03.019]
Wende, G. W., Bauckus, H. H. A hitherto undescribed generalized pigmentation of the skin appearing in infancy in brother and sister. J. Cutan. Dis. 37: 685-701, 1919.
Westerhof, W., Beemer, F. A., Cormane, R. H., Delleman, J. W., Faber, W. R., De Jong, J. G. Y., van der Schaar, W. W. Hereditary congenital hypopigmented and hyperpigmented macules. Arch. Derm. 114: 931-936, 1978. [PubMed: 666331]
Zanardo, L., Stolz, W., Schmitz, G., Kaminski, W., Vikkula, M., Landthaler, M., Vogt, T. Progressive hyperpigmentation and generalized lentiginosis without associated systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany. Acta Derm. Venereol. 84: 57-60, 2004. [PubMed: 15040480] [Full Text: https://doi.org/10.1080/00015550310005780]