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Familial progressive hyperpigmentation and hypopigmentation without KITLG mutation

Familial progressive hyperpigmentation and hypopigmentation (FPHH) is a rare autosomal dominant genodermatosis presenting as dyschromatosis at birth or in the first year. This disorder is characterized by diffuse and progressive hyperpigmentation and hypopigmentation. Caf e-au-lait macules or ash-leaf-like white macules are also present. Westerhof et al. first described a large family with FPHH associated with retarded growth and mental deficiency. In 2011, Amyere et al. identified three different mutations in the KITLG gene in four of seven families with FPHH, and considered that KITLG was an important modulator of skin pigmentation. We recruited a four-generation Chinese family with distinct dyschromatosis. The study was approved by the ethics committee of Anhui Medical University, and all participants provided written informed consent. In total, 49 family members were investigated: 19 affected (9 males and 10 females) and 30 unaffected members. The pedigree chart suggested an autosomal dominant pattern of inheritance (Fig. 1). The skin of all affected individuals appeared normal at birth, and gradually developed skin pigmentary changes in 10 days to 1 month after birth. Physical examination showed diffuse irregular lightbrown hyperpigmented macules intermingled with numerous hypopigmented macules, producing a mottled appearance on a background of normal-appearing skin. In addition, some affected members had caf e-aulait macules or ash-leaf-like white macules > 30 mm in diameter (Fig. 2a–f). However, the face, hands, feet and mucosa were spared in all affected members. Furthermore, the patients’ general health and mental development were normal. Interestingly, considerable variation in the phenotype was noted within this family. The affected individual II:4 presented with some inconspicuous, scattered, hypopigmented macules on his abdomen and waist, with a few small caf e-au-lait spots and some lentigines dispersed on his waist,. By contrast, the affected individual IV:6 had generalized brown macules and patches on a background of light complexion (Fig. 2g–i). Blood samples were collected from eight affected members and six unaffected members of this family and from 200 healthy controls. Genomic DNA was extracted (FlexiGene DNA kit; Qiagen Inc. Valencia, CA, USA). Primers to amplify all coding exons and exonintron boundaries of the KITLG gene were designed using Primer Premier software (version 5.0; Premier Biosoft, Palo Alto, CA, USA). Amplification was performed with a touchdown PCR program using Taq DNA polymerase, and the purified PCR products were sequenced on an automated sequencer. Sanger sequencing of two affected members did not identify any known causative mutation of KITLG. We are currently carrying out further analysis of this family to identify the pathogenic gene. Clinically, generalized dyschromatosis is observed in many disorders such as dyschromatosis universalis hereditaria, familial progressive hyperpigmentation, amyloidosis cutis dychromica and Legius syndrome as well as FPHH. There are no specific histopathological features for FPHH. Moreover, this disorder shows considerable variation in the phenotype within families. Thus, it is recommended that the diagnosis of FPHH be established on the basis of careful physical examination of most of the affected members. Although progressive