Familial Progressive Hyper Research Articles

Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss.

BackgroundPathogenic variants in KITLG, a crucial protein involved in pigmentation and neural crest cell migration, cause non‐syndromic hearing loss, Waardenburg syndrome type 2, familial progressive hyperpigmentation and familial progressive hyper‐ and hypopigmentation, all of which are inherited in an autosomal dominant manner.ObjectivesTo describe the genotypic and clinical spectrum of biallelic KITLG‐variants.MethodsWe used a genotype‐first approach through the GeneMatcher data sharing platform to collect individuals with biallelic KITLG variants and reviewed the literature for overlapping reports.ResultsWe describe the first case series with biallelic KITLG variants; we expand the known hypomelanosis spectrum to include a ‘sock‐and‐glove‐like’, symmetric distribution, progressive repigmentation and generalized hypomelanosis. We speculate that KITLG biallelic loss‐of‐function variants cause generalized hypomelanosis, whilst variants with residual function lead to a variable auditory‐pigmentary disorder mostly reminiscent of Waardenburg syndrome type 2 or piebaldism.ConclusionsWe provide consolidating evidence that biallelic KITLG variants cause a distinct auditory‐pigmentary disorder. We evidence a significant clinical variability, similar to the one previously observed in KIT‐related piebaldism.

De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH).

Familial Progressive Hyper‐ and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo‐ and hyperpigmented lesions, café‐au‐lait spots and hypopigmented ash‐leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper‐ and Hypopigmentation and malignancy due to its’ location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation

BackgroundFamilial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs). Heterozygous mutations of the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype–phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients.MethodsDirect sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsThe novel mutation c.104A > T (p.Asn35Ile) and the recurrent mutation c.101C > T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A > T was ‘likely pathogenic’.ConclusionsTo date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33–37) in exon 2. The known mutations are only involved in 33 V, 34 T, 36 N, and 37 V but not 35 N. We have now identified a novel mutation in KITLG, c.104A > T, that was first reported in FPHH within the conserved 35 N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

Familial progressive hyper- and hypopigmentation: a report on a Chinese family and evidence for genetic heterogeneity.

BackgroundFamilial progressive hyper- and hypopigmentation (FPHH) is a rare genodermatosis that is characterized by diffuse hyper- and hypopigmented spots on the skin and mucous membranes. It is caused by a pathogenic mutation of the KITLG gene.ObjectivesTo investigate the clinical features and mutation of the KITLG gene in a Chinese family with FPHH.MethodsHistopathological and immunohistochemical analysis of lesions from the proband was performed. The KITLG gene was screened for the presence of mutations.ResultsA Chinese family containing 14 individuals with FPHH was described, and the proband was a 5-year-old girl showing diffuse hyper- and hypopigmented lesions on her extremities and trunk. Histopathological and immunohistochemical staining for S100 and HMB45 of skin biopsy specimens from the hyperpigmented areas showed a striking increase in melanin throughout the epidermis, especially in the basal cell layer, and staining of hypopigmented area specimens displayed lower levels of melanin in the epidermis. Mutation analysis of the KITLG gene was performed, but no mutation was found.Study limitationsThe new pathogenic gene was not found.ConclusionA family with FPHH was described. Analysis revealed that its members did not have any mutations of the KITLG gene, which provided evidence for genetic heterogeneity of this genodermatosis.

Familial progressive hyper- and hypopigmentation and malignancy in two families with new mutations inKITLG

Familial progressive hyper- and hypopigmentation (FPHH) is an autosomal dominant skin condition presenting in childhood with generalized macular dyspigmentation, usually reported in patients of East Asian origin. It overlaps phenotypically with other dyschromatoses, but can now be distinguished by mutations in the KIT ligand gene (KITLG). We report two unrelated white families with similar phenotypic presentations of FPHH developing in early childhood in several generations. Sanger sequencing of the exons and flanking introns of KITLG was performed. This identified a new heterozygous missense mutation in each family (p.Thr34Asn and p.Val37Gly, respectively). Of the six affected individuals examined by us, two had cancer: a 62-year-old man in family 1 had developed two primary melanomas and a pharyngeal carcinoma, and a 42-year-old woman in family 2 had developed thyroid carcinoma. All had unusually sparse lateral eyebrows, a finding not previously reported in this condition. We summarize the genetic spectrum of the dyschromatoses and discuss a possible increased risk of malignancy in FPHH.

Familial progressive hypo- and hyperpigmentation: A variant case

Familial progressive hyper- and hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation with variable intensity. Cafe'-au-lait macules and larger hypopigmented ash-leaf macules are also present. Herein, we reported a variant case of FPHH. The patient was a two-year-old Chinese girl showing diffuse hyper- and hypopigmented lesions, longitudinal melanonychia in both thumbs, and infantile seizures, without any lentigines.

KITLG Mutations Cause Familial Progressive Hyper- and Hypopigmentation

Familial progressive hyper- and hypopigmentation (FPHH) is thought to be an autosomal dominant disorder with reduced penetrance. Clinical signs consist of progressive diffuse, partly blotchy hyperpigmented lesions, multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae, and lentigines. FPHH is distinct from familial progressive hyperpigmentation (FPH), in which no hypopigmented features 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. We performed a genome-wide linkage analysis in seven families with FPHH, and identified linkage on 12q21.12-q22, which overlaps with the DUH2 locus. We investigated whether KITLG in the locus is mutated in FPHH. We discovered three different mutations in four families. A reported FPH substitution was observed in two FPHH families, and two, to our knowledge, previously unreported substitutions, p.Val33Ala and p.Thr34Pro, cosegregated with FPHH in two separate families. All three mutations were located in a conserved β-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. Therefore, KITLG is an important modulator of skin pigmentation.