Noonan syndrome (NS) and LEOPARD syndrome (LS) are well-characterized RAS/MAPK pathway-related disorders with strong genotype-phenotype correlations. Most cases of both syndromes are caused by variants in the PTPN11 gene, with specific sites predisposing to either NS or LS. The association between PTPN11 and granular cell tumours (GCTs) remains largely unexplored. To further investigate the phenotypic spectrum of patients with PTPN11 variants. We performed whole-exome sequencing on four Chinese children who presented with café-au-lait macules as the initial cutaneous manifestation. To confirm the mutation, Sanger sequencing was performed on DNA samples obtained from the patient and both parents. Histopathological examination and immunohistochemical staining were performed on a subcutaneous nodule from patient 1 to characterize the lesion. Three PTPN11 variants were identified: c.1391G>C (p. Gly464Ala), c.1403C>T (p. Thr468Met), and c.1493G>T (p. Arg498Leu). Notably, patient 1, who carried the PTPN11 c.1391G>C variant, presented with coexisting granular cell tumours -an association that has not previously been reported for this specific variant. The association with granular cell tumours highlights the clinical importance of long-term surveillance of neural crest-derived neoplasms in PTPN11 variant carriers and broadens our understanding of the diverse phenotypic outcomes associated with PTPN11 variants.
Piao-Ping Zhao, Qin Zeng, Q. Cao et al.· EJD. European journal of der...· 0 citations
BACKGROUND
Non-syndromic hereditary hypotrichosis (NSHH) is a genetically heterogeneous disorder characterized by sparse or absent hair growth. Comprehensive genotype-phenotype correlation analyses remain limited, particularly in the Chinese population.
OBJECTIVES
To define the genetic and phenotypic spectrum of NSHH in a Chinese cohort and to explore genotype-phenotype correlations with potential clinical utility.
METHODS
This observational multicenter study included 47 unrelated families (107 affected individuals) with clinically and genetically confirmed NSHH. Genetic analysis was performed using next-generation sequencing with Sanger validation. Clinical features, including age at onset, severity, hair shaft morphology, and extracranial hair involvement, were systematically analysed and correlated with causative genes.
RESULTS
Eleven causative genes were identified in 47 unrelated families, with LIPH (n=18, 38.3%), LSS (n=10, 21.27%), and HRURF (n=7, 14.89%) being the most prevalent. NSHH showed marked phenotypic heterogeneity with genotype-dependent patterns in age at onset, severity, and hair shaft morphology. Congenital onset was common in LIPH, LSS, and HRURF, whereas postnatal onset was observed in APCDD1, KRT86, and HR. Preliminary genotype-phenotype analysis of LIPH demonstrated allele-specific effects, with c.736T>A associated variants linked to more severe hypotrichosis compared with c.742C>A. In HRURF, two recurrently affected regions were observed, involving the start codon and the region encoding amino acids 23-28. Based on these findings, a preliminary phenotype-driven candidate-gene prioritisation framework was proposed. Exploratory analysis of topical minoxidil showed variable treatment responses.
CONCLUSIONS
This study defines the genetic architecture and genotype-phenotype correlations of NSHH in the Chinese population and provides a preliminary phenotype-driven framework that may assist clinical evaluation and candidate-gene prioritisation.
An-Qi Zhao, Qiao-Yu Cao, Han Chen et al.· British Journal of Dermatolo...· 0 citations
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