Different phenotypic presentations of congenital insensitivity to pain with anhidrosis in siblings with identical NTRK1 mutations: a case report and literature review

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder mainly caused by mutations in the NTRK1 gene. Its cardinal features include insensitivity to pain, anhidrosis, recurrent fever, and self-mutilating behavior. While CIPA siblings predominantly show similar phenotypes or severity differences positively correlated with age, phenotypic divergences that are age-independent, inversely correlated with age, or affect distinct organ systems have been rarely reported in siblings with identical NTRK1 mutations. We report two Han Chinese males, aged 29 and 16 years, who carried identical compound heterozygous NTRK1 mutations (c.446_447insTCTG, p. P149fs from the father and c.2293C>T, p. R765C from the mother) but exhibited markedly different clinical manifestations: the elder brother presented with chronic elbow ulcer, severe nail damage, and partial preservation of lingual temperature sensation with mild intellectual disability, whereas the younger brother had recurrent painless fractures, severe knee joint destruction, inability to stand independently, and severe intellectual disability with relatively mild skin and soft tissue involvement. A structured literature review identified 27 CIPA sibling families, among which phenotypic differences mostly manifested as age-positive severity or age-independent phenotypes. In contrast, our siblings exhibited a rare age-inverse divergence across distinct organ systems under an identical genotype. The elder brother was predominantly affected by skin and soft tissue, whereas the younger brother suffered from severe skeletal complications. This phenotypic divergence is unlikely to be fully explained by age or cumulative injury alone. These findings highlight this unexpected age-inverse phenotypic divergence among siblings with identical NTRK1 genotype, emphasizing the need for independent, comprehensive multi-organ assessments for each CIPA patient rather than predicting disease patterns in siblings solely based on the proband’s phenotype.