Case Report: A novel PTHLH nonsense variant in a mother-son pair with brachydactyly type E and short stature, with a genotype-stature review.

BACKGROUND: Brachydactyly type E is a rare skeletal disorder characterized by variable shortening of the metacarpals and/or metatarsals. Heterozygous pathogenic variants in PTHLH, which encodes parathyroid hormone-related protein, are an established cause of autosomal dominant brachydactyly type E and are variably associated with short stature.

CASE PRESENTATION: We report a mother-son pair with brachydactyly type E and short stature caused by a novel heterozygous nonsense variant in PTHLH. The proband, a boy aged 7 years and 8 months, presented with short stature, brachydactyly involving both hands and feet, mild global developmental delay, and subtle craniofacial features. Radiographs showed generalized shortening of the metacarpals, metatarsals, and phalanges, premature epiphyseal fusion, and metaphyseal widening. His mother had marked adult short stature and brachydactyly, with more prominent shortening of the third to fifth digits. Biochemical and endocrine evaluation revealed no evidence of hormone resistance or major metabolic abnormalities. Trio whole-exome sequencing identified a novel heterozygous nonsense variant in PTHLH(NM_198965.2) c.82G>T, p.(Glu28Ter), and Sanger sequencing confirmed segregation with the affected mother. Our pooled descriptive review of previously published individual-level cases showed that short stature is common but incompletely penetrant in PTHLH-associated brachydactyly type E. Predicted loss-of-function variants, especially early truncating, frameshift, and signal peptide/initiation-region variants, were more often reported with growth impairment, whereas recurrent variants and familial cases showed marked inter- and intrafamilial variability.

CONCLUSION: This report expands the mutational spectrum of PTHLH and supports the role of PTHLH haploinsufficiency in impaired skeletal growth. This family further illustrates that PTHLH-associated brachydactyly type E can present with generalized involvement of the metacarpals, metatarsals, and phalanges. Variant consequence and protein location may help clinical risk stratification but are insufficient for reliable individual-level prediction of short stature. The molecular diagnosis also informed management by supporting longitudinal growth monitoring rather than recombinant growth hormone therapy in the absence of GH-IGF-1 axis abnormalities. Recognition of brachydactyly with short stature and normal biochemical findings should prompt consideration of PTHLH-related disease and molecular testing.