Endocrine Abstracts

JOINT899

Background: Brachydactyly type E (BDE), a rare skeletal dysplasia (OMIM: 113300), is characterized by metacarpal/metatarsal shortening and variable skeletal anomalies. BDE2 (OMIM: 613382), a distinct subtype, arises from pathogenic variants in the PTHLH gene (12p12. 1-p11. 22), which regulates endochondral ossification via parathyroid hormone-related protein signaling. Heterozygous loss-of-function variants in PTHLH are associated with a characteristic skeletal pleiotropy, classically manifesting as severe generalized bilateral brachydactyly, proportionate short stature, pectus carinatum deformity, and radiologically confirmed premature epiphyseal fusion.

Clinical Case: A 5-year-7-month-old girl presented with symmetrical brachydactyly. Her height(115 cm, 50th percentile), weight(19 kg, 50th percentile) and neurodevelopment were age-appropriate. Her hand radiographs showed dysplastic epiphyses in all digits, and her bone age was 6 years old with mild thoracolumbar scoliosis (Cobb angle 10°). Familial evaluation revealed no brachydactyly or skeletal anomalies. Trio-based whole-exome sequencing (WES) identified a de novo 1. 90 Mb heterozygous deletion at 12p12. 1-p11. 22 (GRCh37: chr12:26, 217, 430-28, 122, 427), encompassing PTHLH exons 3-4. Quantitative PCR confirmed the proband-specific deletion, absent in parental genomes. Decipher/ClinVar databases classified this CNV as pathogenic for BDE2. During 3-year follow-up, scoliosis remained stable (Cobb angle 10°), with height growth velocity of 6 cm/year. She did not yet exhibited signs of pubertal development at eight and half years old.

Conclusion: This study expands the mutational spectrum of BDE2 by identifying the PTHLH intragenic deletion. The absence of familial transmission supports de novo dominance. Notably, preserved stature and non-progressive scoliosis contrast with typical BDE phenotypes, highlighting the broad phenotypic spectrum of PTHLH-related skeletal dysplasias, and necessitating integrated genomic diagnostics to delineate genotype-phenotype correlations. Despite preserved anthropometric parameters (height Z-score: 0. 0) and age-appropriate neurodevelopment, structured surveillance protocols remain critical to monitor potential skeletal sequelae, including scoliosis progression and metaphyseal dysplasia.