Upstream SOX9 deletion in a 46,XY girl with acampomelic campomelic dysplasia and absent minipuberty.

BACKGROUND: Campomelic dysplasia (CD) is a rare congenital skeletal dysplasia frequently associated with differences of sex development (DSD). In about 10% of affected individuals, the bowing of the long bones (campomelia) is absent, referred to as acampomelic campomelic dysplasia (ACD). Most patients with ACD carry heterozygous pathogenic variants within the SOX9 coding region or balanced chromosomal rearrangements involving the 17q24 region. A rarer mechanism involves deletions located upstream of the SOX9 gene. Only five ACD cases with upstream deletions of SOX9 have been reported in the medical literature.

RESULTS: We report a female patient affected by ACD with Pierre Robin sequence, complete gonadal dysgenesis (CGD), and hypotonia. Genetic testing revealed a de novo 1.671 Mb deletion located 191 kb upstream of the SOX9 gene. This chromosomal aberration represents the second-largest deletion upstream of SOX9 reported to date. In addition, we describe the patient's endocrine profile, which revealed an absent gonadotropin rise during minipuberty, followed by a delayed increase in infancy.

CONCLUSIONS: This study expands the clinical and molecular spectrum of ACD, enhancing our understanding of genotype-phenotype correlations of this condition. The phenotypic and endocrinological description of the proband may be helpful for clinicians who consult patients with DSD and skeletal dysplasia.