A novel SOX9 nonsense mutation, q401x, in a case of campomelic dysplasia with XY sex reversal.

Summary: A novel SOX9 nonsense mutation, Q401X, in a case of campomelic dysplasiawith XY sex reversal: Campomelic dysplasia(CD, MIM 114290) is a rare, often lethal, dominantly inherited, congenital skeletal dysplasia, associated with male-to-female autosomal sex reversaland due to de novo mutationsof the SOX9gene, a tissue-specific transcription factor gene involved both in skeletogenesis and male sexual differentiation. Here we report on a 4 months-old 46,XY sex reversedinfant with typical clinical features for CD due to a novel mutation of the SOX9gene, Q401X, leading to synthesis of a truncated SOX9protein that completely lacks the C-terminal transactivation domain. Key-words: Campomelic dysplasia- Skeletal dyplasia - Sex reversal- SOX9- Nonsense mutation. INTRODUCTION Campomelic dysplasia(CD, MIM 114290) is a rare, autosomal dominant, skeletal dysplasia characterized by macrocephaly, midface hypoplasia, Robin sequence, hypoplastic scapulae, bowing and angulation of long bones, congenital dislocationof hips, pelvic and chest malformations, clubbed feet, and is associated with male-to-female sex reversalin two-thirds of the affected karyotypic males (3, 4, 5, 6). Diagnostic criteria were proposed by Mansour et al (4). De novo mutationsof the SOX9gene are known to be responsible for both CD and XY sex reversal(2, 9). The SOX9gene is coding for a 509 amino acids tissue-specific transcription factor containing an SRY-related DNA-binding domain and is involved both in skeletogenesis and male sexual differentiation. At least 37 different mutations have been described so far (1, 7). They include frameshift, splice, nonsenseand missense mutations without an obvious genotype-phenotype correlation. The most common described mutation is Y440X, accounting for 8% of all coding region SO X9 mutations in CD (6). Here we report on a novel nonsense mutationof the SOX9gene, Q401X, as a cause of campomelic dysplasiain a 4-months-old infant. CASE REPORT The proband was born at 37 weeks of gestation as the first child of healthy young non-consanguineous parents, both of Turkish minority in Bulgaria, coming from a small village. At 36 weeks of gestation, ultrasound examination detected shortened and bowed femora, and macrocephaly. The birth weight was 2420 g (SD -2.96), length 37 cm (SD -7.7), and head circumference 37 cm (SD 0.3). Short umbilical cord was noticed. Respiratory failure developed immediately after birth, requiring intubation and long term ventilation support. Upon clinical examination, the following dysmorphic featuresand congenital anomalies were noted (Fig. 1): remarkably short neck, trunk and limbs, macrocephaly, flat face, small saddle nose, micrognathia, median cleft palate, narrow asymmetric thorax, extremely bowed limbs, club feet, short deformed toes, and bilateral palmar crease. In addition, echocardiography detected persistent foramen ovale. Ambiguous genitalia with prominent clitoriswere noted and standard G-bandedcytogenetic analysis revealed normal male karyotype. X-rays of pelvis and lower limbs documented hypoplastic pelvic bones with steep acetabulum, dislocation of the hips, curved femora, tibial deviation and hypoplastic fibulae(Fig. 2). Due to progressive respiratory and heart failure, the infant deceased at the age of 3 months and 24 days. At autopsy the presence of uterus and ovaries was noted. Mutation analysis of the SOX9gene using the PCR followed by DNA sequencing was performed. The entire coding region and the four exon/intron boundaries of the gene were analyzed. The primers and conditions used in the PCR are as described in Wagner et al. (9). A heterozygous nonsense mutationc.1201C>T (Q401X) in exon 3 of the SOX9gene was identified, changing a glutamine (Q) codon (CAG) to a stop (X) codon (TAG). Both parents have a normal DNA sequence at this position (Fig. 3). DISCUSSION Here we report on a newborn with clinical presentation consistent with the classical description of campomelic dysplasiaassociated with XY sex reversaland due to a previously unreported mutation of the SOX9gene, Q401X. …