Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester

Abstract

This is the first report of a fetus affected with campomelic acampomelic dysplasia presenting with increased nuchal translucency. Ultrasonography at 13 weeks of amenorrhea showed a nuchal translucency 5.6 mm thick. The karyotype performed on amniotic fluid cells was normal (46,XY). Ultrasonography at 22 weeks revealed a normal femoral length and female genitalia. A second amniocentesis was performed to confirm the karyotype and for dosage of steroid hormones. Testosterone dosage was low, corresponding to a female fetus. Ultrasonography at 32 weeks showed growth retardation of the long bones (< 3rd centile) that were not curved. A severe malformation syndrome was suspected and the pregnancy was terminated at 33 weeks. The fetus displayed macrocephaly, facial dysmorphism and female external genitalia. X ray showed straight and thickened long bones, hypoplastic scapulae and moderate platyspondyly. In view of the association of sex reversal, hypoplasia of the scapulae, and the presence of straight long bones, campomelic acampomelic dysplasia was suspected and confirmed by the finding of a SOX9 mutation. This case shows the importance of a careful echographic survey in a fetus with a nuchal translucency > 4 mm, especially if there is discordance between phenotypic and genotypic sex, since growth retardation may occur later during the pregnancy.

Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9

“…The transactivating activity of p.Arg394Gly and p.Arg437Cys mutants was compared to that of the known ACD ‐associated SOX 9 mutant p.Pro176Leu (Michel‐Calemard et al. 2004). The results are expressed as the mean ± one standard deviation.…”

“…In this study, we compared the transactivating activity of newly identified mutants to that of the known ACD‐associated SOX9 mutant c.527C>T (p.Pro176Leu) (Michel‐Calemard et al. 2004). We used a PGL3 reporter vector (Promega, Madison, WI) containing the murine Amh promoter sequence (from −231 to 0 to the transcription start site of Amh , NC_000076.6) and a PGL4 reporter vector (Promega) containing the murine Col2a1 enhancer sequence (from +1958 to +2485 to the transcription start site of Col2a1 , NC_000081.6).…”

“…1997; Michel‐Calemard et al. 2004). As CD/ACD‐compatible skeletal abnormalities were described in all patients with SOX9 mutations and disorders of sex development (DSD) were shared only by ~70% of 46,XY patients (Mansour et al.…”

Heterozygous SOX9 Mutations Allowing for Residual DNA-binding and Transcriptional Activation Lead to the Acampomelic Variant of Campomelic Dysplasia

“…While a clear genotypephenotype correlation could not be established to date, the acampomelic form appears to be mild by comparison. Of 11 ACD cases in the literature in whom SOX9 mutations were reported, five carry missense mutations (Friedrich, et al, 2000;Michel-Calemard, et al, 2004;Moog, et al, 2001;Sock, et al, 2003; while the other six carry deletions or rearrangements directly affecting a cis-acting element upstream of the SOX9 coding region but not the coding region itself (Hill-Harfe, et al, 2005;Lecointre, et al, 2009;Leipoldt, et al, 2007;Ninomiya, et al, 1996;Velagaleti, et al, 2005). Of 8 cases with ACD and a XY karyotype, 4 cases (1 balanced translocation with a breakpoint upstream from the coding region, 3 missense mutations) do not show sex reversal.…”

Campomelic Dysplasia: Echographic Suspicion in the First Trimester of Pregnancy and Final Diagnosis of Two Cases

“…Its antenatal diagnosis is more difficult to make [11] . CD may be suspected after ultrasonography discloses shortened lower limbs and femoral angulation.…”