RAB23 Mutation in a Large Family from Comoros Islands With Carpenter Syndrome

Réanimation Néonatale et Pédiatrique, Centre Hospitalier Régional Félix Guyon, La Réunion, France.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 04/2010; 152A(4):982-6. DOI: 10.1002/ajmg.a.33327
Source: PubMed


We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in four relatives of Comorian origin with Carpenter syndrome. All children presented with acrocephaly and polysyndactyly. However, intrafamilial variability was observed with variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge. All children also presented with a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly (2/4) in the hands, and preaxial polydactyly (3) and syndactyly (4) in the toes. Mental development was normal in all four children but the eldest one presented with impaired motor development as a result of orthopedic complications. Brain imaging showed hydrocephalus in 2/4 and additional features included genu valgum (2/4), abnormal genitalia (3/4), corneal anomaly (2/4), umbilical hernia (1/4), severe cyphoscoliosis (1), patent ductus arteriosus (1/4), and accessory spleen (1). In contrast to previous reports, growth was below average except for one patient and the eldest one became moderately overweight with time. We conclude from the report of this large unique family with four affected children that Carpenter syndrome is a genetically homogenous but a clinically variable condition.

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    • "[Color figure can be viewed in the online issue, which is available at] with a RAB23 mutation, but has not been reported prenatally [Jenkins et al., 2007, 2011; Alessandri et al., 2010]. Heart defects are part of numerous malformation syndromes and therefore are not specific of a particular diagnosis. "
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    ABSTRACT: Carpenter syndrome is caused by mutations of the RAB23 gene. To date, 12 distinct mutations have been identified among 34 patients from 26 unrelated families. We report on the prenatal findings in a fetus with Carpenter syndrome with a novel RAB23 mutation. Cystic hygroma, bowed femora, abnormal skull shape and a complex heart defect were seen on ultrasound scan, and Carpenter syndrome was diagnosed at birth. Craniosynostosis and preaxial hexadactyly of the feet were retrospectively detectable on the fetal CT scan. Sequencing of RAB23 identified a homozygous mutation leading to skipping of exon 6 and premature termination codon (c.481G > C; p.Val161Leufs*16). This observation illustrates the difficulty of prenatal ultrasound diagnosis of Carpenter syndrome. To our knowledge, this diagnosis was suggested on ultrasound scan in only one prior patient, although in five other patients abnormal skull shape and variable findings, mainly limb anomalies including bowed femora in one case, were described during the pregnancy. Heart defect and bowed femora are rare postnatal findings. The diagnosis of Carpenter syndrome should therefore be considered on prenatal imaging in cases of bowed femora and/or cardiac defect associated with abnormal skull shape. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 11/2014; 164A(11). DOI:10.1002/ajmg.a.36726 · 2.16 Impact Factor
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    • "These mutations are associated with a similar phenotypic spectrum to nonsense mutations, thereby identifying key residues that are essential for protein function. The cases presented here, together with those previously published by Jenkins et al. [2007] and Alessandri et al. [2010] provide an expanded series in which to examine the phenotypic spectrum of Carpenter syndrome. The only universal features are craniosynostosis and soft-tissue syndactly, usually accompanied by insertional/preaxial "
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    ABSTRACT: Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.
    Human Mutation 04/2011; 32(4):E2069-78. DOI:10.1002/humu.21457 · 5.14 Impact Factor
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