Cranioectodermal Dysplasia 3

A number sign (#) is used with this entry because cranioectodermal dysplasia-3 (CED3) is caused by homozygous mutation in the IFT43 gene (614068) on chromosome 14q24. One such family has been reported.

Description

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive heterogeneous ciliopathy that is primarily characterized by skeletal abnormalities, including craniosynostosis, narrow rib cage, short limbs, and brachydactyly, and ectodermal defects. Nephronophthisis leading to progressive renal failure, hepatic fibrosis, heart defects, and retinitis pigmentosa have also been described (summary by Arts et al., 2011).

For discussion of genetic heterogeneity of cranioectodermal dysplasia, see CED1 (218330).

Clinical Features

Arts et al. (2011) reported a sister and brother from a consanguineous family of Moroccan descent with cranioectodermal dysplasia. Both sibs had short stature, narrow thorax, rhizomelic shortening of limbs, hypoplastic and widely spaced teeth, and nephronophthisis. The 7-year-old sister, who lacked the typical craniofacial features of Sensenbrenner syndrome, had bilateral 2-3-4 toe syndactyly, and brachydactyly with webbing of fingers and short, broad nails. Her 5-year-old brother displayed macrocephaly, scaphocephaly, sagittal suture synostosis, frontal bossing, telecanthus, everted lower lip, micrognathia, and sparse, fine hair. In addition, he had bilateral postaxial polydactyly of hands and feet, brachydactyly and webbing of fingers with short, broad nails, bilateral 2-3 and 5-6 toe syndactyly, and sandal gap between toes 1-2. The brother also had peripheral pulmonary stenosis, neonatal cholestasis and cirrhosis, and end-stage renal disease requiring dialysis.

Mapping

In a consanguineous family of Moroccan descent in which a brother and sister had cranioectodermal dysplasia, Arts et al. (2011) performed genomewide homozygosity mapping and found that the 2 largest regions of homozygosity overlapped in a 25.2-Mb region on chromosome 14.

Molecular Genetics

In a brother and sister from a consanguineous family of Moroccan descent with cranioectodermal dysplasia mapping to chromosome 14, Arts et al. (2011) analyzed 2 candidate genes and identified homozygosity for a mutation in the translation initiation codon of the IFT43 gene (614068.0001). The first-cousin parents were each heterozygous for the mutation. Arts et al. (2011) noted that IFT43 directly binds to WDR35 (613602) in the intraflagellar transport (IFT)-A protein complex. No mutations in the IFT43 gene were detected in 4 additional unrelated patients with CED who were known to be negative for mutation in WDR35, and homozygosity mapping in 2 consanguineous CED families revealed no major intervals of homozygosity in regions containing the 3 known CED-related genes, indicating the likelihood of further genetic heterogeneity in the disorder.

Pathogenesis

Consistent with disruption of a member of the IFTA protein complex, fibroblasts from 1 of the affected sibs and from a previously studied patient (Gilissen et al., 2010) with CED2 (613610) and mutations in WDR35 showed similar ciliary defects, with accumulation of IFTB-complex proteins in the ciliary tip. In addition, cilia in mutant IFT43 fibroblasts were somewhat shorter than those of control fibroblasts, as had previously been reported (Walczak-Sztulpa et al., 2010) in patients with CED1 (218330) and mutation in the IFT122 gene (606045). Arts et al. (2011) concluded that their findings demonstrated that CED results from defects in retrograde intraflagellar transport.