Cranioectodermal Dysplasia 2

A number sign (#) is used with this entry because of evidence that cranioectodermal dysplasia-2 (CED2) is caused by compound heterozygous mutation in the WDR35 gene (613602) on chromosome 2p24.

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

Clinical Features

Gilissen et al. (2010) reported 2 unrelated Dutch boys with a similar phenotype that was reminiscent of Sensenbrenner syndrome. Both had short stature (less than 2.5 SD below the average), dolichocephaly, craniosynostosis, narrow thorax with pectus excavatum, short limbs, and brachydactyly. Facial features included narrow palpebral fissures, telecanthus with hypertelorism, low-set simple ears, everted lower lip, and short neck. Teeth abnormalities included widely spaced, hypoplastic, and fused teeth. Both had joint laxity, inguinal hernia, and webbed fingers. There was no evidence of renal or hepatic disease, and both had normal intelligence.

Bacino et al. (2012) studied a Mexican family in which 4 sibs exhibited features that were characteristic of Sensenbrenner syndrome but also overlapped those of short-rib polydactyly syndromes (see SRTD7, 614091). Findings included cystic hygroma, dolichocephaly (associated with sagittal synostosis in 1 sib), prominent or tall forehead, low-set simple ears, high-arched or cleft palate, short stature, narrow thorax with short ribs, brachydactyly, polydactyly, hepatomegaly, renal and cardiac anomalies, and developmental delay. One sib was alive at 4 years of age, 2 of the sibs died at 9 months and 13 months of age, and an affected fetus was terminated at 21 weeks' gestation.

Lin et al. (2013) studied an 8-month-old boy with multisutural craniosynostoses resulting in a small 'cloverleaf' cranium, bitemporal narrowing, tall forehead, and posteriorly displaced anterior fontanel. Head CT showed closure of the metopic, left coronal, and sagittal sutures, and partial closure of the left lambdoid suture. Facial dysmorphic features included markedly upslanting and large palpebral fissures, epicanthal folds, flat nasal bridge, upturned nares, and long smooth philtrum. Scalp hair, eyebrows, and eyelashes were sparse. Neck skin was redundant, limbs were short, and fingers were short and broad.

Smith et al. (2016) described a 15-year-old boy from a consanguineous Pakistani family who exhibited a relatively mild skeletal ciliopathy, presenting at age 10 years for evaluation of short stature, renal cysts, and dental anomalies. He had multiple missing permanent teeth, chronic renal failure, and hypertension; other features included narrow chest, short ribs, brachydactyly, and abnormal echogenicity of the liver.

Walczak-Sztulpa et al. (2017) reported 2 Polish sisters with Sensenbrenner syndrome. The proband was 9 years old, and her older sister had died at age 4 months of respiratory, hepatic, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of the left hand, narrow chest, craniosynostosis with dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, and low-set ears. Ectodermal abnormalities included joint and skin laxity, slow-growing fine sparse hair, and small, abnormally shaped, and widely spaced teeth. The proband presented with chronic tubulointerstitial renal disease, with abnormal echogenicity on renal ultrasound, reduced glomerular filtration, proteinuria, and prehypertension; the authors designated the renal disease as nephronophthisis.

Molecular Genetics

By exome sequencing in 2 unrelated Dutch boys with cranioectodermal dysplasia, Gilissen et al. (2010) identified compound heterozygous mutations in the WDR35 gene (613602.0001-613602.0004). Gilissen et al. (2010) postulated that the WDR35 mutations resulted in ciliary dysfunction due to disrupted intraflagellar transport.

Using exome capture in a 4-year-old Mexican boy with CED, Bacino et al. (2012) identified homozygosity for a missense mutation in the WDR35 gene (L520P; 613602.0008). The unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in public variant databases. DNA was unavailable from 3 more affected sibs in the family, including 2 who died at 9 months and 13 months, and an affected fetus terminated at 21 weeks' gestation.

In an 8-month-old boy with CED and multisutural craniosynostoses, who was negative for mutation in the IFT122 gene (606045), Lin et al. (2013) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the WDR35 gene, H1031Y (613602.0009) and Y1068C (613602.0010).

In a 15-year-old Pakistani boy with skeletal ciliopathy, Smith et al. (2016) performed autozygosity mapping and candidate gene sequencing, and identified homozygosity for a missense mutation in the WDR35 gene (W1153C; 613602.0012). His fourth-cousin parents were each heterozygous for the mutation, which was not found in public variant databases. The authors stated that the mutation was the most distal yet reported, noting that it corresponded to a relatively mild phenotype in this patient.

In a 9-year-old Polish girl with Sensenbrenner syndrome, Walczak-Sztulpa et al. (2017) sequenced the candidate genes IFT122 and WDR35 and identified compound heterozygosity for mutations in the WDR35 gene: L641X (613602.0015) and D841V(613602.0016). The authors noted that this family exhibited intrafamilial variability, in that the proband's affected older sister had more severe expression of the phenotype and had died in infancy.

Pathogenesis

Arts et al. (2011) observed similar ciliary defects in fibroblasts from 1 of the CED2 patients with mutations in WDR35 reported by Gilissen et al. (2010) and from a patient with CED3 (614099) and mutation in the IFT43 gene (614068.0001): both showed accumulation of IFTB-complex proteins in the distal part of the ciliary axoneme and in the ciliary tip, whereas in the cilia of control fibroblasts, those proteins were less abundant and primarily located at the basal body and transition zone. Arts et al. (2011) concluded that CED results from defects in retrograde intraflagellar transport.