A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome XIV (OFD14) is caused by homozygous or compound heterozygous mutation in the C2CD3 gene (615944) on chromosome 11q13.

Thauvin-Robinet et al. (2014) reported a 4-year-old boy, born of consanguineous parents, with a severe form of orofaciodigital syndrome. Facial features included microcephaly (-5 SD) with trigonocephaly, telecanthus, upslanting palpebral fissures, microretrognathia, cleft palate, cleft and lobulated tongue, buccal frenula, lingual hamartoma, absent epiglottis, and supernumerary teeth. He had broad and duplicated halluces, postaxial polydactyly of the hands, and micropenis. Neurologic features included retinopathy and severe intellectual disability with no speech. Brain imaging showed vermian hypoplasia with the molar tooth sign, hypoplasia of the corpus callosum, subarachnoid cysts in the posterior fossa, and incomplete myelination of the white matter. A similarly affected sib, who also had cardiac manifestations, died in the neonatal period. In an unrelated family, a 22-week-old fetus was found to have postaxial polydactyly of the hands and broad, duplicated halluces similar to the first patient. Dysmorphic facial features, microcephaly, and micropenis were also reported in the fetus.

Cortes et al. (2016) described 2 fetuses from a Lebanese-Palestinian family with a 'skeletal ciliopathy.' In the first fetus (G2P1), prenatal ultrasound showed Dandy-Walker malformation, short tubular bones, polydactyly, and renal cysts. Autopsy revealed a female fetus with facial dysmorphism including microphthalmia, hypertelorism, flat and broad nasal bridge, dysplastic and posteriorly rotated ears, micrognathia, and high-arched palate, as well as preaxial polydactyly of the feet presenting as a duplicated and bent hallux, brachydactyly, short ribs, short bent tubular bones, trident acetabula, and a number of ductal kidney cysts. The anus was anteriorly located, and atypical lung lobation, symmetrical liver, and mobile cecum were observed. The brain was not examined, in accordance with parental wishes. The second fetus (G3P1) was male and exhibited similar features, including preaxial polydactyly of the hands and feet that presented as duplication of the thumb and triplication of the hallux, and postaxial polydactyly of the hands. In addition, atrial septal defect, ambiguous genitalia with micropenis, and mobile cecum were observed. Brain autopsy showed holoprosencephaly, Dandy-Walker malformation with a dilated cisterna magna and vermis aplasia, cerebellar hypoplasia, polymicrogyria, and hydrocephalus. The authors noted clinical overlap between various forms of orofaciodigital syndrome (OFDS) and short-rib thoracic dysplasia syndromes (see 208500).

Boczek et al. (2018) studied 5 patients from 3 families with 'ciliopathy pedigrees' and mutations in the C2CD3 gene (see MOLECULAR GENETICS). In family 1, the proband had microcephaly, orofacial clefting, natal tooth on mandibular alveolus, lingual masses, microretrognathia, bilateral retinal colobomas, postaxial polydactyly of the feet and left hand, bilateral cryptorchidism, and hypotonia. MRI showed a Dandy-Walker malformation, molar tooth sign (MTS), bilateral symmetric hyposulcation of the brain with rudimentary/absent sylvian fissures, insula, and operculum, subependymal gray matter heterotopia, and rudimentary-appearing hippocampal formations. Renal ultrasound showed bilateral pelviectasis, and echocardiogram revealed a small patent ductus arteriosus (PDA). At 23 months of age, the patient was tracheostomy- and gastrostomy-dependent, and had global developmental delays and sleep-disordered breathing. His older sister, who had a clinical diagnosis of OFD, exhibited similar congenital anomalies, including microcephaly, ankyloglossia, bifid tongue, tongue hamartomas, incomplete cleft of the upper lip, polydactyly of all 4 extremities, and bilateral optic nerve colobomas. She also had global developmental delay, and MRI showed a simplified gyral pattern, limbic system hypoplasia, mild cerebellar hypoplasia, and gray matter heterotopia. In the second family, 2 pregnancies were terminated due to occipital encephalocele on prenatal ultrasound at 13 to 14 weeks. Other abnormalities included sloping forehead, bifid tongue, microretrognathia, ventricular septal defect, and short webbed neck. In family 3, the male proband exhibited significant micrognathia, malformed nodular tongue with absence of the anterior third of the tongue, tight frenulum, bilaterally low-set posteriorly rotated ears, bulbous nose with long vertical crease, and very mild epispadias. Brain MRI showed MTS, dilation of third and fourth ventricles, midline cerebellar cleft, and thinning of the corpus callosum with atrophy of the posterior aspect of the body and absence of the splenium, features which the authors noted were consistent with a diagnosis of Joubert syndrome. Skeletal survey and renal ultrasound were normal. At last follow-up, the patient was being fed via gastrostomy to prevent aspiration, and had bilateral retina colobomas, global hypotonia with stiff upper extremities, and developmental delays.

The transmission pattern of OFD14 in the family reported by Thauvin-Robinet et al. (2014) was consistent with autosomal recessive inheritance.

In a 4-year-old boy with orofaciodigital syndrome, Thauvin-Robinet et al. (2014) identified a homozygous truncating mutation in the C2CD3 gene (R62X; 615944.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Sequencing the coding exons of the C2CD3 gene in 34 patients with OFD identified 1 fetus who was compound heterozygous for 2 mutations in the C2CD3 gene (615944.0002 and 615944.0003). Functional studies of the 3 variants were not performed, but Thauvin-Robinet et al. (2014) demonstrated that C2CD3 is required for cilium assembly and function, consistent with OFD being a ciliopathy. Moreover, hypomorphic or null mutations in this gene in mice cause a phenotype consistent with a ciliopathy.

From a cohort of 43 French Canadian patients from 35 families diagnosed with Joubert syndrome (see 213300), Srour et al. (2015) identified 2 sibs (family 472) who were compound heterozygous for a missense (G1743C) and a nonsense (R1977X) mutation in the C2CD3 gene. The patients exhibited MTS and severe global developmental delay with hypotonia and ataxia, but information regarding oral, facial, and digital features was not reported.

In 2 fetuses with a 'skeletal ciliopathy' from a Lebanese-Palestinian family, Cortes et al. (2016) identified compound heterozygosity for a missense (W65C) and a nonsense (I477X) mutation in the C2CD3 gene.

In 5 children from 3 unrelated 'ciliopathy pedigrees,' Boczek et al. (2018) performed whole-exome sequencing and identified compound heterozygous mutations in the C2CD3 gene in all (see, e.g., 615944.0004 and 615944.0005). The unaffected parents were each heterozygous for 1 of the mutations, which were either not present or present at extremely low frequency (less than 0.001%) in the gnomAD database. Noting the phenotypic diversity exhibited by their patients, the authors concluded that biallelic variants in C2CD3 can cause a spectrum of ciliopathy disorders.