Orofaciodigital Syndrome Iv

A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome IV (OFD4) can be caused by homozygous or compound heterozygous mutation in the TCTN3 gene (613847) on chromosome 10q24.

Mutation in TCTN3 can also cause a form of Joubert syndrome (JBTS18; 614815).

Clinical Features

Baraitser (1986) suggested the existence of a fourth type of orofaciodigital syndrome but recognized that considerable overlap of the features of the various forms gives rise to difficulties in precise clinical differentiation. The autosomal recessive mode of inheritance and the presence of severe tibial dysplasia differentiated type IV from type I (311200).

Burn et al. (1984) described 2 sisters, the children of first-cousin Pakistani Moslem parents, who had unusual facies, tongue hamartomata, pre- and postaxial polydactyly, severe talipes, and mesomelic limb shortening associated with tibial dysplasia. Many of the features resembled those of the Majewski type of short rib-polydactyly syndrome (263520). Indeed, the older of the 2 sibs reported by Burn et al. (1984) had been reported as having either that syndrome (Cooper and Hall, 1982) or the Mohr-Majewski compound (Baraitser et al., 1983). Temtamy and McKusick (1978) had described a patient who they thought showed features of both syndromes.

Nevin and Thomas (1989) reported a fifth patient with OFD IV. The clinical characteristics included lobulated tongue, pseudo-cleft of the lip, pre- and postaxial polydactyly of the hands and feet, severe talipes equinovarus, mesomelic limb shortness associated with tibial hypoplasia, and severe bilateral deafness. Nevin et al. (1992) added to the genetic understanding of this disorder by describing an affected second cousin of the patient reported by Nevin and Thomas (1989).

Meinecke and Hayek (1990) described a severely affected infant.

Ades et al. (1994) entertained a severe form of OFD IV as the diagnosis in a child of first-cousin Lebanese parents who was spontaneously delivered stillborn at 27 weeks' gestation. The fetus showed occipitoschisis, polydactyly, campomelia, cleft palate, laryngeal dysplasia, ocular colobomata, hepatic fibrosis with intrahepatic cyst, ambiguous genitalia, cystic dysplastic kidneys, and brain malformation.

Digilio et al. (1995) described a female patient with OFD IV who, in addition to typical manifestations of the syndrome, had previously undescribed malformations and deformations, including cerebral and renal anomalies, anal atresia, and dislocation of elbows and knees. They stated that this was the tenth reported patient.

Toriello et al. (1997) described 6 children diagnosed as having OFD syndrome with tibial defects. They concluded that the patients probably had different conditions, although all had oral, facial, digital, and tibial defects.

Thomas et al. (2012) examined a male fetus from a consanguineous Senegalese family; the pregnancy was terminated at 19 weeks due to brain anomalies, cystic kidneys, and severe skeletal dysplasia. He had facial dysmorphism with a lobulated tongue, polydactyly of all 4 limbs, severe cystic kidney disease, ductal plate proliferation in the liver, and occipital encephalocele. Neuropathologic assessment disclosed absent olfactory system, corpus callosum agenesis, and vermian hypoplasia. X-rays showed bowing of long bones with severe tibial hypoplasia. The acetabular margin had a trident appearance, but there were no short ribs. Thomas et al. (2012) concluded that the fetus fulfilled the diagnostic criteria for OFD4.

Inheritance

Consanguinity in several reported families segregating OFD IV (e.g., Burn et al., 1984; Ades et al., 1994) supported autosomal recessive inheritance.

Molecular Genetics

In a fetus from a consanguineous Senegalese family that fulfilled diagnostic criteria for OFD4, Thomas et al. (2012) performed genomewide homozygosity mapping and identified 14 regions of homozygosity. Targeted capture strategy combined with next-generation sequencing and filtering yielded a single nonsense mutation in the TCTN3 gene (E408X; 613847.0001) that was present in homozygosity in the fetus. Homozygosity mapping analysis in 18 additional cases presenting with lethal ciliopathies with various combinations of brain, renal, skeletal, and orofacial abnormalities and polydactyly revealed 6 with regions of homozygosity at the TCTN3 locus; direct sequencing of the TCTN3 gene identified 2 different homozygous truncating mutations in 3 of the fetuses (613847.0002 and 613847.0003). Sequencing of TCTN3 in an additional 82 nonconsanguineous fetal cases with a severe ciliopathy revealed compound heterozygosity for frameshift mutations in 2 affected French sibs (613847.0004-613847.0005). Thomas et al. (2012) noted that some of the affected fetuses did not display orofacial anomalies, thus confirming the variable phenotypic spectrum of OFD4.