Orofaciodigital Syndrome Xviii

A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome-18 (OFD18) is caused by homozygous mutation in the IFT57 gene (606621) on chromosome 3q13. One such family has been reported.

Description

Orofaciodigital syndrome-18 is characterized by short stature, brachymesophalangy, pre- and postaxial polysyndactyly, and stocky femoral necks, as well as oral anomalies and dysmorphic facial features (Thevenon et al., 2016).

Clinical Features

Phadke et al. (1999) described a 7-year-old girl from a consanguineous Indian family who exhibited acromelic short stature, midline cleft lip, absence of lower central incisors, multiple oral frenula, postaxial polydactyly of all limbs, and genu valgum. She had pronounced brachydactyly, and hand x-rays showed markedly short middle and distal phalanges. She also had continuous dribbling of urine; cystoscopy revealed a short urethra but normal bladder neck. Hearing, speech, and mental development were normal. She had 2 brothers, aged 9 and 2 years, who were similarly affected except for the urinary incontinence. Their first-cousin parents were unaffected. The authors suggested that the phenotype in this family represented a newly recognized syndrome comprising features of both orofaciodigital (OFD) syndrome and Ellis-van Creveld syndrome (EVC; see 225500).

Thevenon et al. (2016) provided follow-up on the 3 sibs reported by Phadke et al. (1999). The youngest brother (II-3) had died at age 17 years of a complicated pulmonary infection. The 25-year-old brother (II-1) and 22-year-old sister (II-2) had normal intelligence, short stature, square face with small forehead, upslanting palpebral fissures, midline cleft lip, missing incisors, and supernumerary frenula. Both sibs also exhibited marked brachydactyly as well as polydactyly of all 4 extremities. Neither showed a thoracic deformity. X-rays of the hands and feet showed severe mesophalangeal shortening, upper limb postaxial polydactyly, and lower limb preaxial polydactyly, with duplication of the first metatarsals. Both sibs had bilateral short femoral necks with varus femurs and symmetric genu valgus; in addition, the sister had bilateral cervical ribs, abnormal vertebral bodies with medial notches, and gracile long bones. Brain MRI, echocardiography, and abdominal ultrasound were normal in both sibs.

Inheritance

The transmission pattern of OFD in the family reported by Phadke et al. (1999) was consistent with autosomal recessive inheritance.

Mapping

In 2 affected sibs from a consanguineous Indian family with orofaciodigital syndrome, Thevenon et al. (2016) performed homozygosity mapping and identified 2 regions of shared homozygosity on chromosomes 3 and 10 (chr3:104,822,019-111,691,862 and chr10:1,372,501-6,029,726; GRCh37).

Molecular Genetics

In a 25-year-old man from a consanguineous Indian family with orofaciodigital syndrome, Thevenon et al. (2016) performed exome sequencing and identified homozygosity for a synonymous mutation in the IFT57 gene (K259K; 606621.0001) on chromosome 3, within a region of shared homozygosity with another affected sib. Sanger sequencing confirmed that all 3 affected sibs were homozygous for the mutation, which was not found in 50 Indian controls or in the ExAC database. Functional analysis revealed that the mutation causes splicing anomalies and significantly reduced mRNA, resulting in a ciliary transport defect that alters SHH (600725) pathway signaling. Sequencing of IFT57 in 25 patients with OFD or EVC did not identify any causative mutations, and analysis of exome or ciliome data from 172 individuals with ciliopathy phenotypes did not reveal any biallelic causative mutations.