OROFACIODIGITAL SYNDROME TYPE 1: CLINICAL AND GENETIC HETEROGENEITY

Orofaciodigital syndrome type 1 (OFD1) is an orphan disease with a prevalence of 1:50,000 - 1:250,000, manifested by abnormalities of the facial part of the skull, oral cavity and fingers, as well as damage to internal organs, including the kidneys.  The disease is caused by a mutation in the OFD1 gene, which encodes the proteins of the centrosome and the basal body of primary cilia, is inherited according to an X-linked dominant mode of inheritance and occurs predominantly in females, leading to the intrauterine death of male embryos.

Clinical observation of patient A., 12 years old, diagnosed with OFD1.  Search in ClinVar, OMIM databases, mutation visualization in NCBI Variation Viewer.

Patient A., 12 years old, was admitted to the Academician Yu.E. Veltishchev Research Clinical Institute of Pediatrics of the N.I. Pirogov Russian National Research Medical University with complaints of periodic abdominal pain. During life, a number of reconstructive operations were performed: removal of fibromas on the lateral surface of the tongue on the right and left, plastic surgery of the cleft tip of the tongue, dissection of embryonic strands of the mucous membrane in the upper lip, electrocoagulation of formations on the posterior surface of the right auricle, elimination of syndactyly II-III, IV-V fingers of the right hand, I-II, III-IV fingers of the left hand, surgical correction of brachydactyly.

An objective examination reveals numerous anomalies: asymmetrical face, hypertelorism, high forehead, periorbital fullness, wide flat dorsum of the nose, hypoplasia of the nasal wings, cleft midline of the upper lip, cleft tip of the tongue, lobed tongue, absence of the lateral incisors, epicanthus, alopecia areata, syndactyly, shortening of the left leg and the left arm.

MRI of the brain - complete agenesis of the corpus callosum of the brain, hypoplasia of the cerebellar vermis, compensated hydrocephalus of the lateral ventricles. According to MRI of the kidneys and abdominal organs, cystically dilated intrahepatic bile ducts and common bile duct at the level of the head of the pancreas, liver calcification, small pancreatic cysts, kidneys are located correctly, enlarged, multiple small cysts up to 4 mm in diameter are visualized.  Laboratory examination revealed a moderate decrease in the filtration function of the kidneys, creatinine 68 µmol/l, GFR – 78.7 ml/min/1.72 m2 (stage 2 of CKD), no microalbuminuria, no proteinuria, β2 microglobulin was normal, cytolysis and intrahepatic cholestasis were not detected. Signs of labile diastolic arterial hypertension were diagnosed.

Genetic examination - karyotype 46.XX (normal female). Sporadic heterozygous deletion (chrX: 13773332 CAATC>C) was identified in exon 12 of the OFD1 gene with a reading frame shift and the formation of a stop codon.  The mutation was confirmed by Sanger sequencing: the pathogenic variant c.1193_1196 del was identified in the heterozygous state.  Segregation analysis confirmed the de novo origin of the variant.

The case we described suggests a significant range of clinical polymorphism in patients with a mutation in the OFD1 gene. The sporadic heterozygous mutation found in patient A. has not been previously described in the literature. The symptom complex of patient A. includes all the characteristic signs of this syndrome.