Endocrine Abstracts

JOINT1474

Introduction: Hypoparathyroidism-retardation-dysmorphia syndrome (HRD), also known as Sanjad-Sakati syndrome (SSS), is an autosomal recessive disorder characterized by permanent parathyroid hormone (PTH) deficiency, hypocalcemia, hyperphosphatemia, facial dysmorphism, and occasionally, psychomotor retardation. A similar syndrome, with additional features such as osteosclerosis and recurrent infections, is the autosomal recessive Kenny-Caffey syndrome (KCS1). Both syndromes have been associated with abnormalities in the gene encoding tubulin folding cofactor E (TBCE, 1q42.3). Mutations in FAM111A (11q12.1), which encodes a serine protease FAM111A, have also been described in a clinical variant of Kenny-Caffey syndrome (KCS2). We here-in describe a male patient with HRD, presenting previously unreported molecular abnormalities in both, the TBCE and FAM111A genes.

Methods: Whole exome sequencing was performed on peripheral blood genomic DNA of a 15-year-old male who sought medical care because of severe hypocalcemia and hyperphosphatemia, as well as facial dysmorphism. Born to non-consanguineous parents of Syrian-Jewish origin, he was found to have micrognathia, low ear implantation and retention of primary teeth. On the physical exam he was found in frank tetany with positive Trousseau and Chvostek signs, as well as bilateral cataracts. He has adult-like axillary and pubic hair and external genitalia were fully developed. Neuropsychological testing was normal, without evidence of mental retardation. Relevant laboratory results included a serum Ca of 4 mg/dL, P 7 mg/dL, intact PTH undetectable, 25-hydroxi-vitamin D3 10 ng/mL and mild eosinophilia. Renal and hepatic function tests, as well as thyroid function tests were all within normal limits. The ECG showed prolonged QT interval. Head CT revealed multiple bilateral calcifications, particularly in basal ganglia, thalami and cerebellum. He started on large doses of calcium carbonate, calcitriol and teriparatide with important symptomatic improvement.

Results and conclusions: The patient showed a highly polymorphic exome but none of the known mutations in TBCE and FAM111A genes. However, he harbored several compound heterozygous variants that have not been previously described. An insertion, two deletions and 5 single nucleotide changes in the intronic region of TBCE were identified (235372627insAG, 235380162_183delTGTGTGTGTGTGTGTGTGTG, 235412798_803delATTATT, 235427244G>A, 235430867A>G, 235435658C>T, 235438643G>T, 235439089G>A). An apparently non-pathogenic, synonymous variant in FAM111A (c.A672G p.Ala224Ala) was also found. HRD syndrome represents an overlapping spectrum, as illustrated by our patient, who despite having an unequivocal clinical and biochemical phenotype, he lacked the TBCE and FAM111A mutations known to be associated with SSS and KCS. Further research is needed to ascertain if the polymorphic intronic variants found in our patient are of pathogenic relevance.