High Risk of Parathyroid Carcinoma and Genetic Screening in the First Diagnosed Romanian Family with Hyperparathyroidism-Jaw Tumor Syndrome and a Germline Mutation of the CDC73 Gene

Abstract

Context. Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of familial hyperparathyroidism associated with ossifying fibromas (OF) of the maxillofacial bones and increased risk of parathyroid carcinoma, caused by inactivating germline mutation of the cell division cycle 73 (CDC73) gene.Objective. To report the first Romanian family with HPT-JT and genetic screening of CDC73 gene.Subjects and Methods. Mutational analysis of the CDC73 gene and genetic screening of the family of a proband with HPT-JT. Histological diagnosis of parathyroid tumors (WHO criteria) and immunohistochemistry (parafibromin) were performed.Results. Three of the six screened family members had evidence of PHPT and surgically proven parathyroid tumours. Two of the three affected members had parathyroid carcinomas and one had two parathyroid adenomas. Genetic screening of CDC73 gene revealed that 4 of 6 patients showed a heterozygous germline deletion of one nucleotide: c.128-IVS1+1 delG. All the three affected patients, resulted to be carriers of the CDC73 mutation, but each one bearing a different CDC73 polymorphism.Conclusions. We identified a new CDC73 germline mutation in a Romanian family of HPT-JT. Analysis of clinical phenotypes in the four mutated individuals confirmed the incomplete penetrance and the variable clinical expression of the disease.

Hyperparathyroidism-jaw tumor syndrome: A rare disorder with significant clinical features

“…CDC73 gene encodes for an evolutionary conserved protein, known as parafibromin 8,12 . This protein consists of 531 amino acids, is predominantly expressed in the nucleus of the cells and can be found in many tissues of the human body such as parathyroid and adrenal glands, kidneys, heart, hypophysis and skeletal muscles 8,18,19 . Parafibromin shows off strong anti-proliferative properties and is a component of Polymerase-Associated Factor 1 complex (PAF1c) that includes, overall, five more proteins 17,20 .…”

“…The vast majority of germline mutations is related to frameshift and nonsense ones, which are detected in 50-60% and 30% of the syndromic probands, respectively, whilst missense and splice-siting mutations are found more rarely (5-13%) 9,20 . Strikingly, 65-80% of these mutations are predominantly located in exons 1, 2 and 7, howbeit they can be scattered out along the whole coding area 9,16,18,20 . Also, as it has been shown by numerous studies, in 1/3 of the cases a gross deletion of whole exons, that might even expand beyond CDC73 gene, is observed, yet without being necessarily linked to more severe clinical features 11,23,[27][28][29][30][31][32] .…”

“…All research advocates that the penetrance of the syndrome is incomplete and it usually ranges from 70% to 95% 7,8,25,29,30,34 . That means approximately 10-30% of the probands bearing a CDC73 germline mutation will lack any clinical feature related to the syndrome 5,9,18,33 . Recent cohort studies in affected families demonstrated that penetrance seems to increase with age and, more specifically, it is formulated as follows: 25-30 years old: 15%, 40-50 years old: 60%, 70 years old: 85% 4,25 .…”

“…Expressivity of the syndrome is variable and, to date, an unequivocal phenotype-genotype correlation has not been established 4,7,8,18,[23][24][25] . A prominent example is the case currently described by Le Collen et al, where two monozygotic twins manifested a completely contrasting expression, with the first suffering from acute hypercalcemia and renal failure, whilst the second presented almost normal serum calcium levels 25 .…”

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“…Because of its incomplete penetrance, patients with germline CDC73 mutation can present with a spectrum of phenotypes including seemingly sporadic parathyroid cancer ( CDC73 PV/LPVs have been identified in 20–29% of parathyroid carcinomas), familial isolated hyperparathyroidism (FIHP) with or without parathyroid cancer, or full expression of hyperparathyroidism-jaw tumor syndrome (HPT-JT) [ 107 , 108 ]. HPT-JT is a rare autosomal dominant syndrome with typical onset in late adolescence or early adulthood that causes familial hyperparathyroidism associated with ossifying fibromas of the maxillofacial bones and increased risk of parathyroid carcinoma.…”