Primaryhyperparathyroidism (PHPT) is a disorder of mineral metabolism caused by inappropriate or excessive secretion of parathyroid hormone. It occurs sporadically in approximately 95% of cases but may also be associated with complex syndromes and/or a familial (i.e., hereditary) history. We report the clinical, laboratory, and genetic profiles of a case series with familial isolated hyperparathyroidism. Diagnosis was established in patients aged 22-41 years (median = 32), and recurrence was identified in four patients (three with adenoma and one with hyperplasia and parathyroid carcinoma). Six family members presented with a heterozygous mutation in the CDC73 gene, and one patient had a copy number variation of undetermined clinical significance in the same gene. In addition, we review the particularities of each condition associated with PHPT, indications for genetic evaluation, and recommendations for follow-up and treatment.

Hereditary primary hyperparathyroidism (PHPT) is a monogenic autosomal disorder, constituting 5-10% of all PHPT cases. Data on hereditary PHPT in the Chinese population are scarce. This study aimed to delineate the etiology, phenotype, genotype, management, and prognosis of hereditary PHPT in Tianjin Medical University General Hospital, expanding the spectrum of pathogenic genes and evaluating the age-dependent penetrance of clinical phenotypes. Additionally, genotype-phenotype correlations were explored in multiple endocrine neoplasia type 1 (MEN1). A retrospective analysis of medical records from January 1st, 2008 to July 31st, 2024 included clinical presentations, biochemical markers, imaging findings, and whole exome sequencing. The study comprised 73 cases. MEN1 was predominant (80.8%), followed by hyperparathyroidism-jaw-tumor syndrome (9.6%), familial hypocalciuric hypercalcemia (5.5%), MEN2A (2.7%), and familial isolated hyperparathyroidism (1.4%). The male:female sex ratio was 1:1.6. Thirty patients (41.1%) exhibited multiglandular parathyroid involvement. Genetic testing in 57 patients identified 12 novel mutations, with 70.2% harboring pathogenic or likely pathogenic variants. Mean age at initial presentation for PHPT mutation carriers was 42.0±14.5 years, with 64.3% penetrance by 45 years of age. No significant genotype-phenotype correlations were observed for MEN1 mutations. This case series provided insight into the clinical phenotypes and mutational spectrum of hereditary PHPT, emphasizing the role of genetic testing for subtype classification, complications monitoring, treatment guidance and family surveillance. Genetic testing is recommended for PHPT patients with early-onset, complex clinical presentations, multiglandular parathyroid involvement or family history.

Familial or heritable hyperparathyroidism (FHPT) is seen in approximately 10-15 % of patients with primary hyperparathyroidism (PHPT). Once the diagnosis of PHPT is established, consideration of heritable forms should be made in patients with positive family history, young onset, multi-glandular disease, and recurrent or persistent disease. FHPT encompasses both syndromic and non-syndromic forms. Syndromic forms include multiple endocrine neoplasia (MEN) types 1, 2, 3 and 4, hyperparathyroidism-jaw tumor syndrome, hereditary pheochromocytoma and paraganglioma, and the more recently reported, Birt-Hogg-Dubé (BHD) syndrome, and X-linked intellectual disability syndrome. Non-syndromic forms include familial hypocalciuric hypercalcemia (FHH)- types 1,2, and 3, neonatal severe hyperparathyroidism, GCM2-mediated hyperparathyroidism, transient neonatal hyperparathyroidism, and familial isolated hyperparathyroidism. In this review we aim to review the heritable forms of PHPT and highlight the important genetics insights and clinical implications.

Primary hyperparathyroidism is a constitutive excess of parathyroid hormone (PTH) in the blood, caused by an idiopathic defect of growth and/or function of the parathyroid glands. PHPT is usually an acquired disease, due to the sporadic development of parathyroid hyperplasia, adenoma, and, in extremely rare cases, malignant carcinoma, mainly occurring by the sixth decade of life. In about 5-10 % of cases PHPT manifests in the context of congenital disorders, having a genetic base and occurring much earlier in life, compared to the sporadic counterpart. Congenital PHPT can manifest as isolated PHPT or as syndromic PHPT in the context of complex multiorgan disorders. Non-syndromic inherited PHPT includes Familial Hypocalciuric Hypercalcemia types 1, 2 and 3, Neonatal Severe Primary Hyperparathyroidism, and three different genetic forms of Familial Isolated Hyperparathyroidism, while syndromic inherited PHPT includes Hyperparathyroidism-Jaw Tumor Syndrome and Multiple Endocrine Neoplasias types 1, 2 A and 4.

Germline and somatic pathogenic variants in the CDC73 gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for CDC73-related conditions, including deletion, truncating, missense, and splice site mutations. Here, we report identification of a non-coding germline CDC73 variant (CDC73 c.1155-3A > G), previously categorized as a variant of uncertain significance (VUS), in a family with HPT-JT. This variant, found in two family members with PHPT, altered CDC73 splicing in peripheral blood cells and disrupted parafibromin immunostaining in associated parathyroid adenomas, strongly evidencing its pathogenicity. Sestamibi scintigraphy yielded nondiagnostic localization results for both patients' parathyroid adenomas, consistent with prior studies suggesting lower sensitivity for small or cystic lesions. Our findings demonstrate key aspects of CDC73-related disorders, highlight the diagnostic value of RNA testing, and exemplify the importance of obtaining a thorough, three-generational family history.