Primary hyperparathyroidism is an endocrine disorder characterized by chronic hypercalcaemia resulting from the unregulated excessive production of parathyroid hormone. This study aimed mainly to determine the clinical manifestations of primary hyperparathyroidism within the African population. This study was a systematic review carried out in strict compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The meta-analysis was executed utilizing Meta XL version 5.3, applying the DerSimonian Laird random-effects model. A total of 52 studies met the eligibility criteria, resulting in an overall sample size of 2,807 patients. The average age was 55.1 years. Seventy-nine percentage of the patients were women. Asymptomatic individuals represented 26% of the population. The most common symptoms include bone pain, lethargy, and features related to renal stones. Familial primary hyperparathyroidism is observed in 6% of patients. The majority of individuals diagnosed with primary hyperparathyroidism are women in their sixth decade. In contrast to developed countries, a considerable number of Africans suffering from primary hyperparathyroidism have already shown symptoms, which are frequently non-specific or have encountered complications before obtaining a diagnosis.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is the most common inherited cause of familial primary hyperparathyroidism. Diagnosis can be clinical, with at least 2 MEN1-associated tumors, or with 1 tumor plus a family history, or through genetic testing. A 31-year-old woman presented with hypercalcemia due to primary hyperparathyroidism. A 4-dimensional computed tomography (4D CT) and ultrasonography (US) of neck revealed 1 right-sided and 1 left-sided lesion consistent with parathyroid adenomas. Given her young age and a maternal history of primary hyperparathyroidism genetic testing was pursued and identified an MEN1 (NM_130799.2): c.652C>T (p.Arg218Trp) variant, reported as a variant of uncertain significance (VUS) with conflicting interpretations across laboratories. This variant had conflicting interpretations of VUS or pathogenic among several genetic testing laboratories. Further evaluation revealed a pancreatic neuroendocrine tumor and a pituitary cyst, with otherwise normal hormonal testing. Genetic testing in the patient's mother identified the same MEN1 variant. The presence of a clinical MEN1 diagnosis and familial segregation in 2 affected individuals provides additional evidence supporting reclassification of this variant from VUS to likely pathogenic.

Limited data exist on the genetic profile of Familial primary hyperparathyroidism (FPHPT) in the Indian population. This study was conducted to determine the prevalence of targeted gene mutations in high-risk patients with PHPT. This prospective cross-sectional study was conducted in the Department of Endocrinology at our University Hospital from February 2021 to February 2023, in which 103 patients diagnosed with PHPT were taken. A customised gene panel (MEN1, RET, CDKNIB, and CDC73) using next-generation sequencing (NGS) was performed in 39 patients with a strong suspicion of FPHPT based on age <35 years, family history of PHPT, multiglandular disease, hyperparathyroidism jaw tumour, cystic parathyroid adenoma (PA), parathyroid carcinoma (PC) and suspicion of MEN 1/2A/4 syndrome. Germline variants were observed in 11/39 (28.2%). MEN1 mutations were found in 7 patients (17.9%) and CDC73 mutations in 4 (10.2%). MENI mutations included c. 1351-2A>G, c. 249_252del (p.Ile85fs), c. 1763C>T(p.S588L) and c. 415C>T(p.H139Y). Clinical features in MEN1-positive patients included microprolactinomas (n = 2), multiglandular disease (n = 5), recurrent PHPT (n = 1), persistent PHPT (n = 1), and gastric neuroendocrine tumour (n = 1). Among CDC73 mutation patients, 2 (50%) had familial PHPT, 2 (50%) had hyperparathyroidism jaw tumour syndrome (one had multiple bilateral renal cysts and one had multiple uterine leiomyomas); however, none had either ossifying fibroma of the jaw. Identified CDC73 mutations included c. 664C>T(p.R222X), c. 415C>T(p.R139X), c. 687_688dellAG(p.Arg229Serfs37), and c76delA(p.Ile26SerfsX11). The mutations were statistically associated with age, higher serum calcium levels, elevated ALP, and greater skeletal involvement. For optimal management, PHPT patients with high-risk features should be subjected to customised genetic testing in resource-limited settings.

Around 10% of cases of primary hyperparathyroidism are thought to be genetic in origin, some of which are part of a syndromic form such as multiple endocrine neoplasia types 1, 2A or 4 or hyperparathyroidism-jaw tumor syndrome, while the remainder are cases of isolated familial primary hyperparathyroidism. Recognition of these genetic forms is important to ensure appropriate management according to the gene and type of variant involved, but screening for a genetic cause is not justified in all patients presenting primary hyperparathyroidism. The indications for genetic analysis have made it possible to propose a decision tree that takes into account whether the presentation is familial or sporadic, syndromic or isolated, patient age, and histopathological type of parathyroid lesion. Thus, the first consensus recommendation is to propose genetic screening to any patient with a familial form of primary hyperparathyroidism (≥2 1st or 2nd degree relatives) or in syndromic presentation or a sporadic isolated presentation if the patient is under 50 years of age, or over 50 with a recurrent or multi-glandular form, carcinoma, atypical parathyroid tumor and/or loss of parafibromin expression. The panel of genes currently recommended for first-line treatment comprises MEN1, CDKN1B, CDC73, CASR, GNA11, AP2S1 and GCM2. Other genes may also be involved in familial primary hyperparathyroidism, but in a much more rarely and less consistently. The second recommendation is to propose genetic screening, up to and including whole-genome sequencing in the event of inconclusive panel analysis, to patients with proven familial primary hyperparathyroidism and/or pediatric onset. The role of the genetic practitioner is to interpret the sequencing data by categorizing the variants into 5 classes of pathogenicity. The aim of genetic analysis is to identify the genetic variant involved in the patient's phenotype, in order to make or refute a diagnosis of hereditary primary hyperparathyroidism, and to adapt management and monitoring. Appropriate genetic counseling should then be provided for patient and family.

Familial primary hyperparathyroidism (PHPT) includes syndromic and non-syndromic disorders. The former are characterized by the occurrence of PHPT in association with extra-parathyroid manifestations and includes multiple endocrine neoplasia (MEN) types 1, 2, and 4 syndromes, and hyperparathyroidism-jaw tumor (HPT-JT). The latter consists of familial hypocalciuric hypercalcemia (FHH) types 1, 2 and 3, neonatal severe primary hyperparathyroidism (NSHPT), and familial isolated primary hyperparathyroidism (FIHP). The familial forms of PHPT show different levels of PHPT penetrance, developing earlier and with multiglandular involvement compared to sporadic counterpart. All these diseases exhibit Mendelian inheritance patterns, and for most of them, the genes responsible have been identified. DNA testing for predisposing mutations is helpful in index cases or in individuals with a high suspicion of the disease. Early recognition of hereditary disorders of PHPT is of great importance for the best clinical and surgical approach. Genetic testing is useful in routine clinical practice because it will also involve appropriate screening for extra-parathyroidal manifestations related to the syndrome as well as the identification of asymptomatic carriers of the mutation. The aim of the review is to discuss the current knowledge on the clinical and genetic profile of these disorders along with the importance of genetic testing in clinical practice.