Familial states of primary hyperparathyroidism: an update.

BACKGROUND: 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. PURPOSE: 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.

Genetics of monogenic disorders of calcium and bone metabolism.

Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%-10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium-related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.

Molecular genetics in primary hyperparathyroidism: the role of genetic tests in differential diagnosis, disease prevention strategy, and therapeutic planning. A 2017 update.

Primary hyperparathyroidism (PHPT) is one of the most frequent endocrine disease in developed countries. It mainly occurs as sporadic cases (about 90-95% of cases), while only the remaining 5-10% is represented by familial inherited parathyroid disorders due to causative mutations in specific target genes. Clinical variability among the different familial parathyroid syndromes is generally linked to the specific mutated gene and it can predispose subjects to different manifestations of parathyroid pathology, various degrees of PHPT severity, persistence and/or after-surgery recurrences. Genetic tests is helpful in differential diagnosis favouring the recognition of the specific familial PHPT syndrome and, subsequently, in planning the most suitable surgical procedures and/or pharmacological interventions. Moreover, genetic test is important to recognise mutation carriers, within PHPT familial forms, even before the appearance of biochemical and/or clinical symptoms. This review resumes general concepts about genetic diagnosis of PHPT in familial hereditary syndromes, specifically describing why, when, and which genetic screenings should be performed in every specific PHPT-associated parathyroid disease.

Hereditary Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a commonly encountered clinical problem and occurs as part of an inherited disorder in ∼10% of patients. Several features may alert the clinician to the possibility of a hereditary PHPT disorder (eg, young age of disease onset) whilst establishing any relevant family history is essential to the clinical evaluation and will help inform the diagnosis. Genetic testing should be offered to patients at risk of a hereditary PHPT disorder, as this may improve management and allow the identification and investigation of other family members who may also be at risk of disease.

Clinical profile of juvenile primary hyperparathyroidism: a prospective study.

INTRODUCTION: Juvenile primary hyperparathyroidism is uncommon and more symptomatic than the adult counterpart. The aim of this prospective monocentric study, conducted in a tertiary referral center, was to evaluate the clinical, biochemical, and densitometric data, and the outcome of a series of patients with juvenile primary hyperparathyroidism. MATERIAL AND METHODS: The study group included 154 patients with sporadic and familial juvenile primary hyperparathyroidism, aged ≤40 years. Relative frequency of sporadic and familial forms, comparison of the clinical and biochemical characteristics, rate of cure after parathyroidectomy and the outcome of patients not undergoing surgery were evaluated. RESULTS: Familial cases (n = 42) were younger, less frequently females, and had milder disease compared to sporadic cases (n = 112). No difference was observed in biochemical and densitometric parameters. Among patients undergoing parathyroidectomy (n = 116), familial cases had a higher rate of multigland disease and a higher persistence/relapse rate compared to sporadic cases (73 vs. 3.6% and 48.1 vs. 5.7%, respectively). Patients who did not undergo parathyroidectomy had stable clinical, biochemical, and densitometric parameters during follow-up (median 27 months). Using the cut-off age of 25 years, there was no difference in clinical, biochemical and densitometric parameters between younger and older patients, with the exception of parathyroid hormone and phosphate, which were significantly lower and higher, respectively, in patients <25 years. CONCLUSIONS: In conclusion, this prospective study shows that juvenile primary hyperparathyroidism is frequently a sporadic disease, with no difference in the biochemical phenotype between sporadic and familial forms. Patients with familial juvenile primary hyperparathyroidism have a milder clinical phenotype and higher rate of persistence/recurrence after PTx than those with sporadic juvenile primary hyperparathyroidism.

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach? / Formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2: estudos moleculares poderiam direcionar procedimentos cirúrgicos?

It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafibromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafibromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75 percent), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotype-genotype correlation in larger series, to best define their treatment.

A melhor conduta nas formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2 ainda é controvertida. Cirurgias conservadoras, minimamente invasivas ou mais agressivas já foram propostas por diferentes grupos. Objetivamos estudar a seqüência e a expressão do gene HRPT2, além do desfecho clínico, após seguimento de até 32 anos de uma família brasileira com hiperparatireodismo familiar isolado (FIHP). Utilizamos dados clínicos e bioquímicos, seqüenciamento direto do HRPT2 além de análise da expressão da parafibromina através da RT-PCR e imunohistoquímica. Foi identificada mutação nonsense no éxon 1 (c.96G>A)(p.Trp32X) em todos os membros afetados que foram estudados. A análise do mRNA transcrito, através da RT-PCR, demonstrou ausência do transcrito no tecido tumoral. A imunohistoquímica também evidenciou ausência da parafibromina. Nessa família houve alta (75 por cento) prevalência de recorrência ou persistência da doença após paratireoidectomia parcial o que nos levou a considerar fundamental discutir uma abordagem cirúrgica mais agressiva com os outros familiares portadores da mutação caso critérios de indicação cirúrgica sejam atingidos. Dessa maneira, até que estudos mais amplos estabeleçam uma correlação genótipo-fenótipo no hiperparatireoidismo familiar relacionado a mutações no HRPT2, a abordagem cirúrgica deverá ser individualizada.