Familial Primary Hyperparathyroidism Research Articles

Primary hyperparathyroidism in children and adolescents

Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. Awareness should improve in order to lower threshold for screening and allow intervention before serious and permanent sequelac occur. A retrospective analysis of 15 children and adolescents with PHPT (age <20 yr) seen in our clinic between 1993 and 2006. Mean age of patients was 17.73 yr (Range - 13-20, Male-3: Female-12). Average duration of symptoms was 18.87 (range: 0-48) mo. Clinical features at presentation included bone pain (86.67%), proximal myopathy (46.67%), bony deformities (53.33%), fractures (60%), palpable osteitis fibrosa cystica (33.3%), renal calculi (40%), palpable neck swelling (13.3%) and acute pancreatitis (6.67%). None had positive family history or features suggestive of multiple endocrine neoplasia (MEN). After biochemical confirmation, tumor was localised in all prior to surgery. Histopathology confirmed adenoma in all cases. Post-operative hungry bone syndrome occurred in 33.3%. PHPT is more common in females. Presentation of the disease is similar to their adult counterparts except for more severe bone disease and less severe renal disease. MEN and familial non-MEN PHPT do not constitute a major cause of pediatric PHPT as against to worldwide data. The incidence of hyperplasia as a cause of PHPT is rare in our pediatric population.

DNA‐based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes

Several cancer-related genes have been discovered and molecular test for the cancer genetic risk assessment has been widely increasing. Disorders such as Multiple Endocrine Neoplasia syndromes have received benefits from the identification of the responsible genes whose mutations account for the genetic susceptibility to develop endocrine tumours. Primary hyperparathyroidism (PHPT)is a clinical phenotype frequently associated to Multiple Endocrine Neoplasia syndromes, but it can also represent the unique endocrinopathy recurring as a familial cluster. In recent years, care options have been made available to patients and families with hereditary PHPT, and the process of systematically assessing the genetic risk has been becoming increasingly important. This review aims to help health providers not frequently dealing with genetic testing use and it will introduce some general concepts concerning genetic diagnosis issues. As an example the role and the practical usefulness of DNA-based diagnosis in patients affected by different forms of congenital PHPT is described, with a close look on why, when and how genetic testing should be performed in these subjects and their relatives. Some practical recommendations and suggestions concerning on how to deal when a suspect or known case of familial PHPT has to be faced conclude this manuscript.

Parathyroid hormone-dependent hypercalcemia

The past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

Bilateral Neck Exploration in Primary Hyperparathyroidism—When Is It Selected and How Is It Performed?

Although most patients with primary hyperparathyroidism (PHPT) are ideal candidates for minimally invasive parathyroidectomy, some will have more than one enlarged gland and require bilateral neck exploration to achieve biochemical cure. We evaluated the clinical evidence for when to choose bilateral neck exploration for patients with PHPT. We searched PubMed for English-language studies published from 1996 to 2008. The level of clinical evidence was determined according to the criteria proposed by Sackett (Chest 95[2 Suppl]:2S, 1989), and the grade of recommendation was established according to the criteria proposed by Heinrich et al. (Ann Surg 243:154, 2006). Level III-IV evidence shows that patients with multiple endocrine neoplasia (MEN) 1 and PHPT should have a bilateral neck exploration (grade C recommendation). Only level IV evidence indicates that patients with familial PHPT should do so (no recommendation). Although most patients with MEN 2A have single-gland disease, bilateral neck exploration is still indicated, because they will have either a therapeutic or prophylactic total thyroidectomy for medullary thyroid cancer. A history of head and neck irradiation is associated with PHPT, but the risk of multi-gland parathyroid disease is apparently no higher than in sporadic cases (level IV evidence, no recommendation). Previous or current lithium therapy confers a higher risk of multi-gland disease (25%-45%; level IV-V evidence), which may require bilateral neck exploration. Preoperative localizing studies reliably identify most patients with single-gland but not multi-gland disease (level II-IV evidence). Negative localizing studies confer an approximately 50% risk of multi-gland disease and indicate that bilateral neck exploration is necessary. If two localizing studies are concordant, few patients will require bilateral neck exploration (level IV, no recommendation). No level I or II evidence reliably identifies preoperative clinical risk factors for determining which patients should have routine bilateral neck exploration for multi-gland disease or for intraoperative decision making to convert to bilateral neck exploration. Imaging studies are positive in most patients (level II). No randomized studies exist to determine when a bilateral neck exploration is indicated based on clinical risk factors or imaging studies that may suggest multi-gland disease.

Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow‐up study on methods

Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented. To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards. Follow-up approach (direct design). We included 54 FHH patients (17 males and 37 females, aged 18-75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19-86 years). All PHPT patients became normocalcaemic following successful neck exploration. Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0.923 +/- 0.021 (SE)), than the 24-h calcium/creatinine excretion ratio (AUC = 0.903 +/- 0.027) and the 24-h calcium excretion (AUC = 0.876 +/- 0.029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut-off points. Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity of 0.80. Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients. Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis in patients with FHH or PHPT.

Plasma 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone in familial hypocalciuric hypercalcemia and primary hyperparathyroidism

Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign, inherited condition caused by inactivating mutations in the calcium-sensing receptor (CASR) gene. Both FHH and primary hyperparathyroidism (PHPT) are characterized by elevated P-calcium, normal or elevated plasma-parathyroid hormone (P-PTH), and typically normal renal function. In PHPT, vitamin D metabolism is typically characterized by low plasma levels of 25-hydroxyvitamin D (25OHD), and high plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). In FHH, the vitamin D metabolism is not very well known. To compare and evaluate plasma 25OHD, 1,25(OH)(2)D, and PTH in FHH and PHPT. Cross-sectional study. About 66 FHH patients with mutations in the CASR gene, 147 patients with surgically verified PHPT, and 46 controls matched to FHH patients according to age (+/-5 years), sex, and season. All patients had a P-creatinine <140 micromol/l. We measured P-calcium, P-Ca(2)(+), P-albumin, P-creatinine, P-phosphate, P-magnesium, and P-PTH by standard laboratory methods. P-25OHD and P-1,25(OH)(2)D were measured by RIA or enzyme immunoassay. In FHH, all protein-coding exons in the CASR gene were sequenced and aligned to GenBank reference sequence NM_000388.2. PHPT patients had higher body mass index (2p<0.01), together with higher P-PTH (2p<0.01) and P-1,25(OH)(2)D (2p<0.01) compared with FHH patients. The groups had similar levels of P-Ca(2)(+) and of P-25OHD. The phenotypic expression of the CASR mutations (as determined by the degree of hypercalcemia) did not influence the levels of P-1,25(OH)(2)D. Even though P-calcium and P-25OHD were comparable, P-1,25(OH)(2)D and P-PTH differed between FHH and PHPT.

Role for Limited Neck Exploration in Young Adults with Apparently Sporadic Primary Hyperparathyroidism

The risk of multiglandular disease (MGD) dictates the extent of exploration in patients with primary hyperparathyroidism (PHPT). Historically, young patients with PHPT were more likely to have MGD, but the existing literature is sparse and conflicting. We hypothesized that young adults (ages 16-40 years) without familial PHPT have a disease process similar to that in older patients. A 22-year retrospective chart review was performed on patients who underwent neck exploration for PHPT at our tertiary care center. Altogether, 708 charts were reviewed for demographics, family history, laboratory values, operative findings, pathology, and outcomes. As a group, young adults comprised 14.0% of the total population and were more likely to have preexisting familial disorders of PHPT (p < 0.01), therapeutic failure (p < 0.01), failure to identify an abnormal parathyroid at operation (p < 0.01), and higher reoperative rates (p = 0.02); they were less likely to have single-gland disease (p = 0.04). Young adults without a family history of the disease demonstrated no disease differences except for a higher rate of symptoms (p < 0.01). Additional analysis found that patients with a family history of hypercalcemia, a sole family member with PHPT, or nephrolithiasis ("possible" family history) were more likely to have MGD (relative risk 2.0). In this largest single-institution study of young adults with sporadic PHPT, we conclude that sporadic PHPT in young adults represents a disease entity similar to that in older patients, with no increased risk for MGD, and hence they can be managed with a similar surgical approach. Further studies are needed to assess the role of a "possible" family history as a risk factor for MGD.

Genotype and phenotype correlation of calcium-sensing receptor variants

Mutations of the calcium-sensing receptor (CaR) gene give rise to disorders of renal calcium excretion. It is now demonstrated that even common variants of CaR can cause alteration in tissue sensitivity to extracellular calcium and are associated with primary hypercalciuria. Agents targeting these functional domains may well be an option for the management of hypercalciuria and renal stones.

Rapid Mutation Screening for HRPT2 and MEN1 Mutations Associated with Familial and Sporadic Primary Hyperparathyroidism

Familial hyperparathyroidism, a disease of the parathyroid glands, may occur in conjunction with pituitary and pancreatic tumors (multiple endocrine neoplasia type I), kidney and bone tumors (hyperparathyroidism jaw tumor syndrome), or alone (familial isolated hyperparathyroidism). This study describes the development and validation of rapid scanning for mutations in two tumor suppressor genes linked to familial hyperparathyroidism-MEN1 and HRPT2. Denaturing high-performance liquid chromatography mutation scanning for MEN1 was performed using a set of 10 amplicons covering the nine coding exons and flanking intronic regions and for HRPT2 using a set of three amplicons for exons 1, 2, and 7 and flanking intronic regions, in which 80% of the mutations identified to date are located. All 52 MEN1 mutations or polymorphisms, 46 known and six unknown, were successfully detected. Mutation detection in exon 9 was not confounded by the presence of the common polymorphism D418D. In addition, all 10 HRPT2 mutations were successfully detected, and a two-step approach was able to distinguish IVS2 common polymorphisms from exon 2 mutations. The development of rapid denaturing high performance liquid chromatography mutation scanning of MEN1 and HRPT2 facilitates a molecular diagnosis of the associated familial syndromes for both clinically affected and at-risk family members.

Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management

Familial isolated primary hyperparathyroidism (FIPH) can result from either incomplete expression of a syndromic form of familial primary hyperparathyroidism [multiple endocrine neoplasia type 1 (MEN 1), hyperparathyroidism-jaw tumour syndrome (HPT-JT) or familial hypocalciuric hypercalcaemia (FHH)] or still unrecognized causes. Design Genetic analyses of MEN1, HRPT2 and CASR genes in FIHP. Seven well-characterized Italian kindreds with FIHP, with negative clinical features for MEN 1, HPT-JT and FHH. The mean age (+/- SD) at diagnosis was 45 +/- 17 years (range 18-70 years) in the probands and 42 +/- 18 years (range 15-69 years) in the other affected subjects. Direct sequencing of germline DNA of the MEN1, HRPT2 and CASR genes from probands. The region of interest was amplified in some family members. Germline MEN1 mutations were detected in three kindreds. Multiglandular involvement was found in all but one affected subject belonging to the three kindreds with MEN1 mutations. In these patients persistence/relapse of the disease was observed unless an extensive parathyroidectomy (excision of 3(1)/(2) glands) had been performed, with the exception of one patient, who is currently normocalcaemic 168 months after excision of two glands. No mutations of MEN1, HRPT2 and CASR genes were identified in the remaining four families. MEN1 genotyping appears worthwhile in FIHP families, as the finding of mutation(s) may predict multiglandular involvement and therefore have practical surgical implications, and prompt further investigation in the family, with the possibility of identifying new cases and beginning a programme of periodic surveillance for emergence of tumours in all carriers.

Familial parathyroid hyperplasia: Is there a place for minimally invasive surgery? Description of the first treated case

While the majority of patients affected with sporadic primary hyperparathyroidism (sPHPT) can be selected for minimal access surgery, patients affected with 4-gland hyperplasia still do not represent an indication for it. Minimally invasive video-assisted parathyroidectomy (MIVAP) was introduced in 1996; this technique relies on a single central incision and external retraction and therefore allows a bilateral neck exploration. This was the case of a 27-yr-old female with familial primary hyperparathyroidism (FPHPT). Three enlarged glands were immediately identified in orthotopic positions and the fourth was intrathyroideal. A subtotal parathyroidectomy was then performed, leaving a small fragment of the inferior right gland and completed with the cervical thymectomy by inverting the positions of the camera and the retractor assistants with regard to the positions originally described. Quick intraoperative PTH assay (QPTH) confirmed the surgical cure of the disease.

Diseases associated with the extracellular calcium-sensing receptor

The human calcium-sensing receptor (CaSR) is a 1078 amino acid cell surface protein, which is predominantly expressed in the parathyroids and kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q21.1 and loss-of-function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FHH, FBH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT). However, some individuals with loss-of-function CaSR mutations remain normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and this is referred to as FHH type 1. However, in one family, the causative gene for FHH is located on 19p13, referred to as FHH type 2, and in another family it is located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have been shown to result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter’s syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations, and in patients with an acquired form (i.e. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with three hypercalcaemic and three hypocalcaemic disorders.

Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism.

A large number of families with familial isolated hyperparathyroidism (FIHP) have been reported. We wanted to determine if some of these families represent early manifestations of full-blown syndromes such as multiple endocrine neoplasia type 1 (MEN-1), as early identification may alter surgical and medical management. Four small families with a family history of hyperparathyroidism without clear-cut MEN-1 features were screened for a MEN1 mutation. The 10 exons of the MEN1 gene were amplified and analyzed by single-strand conformation analysis (SSCA). Abnormal SSCA shifts were then sequenced using an automated sequencer. Two germline mutations were found: R527X and P277H. The former was detected in three members of a family consisting of two children and a mother. At the time of testing the youngest son was normocalcemic and clinically normal but subsequently developed hyperparathyroidism (HPT). Since the initial testing, the family has been confirmed to be a MEN-1 family as the mother has developed abdominal pain and an elevated serum pancreatic polypeptide and the younger brother an anterior pituitary tumor and recurrent HPT. The latter P277H mutation was identified in two of three members tested from another family. Manifestations of MEN-1 syndrome have also developed. The father now has developed diarrhea and elevated serum gastrin; and the daughter has developed recurrent HPT. Genetic screening of families who clinically have FIHP is important and may influence the type of medical and surgical treatment and follow-up, as some have MEN-1 syndrome. Long-term screening for MEN syndromes should be included in this set of patients. Positive screening may predict disease and allow early detection and appropriate treatment before initiation of symptoms.

Parathyroidectomy in familial hypercalcemia with clinical characteristics of primary hyperparathyroidism and familial hypocalciuric hypercalcemia

Background. Familial primary hyperparathyroidism is associated with tumor-susceptibility syndromes, which are unrelated to mutations in the calcium receptor gene. This study describes parathyroidectomy in a kindred with hypercalcemia due to a heterozygous point mutation in the calcium receptor gene. Methods. Seventeen family members were studied, and postoperative follow-up averaged 5.1 years. Results. Radical parathyroid resection with total parathyroid remnants of 10 to 20 mg or total parathyroidectomy with autotransplantation normalized the serum calcium and parathyroid hormone values in 12 family members. Persistent hypercalcemia was noted in 3 of 5 patients subjected to less radical procedures. Diffuse to nodular hyperplasia and microscopic findings, interpreted incorrectly as a single adenoma, were found. Weight of the parathyroid tissue increased with the age of the patients (P <.05), and almost one third of them (29%) had 1 to 3 atypically located glands. There were no patients with recurrent hypercalcemia during follow-up. Conclusions. The heterozygous inactivating mutation of the calcium receptor gene of this family is accompanied by mild increases in parathyroid gland × weight and diffuse parathyroid hyperplasia with possibly secondary genetic events causing nodule formation. Radical parathyroid resection is advocated in this hypercalcemic disorder, which may represent an intermediary stage between primary hyperparathyroidism and familial hypocalciuric hypercalcemia. (Surgery 2002;131:257-63.)

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region.

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

Clinical review 109: Contrasting paradigms for hereditary hyperfunction of endocrine cells.

Hereditary endocrine hyperfunction is categorized here as neoplastic or not neoplastic. The disorders and their mutated genes are subdivided further by hyperfunctional hormone secretory tissue (Table 1). For example, the parathyroids hyperfunction in at least three hereditary neoplastic syndromes [multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2a (MEN2a), and hyperparathyroidism-jaw tumor syndrome (HPT-JT)], each associated with one distinct gene (1, 2) or locus (3–5). Alternately, the parathyroids can be overactive in two hereditary non-neoplastic syndromes–familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSHPT). Either is usually caused by mutations of the CaSR gene (6–9); two other undiscovered genes account for FHH in a few families (10, 11). A similar classification dichotomy applies to hereditary hyperfunction of pancreatic islet b cells (1, 12–17), of thyrocytes (18–23), or of Leydig cells (19, 24–26) (Table 1). For didactic purposes, this analysis omits endocrine tissue without separate hereditary disorders in each of the two categories. For example, hereditary pheochromocytoma may arise from neoplasia with germline mutation of VHL (12), RET (2), or NF1, but apparently not from non-neoplastic processes. This analysis also excludes dysfunctions outside the hyperfunctional endocrine tissue (for example, hereditary hyperandrogenism can be caused by activation of the CRF/ACTH axis secondary to defective cortisol synthesis).

Minimally invasive videoscopic parathyroidectomy by lateral approach.

A videoscopic parathyroidectomy was performed in 22 patients presenting with primary hyperparathyroidism (PHPT). No patient had undergone previous neck surgery, presented with goiter or had a history of familial PHPT. Ultrasonography and Sestamibi scanning were performed preoperatively. Rapid intact parathormone assay was used during surgery. Through a 15-mm transversal skin incision on the anterior border of the sternocleidomastoid muscle (SCM), the fascia connecting the lateral portion of the strap muscles and the thyroid lobe with the carotid sheath was gently divided, far enough to visualize the prevertebral fascia. Once enough space was created, three trocars were inserted: a 12-mm trocar through the incision and two 2.5-mm trocars on the line of the anterior border of the SCM, above and below the first trocar. Carbon dioxide was insufflated to 8 mmHg. Unilateral video-assisted parathyroid exploration was then carried out using a 10-mm O(o) endoscope. Once the adenoma had been identified, the trocars were removed. Then, directly through the skin incision, the thyroid lobe was retracted medially and the adenoma was extracted after clipping its pedicle. Among the 23 enlarged glands, 20 (80%) were correctly identified by endoscopic exploration: mean weight 843 mg (100 mg to 5 g). The exploration was unilateral in 17 patients but bilateral in 5. Mean time of unilateral endoscopic exploration was 84 min (40-130 min). Morbidity was represented by two superficial hematomas. All 22 patients were biochemically cured, follow-up ranging from 3 months to 14 months. This preliminary study demonstrates that minimally invasive videoscopic parathyroidectomy by lateral approach is a feasible surgical procedure.

Disorders of the calcium-sensing receptor

The human calcium-sensing receptor (CaSR) is a 1078-amino-acid cell surface protein which is expressed in the parathyroids, thyroid cells and the kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q13.3–q21, and loss of function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). In addition, gain of function CaSR mutations have been observed in a novel familial syndrome of hypocalcaemia with hypercalciuria. The human CaSR gene on chromosome 3q13.3–q21 is likely to be one of several, as two other loci for FBH have been located on chromosome 19p and 19q13. Cloning and characterisation of these genes will help to further elucidate the mechanisms regulating extracellular calcium.

Germline mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in a family with primary hyperparathyroidism.

Familial primary hyperparathyroidism (FHP) is a rare hereditary disorder characterized by isolated parathyroid tumors without any other lesions related to multiple endocrine neoplasia (MEN). Primary hyperparathyroidism is usually expressed at an early age and is highly penetrated in MEN type 1 (MEN1), suggesting that some FHP may be a variant type or early stage of MEN1. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We studied a Japanese family with primary hyperparathyroidism which included 4 patients. To investigate the possible relationship between primary hyperparathyroidism in this family and the MEN1 gene, we analyzed a proband for a germline mutation of the MEN1 gene in this study. We identified a novel heterozygous mutation (1350del3) at codon 414 in exon 9. Restriction digestion analysis revealed the same mutation pattern in his brother with hyperparathyroidism. These findings suggest that our patients may belong to a variant type of MEN1.

FAMILIAL PRIMARY HYPERPARATHYROIDISM

We experienced a family consisting of three members with familial primary hyperparathyroidism without other endocrinal tumors. Case-1: A 48-year-old woman, who had been followed at our outpatient clinic after an operation for a breast cancer, was accidentally pointed out hypercalcemia. She was diagnosed as hyperparathyroidism, and was operated on. The pathological diagnosis was hyperplasia. Case-2: A 63-year-old woman, the aunt of case-1 patient, had been suffering from attack of renal stone several times. She was diagnosed as hyperparathyroidism, and was also operated on. The pathological diagnosis was two adenomas of the parathyroid glands. The patient experienced a recurrence of hypercalcemia 12 years after the operation. Case-3: The patient was a 38-year-old woman, the sister of case-1 patient. A familial disease was suspected, and serum calcium levels of the family members were measured. The value of this patient was above the normal range. Ulrasonography of the neck revealed a tumor lesion, which appeared like a parathyroid gland. The patient was diagnosed as early stage of hyperparathyroidism. We conclude that familial primary hyparparathyroidism is an incomplete type of multiple endocrine neoplasia. Its pathological type and the policy of operation are discussed.