Familial hypocalciuric hypercalcaemia: a study of four kindreds

Four kindreds with hereditary hypercalcaemia have been investigated. Thirty-seven of 72 subjects examined had hypercalcaemia with an autosomal dominant pattern of inheritance. Hypercalcaemic patients had total serum calcium of 2.91 +/- 0.12 mmol l-1. Serum parathyroid hormone (PTH) was normal while daily urinary calcium excretion was subnormal (below 2.5 mmol) in 45%. Comparison with an age-matched group of patients with primary hyperparathyroidism gave a small overlap regarding serum human PTH, urinary calcium and the ratio between calcium clearance and creatinine clearance. Family screening therefore is of diagnostic importance. Twelve subjects had been subjected to parathyroid surgery before the correct diagnosis was settled, none of the cases had an adenoma. Three patients became normocalcaemic and the others had persistent hypercalcaemia. One male non-abuser had seven episodes of acute pancreatitis before surgery and none after. The findings in all four kindreds are compatible with familial hypocalciuric hypercalcaemia (FHH). This hereditary disorder of unknown aetiology, therefore, also exists in Scandinavia. It is of importance to consider FHH in the differential diagnosis of hypercalcaemia, since this disorder usually has a benign prognosis if untreated.     

Familial embryonal carcinoma in a cancer-prone kindred

Familial testicular cancer is rare. This report describes a family with an unusual cancer spectrum that included the infantile form of embryonal carcinoma of the testis in the son of a cancer-free but putative obligate gene carrier mother, and the adult form of embryonal carcinoma in this women's maternal half-brother (their mutual mother had malignant melanoma and urinary bladder carcinoma). Hereditary syndrome designation remains elusive. Priority attention to biomarker research in families of this type for elucidation of cause and control is discussed.     

Familial dysalbuminemic hypertriiodothyroninemia in a Japanese kindred

A 56-year-old Japanese housewife had been diagnosed as having Graves' disease and was treated with methimazole. When she was referred to our hospital, the serum T3 level was high irrespective of high TSH level. High serum T3 levels were also observed in two out of her three sisters. Electrophoresis revealed that binding of 125I-T3 to serum albumin was markedly increased whereas the binding of 125I-T4 to serum albumin was slightly increased in the three sisters whose serum T3 levels were high. These data indicate that the presence of an albumin variant is the cause of hypertriiodothyroninemia in this family.     

Familial combined hyperlipidemia and otosclerosis--the occurrence in a large kindred

The occurrence of otosclerosis and hyperlipidemia in four generations of a single family is described. The lipid abnormality fulfilled the characteristics of combined familial hyperlipidemia. Whereas a genetic linkage between combined hyperlipidemia and otosclerosis is feasible, our study indicates that both conditions are inherited through autosomal but unlinked genes.     

Familial hypocalciuric hypercalcaemia and pancreatitis: no causal link proven

A case of a patient with pancreatitis and familial hypocalciuric hypercalcaemia is presented and the literature linking FHH and pancreatitis is reviewed. The case for a causal link between the two conditions is not proven and seems unlikely. In view of this we strongly challenge the recommendation of total parathyroidectomy in such cases.     

Familial dilated cardiomyopathy: echocardiographic diagnostic criteria for classification of family members as affected.

BACKGROUND: Echocardiographic criteria for left ventricular enlargement (LVE) used to classify subjects as affected in families with familial dilated cardiomyopathy (FDC) have been inconsistent. A recent report from a large Framingham echocardiographic study provides an opportunity to improve the assignment of LVE and FDC in kindreds, principally with a dilated phenotype. The objective of this study is to evaluate an alternative diagnostic criteria for FDC based only on LVE with no measure of fractional shortening (FS). METHODS AND RESULTS: We compared our proposed criteria for LVE and FDC with previous approaches by applying them to 166 adults derived from three large FDC pedigrees. Our proposed FDC diagnostic criteria are a sex- and height-specific method based only on LVE, without regard for FS, set as a 97.5% upper limit for left ventricular end-diastolic dimension (LVEDD) from the Framingham study. Other methods used to assign LVE were (1) a 95% upper limit for LVEDD by the Framingham study; (2) the method of Henry et al. (1980) based on age and body surface area (BSA); and (3) the National Heart, Lung, and Blood Institute (NHLBI) method with a cut point of LVEDD greater than 2.7 cm/BSA. Three other commonly used diagnostic criteria for FDC were based on various LVE standards combined with an FS of 27% to 30%. For LVE, the Framingham-97.5% was the most stringent (21 of 134 subjects identified; 15.7%), the NHLBI standard the least stringent (57 of 161 subjects identified; 35.4%), and the Henry-112% method intermediate (44 of 161 subjects identified; 27.3%). More women were identified with the Framingham method (57.1%) versus the Henry-112% (40.9%). The Henry-112% and NHLBI methods identified 11.4% and 7.0% of subjects with body mass indices (BMIs) of 35 or greater, respectively. For FDC, our proposed FDC diagnostic criteria identified similar numbers of subjects (21 subjects) as the three other criteria (range, 22 to 27 subjects), but inconsistency was noted (54.2% to 66.7%), with kappa values from 0.49 to 0.55 resulting from different sensitivities to sex, LVE, FS, and BMI. CONCLUSION: Our proposed FDC diagnostic criteria are stringent to assign FDC family members as affected compared with other commonly used criteria. The use of LVEDD alone may be preferable for FDC family screening, although further validation of this approach with phenotypic and genotypic data from other large FDC pedigrees is needed.     

An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor

Inactivating mutations in the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcaemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Earlier investigations showed patients with FHH are heterozygous, and NSHPT are homozygous for inactivating mutations. However, one adult patient with severe hypercalcaemia and hypocalciuria has been reported to have a homozygous inactivating mutation in CaSR (Pro39Ala). This suggested that mutant CaSR in this patient had some residual activity and hypercalcaemia was not so severe as to be fatal. However, the function of this mutant CaSR was not evaluated. In the present study, we describe a novel homozygous mutation in an adult patient with severe hypercalcaemia and hypocalciuria, and evaluate the function of the mutant CaSRs. The DNA sequence of CaSR gene was determined by direct sequencing of the polymerase chain reaction product. The function of mutant CaSR was analysed by creating mutant cDNAs by in vitro mutagenesis, transfection of mutant cDNAs into HEK293 cells and measuring intracellular ionized Ca in response to changes in extracellular Ca. A 26-year-old Japanese woman showed marked hypercalcaemia with an elevated parathyroid hormone (PTH) level. Her consanguineous parents had asymptomatic hypercalcaemia with relative hypocalciuria. The proband had a homozygous mutation at codon 27 of CaSR gene (CAA-->CGA, Gln27Arg). Her parents were heterozygous for this mutation. EC50 for Ca of this mutant CaSR (GIn27Arg) was 4.9 mM. EC50 of another mutant CaSR (Pro39Ala) whose homozygous mutation was discovered in an adult patient was 4.4 mM. These EC50s were significantly higher than that of wild-type CaSR (3.7} 0.1 mM), but were the lowest among the reported EC50s for inactivating mutations of CaSR. These results indicate that serum Ca and PTH levels are determined by residual function of mutant CaSR in patients with homozygous mutation in CaSR, and that patients having homozygous mutant CaSRs with mild dysfunction do not suffer from fatal hypercalcaemia in infancy and can survive into adulthood.     

Preliminary report of a kindred affected from MEN IIa

Preliminary data of a kindred with multiple endocrine neoplasia type IIa (MEN IIa) are presented. The study concerns 20 subjects belonging to 4 generations. The first is a man, previously adrenalectomized for pheochromocytoma, suffering from thyroid node with high serum calcitonin (CT) and normal tests for parathyroid function, who underwent total thyroidectomy, removal of a grossly enlarged parathyroid and subsequent autotransplantation, because the other glands seemed to be macroscopically uninvolved. In 4 further patients total thyroidectomy and removal of the parathyroid glands with autotransplantation were performed. In all patients, despite biochemical tests had disclosed parathyroid hyperfunction in only one, one or more enlarged parathyroid glands were found, subsequently diagnosed as adenomatous or with focal areas of "chief-cell" hyperplasia. In 3 out of 4 patients, a single test among those performed to detect the presence of a pheochromocytoma was positive. However, because of the lack of a clear correlation among data from biochemistry, stimulation tests and morphological investigations, adrenalectomy has not been performed. Nevertheless these patients will be closely followed up, in order to promptly state when andrenalectomy has to be performed.     

von Hippel-Lindau disease affecting 43 members of a single kindred

We present a 6-generation kindred of over 221 members, 43 of whom were affected with von Hippel-Lindau (vHL) disease. Through a simple screening protocol, we diagnosed vHL retrospectively in 15 cases, and for the first time in 28, 11 of whom were presymptomatic. We found many complications of vHL in previously diagnosed relatives and in new cases. This study has demonstrated the utility and benefit of preventive surveillance in those known to have vHL, and of presymptomatic screening for affected relatives in families with vHL. The features of vHL were reviewed in our 43 cases and 511 cases from the medical literature. The patterns, frequencies, and ages of onset for each lesion were compared. Renal malignancies caused almost as much mortality in vHL as CNS malignancies. This family was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for slightly fewer eye or CNS lesions. Bilateral renal adenocarcinomata were found presymptomatically in five young subjects, who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five relatives had pancreatic malignancies, which are definite although uncommon manifestations of vHL. Recommendations are made for family screening, which was economical and effective. Bayesian calculations help to predict risks for genetic counseling. The molecular basis of vHL may soon be found, since it has been linked to DNA markers on the short arm of chromosome 3.     

SLC34A3 intronic deletion in a new kindred with hereditary hypophosphatemic rickets with hypercalciuria

Objective: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form of hypophosphatemia with hyperphosphaturia, hypercalciuria, and hypercalcemia. In two reports on six affected kindreds with HHRH, the disease was mapped to chromosome 9q34, which contains the SLC34A3 gene that encodes the renal type 2c sodium-phosphate cotransporter. Our objective was to define the clinical course of these cases in a family with HHRH and to screen for SLC34A3 gene in order to determine whether these mutations are responsible for HHRH.Methods: After clinical and biochemical evaluations, the entire SLC34A3 gene was screened using PCR amplification followed by direct sequencing technique. In this paper, we describe a new kindred with HHRH and a case of progressive and complicated HHRH presenting at age 27 years.Results: We found 101-bp deletion in intron 9 of the SLC34A3 gene. The index patient was homozygous for this mutation which has been previously reported in a Caucasian population. This is the first report for presence of SLC34A3 intron 9 deletion in an Iranian population.Conclusions: These data showed that HHRH can be easily missed or underdiagnosed. Genetic evaluation of patients with familial hypercalciuria, hypophosphatemia and nephrolithiasis is needed for further information on the prevalence and management of this rare disorder. Conflict of interest:None declared.     

Familial hypocalciuric hypercalcaemia: observations on vitamin D metabolism and parathyroid function

Serum vitamin D metabolites, the renal tubular maximum reabsorptive rate for phosphate (TMP/GFR) nephrogenic cyclic AMP (NcAMPI, and CaE (urinary calcium excretion per litre of glomerular filtrate) were measured in 14 adults with familial hypocalciuric hypercalcaemia (FHH). The findings were compared with analyses in 14 patients with surgically proven primary hyperparathyroidism matched for serum calcium, creatinine clearance and vitamin D status (assessed by serum concentrations of 25 hydroxyvitamin D). Vitamin D metabolites were also measured in 16 normocalcaemic relatives of patients with FHH. The serum concentration of 24,25 dihydroxycholecalciferol was appropriate for the prevailing 25 hydroxyvitamin D and no difference was found between groups. The serum concentration of 1,25 dihydroxycholecalciferol was significantly greater in primary hyperparathyroidism (P less than 0.0005) compared with patients with FHH and their normocalcaemic relatives. TMP/GFR was reduced in both primary hyperparathyroidism (0.53 +/- 0.12 mmol/l GF, mean +/- SEM) and FHH (0.86 +/- 0.14 mmol/l GF). Patients with primary hyperparathyroidism showed an increase in NcAMP output in the urine (38.5 +/- 16 mmol/l GF) which was significantly greater (P less than 0.0001) than the normal NcAMP (13.5 +/- 9.2 nmol/l GF) found in FHH. CaE was low in FHH indicating increased renal tubular reabsorption of calcium. It is concluded that there is no abnormality of vitamin D metabolism in FHH comparable with the changes observed in primary hyperparathyroidism. It is suggested that the biochemical abnormalities in FHH cannot be explained solely upon an increased sensitivity of the renal tubules to the effects of endogenous parathyroid hormone.     

Familial abnormalities of lymphocyte function in a large Sj?gren's syndrome kindred

A large kindred (32 members), whose proband had primary Sj?gren's syndrome, was investigated to ascertain whether abnormalities of lymphocyte function were present in family members of patients with Sj?gren's syndrome. Ten members of the kindred with autoimmune diseases, 17 blood relatives, 5 spouses, and 32 matched controls were studied. Concanavalin A induced suppression of pokeweed mitogen stimulated immunoglobulin synthesis was decreased in patients and blood relatives both with and without autoimmune diseases. Elevations of the mean T4/T8 ratio, due to decreased numbers of suppressor/cytotoxic lymphocytes, were present in both the disease group and the blood relatives. These abnormalities occurred independently of HLA and were not necessarily associated with autoantibodies.     

Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred

The disease phenotype of transthyretin (TTR) is dramatically influenced by single point mutations in the TTR gene. Herein, we report on a novel mutation D99N (Asp99Asn) in TTR found in a Danish kindred. None of the family members carrying this mutation have so far shown any clinical signs of amyloidosis. One carrier found compound heterozygous for TTR D99N and L111M (Leu111Met) associated with cardiac amyloid is asymptomatic (42 years). Disease severity can often be linked to both the kinetics of fibril formation and the degree of destabilisation of the native state. In this study, we show that the thermodynamic stability and rate of tetramer dissociation of the variant TTR D99N is unchanged or slightly more stable than wild type (WT) TTR. Furthermore, the in vitro fibrillation kinetics of the variant reveals an unchanged or slightly suppressed tendency to form fibrils compared to WT. Thus, the in vitro experiments support the lack of clinical symptoms observed so far for the TTR D99N carriers. In line with this, studies on kinetic stability and fibrillation kinetics reveal indistinguishable stability of TTR heterotetramers D99N/L111M compared to the heterotetramers WT/L111M. In conclusion, TTR D99N is predicted to be a non-pathogenic benign mutation with WT properties.     

Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.     

Some genetic aspects of familial multiple polyposis of the colon in a kindred of 1,422 members

Summary Genetic analysis of the kindred in this presentation indicates that the polyposis gene was transmitted as a simple mendelian dominant trait. The data showed no significant deviation from the hypothesis that the sexes are equally affected in polyposis; however, affected fathers produced a slight excess of affected sons, while affected mothers produced a marked excess of affected daughters which approached the P 0.05 level of significance. The incidence at birth of individuals with the polyposis gene was one in 6,850 for this Kentucky survey. Individuals possessing the polyposis gene had a relative biologic fitness of 84.85 per cent when compared with the general population. The penetrance of the polyposis gene in the kindred at the time of the investigation was 49.43 per cent. The mutation rate for the polyposis locus was 12 mutations per million loci per generation. Possible sources of error and bias entering into the above calculations have been discussed. Adapted from Ph.D. dissertation submitted to University of Louisville. This work was supported by a grant from the American Cancer Society and a National Science Foundation Fellowship Award.