Familial Hypoparathyroidism Research Articles

6408 Familial Hypoparathyroidism With Elevated Parathyroid Hormone Due To A PTH Mutation Responsive To Teriparatide

Abstract Disclosure: N. Mukhtar: None. B. Alghamdi: None. M. Alswailem: None. A.S. Alzahrani: None. Introduction: Apart from vitamin D disorders, causes of congenital hypocalcemia (HypoCa) include genetic defects causing familial hypoparathyroidism (FH), and defects in PTH receptor or its signalling pathway (PTH resistance). The former is typically characterized by low plasma PTH and the latter by elevated PTH levels. In this report, we describe a family with FH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic impact of recombinant human PTH (teriparatide) therapy on HypoCa in one of these siblings who was not well controlled on calcitriol and calcium replacement. Case description: The proband is a 34-year-old lady who has history of chronic HypoCa since birth with several admissions for severe HypoCa and recurrent seizures during childhood. She and her three brothers (a 32-year-old male twin and an 18-year-old male) were diagnosed to have Pseudohypoparathyroidism type 1b based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Laboratory workup of the proband recently showed: PTH 514 ng/L (NR 15-65) , calcium 1.81 mmol/l (NR 2.1-2.6), phosphate 1.67mmol/L (NR 0.8-1.4), magnesium 0.73 mmol/L (NR 0.7-1.0), albumin 38 g/L (NR 40-50), Alkaline phosphatase 56 U/L, eGFR >60 ml/min/1.73 m2, creatinine 78 umol/L and 25-hydroxyvitamin D 77 nmol/l (NR 50-120). Daily excretion of calcium was normal at 3.38 mmol and an ultrasound of the kidneys suggest nephrocalcinosis. Skeletal X-rays and bone mass densitometry were normal. Molecular studies: WES showed no potentially pathogenic variants in GNAS, PTHR, CASR, VDR, and CYP27B1 but a previously reported homozygous variant in the PTH, exon 3 (NM_000315.4: c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and two of her brothers. This variant was assessed to be likely pathogenic or likely damaging by several in silico analysis tools including Polyphen2, MutPred, PROVEAN, DEOGEN2 and VUS by ACMG, SIFT, Mutation Assessor and FATHMM. Management: Because the patient’s HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily resulted in normalization of calcium and PTH levels. The patient reported significant improvement in her general wellbeing with loss of numbness, tingling, muscle spasms and tetany of the fingers. She has been on teriparatide for the last year with excellent improvement in her quality-of-life Conclusion: High PTH in the presence of congenital hypoCa is not always due to receptor or post-receptor defect and can be due to a mutated biologically inactive PTH. In such cases, treatment with Teriparatide may result in stabilization of biochemical profile and improve quality of life. Presentation: 6/2/2024

7331 A Rare Case Of Familial Hypoparathyroidism

Abstract Disclosure: N. Sekhon: None. K.Z. Win: None. Background: Autosomal dominant hypoparathyroidism disorders are very rare and mostly asymptomatic. We present an interesting case of autosomal hypoparathyroidism with a new variant of gene defect on genetic analysis. Case: A 66-year-old female was referred to the endocrinology clinic for familial hypoparathyroidism and calcium oxalate nephrolithiasis. She had onset of seizures at age 16. She was diagnosed with hypocalcemia and hypoparathyroidism at age 30 when she had her first episode of nephrolithiasis. She had recurrent nephrolithiasis and lithotripsies, ultimately developing chronic kidney impairment that was at stage 3b at the time of evaluation. Renal Ultrasound revealed bilateral nephrolithiasis, and nephrocalcinosis. There was a history of hypoparathyroidism in her father, paternal uncle, and son. Her medications included calcium carbonate-vitamin D3 600-400 mg-unit oral 2 tablets daily and calcitriol 0.5 mcg daily. The pertinent physical examination finding was a short stature with height 4’11” and calluses in fingers. Her recent serum chemistry showed calcium 8.8 mg/dL (reference range 8.3 - 10.6 mg/dL), PTH < 6.3 pg/mL (reference range 18.4 - 80.1 pg/ mL), and phosphorus 3.3 mg/dL (reference range 2.4 - 5.5 mg/dL). 24 hr urine calcium was 96 mg (reference range 50-300 mg/24h). She was treated with hydrochlorothiazide for nephrolithiasis but was discontinued due to hypokalemia. We performed genetic testing that resulted positive for CASR NM_001178065.1 with heterozygosity and damaging missense predictions inherited as autosomal dominant or recessive. Discussion: The calcium-sensing receptor (CaSR) has an important role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion. Familial hypoparathyroidism disorders are divided into Autosomal dominant hypocalcemia (ADH) type 1 and Autosomal dominant hypocalcemia (ADH) type 2. ADH1 is caused by an activating mutation of calcium-sensing receptor (CASR). The estimated prevalence of ADH1 ranges from 1 per 70,000 to 3.9 per 100,000. It is characterized by mild to moderate hypocalcemia, hyperphosphatemia, hypercalciuria, and inappropriately low but detectable PTH levels. It can be associated with Bartter syndrome Type 5. ADH2 is due to mutations in the alpha subunit of the G protein G11 (Gα11). Our patient had classic symptoms of hypocalcemia including short stature, seizures, kidney stones and its sequelae. Her 24-hour urine analysis showed inappropriately normal urine calcium with low normal serum calcium, undetectable serum PTH, and normal phosphorus. Our patient’s genetic analysis revealed a heterozygous defect in gene CASR with DNA variants c.2564G>A with damaging missense predictions. There is no such variant reported or listed in the ClinVar database. To our knowledge, this is the first such case of an autosomal dominant hypoparathyroidism with this gene defect. Presentation: 6/1/2024

ODP104 Isolated familial hypoparathyroidism with Tbx1 mutation in Korea

Abstract Background Non-surgical hypoparathyroidism due to lack of PTH secretion or action is uncommon disorder characterized by hypocalcemia and hyperphosphatemia. Familial hypoparathyroidism is classified into syndromic hypoparathyroidism, including DiGeorge syndrome and isolated familial hypoparathyroidism. Deletion of Tbx1 is the cause of DiGeorge syndrome characterized by hypoparathyroidism, immunodeficiency, and congenital heart disease. Most cases of isolated familial hypoparathyroidism are caused by GCM2, SOX3, CASR, Gα11, and PTH. Isolated familial hypoparathyroidism also can be caused by mutations in TBX1 genes(1). In this study, we also identified a splice-altering mutation in TBX1 (c.1009+1G. C), leading to skipping of exon 8 in an idiopathic hypoparathyroidism patient in Korea. Case A 35-year-old woman was referred to our hospital in March 2016 for hypocalcemia. It had been detected after recurrent abortion and seizure during exercise. Her second older brother was diagnosed as idiopathic hypoparathyroidism with no abnormalities in the TUPLE1 FISH test and chromosome test eight years ago. Initial laboratory studies showed low corrected calcium (7.4 mg/dL, normal range: 8.5-10.5), hyperphosphatemia (4.7 mg/dL, normal range: 2.5-4.1), inappropriately normal parathyroid hormone (18.4 pg/mL, normal range: 15-65), corresponded to hypoparathyroidism. A brain computed tomography showed bilateral globus pallidi calcification. She had no history of renal stones or cataracts. She did not show congenital anomaly including cleft palate, facial dysmorphism, conotruncal heart defects, and immunodeficiency, and neither did her brother. Molecular diagnoses were analyzed by whole-exome sequencing, identifying the heterozygous TBX1 mutation (c.1009+2T/A). She was treated with conventional therapy such as calcium and calcitriol. The patient gave birth 18 months after referring to our hospital, and the child did not show any abnormalities in calcium or phosphorus. During a follow-up of 6 years, the patient had no additional symptoms related to hypocalcemia with the lower normal range of calcium and normal phosphorous. Conclusion We identified a rare heterozygous TBX1 mutation in a patient with isolated familial hypoparathyroidism in Korea.

Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism.

ObjectiveThe autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.MethodsProbands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.ResultsBiallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.ConclusionsThis study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.

Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders.

ObjectiveThe aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma.DesignWe characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants.MethodsLeukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses.ResultsA novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter.ConclusionsWe provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

A Novel GATA3 Variant Causing Familial Hypoparathyroidism, Renal Agenesis and Sensorineural Deafness Presenting With Atypical Symptoms of Chronic Hypocalcaemia

Introduction: Familial hypoparathyroidism is a rare cause of hypocalcaemia. We report a case of long-standing hypocalcaemia secondary to hypoparathyroidism caused by a novel GATA3 variant resulting in multiple organ involvement. Case: A 20 year old girl was referred to our bone metabolic clinic for hypocalcaemia. Her past medical history included Bechet’s disease, epilepsy and depression. She had bilateral sensorineural hearing loss and encephalitis as a child. She underwent right nephrectomy for an atrophic non-functioning kidney at the age of 16. Current medication included hydroxychloroquine, diazepam, oral calcium and cholecalciferol. It was noted that the hypocalcaemia dated back to 8 years, she denied any typical symptoms of hypocalcaemia but she did report visual and auditory hallucinations, fatigue and had low seizure threshold. She sustained recurrent fractures of her arm, elbow and wrist. Initial investigations: Corrected calcium 1.88 (2.20-2.60mmol/L), Phosphate 1.54 (0.80–1.50mmol/L), PTH 1.2 (1.6–6.9pmol/), 25-OH vitamin D 37 (50-120nmol/L). Myeloma screen, thyroid, renal and liver functions were all within the normal reference range. Other bone markers: Serum Procollagen Type 1 Amino Terminal Peptide was mildly raised at 82 (19-69ug/L), CTX 0.42 (0.1-0.5ug/L), 1,25 OH Vitamin D 29 (55-139pmol/L), 24,25-dihydroxyvitamin D was normal with normal 25:24,25 Dihyroxyvitamin D ratio at 18 normal. Bone density was in the normal range for her age. MRI of the brain was normal with no evidence of calcification. There was a family history of hypocalcemia in her estranged father. Subsequent genetic analysis showed a novel likely pathogenic GATA3 missense variant (c.961T>C p.(Cys321Arg). She was started on alfacalcidol and achieved near normocalcemia with adjusted calcium levels of 2.18nmol/L. Conclusion: Pathogenic variants in the GATA3 gene are responsible for Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome. In our patient, a novel missense variant in GATA3, p.(Cys321Arg), has been detected. This variant disrupts one of four conserved cysteine residues within a zinc-finger domain, which is involved in DNA binding and is presumed to have a deleterious effect on protein function. Patients may have longstanding asymptomatic hypocalcaemia with atypical features hence genetic testing is recommended in patient with multi-organ involvement. Alfacalcidol successfully restored calcium homeostasis in this case.

Congenital Hypoparathyroidism Associated With Elevated Circulating Nonfunctional Parathyroid Hormone Due to Novel PTH Mutation.

Familial hypoparathyroidism has a heterogeneous presentation where patients usually have low parathyroid hormone (PTH) levels due to impaired production or secretion. This contrasts with pseudohypoparathyroidism, in which PTH resistance is usually associated with an elevated serum PTH. High levels of circulating PTH can also be due to bioinactive PTH, which is difficult to distinguish from pseudohypoparathyroidism on biochemical grounds. We report on 2 sisters from consanguineous parents who presented with tetany at birth and were diagnosed with congenital hypocalcemia. Serum PTH levels were normal for many years, but progressively increased in midadulthood to greater than 100x the upper limit of normal on multiple assays. Homozygosity mapping was performed on 1 sister that demonstrated loss of heterozygosity (LOH) around PTH. Sequencing revealed a previously unreported variant, c.94T>C, predicting a codon change of p.Ser32Pro that is biologically inactive. This case report shows a previously unreported unusual biochemical phenotype of a rising PTH in the context of a novel PTH mutation. This expands the evolving genotypes associated with hypoparathyroidism without established gene mutations.

MON-193 RENAL TRANSPLANTATION IN A PATIENT WITH FAMILIAL SYNDROME OF HYPOCALCEMIA WITH HYPERCALCIURIA

The calcium sensing receptor regulates the secretion of parathyroid hormone in response to changes in the extracellular calcium concentration and mutations that result in gain of function of this receptor are associated with with familial hypocalcemia with hypercalciuria. The high urinary calcium excretion leads to nephrocalcinosis and renal insufficiency. We present a case of a patient with end stage kidney disease due to nephrocalcinosis from familial hypocalcemia with hypercalciuria, who subsequently underwent renal transplantation with complete resolution of hypercalciuria. This is the first reported case of renal transplantation in a patient with familial hypocalcemic hypercalciuria. Case report: 58 year old female developed end stage kidney disease due to nephrocalcinosis. Nephrocalcinosis was secondary to familial hypoparathyroidism and she had known mutations in calcium sensing receptors and hence chronic hypocalcemia (1.8-1.9mmol/l) and hypercalciuria( 3.2mmol/l) . She subsequently underwent non directed living donor transplantation. Within 1 week after renal transplantation the urinary calcium concentration was measured and this was completely within normal limits with urine calcium concentration of 1 mmol/l and calcium/creatinine ratio of 0.29 ( normal range 0.06- 0.45mole ratio). Subsequent urine calcium concentrations are less than 0.20mmol/l and her graft function remains excellent. Discussion: This is the first case report of successful renal transplantation in a case of familial hypoparathyroidism with known gain of function or activating mutation of calcium sensing receptor which results in hypocalcemia and hypercalciuria. The calcium sensing receptor gene is expressed in the parathyroid glands and kidneys . This receptor regulates the the secretion of parathyroid hormone and reabsorption of calcium by the renal tubules in response to alterations of serum calcium levels. Gain of function mutation of the calcium sensing receptor gene will suppress the parathyroid hormone and increase the excretion of urinary calcium at inappropriately low serum calcium levels. The high urinary calcium concentration drives polyuria and dehydration and hence subsequently leads to nephrocalcinosis and renal insufficiency. With renal transplantation, we are essential replacing the affected abnormal calcium sensing receptors with normal calcium sensing receptor and hence normalising urinary calcium, thereby eliminating the risk of nephrocalcinosis in the graft. Conclusions: Renal transplantation is a safe and effective way of treating end stage kidney disease in patients with nephrocalcinosis due to familial hypocalcemia and hypercalciuria.

A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism

Isolated familial hypoparathyroidism is an extremely rare disorder, which to date has been linked to several loci including mutations in CASR, GCM2, and PTH, as well as a rare condition defined as X-linked recessive hypoparathyroidism, previously associated with a 1.5 Mb region on Xq26-q27. Here, we report a patient with hypocalcemia-induced seizures leading to the diagnosis of primary hypoparathyroidism. Mutations in CASR, GCM2, and PTH were ruled out, while whole exome sequencing of the family suggested FHL1, located on chromosome Xq26, as the most likely causative gene variant (FHL1, exon 4, c.C283T, p.R95W). Since FHL1 has not been linked to calcium regulation before, we provide evidence for its functional role in hypoparathyroidism by: (i) bioinformatics analysis coupling its action to known modulators of PTH function; (ii) observing strong expression of fhl1b in Corpuscles of Stannius, gland-like aggregates in zebrafish that function in calcium regulation similar to mammalian PTH; and (iii) implicating fhl1b and FHL1 as regulators of calcium homeostasis in zebrafish and human cells, respectively. Altogether, our data suggest that FHL1 is a novel regulator of calcium homeostasis and implicate it as the causative gene for X-linked recessive hypoparathyroidism.

A Neonatal Case of Autosomal Dominant Hypoparathyroidism without Mutation of the CASR Gene.

We experienced a case of familial hypoparathyroidism with an autosomal dominant pattern of transmission and performed molecular analysis of the calcium-sensing receptor (CASR) gene. The patient was a female neonate, born by cesarean section at term because of breech presentation. Her mother had been diagnosed with idiopathic hypoparathyroidism at the age of 9 yr and had been receiving vitamin D treatment since then. At birth, the patient’s serum calcium concentration was 8.4 mg/dl, but it fell to 4.0 mg/dl on the fifth day after birth. Furthermore, her serum intact PTH level was inappropriately low, while hyperphosphatemia and hypomagnesemia were found. She was diagnosed with familial hypoparathyroidism, and was immediately started on oral administration of 1α(OH)D3 (0.1 µg/kg/day) and continuous intravenous infusion of 8.5% calcium gluconate. Additionally, trichlormethiazide was administered because of elevated urinary calcium/creatinine (Ca/Cr) ratio. Her serum calcium concentration gradually improved thereafter. In this case, autosomal dominant hypocalcemia (ADH) due to abnormality in the CASR gene was clinically suspected, but DNA sequencing analysis revealed no mutation of the CASR gene in either the patient or her mother. This result suggests that the patient’s hypoparathyroidism may have been caused by abnormality in a gene other than CASR.

Mutational analysis of the PTH 3′‐untranslated region in parathyroid disorders

Sequence alterations in untranslated regions (UTRs) of genes are important contributors to human diseases, including hereditary thrombophilia, hereditary hyperferritinaemia-cataract and fragile X mental retardation syndromes. Recently, functional studies of the 3'-UTR of the PTH gene, encoding parathyroid hormone, have highlighted it as a potential target for pathogenic mutations in patients with parathyroid dysfunction. Regulation of PTH gene expression occurs in part through protein binding to a specific 26 nucleotide instability element in the 3'-UTR of PTH mRNA, in a sequence-dependent manner. Thus, the PTH 3'-UTR has emerged as an important potential contributor to parathyroid dysfunction. Therefore, we sought to rigorously examine the PTH 3'-UTR in patients with primary and secondary parathyroid disorders, including primary parathyroid hyperplasia, secondary parathyroid hyperplasia, sporadic parathyroid adenoma and familial hypoparathyroidism of unknown genetic basis. Twenty-one parathyroid glands from 14 patients with primary parathyroid hyperplasia, 40 sporadic parathyroid adenomas from 40 patients, 42 parathyroid glands from 29 patients with secondary parathyroid hyperplasia and peripheral blood leucocytes from 24 affected members of eight kindreds with familial hypoparathyroidism of unknown genetic basis were examined for mutations in the 3'-UTR of the PTH gene. No alterations from the normal sequence were detected in any of the 127 samples examined. Based on the absence of identifiable DNA sequence alterations in these forms of parathyroid dysfunction, it is unlikely that mutation of the PTH 3'-UTR contributes frequently to their pathogenesis.

Identification of Three Novel Mutations in theGATA3Gene Responsible for Familial Hypoparathyroidism and Deafness in the Chinese Population

Familial hypoparathyroidism may be caused by mutations of several genes. The CaSR and GATA3 genes are the two candidates most commonly responsible for this condition. We collected five unrelated families with familial hypoparathyroidism and examined their CaSR and GATA3 genes. Blood samples from these five families and 50 ethnically matched unrelated controls were acquired. Biochemistry screening and formal audiogram were performed to evaluate the affected individuals. All the exons and exon-intron boundaries of the GATA3 and CaSR genes were sequenced. We identified three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness: 1) a frameshift deletion occurring in codon 160 (478delG) was hypothesized to disrupt dual zinc fingers as well as one transactivating domain; 2) a donor splice site mutation at exon 4/intron 4 boundary (IVS4 + 2 T to GCTTACTTCCC) was predicted to lead to truncated GATA3 proteins that lack both N- and C-terminal zinc-containing fingers; and 3) a missense mutation R353S was predicted to disrupt the helical turn and thus changed the angle between the C-terminal zinc finger and the adjacent C-terminal tail. Except for a previously described polymorphism, G990R, we did not find any genetic variants in the CaSR gene. This is the first article presenting mutations of the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. Our results expand the spectrum of mutations and report the first splice donor site mutation of the GATA3 gene. In contrast, we do not find causal sequence variants of the CaSR gene from our collection of familial hypoparathyroidism.

Absence of pathogenic calcium sensing receptor mutations in sporadic idiopathic hypoparathyroidism

Sporadic idiopathic hypoparathyroidism (SIH) is the most common cause of hypoparathyroidism. While calcium sensing receptor (CaSR) autoantibodies are observed in 49% of cases, aetiopathogenetic mechanisms in others are under investigation. Mutations in the PTH gene including its 3' untranslated region, autoimmune regulator gene and lead CTLA-4 gene single nucleotide polymorphism (SNPs) are not associated with the disease. There are reports of de novo activating mutations of the CaSR gene in a few patients with SIH. To assess the frequency of CaSR mutations in patients with SIH. DNA sequencing of all six translating exons and nine of 12 intron/exon boundaries of the CaSR gene was performed by Sangers dideoxy chain termination method using an automated sequencer in 39 patients with SIH. Spot urinary calcium/creatinine ratio in the fasting state and ultrasonography of the abdomen was performed to assess hypercalciuria and nephrolithiasis. The PCR-RFLP analysis was performed using Hin1II restriction endonuclease in 32 additional patients with SIH and 90 healthy controls to further assess the prevalence of a novel missense SNP observed in the DNA sequencing. Nucleotide sequence analysis revealed the presence of a wild type CaSR gene in all subjects, except in one patient who showed a missense mutation (Val621Met) due to substitution of base G-->A in the heterozygous state at position 79877 in exon 7 (codon 621) coding for the first transmembrane loop of the CaSR. The V621M polymorphism was confirmed by PCR-RFLP and was due to a maternal allele. However, the mother and brother of this patient with the same SNP were asymptomatic and had normal serum chemistry indicating the functionally inert nature of the polymorphism. None of the additional 32 patients with SIH and 90 controls showed V621M SNP. The urinary calcium/creatinine ratio and ultrasonography were normal in all patients with SIH. De novo activating mutation of the CaSR gene typical of familial hypoparathyroidism is not common among patients with SIH in India.

A Ca2+-Sensing Receptor Mutation Causes Familial Hypoparathyroidism by Increasing Receptor Sensitivity to Ca2+ and Maximal Signal Transduction. • 403

A Ca2+-Sensing Receptor Mutation Causes Familial Hypoparathyroidism by Increasing Receptor Sensitivity to Ca2+ and Maximal Signal Transduction. • 403

Ca2+-SENSING RECEPTOR MUTATIONS IN SPORADIC HYPOPARATHYROIDISM.• 507

Missense mutations of the Ca2+-sensing receptor (CSR) gene have been identified in 4 families with autosomal dominant hypoparathyroidism and in one child with sporadic hypoparathyroidism. To cause the phenotype, these mutations must activate the CSR, since the receptor negatively regulates parathyroid hormone (PTH) secretion. We showed previously that patients with CSR mutations, while hypocalcemic, manifested greater hypercalciuria than did patients with other causes of hypoparathyroidism, apparently because the CSR negatively regulates Ca2+ resorption from the glomerular filtrate. Thus, we hypothesized that this disproportionate hypercalciuria could be used to distinguish sporadic hypoparathyroidism due to de novo CSR mutations from hypoparathyroidism due to other causes. To test this hypothesis, we studied two unrelated female patients with no family history of hypoparathyroidism, both of whom had hypocalcemia, hyperphosphatemia, low serum PTH, and disproportionate hypercalciuria. Patient A presented with mild symptoms of hypocalcemia at age 18, whereas patient B was severely symptomatic from infancy. Polyacrylamide gel electrophoresis of PCR-amplified genomic DNA showed heteroduplex bands in exon 6 for patient A and in exon 2 for patient B. In patient A, direct sequencing of the PCR product identified a T2318G base-pair substitution encoding a Leu to Arg change at residue 773 of the fifth transmembrane domain. Patient B showed a C354A substitution encoding an Asn to Lys change at residue 118 in the N-terminal extracellular domain. Family studies suggested that both mutations arose de novo. We conclude that 1) mutations of the CSR gene cause sporadic as well as familial hypoparathyroidism, 2) phenotypic severity varies greatly depending on the specific mutation, and 3) levels of 24h Ca2+ excretion can identify hypoparathyroid patients with CSR gene mutations, which has implications for genetic counseling, prognosis, and therapy.

Brief report: autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia.

FAMILIAL hypoparathyroidism is an unusual condition that can present at any time from early infancy until well into adulthood.1 2 3 4 It can be inherited in an autosomal dominant,3 , 4 autosomal recessive,5 or X-linked recessive6 , 7 pattern. Its presence has been associated with other congenital abnormalities, such as absence of the thymus (DiGeorge's syndrome).8 We recently encountered a patient with long-standing sensorineural deafness who presented with symptoms of thirst and polyuria and was found to have diabetes mellitus. He also had hypocalcemia, subsequently proved to be due to hypoparathyroidism, and a high serum creatinine concentration; further studies revealed small kidneys with a large right-sided . . .

Moderate hypocalcemia due to normal serum 1,25-dihydroxyvitamin D levels in an asymptomatic kindred with familial hypoparathyroidism

Hypoparathyroidism was diagnosed in nine members of a kindred of three generations. This study investigated why these persons were asymptomatic and without developmental abnormalities, in contrast to the common presentation of idiopathic hypoparathyroidism. In the hypocalcemic subjects, serum calcium level was 7.4 ± 0.8 mg/dl) mean ± SD) and ionized serum calcium level was 3.48 ± 0.21 mg/dl. Immunoreactive parathyrold hormone values were inappropriately low. Injection of EDTA in one patient lowered ionized calcium levels, but immunoreactive parathyroid hormone values did not rise. Serum levels of 1,25-dihydroxyvitamin D and other vitamin D metabolites were normal or elevated and substantially higher than in other hypoparathyroid states. The normally observed positive correlation between the fasting urinary calcium/creatinine ratio and serum 1,25-dihydroxyvitamin D that reflects the dependence of net bone resorption on 1,25-dihydroxyvitamin D was upheld in hypoparathyroid patients. It is proposed that the subjects with familial hypoparathyroidism in this kindred had moderate asymptomatic hypocalcemia without developmental abnormalities because normal or elevated serum 1,25-dihydroxyvitamin D levels enhanced intestinal calcium absorption. This may represent one point in the spectrum of idiopathic hypoparathyroidism. Alternately, both the moderate degree of hypocalcemia and the normal serum calcitriol values could have been related to mild, partial hypoparathyroidism, which could have been inherited in this kindred.

Selenium and vitamin E status in cystic fibrosis

3. Rao GJS, Platt M W, and Nadler HL: Reaction of 4methylumbelliferylguanidinobenzoate with proteases in plasma of patients With cystic fibrosis, Enzyme 23:314, 1978. 4. Clayton RJ, Iber FL, Ruebner BH, and McKusick VA: Byler's disease: Fatal familial intrahepatic cholestasis in an Amish kindred, Am J Dis Child 117:112, 1969. 5. Oppenheimer EH, and Esterly JR: Hepatic changes in young infants wit h cystic fibrosis, J PEDIATR 86:683, 1975. 6. Bonin A, Roy CC, LaSalle R, Weber A, and Morin CL: Fecal chymotrypsin: A reliable index of exocrine pancreatic function in children, J PEDIATR 83:594 , 1973. 7. Hahn TJ, Squires AE, Halstead LR, and Strominger DB: Reduced serum 25-hydroxyvitami n D concentration and disordered mineral metabolism in patients with cystic fibrosis, J PEDIATR 94:38, 19791 8. Schwachman H: Cystic fibrosis, Curr Probl Pediatr 8:1, 1978. 9. MacLean WC, and Tripp RW: Cystic fibrosis with edema and falsely negatfve sweat test, J PEDIATR 83:86, 1973. 10. Mace JW, and Schanberger JE: Elevated sweat chlorides in a child with malnutrition, Clin Pediatr 10:285, 1971. 11. Morse WI, Cochrane WA, and Landrigan PL: Familial hypoparathyroidism With pernicious anemia, steatorrhea and adrenocortical insufficiency, N Engl J Med 264:1021, 1961. 12. Gibson LE, Matthews WJ, Minihan PT, and Patti JA: Relating mucus, calcium and sweatin a new concept of cystic fibrosis, Pediatrics 48:695, 1971. 13. Weber A, and Roy CC: The malabsorption associated with chronic liver disease in children, Pediatrics 50i73, 1972. 14. Hubbard VS, Dunn GD, and Di Sant'Agnese PA: Abnormal fatty acid compositions of plasma lipids in cystic fibrosis--A primary or a secondary defect? Lancet 2:1302, 1977. 15. Alagille D, and Odievre M: Cholestasis in children, in Alagille D, and Odievre M, editors: Liver and biliary tract disease in children, New York, 1979, John Wiley & Sons, lnc, p 163. 16. Gibson LE, and Cooke RE: A test for concentration of electrolytes in sweat in cystic fibrosis Of tile pancreas utilizing pilocarpine by iontophoresis, Pediatrics 23:545, 1959.

Lenticulodentate calcification.

Eleven cases of basal ganglion calcification are discussed, and the radiologic finding of calcification of the red nucleus is described for the first time. Examples are included of familial hypoparathyroidism and familial idiopathic basal ganglion calcification. It is thought that lowered serum calcium is usually the prime factor in this condition. The resultant increase in neuromuscular excitability disturbs the neurochemical processes. The location of the calcifications can then be understood as being in centers which inhibit the increased activity of the spinal reflex arcs.

Familial Hypoparathyroidism with Pregnancy- Challenging Issue for Patient as well as for Physician

Familial hypoparathyroidism is a rare cause of hypoparathyroidism. It may be x-linked recessive, autosomal dominant or autosomal recessive. In autosomal dominant hypoparathyroidism there is activating mutation of the calcium sensing receptor leading to inhibition of Parathormone (PTH) secretion at inappropriately low serum ionized calcium level. The disease often manifests in the first decade but may appear later. Clinical signs primarily involving neuromuscular disturbances including generalized seizure. Management of pregnancy in hypoparathyroidism is challenging as both under treatment and over treatment is dangerous for fetus. Treatment of hypoparathyroidism in pregnancy includes combination of oral calcium supplementation with calcitriol with an aim to keep serum calcium within normal range. Here we discussed a case of 21 year pregnant lady with familial hypoparathyroidism with successful delivery of a healthy baby. Key words: Hypoparathyroidism; Hypocalcaemia; Hyperphosphataemia; Epilepsy. DOI: http://dx.doi.org/10.3329/fmcj.v6i2.9215 FMCJ 2011; 6(2): 113-115