Hypoparathyroidism (HP) is a rare endocrine disorder caused by parathyroid hormone (PTH) deficiency. The PTH is a candidate gene for familial isolated hypoparathyroidism (FIH). This study aimed to investigate the pathogenicity of two novel rare variants (RVs) of PTH through in vitro functional study. Targeted next-generation sequencing was used to identify candidate gene mutations. Clinical data were retrospectively collected. Wild-type (WT) PTH was used as a template for site-directed mutagenesis to create mutant eukaryotic expression plasmids, which were transfected into cells. Treated with or without 4-phenylbutyric acid (4-PBA), the levels of intact PTH (iPTH) and PTH (1-84) were measured by chemiluminescence, and protein expression was assessed using Western blotting. Two patients carrying PTH mutations (c.154G > A: p.Val52Ile, c.270G > T: p.Leu90Phe) were identified. Patient 1, a 45-year-old male, presented with carpal and pedal numbness, muscle cramps, and low serum calcium (1.29 mmol/L). Patient 2, a 12-year-old female, had muscle twitches, convulsions, low calcium (1.50 mmol/L), and iPTH of 4 pg/mL. The iPTH or PTH (1-84) levels in the medium transfected with mutant Val52Ile and Leu90Phe PTH decreased by 31%-38%, and 51%-96% compared to WT (allP < 0.05), which were not rescued by 4-PBA. No significant changes in intracellular PTH expression were observed. In this study, two novel RVs of PTH (Val52Ile and Leu90Phe) were identified that may impair hormone synthesis and secretion. Our study has broadened the mutation spectrum of the PTH and shed light on potential mechanisms underlying FIH.

This study aims to evaluate the etiology, clinical presentation, and management of pediatric hypoparathyroidism in a tertiary center. A retrospective review was conducted on pediatric patients diagnosed with hypoparathyroidism at the Pediatric Endocrinology Clinic from March 2021 to June 2023. Data on demographic characteristics, presenting symptoms, laboratory findings, genetic analyses, and treatment outcomes were collected. A total of 56 patients (31 females) were included. The median age at diagnosis of the patients was 5.5 years (range 0.04-17 years), and the median age of symptom onset was 5 years (range 0.04-16.5 years). The etiology was genetic and idiopathic in 39 patients (70.9%), with syndromic forms, familial isolated hypoparathyroidism, and hypomagnesemia identified. DiGeorge syndrome was present in 14 patients, making it the most common syndromic form. The syndromes associated with hypomagnesemia were those with mutations in the TRMP6 and CLDN16 genes. Sixteen patients (29.1%) had acquired causes, primarily post-thyroid surgery and autoimmune conditions. Common symptoms included muscle spasms (32.7%) and seizures (21.8%). Laboratory findings revealed a median serum calcium level of 6.7 mg/dL (3.8-8.5) and median serum phosphorus level of 7.7 (4.9-12.5) mg/dL. Treatment primarily involved calcitriol [The median dose of calcitriol is 25 ng/kg/day (range: 25-50 ng/kg/day)] and calcium [The median dose of calcium gluconate is 0.7 mL/kg (range: 0.5-1 mL/kg) and oral calcium is 1000 mg (range: 700-1300 mg)] supplementation. Intravenous calcium gluconate treatment was administered to 39 (70.6%) patients, oral calcium carbonate therapy was given to 16 (29.1%) patients, and calcitriol treatment was initiated for 51 (91.1%) patients. Complications such as nephrocalcinosis (7, 13.7%) and hypercalciuria (7, 13.7%) were observed in some patients. This study emphasizes the significant genetic component, particularly syndromic, in pediatric hypoparathyroidism, highlighting the need for comprehensive genetic evaluation and a multidisciplinary approach for effective management, especially concerning complications. In this way, early and accurate diagnosis will reduce unnecessary tests, treatment approaches, and repeated hospital visits. Regular monitoring is essential to mitigate potential complications associated with long-term treatment.

We report a patient who initially presented at 4 days old with hypocalcemia, hypoparathyroidism, and elevated phosphorous level. Treatment was initiated with calcitriol, calcium carbonate (CaCO3), vitamin D, and low phosphorous formula. Family history was positive for an activating calcium sensing receptor (CASR) variant (R990G) identified previously in 2 older siblings who were treated with CaCO3 and calcitriol. However, genetic studies were negative for the CASR variant in our patient. She maintained a large calcium requirement and was admitted for multiple episodes of hypocalcemia. Further investigation revealed that the CASR variant identified in the older siblings was now considered a benign, nondisease-causing variant. Whole exome sequencing on our proband revealed a homozygous pathogenic variant in the GCM2 gene (Gln392*) consistent with a molecular diagnosis of familial isolated hypoparathyroidism. Genetic studies revealed the 2 older siblings harbor the same genetic changes and parents are heterozygous carriers for this allele. Due to persistent hypocalcemia, we initiated teriparatide. She weaned off calcitriol and achieved normocalcemia on teriparatide, CaCO3, and vitamin D. Siblings transitioned to the same treatment without complications. These findings demonstrate the importance of adequate diagnostic genetic testing and the role of variant reanalysis over time in promoting accurate diagnoses.

So far, only 11 PTH mutations have been described as causes of familial isolated hypoparathyroidism (FIH). In this report, we describe a family with FIH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic outcome of recombinant human PTH (teriparatide) therapy in one of the siblings who was not well controlled on large doses of calcitriol and calcium replacement therapy. The proband is a 34-year-old woman who has a history of chronic severe hypocalcemia (HypoCa) since birth. She and her three brothers (33-year-old male twins, and a 21-year-old male) were diagnosed with pseudohypoparathyroidism type 1b (PHPT 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. WES showed no pathogenic, likely pathogenic or variants of unknown significance in any known calcium-associated genetic disorder but a bi-allelic variant in the PTH itself ((NM_000315.4:c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and her affected brothers. Because the patient's HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily was started and resulted in normalization of calcium, decline in PTH levels and significant improvement in her general wellbeing. High PTH in the presence of congenital hypocalcemia is not always due to receptor or post-receptor defect and can be due to a biologically inactive mutated PTH. In such cases, treatment with teriparatide may result in stabilization of biochemical profile and improvement in quality of life.

Familial isolated hypoparathyroidism is a rare genetic disorder due to no or low production of the parathyroid hormone, disturbing calcium and phosphate regulation. The resulting hypocalcemia may lead to dental abnormalities, such as enamel hypoplasia. The aim of this paper was to describe the full-mouth rehabilitation of a 15-year-old girl with chronic hypocalcemia due to a rare congenital hypoparathyroidism. In this patient, in the young adult dentition, conservative care was preferred. Onlays or stainless-steel crowns were performed on the posterior teeth, and direct or indirect (overlays and veneerlays) were performed on the maxillary premolars, canines, and incisors, using a digital wax-up. The mandibular incisors were bleached. The treatment clearly improved the patient's oral quality of life, with fewer sensitivities, better chewing, and aesthetic satisfaction. The difficulties were the regular monitoring and the limited compliance of the patient. Despite no clinical feedback in the literature, generalized hypomineralized/hypoplastic teeth due to hypoparathyroidism in a young patient can be treated as amelogenesis imperfecta (generalized enamel defects) with a conservative approach for medium-term satisfactory results. This study provides new insights into the management of enamel hypoplasia caused by familial isolated hypoparathyroidism, helping to improve patient outcomes in similar cases. In primary hypoparathyroidism with hypocalcemia and hyperphosphatemia, deficient parathyroid hormone (PTH) secretion most commonly occurs from surgical excision of, or damage to, the parathyroid glands. The term idiopathic hypoparathyroidism describes isolated cases when a cause is not obvious, and there is no family history. However, hypoparathyroidism is also a feature common to a variety of hereditable syndromes that may present de novo. Familial isolated hypoparathyroidism may show autosomal dominant, autosomal recessive, or X-linked inheritance. Genes involved include PTH, SOX3, CASR, GNA11 and GCM2. Parathyroid hypoplasia is a frequent feature of 22q11.2 deletion syndrome with involvement of the TBX1 gene. The Hypoparathyroidism, Nerve Deafness, and Renal Dysplasia syndrome is due to haploinsufficiency of the GATA3 gene. Antibodies against parathyroid tissue are found in isolated hypoparathyroidism or combined with other endocrine deficiencies. Antibodies against the CASR occur in type 1 autoimmune polyglandular syndrome, due to mutations of the AIRE gene, or in acquired hypoparathyroidism. Disorders characterized by end-organ resistance to PTH are described collectively by the term pseudohypoparathyroidism (PHP), and PHP1A and PHP1B are caused by maternally-inherited changes at the imprinted GNAS complex gene that encodes the Gsα protein. Deleterious mutations of the PTH1R gene show resistance to PTH and PTHrP and present as Blomstrand lethal chondrodysplasia, Eiken syndrome, endochondromatosis, and primary failure of tooth eruption. Calcium and vitamin D are the standard therapy for the management of hypoparathyroidism, with hormone replacement [recombinant human PTH(1-84)] therapy recently becoming an option. Calcilytics, PTH analogs, and orally active small molecule PTH1R agonists may, in the future, join the treatment armamentarium. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.