Short Communication | DOI: https://doi.org/10.31579/2640-1045/134
1 Post-Doctoral Trainee (PDT), Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research/SSKM Hospital, Kolkata- 70020, West Bengal, India.
2 Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research/SSKM Hospital, Kolkata- 700020, West Bengal, India.
*Corresponding Author: Pankaj Singhania, Post-Doctoral Trainee (PDT), Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research/SSKM Hospital, Kolkata- 70020, West Bengal, India.
Citation: Abhranil Dhar, Arunava Ghosh, Pankaj Singhania, Tapas Chandra Das (2023), Idiopathic Hypoparathyroidism: New Insights into an Enigma, J. Endocrinology and Disorders. 7(2): DOI:10.31579/2640-1045/134
Copyright: © 2023, Pankaj Singhania. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 03 February 2023 | Accepted: 11 February 2023 | Published: 23 March 2023
Keywords: hypocalcemia; hyperphosphatemia; hypoparathyroidism; idiopathic; GCM2
Calcium is a very important electrolyte - necessary for neurotransmission, cell signaling, and bone development. Hence, blood calcium levels are to be kept in a safe normal range. The parathyroid hormone has an important role in calcium metabolism at the level of the bone, kidney, or GI tract. Hypoparathyroidism is a condition of reduced formation of parathyroid hormone.
Calcium is a very important electrolyte - necessary for neurotransmission, cell signaling, and bone development. Hence, blood calcium levels are to be kept in a safe normal range. The parathyroid hormone has an important role in calcium metabolism at the level of the bone, kidney, or GI tract [1]. Hypoparathyroidism is a condition of reduced formation of parathyroid hormone. It may lead to hypocalcemia, low calcitriol, and hyperphosphatemia.
Idiopathic hypoparathyroidism (IHP) is an uncommon endocrine disease, with highly variable clinical manifestations. Its incidence ranges from 0.55 to 0.88/ 100,000 in Asian populations [2]. It can occur as an isolated disease or as part of many syndromes. The etiology is labelled as idiopathic if no cause is found after excluding all possible etiologies. Idiopathic hypoparathyroidism may have a hidden genetic etiology [3]. Molecular genetic analyses over the past few decades have recognized mutations in many genes which have given us new insights into embryological development of the parathyroid glands, regulation of parathyroid hormone (PTH) synthesis and secretion, and maintenance of parathyroid gland homeostasis [4]. The quality of life (QoL) is affected in patients causing a reduced sense of well-being. But there is no conclusive evidence regarding increased mortality in patients having hypoparathyroidism [5].
Due to highly nonspecific and varied manifestations, idiopathic hypoparathyroidism often has a long lag period of diagnosis and increased
risk of misdiagnosis. A serum calcium profile in patients with trivial issues like paresthesia may avoid the lengthy delay as well as misdiagnosis of patients having idiopathic hypoparathyroidism [6].
Autoantibodies against cytoplasmic parathyroid tissue may be found in up to 30–70% of patients having IHP. Treatment target is to restore calcium levels. To prevent hypocalcaemia, patients of hypoparathyroidism require lifelong calcium supplementations and calcitriol to stimulate absorption of calcium and phosphate in the gut. A diet containing high-calcium and low phosphorus is recommended.
In a previous report of two cases, we have established the critical role of GCM2 activity in human parathyroid gland development through clinical and genetic analysis of 2 patients with hypoparathyroidism. These conclusions have more immediate relevance for the diagnosis and treatment of cases having isolated hypoparathyroidism [7].
At our institution we have experience of a small but significant number of patients with IHP. Similar reports have been available from other Endocrine departments as well. Hence, with the availability of diagnostic tools like NGS being more common place, we can arrive at a definitive genetic diagnosis; proving useful in prognosticating the disease severity & requirement of therapy. In inherited cases genetic counseling of patients can also be done.
Genetic Disorders Associated with Hypoparathyroidism
| Disease | Inheritance | Gene | Locus | Prevalence | Comorbidities |
| |||||
| Isolated parathyroid aplasia | AR or ADXR | GCM2 SOX3 | 6p23–24Xq26–27 |
|
|
DiGeorge Syndrome type 1 DiGeorge Syndrome type 2 | Sporadic or AD
Sporadic or AD | TBX1
NEBL | 22q11.21-q11.2310p13 | 1:4,000-1:7,692 | Thymic hypoplasia with immune deficiency, conotruncal cardiac defects, cleft palate, dysmorphic facies |
| Charge Syndrome | Sporadic or AD | CHD7 SEMA3E | 8q12.27q21.11 | 1:8,500 | Cardiac anomalies, cleft palate, renal anomalies, ear abnormalities/ Deafness and developmental delay |
| Hypoparathyroi-dism, deafness, and renal dysplasia | AD | GATA3 | 10p14–15 | Deafness and renal dysplasia | |
| Hypoparathyroidism, retardation and dysmorphism | AR | TBCE | 1q42–43 | Growth retardation, developmental delay, dysmorphic facies | |
Kenny-Caffey syndrome type 1
Kenny-Caffey syndrome type 2 | AR
AD | TBCE
FAM111A | 1q42-4311q12.1 | 1:40,000 -1:100,000 in Saudi Arabia | Short stature, medullary stenosis, dysmorphic facies, developmental delay Similar to type 1, but clinically distinguished by the absence of mental retardation |
| Mitochondrial disease Kearns-Sayre syndrome | Maternal | Mt DNA | Encephalomyopathy, ophthalmoplegia, retinitis pigmentosa and heart block | ||
| Pearson Marrow Pancreas syndrome | Mt DNA | Pancreatic dysfunction, sideroblastic anemia, neutropenia, and thrombocytopenia | |||
| MELAS | Mt tRNA | Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes | |||
| LCAHD | MTP | 2p23.3 | Impaired vision, night blindness, rhabdomyolysis, cardiomyopathy | ||
| MCADD | ACADM | 1p31.1 | 1:17,000
| Fasting hypoglycemia, encephalopathy, hepatic dysfunction | |
| |||||
| PTH gene mutations | AD or AR | PTH | 11p15.3-p15.1 |
| |
| AD hypocalcemia type 1 | AD or sporadic | CASR | 3q13.3-q21.1 | Hypercalciuria
| |
| AD hypocalcemia type 2 | AD or sporadic | GNA11 | 19p13.3 | ||
| |||||
| Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy | AR, AD or sporadic | AIRE | 21q22.3 | 1:90,000 – 1:200,000 | Mucocutaneous candidiasis, Adrenal insufficiency, and Primary hypoparathyroidism |
GI- Gastrointestinal
QOL- Quality of Life
IHP- Idiopathic Hypoparathyroidism
PTH- Parathyroid Hormone
NGS- Next Generation Sequencing
GCM2- Glial cell missing homolog 2
Mt DNA- Mitochondrial DNA
MELAS- Mitochondrial Encephalomyopathy, Lactic acidosis, Stroke-like Episodes
ACADM- Acyl CoA dehydrogenase medium chain
LCAHD- Long Chain Hydroxy-acyl CoA Dehydrogenase
None
None
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