Idiopathic Hypoparathyroidism: New Insights into an Enigma

Short Communication | DOI: https://doi.org/10.31579/2640-1045/134

Idiopathic Hypoparathyroidism: New Insights into an Enigma

  • Abhranil Dhar 1
  • Arunava Ghosh 1
  • Pankaj Singhania 1*
  • Tapas Chandra Das 2

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

Abstract

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. 

Introduction

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


 

DiseaseInheritanceGeneLocusPrevalence Comorbidities   
  1. Disorders of parathyroid gland formation
Isolated parathyroid aplasiaAR 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-q11.2310p131:4,000-1:7,692Thymic hypoplasia with immune deficiency, conotruncal cardiac defects, cleft palate, dysmorphic facies
Charge SyndromeSporadic or AD

CHD7

SEMA3E

8q12.27q21.111:8,500

Cardiac anomalies, cleft palate, renal anomalies, ear abnormalities/

Deafness and developmental delay

Hypoparathyroi-dism, deafness, and renal dysplasiaADGATA310p14–15 Deafness and renal    dysplasia
Hypoparathyroidism, retardation and dysmorphismARTBCE1q42–43 Growth retardation, developmental delay, dysmorphic facies

Kenny-Caffey syndrome type 1

 

 

Kenny-Caffey syndrome type 2

AR

 

 

 

 

       AD

  TBCE

 

 

 

 

FAM111A

1q42-4311q12.11:40,000 -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 syndromeMaternalMt 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                     MTP2p23.3 Impaired vision, night blindness, rhabdomyolysis, cardiomyopathy

 

  1. Disorders of parathyroid gland formation
MCADD ACADM    1p31.1

1:17,000

 

Fasting hypoglycemia, encephalopathy, hepatic dysfunction
  1. Disorders of parathyroid hormone synthesis or secretion
PTH gene mutationsAD or ARPTH11p15.3-p15.1

 

 

 
AD hypocalcemia type 1AD or sporadicCASR3q13.3-q21.1 

Hypercalciuria

 

AD hypocalcemia type 2AD or sporadicGNA1119p13.3  
  1. Disorders of parathyroid gland destruction
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophyAR, AD or sporadicAIRE21q22.31:90,000 – 1:200,000Mucocutaneous candidiasis, Adrenal insufficiency, and Primary hypoparathyroidism

Abbreviations

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 

Conflicts

None

Funding

None

References

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