Diverse Genetic Aetiologies and Clinical Outcomes of Paediatric Hypoparathyroidism

Ja Hye Kim; Young-Lim Shin; Seung Yang; Chong Kun Cheon; Ja Hyang Cho; Beom Hee Lee; Gu-Hwan Kim; Jin Ok Lee; Eul Joo Seo; Jin-Ho Choi; Han-Wook Yoo


Clin Endocrinol. 2015;83(6):790-796. 

In This Article

Abstract and Introduction


Context Hypoparathyroidism is characterized by hypocalcaemia, hyperphosphataemia, and low or inappropriately normal parathyroid hormone (PTH) levels. Idiopathic or genetic drivers are the predominant causes of hypoparathyroidism in paediatric-age patients.

Objective This study investigated the aetiology and clinical course of primary hypoparathyroidism in infancy and childhood.

Subjects and Measurements This study included 37 patients (23 males, 14 females) with primary hypoparathyroidism diagnosed prior to 18 years of age. We analysed aetiologies, initial presentation, age at diagnosis, endocrine and radiological findings, and outcomes.

Results The median age at presentation was 1·7 months (range 1 day–17 years), and the mean follow-up duration was 7·0 ± 5·3 years (range 0·5–16·8 years). Our cohort included 22 cases (59·5%) of 22q11·2 microdeletion syndrome. Other aetiologies included hypoparathyroidism–deafness–renal dysplasia syndrome (5/37, 13·5%) and one patient each with autoimmune polyglandular syndrome type 1, Kearns–Sayre syndrome and Kenny–Caffey syndrome. The remaining 7 (18·9%) patients were classified as idiopathic hypoparathyroidism cases. Among the 15 patients who underwent brain imaging, 5 (33·3%) had basal ganglia calcification. Among the 26 patients examined by renal imaging, 5 (19·2%) had either nephrocalcinosis or a renal stone. After 11 months of calcium or calcitriol supplementation, 16 patients (43·2%) discontinued medication. The final PTH levels were significantly higher in patients with transient hypoparathyroidism than those with permanent hypoparathyroidism.

Conclusions Identification of the genetic aetiologies of hypoparathyroidism makes it possible to predict patient outcomes and provide appropriate genetic counselling. Long-term treatment with calcium and calcitriol necessitates monitoring for renal complications.


Hypoparathyroidism is a rare disorder characterized by low or inappropriately normal parathyroid hormone (PTH) levels, despite hypocalcaemia and hyperphosphataemia. This condition results from the inadequate mobilization of calcium from bone, reabsorption of calcium from the distal nephron and stimulation of renal 1α-hydroxylase activity, followed by insufficient production of 1,25-dihydroxyvitamin D3 and decreased intestinal absorption of calcium.[1] Its clinical manifestations include laryngospasm, bronchospasm, tetany and seizures in the neonatal period, and fatigue, confusion, paraesthesia, muscle cramping, twitching and arrhythmia in older children.[2]

In adults, hypoparathyroidism is usually an acquired condition caused by a complication of thyroidectomy, parathyroidectomy, radical neck dissection or radiation.[1] However, in children, this condition most often has an idiopathic or genetic origin, such as 22q11.2 microdeletion syndrome, autoimmune polyglandular syn-drome type 1 (APS1), hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome, hypoparathyroidism-retardation-dysmorphism (HRD) syndrome or mitochondrial disease.[2] Familial isolated hypoparathyroidism has also been identified, which is caused by loss-of-function mutations in GCMB,PTH or SOX3 or gain-of-function mutations in CASR.[2] Patients with hypoparathyroidism require supplementation with calcium and calcitriol and are confronted with the therapeutic dilemma of under- or over-treatment, which can lead to hypocalcaemic seizure or renal complications, such as hypercalciuria, nephrolithiasis or renal insufficiency.[3,4] Therefore, the goal of treatment is to maintain serum calcium levels at the low end of the normal range.

The prevalence of idiopathic hypoparathyroidism was measured at 7·2 per million individuals in a previous nationwide, epidemiological survey in Japan.[5] Although that study included both children and adults, the aetiologies of hypoparathyroidism were uncertain in many cases. Additionally, there have been few studies of the long-term clinical outcomes of patients with hypoparathyroidism.[4,6,7] Because of the rarity of hypoparathyroidism in infants and children, most studies of the aetiology and outcomes have been limited to adults or a small number of children. Therefore, our study investigated the genetic aetiologies, clinical findings and long-term outcomes of primary hypoparathyroidism in infants and children.