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


The present study findings demonstrate that rare Mendelian disorders and chromosome 22q11.2 microdeletion syndrome are the major causes of paediatric primary hypoparathyroidism. Because diverse genetic causes underlie paediatric primary hypoparathyroidism, our current results highlight the importance of extensive genetic analysis based on phenotype delineation for proper disease management and genetic counselling of patients and families who are at risk.

The most common cause of primary hypoparathyroidism in childhood was chromosome 22q11.2 microdeletion syndrome. However, as our institute is one of the largest centres for congenital heart disease in Korea, the number of patients with chromosome 22q11.2 microdeletion syndrome might have been overrepresented in our present analyses. This syndrome is one of the most common contiguous gene syndromes, with an incidence of 1 in 4000 newborns, and results from the deletion of a 1·5- to 3-Mb fragment of human chromosome 22q11.2. This region contains TBX1, a gene that encodes a transcription factor necessary for pharyngeal development.[11] As this syndrome is usually accompanied by other malformations, such as cleft lip/palate, congenital heart disease and renal anomalies, we readily diagnosed 11 patients in the neonatal period and 2 patients in the prenatal period by foetal ultrasonography. In previous studies, hypocalcaemia with reduced PTH has been observed in 17–60% of patients and was restored to normal in over half of the cases.[8,12,13] In our present patient cohort, hypoparathyroidism spontaneously resolved in 43·2% of the subjects, and most of these patients had chromosome 22q11.2 microdeletion syndrome. This finding might be explained by the fact that infants require more calcium intake for a 'growth spurt', although the parathyroid gland is relatively hypoplastic in this syndrome. The PTH levels in our patients with transient hypoparathyroidism were at the lower end of the normal range at the last follow-up (1·56 ± 0·79 pmol/l), with normal levels of calcium and phosphorus without medication. A previous study has reported that patients with this syndrome had normocalcaemia at rest but a reduced ability to secrete PTH in response to pharmacologically evoked hypocalcaemia in 30–50% of cases.[14] Therefore, resolved patients with transient hypoparathyroidism should be monitored for hypocalcaemia during the acute illness period.

It has been reported that more than 90% of patients with HDR syndrome have concurrent hypoparathyroidism and a hearing defect.[15] However, renal anomalies are a heterogeneous feature of HDR syndrome and are not present in ~20% of patients.[15] In our present study, two patients with HDR syndrome did not have a renal anomaly, but a hearing defect was noted 10 years after the onset of hypoparathyroidism in one patient. Consequently, the diagnosis of this patient was changed from idiopathic hypoparathyroidism to HDR syndrome. Interestingly, severe generalized psoriatic arthritis was also observed in this patient. A similar case of HDR syndrome presenting with hypocalcaemia-induced generalized psoriasis has also been reported.[16] GATA3, the causative gene for HDR syndrome, is located 8·1 Mb from the telomere of chromosome 10p and plays an important role in embryonic development of the parathyroid gland, inner ear and kidney.[17] Partial deletion of the 10p terminal region has been reported in a DiGeorge-like phenotype associated with HDR syndrome, which is caused by GATA3 haploinsufficiency.[17] In our current patient cohort, only 1 of 5 unrelated HDR syndrome patients (20%) was paternally inherited. HDR syndrome is inherited in an autosomal dominant manner with varying degrees of penetrance; however, one study has reported that approximately half of the patients had a family history of this disorder.[15]

Hypoparathyroidism is a major endocrine feature of APS1, and a clinical diagnosis of APS1 requires the presence of at least 2 of the following 3 factors: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease.[18] However, in an earlier case series of 22 patients with APS1, 77% of patients initially presented with hypoparathyroidism, and a classic triad was only evident in 58% of patients.[19] In our current patient cohort, a case with APS1 had hypoparathyroidism without other APS1 symptoms for 10 years. Accordingly, the initial diagnosis of this patient was idiopathic hypoparathyroidism, while the other features of APS1 only became apparent with time. APS1 is associated with diverse clinical features, but single or atypical phenotypes can persist for a long time.[18] Therefore, early diagnosis is often problematic.

A recent study indicated that heterozygous mutations in FAM111A are one of the genetic causes of syndromic hypoparathyroidism, that is Kenny–Caffey syndrome.[20] We encountered a patient with hypoparathyroidism, growth retardation and dysmorphism in our current series. Immunological abnormalities have been reported previously in Kenny–Caffey syndrome,[21] and our patient died of sepsis as a consequence of Enterobacter cloacae and Stenotrophomonas maltophilia at 5 months of age.

Notably, genetic causes of hypoparathyroidism were common in our present study series. With the recent progress in understanding the molecular pathophysiology of isolated hypoparathyroidism, the PTH,GCMB,CASR and SOX3 genes are now known to cause familial isolated hypoparathyroidism.[22] Mutations in the PTH gene impair the processing of pre-pro-PTH to active PTH and cause persistent, overt hypoparathyroidism with low or undetectable PTH levels. GCM2 is a transcription factor crucial for the development of the parathyroid glands, and knockout mice of GCM2 lack parathyroid tissue.[23,24]CaSR activates the G-protein signalling pathway, leading to reduced transcription of PTH. Patients with gain-of-function mutations in CASR display treatment-resistant hypocalcaemia with hypercalciuria and are more likely to have nephrocalcinosis.[23]SOX3 is also a transcription factor that plays a role in embryonic development of the parathyroid glands. A few families with X-linked, recessive hypoparathyroidsm caused by SOX3 deletions have been reported.[25] Some of the aforementioned genetic aetiologies were not suspected based on their phenotypes and biochemical profiles. However, those genes were not analysed in our idiopathic group.

We clarified the cause of primary hypoparathyroidism in 28 of our current study patients (75·7%) at presentation, while two patients (5·4%) were considered idiopathic. However, one of these patients was reclassified as HDR syndrome due to a hearing defect and the other was reclassified as APS1 due to Addison's disease. These two patients did not manifest any distinct phenotypes suggesting HDR syndrome or APS1 at diagnosis, and these symptoms only became apparent 10 years later. Thus, idiopathic hypoparathyroidism can sometimes be reclassified as an identifiable disease with a molecular genetic defect.

The prevalence of basal ganglia calcification in hypoparathyroidism has previously been reported to be 50–74%[4,26] However, basal ganglia calcification was only present in 33·3% of our current study patients who underwent brain imaging. A previous study has reported that the occurrence of basal ganglia calcification was related to the duration of hypocalcaemia and the calcium-to-phosphorus ratio.[26] However, in our present analysis, brain imaging was carried out at the time of presentation in only a small number of patients. Therefore, estimations of the prevalence of basal ganglia calcification and predictions of its progression were limited. Although overt neurological symptoms were not observed in our present study cohort, we recommend that a neuropsychiatric assessment should be performed to assess cognitive disturbances throughout life in these cases.

Monitoring renal complications and optimizing treatments to preserve renal function are both critical for patients with hypoparathyroidism, particularly in paediatric patients who require lifelong treatment and monitoring. In adults, regular 24-h urine calcium levels are recommended.[4] Hypercalciuria can occur in the absence of hypercalcaemia, necessitating the quantification of urine calcium using random-spot urine tests in infants and children or 24-h urine collections in co-operative older children. Renal complications were observed in five patients, indicating that cautious monitoring of renal function, imaging and urinary calcium excretion is needed. The high incidence of nephrocalcinosis in our idiopathic group might be explained by a persistent requirement of vitamin D analogue treatment. CASR mutations are known to increase the risk of nephrocalcinosis and renal impairment because of hypercalciuria and vitamin D medication.[24,27,28] Therefore, identifying CASR defects is important for maintaining calcium levels in the low-to-normal range and preventing renal complications.

In conclusion, we have described the aetiological spectrum and clinical course of hypoparathyroidism and demonstrate that the need for lifelong treatment necessitates monitoring for hypercalciuria and renal impairment in affected patients. By understanding the molecular aetiology of hypoparathyroidism, identifying the genetic causes should be possible. We suggest a diagnostic algorithm for hypoparathyroidism based on the present and previous studies (Fig. 2).[1,15,18,21,22] Appropriate genetic testing should be conducted on the basis of clinical suspicion to obtain a confirmatory diagnosis. This strategy has enabled us to predict the natural history of this disease and offer proper management and genetic counselling, along with screening of family members who might be at risk.

Figure 2.

Diagnostic algorithm for primary hypoparathyroidism.