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


Clinical and Endocrine Features at Presentation

The median age at diagnosis in the study series was 1·7 months (range 1 day–17 years), and the mean follow-up duration was 7·0 ± 5·3 years (range 0·5–22 years). The clinical characteristics and aetiologies in this cohort are summarized in Table 1. Among the 37 patients analysed, 21 (56·8%) presented with generalized tonic-clonic seizure and 2 (5·4%) with hypocalcaemic tetany. The remaining 14 patients (37·8%) were diagnosed incidentally because of additional clinical features of 22q11.2 microdeletion syndrome and Kenny–Caffey syndrome. These 14 patients, who presented with congenital heart disease, cleft lip/palate and skeletal dysplasia, were diagnosed significantly earlier than other patients (P < 0·001).

The initial PTH levels were 0·79 ± 0·47 pmol/l (range 0·17–2·16 pmol/l) with low calcium levels (total calcium, 1·6 ± 0·25 mmol/l, range 1·1–2 mmol/l; ionized calcium, 0·7 ± 0·2 mmol/l, range 0·3–0·95 mmol/l) and elevated phosphorus levels (2·3 ± 0·6 mmol/l, range 1·4–3·4 mmol/l). There were 26 patients (70·3%) who presented with overt hypoparathyroidism. Clinical symptoms, including tetany and seizure, were significantly more frequent at presentation in patients with overt hypoparathyrodisim (20/26 patients, 76·9%) compared with patients in the low-to-normal PTH group (3/11 patients, 27·3%) (P = 0·026). Brain imaging was performed in 15 patients with symptomatic hypocalcaemia at presentation, and 5 of these cases (33·3%) exhibited basal ganglia calcification.

Clinical Features According to Genetic Aetiologies of Hypoparathyroidism

A total of 22 patients (59·5%) had chromosome 22q11.2 microdeletion syndrome. Other aetiologies included HDR syndrome (5 patients, 13·5%) as well as APS1, Kearns–Sayre syndrome and Kenny–Caffey syndrome, which each occurred in one pati-ent (2·7%). In patients with chromosome 22q11.2 microdeletion syndrome, the median age at diagnosis was 7 days (range 1 day–14 years), significantly earlier than in patients with other causes of hypoparathyroidism (P < 0·001). Among patients with chromosome 22q11.2 microdeletion syndrome, 13 cases showed no symptoms of hypocalcaemia but were diagnosed because of features such as congenital heart disease, cleft lip/palate or renal anomalies.

There were 5 unrelated patients with HDR syndrome in the study series who were diagnosed at a median age of 9 years (range 0·5–12 years). All of these patients manifested hypocalcaemic seizures. Hearing defects were noted in 4 patients, and 3 patients had renal anomalies, including renal agenesis, dysgenesis and multicystic dysplastic kidney.[9] A total of five different GATA3 mutations were identified, two previously reported nonsense and frameshift mutations (p.R367* and p.F51Lfs*144)[9,10] and three novel variants (p.R86fs*219, p.C284W and p.S237Qfs*67). The p.C284W variant was predicted to be deleterious by in silico analysis using SIFT (http://sift.jcvi.org) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) and was not present in the 1000 genomes browser (http://browser.1000genomes.org) or dbSNP (http://www.ncbi.nlm.nih.gov/snp/). The father of the patient with p.R86fs*219 had the same mutation along with hypoparathyroidism and a hearing defect. The mutations in the other 4 patients occurred de novo, as they had healthy parents.

The patient with APS1 presented with a hypocalcaemic seizure at 5 years of age. Adrenal insufficiency and oesophageal candidiasis developed when this individual was 15 years old. A novel compound heterozygous mutation in the AIRE gene, c.306del (p.K102fs*45) and c.1486_1498del (p.G496_G500delinsPfs*21), was identified.

A 4-month-old male exhibited hypoparathyroidism, growth retardation and dysmorphic features, such as relative macrocephaly, frontal bossing, large fontanelle, deep-set eyes, a beaked nose and small hands and feet, which together strongly suggested Kenny–Caffey syndrome. His long bones were slender and had sclerotic areas in the metaphyseal regions. The clavicles and ribs were thin (Fig. 1). A mutational analysis of the TBCE and FAM111A genes revealed a novel heterozygous variant of p.C485F in FAM111A. This site is a highly conserved residue across various species, as determined by multiple sequence alignment using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo). Additionally, this variant was predicted to alter protein function based on in silico analysis using SIFT (http://sift.jcvi.org) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2) and was not found in either the 1000 genomes browser (http://browser.1000genomes.org) or dbSNP (http://www.ncbi.nlm.nih.gov/snp). His parents were phenotypically normal and had no mutations in the FAM111A gene.

Figure 1.

Infantogram of a case in the current study series with Kenny–Caffey syndrome. (a) Wide fontanelle and suture are shown by a skull X-ray. (b) A relatively large head is observed. Slender and sclerotic areas in the metaphyseal regions of the long bones were noted. Thin clavicles, and rib and soft tissue calcification in both the lower neck and left chest wall were present.

The remaining 7 patients (18·9%) had no known genetic aetiology and were classified as idiopathic hypoparathyroidism cases.

Clinical Outcomes

Calcium and/or calcitriol supplementation were initiated in all patients with symptomatic hypocalcaemia. Sixteen patients (43·2%) were able to discontinue medication after 11 months of therapy at a mean age of 3·2 ± 5·1 years (range 0·4–18·1 years). Most patients with transient hypoparathyroidism had chromosome 22q11.2 microdeletion syndrome, except for one patient with idiopathic hypoparathyroidism. The initial levels of calcium and phosphorus were not significantly different between patients with transient and permanent hypoparathyroidism (P = 0·472 and P = 0·193, respectively). Additionally, the initial PTH levels were not significantly different in either group (transient vs. permanent: 1·01 ± 0·53 vs 0·59 ± 0·33 pmol/l, P = 0·071). The final measurements of serum calcium and phosphorus levels were not different between the groups, but the final PTH levels were significantly higher in the transient group (transient vs. permanent: 1·56 ± 0·79 vs 0·55 ± 0·38 pmol/l, P = 0·003).

To date, 21 of the study patients have received medication, including 2 patients who received calcitriol alone and 19 who received calcium and calcitriol. The mean doses of elementary calcium and calcitriol were 18·9 ± 9·3 mg/kg/day and 30·8 ± 26·1 ng/kg/day, respectively. The recommended treatment goal for hypoparathyroidism is to maintain serum calcium in the low-to-normal range, and the most recent measurements of ionized calcium, total calcium and phosphorus levels were 1·1 ± 0·1 mmol/l (range 0·9–1·4), 2·1 ± 0·2 mmol/l (range 1·8–2·5) and 1·7 ± 0·3 mmol/l (range 1·3–2·2), respectively.[4] During follow-up, renal function in most patients was in the normal range. However, end-stage renal disease developed in one patient with Kearns–Sayre syndrome, which was mainly a consequence of the disease course rather than a complication of medication usage. A total of 26 patients underwent renal imaging during follow-up, with a mean duration of 6·3 ± 6·4 years, and renal imaging was conducted approximately twice per patient and once every 2·5 years. There were 5 patients (19·2%) who developed renal complications, including nephrocalcinosis or renal stones, after 3·5 years (range 1·6–12·5 years) of calcium and calcitriol supplementation. Renal complications were more prevalent in the idiopathic patients compared with cases with an identified genetic aetiology (P = 0·017).