Exploring Childhood Hypoparathyroidism: Stepwise Genetic Evaluation Approach

Tosun Busra Gurpinar; Ceren Alavanda; Ahmet Kahveci; İlknur Kurt; Elif Kelestemur; Abali Zehra Yavas; Didem Helvacioglu; Tulay Guran; Abdullah Bereket; Pınar Ata; Serap Turan

Background: Primary hypoparathyroidism (HP) is a rare disease characterized by hypocalcemia, hyperphosphatemia and low/inappropriately normal parathyroid hormone (PTH) levels. We aim to characterize the clinical findings and molecular aetiology of childhood HP in our cohort.

Method: DiGeorge-VCFS FISH analysis was performed on all patients (n=28) as the initial step after the diagnosis. In whom, FISH analysis was negative, a stepwise approach with next-generation sequencing (19 genes related to HP), cGH array and the mitochondrial panel were applied in their respective order when the prior test concluded negative.

Results: DiGeorge-VCFS FISH analysis demonstrated deletion in 8 patients, two of whom had isolated hypoparathyroidism without syndromic features. Molecular aetiology was detected in three (15%) of 20 patients (AIRE, FAM111A, GATA3) by next-generation sequencing. A homoplasmic variant was detected in the mitochondrial disease panel in one patient who presented with congenital cataracts and hypocalcemic convulsions. The patient with FAM111A mutation (Kenny-Caffey syndrome), presented with short stature, wide fontanel, increased cortical thickness in long bones, and hypercalciuria. The patient with AIRE mutation had no other autoimmunity but hypercalciuria and mild hypomagnesemia suggesting activating CaSR pathway. The patient with GATA3 mutation had no additional abnormality other than basal ganglia calcification. Presenting complaints of the patients were muscular cramps (n=8,28.5%), epileptic seizures (n=8,28.5%), and syncope (n=3,11%). Nine (32%) patients were referred due to incidentally discovered hypocalcemia. Hearing loss was detected in 21% of the patients, congenital heart anomaly in 25%, nephrolithiasis/nephrocalcinosis in 21%, cataracts in 11% and basal ganglia calcification in 18%. Clinical and Laboratory Characteristics of Patients with or without 22q11.2del


	22q11.2del (+) (n=8)	22q11.2del (-) (n=20)	P
Age at onset (years)	6.6±5.5	8.7±5.7	0.5*
Ca (mg/dL)	7.3±1.3	6.5±1.2	0.19*
Phosphorus (mg/dL)	6.6±1.2	7.7±1.5	0.07*
ALP (U/L)	274±173	277±164	0.86*
PTH (ng/L)	18±7.5	20±19	0.53*
Spot urine Ca/creatinine (mg/mg)	0.02±0.01	0.1±0.2	0.46*
Hearing loss (n)	1	5	0.46**
Congenital heart anomaly (n)	3 (ToF-2, VSD-1)	4 (Aortic Stenosis-1, Tricuspid Insufficiency-1, Aortic Insufficiency-1, VSD-1)	0.37**
Nephrolithiasis/nephrocalcinosis (n)	-	6
Cataracts (n)	-	3
Basal ganglia calcification (n)	1	4	0.63**
Mann-Whitney U *Fisher’s Exact Test

Conclusion: Molecular aetiology was detected in 43% of all HP patients. 22q11.2 FISH analysis should be performed in the first step, whether the patient has syndromic features or not. The aetiology of hypoparathyroidism is obscure in more than half of the patients despite stepwise genetic approach.

ESPE Abstracts

P1-420