A child with tetany, convulsions, and nephrocalcinosis: Answers

Abstract

1. What are the diagnostic possibilities in a child with hypocalcemia and nephrocalcinosis? The differential diagnoses for hypocalcemia with nephrocalcinosis are familial isolated hypoparathyroidism (FIH), syndromic hypoparathyroidism, calciumsensing receptor (CaSR)-activating mutations (sporadic and autosomal dominant), pseudohypoparathyroidism (insensitivity to PTH), and acquired causes of hypoparathyroidism (HPT). Familial hypoparathyroidism has autosomal recessive (GCM2, PTH gene mutations), autosomal dominant (CaSR gene mutation and some cases of GCM2 mutations), or X-linked (SOX3 gene mutation) inheritance. DiGeorge syndrome type 1 and type 2, CHARGE syndrome, autoimmune polyendocrine syndrome type 1, Kenny-Caffey syndrome type 1 and type 2, Sanjad-Sakati syndrome, Barakat syndrome, Kearns-Sayre syndrome, MELAS syndrome, mitochondrial trifunctional protein deficiency syndrome, Gracile bone dysplasia, and Pearson syndrome are the syndromic causes of hypoparathyroidism. Activating mutations of the CaSR gene cause autosomal dominant hypocalcemia type 1. Pseudohypoparathyroidism is caused by insensitivity to the PTH hormone due to mutations in genes PTHR1, GNAS, PRKAR1A, and hypomagnesemia [1]. The acquired causes of hypoparathyroidism include activating antibodies to the CasR, maternal hyperparathyroidism, post-surgical and radiation-induced damage to the parathyroid glands, deposition of iron or copper (thalassemia, hemochromatosis, Wilson disease), or infiltration (neoplastic invasion, sarcoidosis, amyloidosis) [2]. Our patient had tetany, convulsions with hypocalcemia, hyperphosphatemia, low serum PTH, nephrocalcinosis, and calcifications in basal ganglia and frontal lobes. Hence, a provisional diagnosis of hypoparathyroidism was considered. Syndromic and acquired causes of hypoparathyroidism were considered unlikely as there were no features or history suggestive of the same. Pseudohypoparathyroidism was ruled out as serum PTH was low. A targeted genetic analysis by clinical exome sequencing was performed in our case which revealed a heterozygous missense variation c.1151C>T in exon 5 of the GCM2 gene (chr 6: 10874598G>A), confirming the diagnosis of familial isolated hypoparathyroidismtype 2 (autosomal dominant inheritance). 2. How should this child be managed? Management of such cases includes evaluation, treatment of acute hypocalcemia, and long-term follow-up. The index case presented with seizures to our pediatric emergency unit. At admission, there were no features suggestive of meningitis, and the blood glucose was normal. The index case had hypocalcemia, hyperphosphatemia with low PTH levels, and normal serum creatinine, confirming hypoparathyroidism. Another condition with similar clinical manifestations (tetany, seizures), hypocalcemia, hyperphosphatemia, and ectopic calcifications in brain and kidneys is pseudohypoparathyroidism. However, specific clinical features (short stature, obesity, rounded face, and brachydactyly mostly affecting the 4th and 5th metacarpals and metatarsals in Albright hereditary osteodystrophy) and high serum PTH levels in pseudohypoparathyroidism differentiate it from hypoparathyroidism [3]. Hypoparathyroidism is associated with ectopic calcifications. Hence, screening for calcifications in the kidney and brain is recommended. This includes urinary calThis refers to the article that can be found at https://doi. org/10.1007/s00467-021-05230-5.