Two new GCM2 mutations tied to severe hypoparathyroidism
Reported to be genetic cause of disease in a woman and an infant in India
Two severe cases of hypoparathyroidism were associated with two newly identified mutations in the glial cell missing homolog 2 (GCM2) gene by scientists in India.
“This report demonstrates the critical role of GCM2 activity in human parathyroid gland development through clinical and genetic analysis of 2 patients with hypoparathyroidism,” the researchers wrote. “These findings have more immediate relevance for the diagnosis and treatment of cases having isolated hypoparathyroidism.”
The study, “Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations,” was published in the Journal of Endocrine Society.
GCM2 gene regulates parathyroid gland development, blood calcium levels
Hypoparathyroidism is characterized by low levels of the parathyroid hormone, produced in the parathyroid glands, resulting in low hypocalcemia (low calcium) and vitamin D levels, and high phosphorus levels in the blood. This results in disease symptoms like muscle cramps, pain, tingling, or burning sensation in the limbs.
Genetic factors can be among the several potential causes of hypoparathyroidism. In particular, the GCM2 gene is a critical regulator of the development of the parathyroid glands, and important for the regulation of calcium levels in the blood.
Researchers in Kolkata described two cases of hypoparathyroidism with clinical features of hypocalcemia and associated with novel mutations in the GCM2 gene.
The first case involved a 32-year-old woman, who came to their hospital with complaints of involuntary muscle contractions in her limbs for three to four days and a burning or prickling sensation and tightness around her mouth and in the hands and feet. She had been treated elsewhere for similar symptoms twice in the last five years, and hospitalized to manage acute hypocalcemia.
Scientists found she had hypocalcemia, low magnesium levels, and calcification of the basal ganglia, a brain region, due to increased phosphorus levels that lead to the deposition of calcium-phosphorus complexes in the brain. She also showed persistent low potassium levels, with increased potassium and calcium levels in the urine, and magnesium renal loss. The parathyroid hormone was at undetectable levels.
She was treated for hypocalcemia with a continuous infusion of calcium gluconate for 48 hours until the hypocalcemia was controlled. After that, she started on oral calcium and calcitriol (activate vitamin D). The patient was treated with magnesium sulfate infusion for the low magnesium levels until the magnesium blood serum levels were above 1.2 mg/dL, followed by oral magnesium tablets. After hospital discharge, she added spironolactone (for the low potassium levels) to the treatment regimen.
Focused exome sequencing, which sequences the exome — parts of the genome used to make proteins — identified a heterozygous mutation in the GCM2 gene. Heterozygous mutations refer to changes in one of the two gene copies a child inherits from parents.
The mutation occurred in exon 5 and had not been reported before. It was predicted to likely be disease causing by leading to the loss of normal GCM2 protein function and removing more than 10% of the protein.
A 1-month-old boy, born to consanguineous (related) parents, and with a normal birth history was the second case. He who was admitted to the pediatrics emergency unit with a sudden onset of involuntary jerky limb movements and rolling up eyeballs followed by unresponsiveness, indicative of seizures. The seizures were controlled with antiepileptics.
Blood analysis revealed low calcium and parathyroid hormone levels, and high phosphorus levels. Focused exome sequencing identified a mutation in the GCM2 gene, at exon 1–2, as likely causing the symptoms. It may lead to loss of function in GCM2 protein, the investigators noted.
The baby was treated with calcium gluconate alone, without significant improvement. Oral calcium and calcitriol then were added to the regimen. However, optimal blood calcium levels were not maintained due to difficulties in keeping the intravenous (into the vein) administration.
He started on a trial with Forteo (teriparatide) — a synthetic parathyroid hormone fragment — twice a day. Of note, Forteo is approved to osteoporosis, a disease marked by weak and fragile bones. After three days, his calcium and phosphorus levels were corrected. The Forteo dose was reduced after three weeks, and treatment ended at four weeks when the child was able to maintain normal calcium levels with oral calcium and calcitriol. At follow-up, the treatment was effective in eliminating seizures.
“Our case describing the neonate who presented with hypoparathyroidism soon after birth underscores the role of GCM2 in early parathyroid gland development and differentiation,” the researchers wrote. “This case also demonstrates the utility of off-label short-term teriparatide to treat severe hypocalcemia and [high phosphorus] in a neonate with hypoparathyroidism.”
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