Discussion and conclusion
Among hereditary causes of primary hyperparathyroidism, NSHPT is a highly uncommon autosomal recessive disorder, mostly caused by homozygous or compound heterozygous inactivating mutations in the gene encoding calicium sensing receptor (CaSR), a G-protein-coupled receptor expressed in the parathyroid glands, renal tubular cells, bones, and other organs, whose primary function is to maintain calcium homeostasis. Decreased sensitivity of the CaSR receptors to extracellular calcium results in PTH-hyperproduction and consequently, severe hypercalcemia (1), which can be potentially fatal or associated with severe neurodevelopmental impairments in untreated NSHPT patients (8, 9). On the other hand, early diagnosis and treatment of NSHPT usually leads to gradual improvement in growth and neurodevelopmental milestones (3,4,6).
Ten years after initial presentation, our patient has mild intellectual disability and microcephay and is under treatment for epilepsy while according to his mother, he has had normal serum calcium and PTH levels on occasional laboratory tests performed during childhood. Although not common, neuromotor retardation may persist even in otherwise successfully-treated NSHPT patients (1), Savas-Erdeve et al. reported mild mental retardation in a 15-year-old girl with a history of NSHPT, in whom normocalcemia was maintained by total parathyroidectomy, followed by calcitriol supplementation (10).
Our findings might be explained by exposure to severe hypercalcemia before parathyroidectomy, since hypercalcemia has been reported to induce cerebral vasoconstriction and subsequently, ischemia (11). At the present follow-up, the brain MRI findings were consistent with hypoxic-ischemic damage which may have been caused by the vasoconstriction induced by hypercalcemia during the neonatal period. Additionally, it has been hypothesized that CaSR plays a role in regulating the growth and development of the brain and inactivating mutations of CaSR may result in neurodevelopmental abnormalities (12).
Another explanation for hypoxic-ischemic damage in this patient is sepsis-associated encephalopathy. The pathophysiology of sepsis-associated encephalopathy is complex and multifactorial, including a number of intertwined mechanisms such as vascular damage,endothelial activation, breakdown of the blood brain barrier, altered brain signaling, braininflammation, and apoptosis (13).
Based on these findings, we suggest that impairment of neurodevelopment caused by NSHPT may be multifactorial in nature. Therefore, we recommend a strict follow-up program for these patients in order to minimize the comorbidities and complications associated with the disease. Moreover, a pediatric neurologist should be involved in the management of these patients in order to facilitate early detection and reduce the neurologic complications that may arise. The major limitation of our study is the absence of genetic testing for the CaSR gene due to the high cost and difficulty of accessing this test in our country. To our knowledge, this is the first case report and the longest follow-up of NSHPT in Iran.