A novel case of homozygous PAX1 mutation associated with hypoparathyroidism

Abstract

The PAX1 gene plays an important role in the development of the parathyroid glands and the thymus. Mouse knockout models of PAX1, PAX3, and PAX9 have been found to have hypoplastic or absent parathyroid glands. To our knowledge, there are no reported cases of PAX1-associated hypoparathyroidism in humans. We present a case of hypoparathyroidism in a 23-month-old boy with a homozygous pathogenic variant in the PAX1 gene ( PAX1 NM_006192.5 c.463_465del variant), predicted to cause an in-frame deletion of asparagine at position 155 (p.Asn155del) of the PAX1 protein. The hypoparathyroidism was unmasked after the patient developed significant hypocalcemia while receiving GoLYTELY (polyethylene glycol 3350, sodium sulfate anhydrous, sodium bicarbonate, sodium chloride, potassium chloride) for bowel cleanout. The patient had mild and asymptomatic hypocalcemia prior to hospitalization. The patient was noted to have inappropriately normal parathyroid hormone (PTH) level at the time of documented hypocalcemia thereby suggesting a diagnosis of hypoparathyroidism. Plain language summary The first human case of hypoparathyroidism associated with a rare genetic disorder: a case report of PAX1 gene mutation The paired box ( PAX) gene family is important for embryo development. One subfamily, PAX1, is necessary for development of the spinal column, thymus (important for the immune system development), and parathyroid (helps regulate the amount of calcium in the body). We present the case of a 23-month-old boy with known PAX1 gene mutation who came in with episodes of vomiting and poor growth. His presentation was thought to be most likely related to constipation. He was started on bowel cleanout medication and intravenous fluids. However, his calcium that had been mildly low subsequently dropped to very low levels. The level of parathyroid hormone (which helps regulate calcium levels) was inappropriately normal, meaning that his body was unable to make more, and was consistent with hypoparathyroidism. He was treated with calcium supplements and vitamin D and calcium levels normalized. He continues to be on calcium and vitamin D and calcium levels have remained stable. Doctors should keep this complication in mind when treating patients with PAX1 gene mutation.

Primary and secondary defects of the thymus

“…192 Homozygous variants in PAX1, a gene that belongs to the paired box family of transcription factors, cause otofaciocervical syndrome type 2 (OTFCS2), a clinical syndrome characterized by external ear anomalies/ear impairment, facial dysmorphic features, skeletal abnormalities in the shoulder girdle and vertebral bodies, and mild intellectual impairment. [193][194][195][196][197] PAX1 is expressed in the sclerotome, from which the vertebral column develops, and in all pharyngeal pouches. Due to its expression also in the third pharyngeal pouch, it regulates thymus development.…”