Diagnosis and Management of HPMRS3 in a 2-Year-Old Boy with Developmental Delay

A 2-year-old boy, the first child of consanguineous parents presented with global developmental delay. He could sit up but had limited speech, only using one meaningful word. Initial tests showed elevated alkaline phosphatase (ALP) levels (1269 IU/L), suggesting rickets. However, even after two months of vitamin D treatment, the child showed no improvement leading to a referral for further evaluation.

Upon examination, there were no signs of rickets or major systemic issues, though mild hypotonia was noted. His measurements were below average for height, while head circumference was within normal limits. Normal vision and hearing were confirmed, and X-rays and metabolic tests were unremarkable. Owing to his developmental delays and high ALP, the diagnosis of hyperphosphatasia with impaired intellectual development syndrome (HPMRS) was suspected, specifically HPMRS3, due to the lack of epilepsy or dysmorphism. The child was treated with high doses of pyridoxine and folinic acid while genetic testing was pending. Exome sequencing later revealed a pathogenic variant in the PGAP2 gene, confirming the diagnosis, and his developmental quotient improved over six months.

HPMRS3 is a rare autosomal recessive disorder associated with mutations in the PGAP2 gene, which is crucial for attaching proteins to cell surfaces and is expressed in the brain, skeletal muscle, heart, and liver. The disorder is characterized by developmental delays, intellectual disabilities, and elevated ALP without significant organ abnormalities. Early treatment with pyridoxine and folinic acid may enhance neurodevelopment and reduce seizures, although the underlying mechanisms require further research.

To conclude, prompt recognition and treatment with pyridoxine and folinic acid in children experiencing developmental delays and elevated ALP levels could prove to be advantageous in patients with HPMRS3.

Source: Panda PK, Palayullakandi A, Gupta D, Sopanam S, Kaur A, Deo VK, Kumar S, Sharawat IK. Hyperphosphatasia with Impaired Intellectual Development Syndrome in a Toddler: Diagnostic Challenges and Therapeutic Approach. Indian J Pediatr. 2024 Dec 23. doi: 10.1007/s12098-024-05372-y. Epub ahead of print. PMID: 39714758.