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

A 2-year-old boy, the first child of consanguineous parents, presented with global developmental delay. He could sit independently but had limited speech, using only a single meaningful word. Initial investigations revealed elevated alkaline phosphatase (ALP) levels of 1269 IU/L, suggestive of rickets. Despite two months of vitamin D supplementation, there was no clinical improvement, prompting referral for further evaluation.

On examination, the child showed mild hypotonia, below-average height, and normal head circumference. Vision and hearing were intact, and X-rays and metabolic tests were unremarkable. Given the combination of developmental delay and persistent hyperphosphatasia, hyperphosphatasia with impaired intellectual development syndrome (HPMRS)—specifically HPMRS3—was suspected, as there was no epilepsy or dysmorphic features. While awaiting genetic confirmation, the child was started on high-dose pyridoxine and folinic acid.

Exome sequencing subsequently identified a pathogenic variant in the PGAP2 gene, confirming the diagnosis. Over six months of treatment, the child’s developmental quotient improved, indicating a positive response to therapy.

HPMRS3 is a rare autosomal recessive disorder caused by mutations in PGAP2, a gene essential for attaching proteins to cell surfaces and expressed in the brain, skeletal muscle, heart, and liver. Clinically, it is characterized by developmental delays, intellectual disability, and elevated ALP, typically without major organ involvement. Early intervention with pyridoxine and folinic acid may enhance neurodevelopment and reduce seizure risk, though the underlying mechanisms remain to be fully elucidated.

Conclusion: Early recognition of elevated ALP in children with developmental delay, coupled with prompt treatment using pyridoxine and folinic acid, may offer therapeutic benefit in HPMRS3, highlighting the importance of genetic evaluation and timely intervention.

Source: Panda PK, Palayullakandi A, Gupta D, et al. 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.