Markedly discordant hypophosphatasia in a young girl

Hypophosphatasia (HPP) is the inborn-error-of-metabolism from deactivating mutation(s) of ALPL, the gene that encodes the cell surface “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP). HPP's “biochemical signature” comprises low serum alkaline phosphatase activity together with elevated plasma levels of the TNSALP natural substrates phosphoethanolamine (PEA), pyridoxal 5′-phosphate (PLP), and inorganic pyrophosphate (PPi). Excess extracellular PPi (ePPi) inhibits mineralization and affected children prematurely shed deciduous teeth and often suffer weakness and rickets. Yet, HPP severity is greatest among all dento-osseous disorders and not fully explained by autosomal dominant versus autosomal recessive inheritance involving >470 ALPL mutations. Discordance of HPP phenotype sometimes manifests even among full siblings sharing an identical ALPL genotype.

Herein, a girl's markedly discordant HPP featured at presentation life-threatening hypercalcemia, failure-to-thrive, and renal compromise. Subsequent pseudotumor cerebri syndrome caused blindness, and then craniosynostosis required cranial vault reconstruction. However, she was not deformed, had moderate hypophosphatasemia, normal plasma PLP level, and mild radiographic features of HPP rickets. Elevated plasma N-terminal parathyroid hormone-related protein (PTHrP) suggested malignancy, but corrected after kidney transplantation. HPP was diagnosed when whole exome sequencing revealed heterozygous ALPL c.1034C>T, p.A345V found in mild pediatric HPP and transmitted by her mother who considered herself well. Genes conditioning ePPi formation and underlying other skeletal diseases were intact. Hypercalcemia, unresponsive to bone antiresorptive drugs, corrected promptly with asfotase alfa TNSALP supplementation therapy. Her markedly discordant findings highlight genotype/phenotype plasticity for pediatric HPP, and her clinical course importance for early diagnosis.