Intrafamilial phenotypic variability in hypophosphatasia: evidence from two families and the literature

Hypophosphatasia (HPP) is a genetic disorder caused by pathogenic mutations in the ALPL gene, resulting in reduced activity of the tissue-nonspecific alkaline phosphatase enzyme. The disease exhibits a wide phenotypic spectrum, varying from extremely severe forms that are often fatal during the prenatal or perinatal periods to very mild cases that are diagnosed in adult patients. Recent data indicate that familial cases account for approximately 50% of the total.

We present two families showcasing significant phenotypic heterogeneity among siblings who share the same genotype. The first family proband exhibited skeletal deformities, bone hypomineralization, early tooth loss, and failure to thrive. In contrast, her older sister displayed only radiographic signs of hypophosphatasia (HPP). The medical history of the second family included a therapeutic abortion due to significant fetal skeletal malformations. The fetus was found to be compound heterozygous for pathogenic variants of the ALPL gene. A villocentesis conducted during a subsequent pregnancy revealed that the fetus had the same genotype. However, ultrasound examinations indicated that the fetus was developing normally and growing as expected. At birth, no overt skeletal malformations were observed; however, radiographs demonstrated hypomineralization, and laboratory findings were consistent with hypophosphatasia. The patient was subsequently diagnosed with craniosynostosis.

Our case history emphasizes that, despite considerable progress in genetic diagnosis, predicting the severity of the phenotype remains difficult. Given the extreme phenotypic heterogeneity, even among family members, it is crucial to broaden the evaluation beyond prenatal findings by incorporating genetic investigations along with anamnestic, biochemical, and instrumental data.