Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype

Context Hypophosphatasia (HPP) is an inborn error of bone metabolism affecting the musculoskeletal and nervous systems. It is caused by monoallelic or biallelic pathogenic variants of the ALPL gene, which encodes the tissue non-specific alkaline phosphatase (TNSAP). Given its marked clinical variability ranging from prenatal presentations to symptoms onset in late adulthood, HPP often runs undetected with potential harms for affected individuals. Methods Clinical, molecular, in silico , in vitro , and, when accessible, family studies were carried out on 12 HPP individuals with variable clinical presentations. Variants were classified according to the American College of Medical Genetics and Genomics recommendations. Results Four cases were diagnosed as infantile, one as adult HPP. The other cases were completely asymptomatic (nr 4) or showed symptoms not strictly HPP-related (nr 3) but were all identified incidentally based on the biochemical low ALP value or severe bone fragility phenotype. Twelve “pathogenic o likely pathogenic variants” were identified including 9 missense (1 novel, 8 previously reported), 2 in frame indels and one multiexonic deletion. In vitro characterization of the seven point variants without previously described functional data confirmed a dramatic decreased enzymatic activity of some mutated enzymes. Conclusions Improving the recognition of HPP is essential because its rarity and extreme variable presentation with many asymptomatic cases lead to misdiagnosis or delay. Increased clinical awareness and attention to persistently low ALP levels are crucial to achieve earlier and more accurate diagnosis.