Endocrine Abstracts

Background: Hypophosphatasia is a rare genetic disease with low serum alkaline phosphatase (ALP) activity and hypophosphatasemia. It is caused by loss-of-function mutations and deletions of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) gene; it has a wide range of severity in its phenotype, from death in utero to asymptomatic disease accidentally diagnosed in adult life. Furthermore, some diseases and drugs may induce hypophosphatasemia. Thus, the genetic and acquired etiology can be hardly distinguishable. Aim of the present study was to identify clinical and/or biochemical parameters predictive of genetic disease.

Materials and methods: This is a retrospective study. Biochemical analyses, including serum vitamin B6 and urinary phosphoethanolamine, DXA results and genetic analyses (NGS, MLPA and direct sequencing) were performed in 21 adults (0.9%) with at least two values of ALP below the reference levels out of 2319 osteoporotic patients referred to our third level Bone Unit. Hypophosphatasemic patients with diseases and therapies known to reduce ALP levels were excluded.

Results: Eight patients harboring mutations and/or polymorphic variants of theTNSALP gene (two males, six females; median age 55.0 years, range 50.9–65.6: group A) were detected. Thirteen patients (three males, Ten females; median age 51, range 45.4–62.2) had a negative genetic molecular analysis (group B). The two groups were similar for most of the investigated biochemical parameters, including vitamin B6 levels, though urinary levels of phosphoethanolamine showed the trend to be higher in the group A patients [median values 5.25 (3.22–6.10) vs 3.0 (2.30–4.85) mmol/mol of creatinine; P = 0.056]. On the other hand, anamnestic data appear more indicative of the genetic origin of hypophosphatasemia: dental anomalies, musculoskeletal symptoms and familiarity for skeletal and extra-skeletal manifestations of the disease occurred more frequently in group A with respect to group B (P = 0.056, P = 0.032, and P = 0.032, respectively). It is note of worth that 7 out of the 13 patients harboring the wild type TNSALP gene experienced low levels of ALP during treatment with tamoxifen, a drug whose hypophosphatasemic effect is uncertain.

Conclusions: Urine levels of phosphoethanolamine may be a useful tool in distinguishing between genetic and acquired forms of hypophosphatasemia, though anamnestic data such as dental anomalies, musculoskeletal symptoms and familiarity for the skeletal and extra-skeletal manifestations of the disease may be even more relevant in the selection of the patients deserving of genetic analysis. Moreover, our data suggested that tamoxifen should be considered as a hypophosphatasemic drug.