HYPOPHOSPHATASIA.

Introduction: Hypophosphatasia is a rare hereditary metabolic disease caused by the deficit of tissue nonspecific serum alkaline phosphatase (TNSALP). The incidence of all forms of hypophosphatasia is estimated at around 1:100 000 liveborns. Recent studies estimate the prevalence of mild autosomaldominant form at 1: 6370. During prenatal developement, this disease may cause severe damage of a fetus and even intrauterine death. During childhood, this disease manisfests with defects of mineralization with rickets signs. The following hypercalcaemia and hypercalciuria may even lead to death. In adults, the main manifestations are osteomalatia, skeletal deformities, fractures and early arthritis. Material and methods: We present the clinical course of hypophosphatasia in two sisters and the clinical features in an unrelated adult woman. Extremely low values of TNSALP were observed (0.06 μkat/l; 0.08 µkat/l; 0.03 µkat/l). To find causal mutations, sequencing of ALPL gene was performed. Results: Diagnosis of hypophosphatasia was confirmed in all three patients. We found a 436G>A and a 1183insT mutation in the adult woman. Very mild phenotype was observed and both mutations were previously not described. In silico 3D modeling of TNSALP was used to demonstrate the mutation causality. Segregation analysis was useful for genetic counselling in affected family. We found a 299C>T and a 571G>A mutation in two sisters, who were the first documented cases with childhood form of the disease in Slovakia. Conclusion: Defects of mineralization of bones and teeth (in the presence of low or moderately decrased values of ALP) is a reason for considering hypophosphatasia. The molecular genetic diagnostics opens the possibility of determinig the molecular cause of hypophosphatasia in Slovak patients. The proper diagnosis is essential for an adequate therapy management, like avoiding the treatment with biphosphonates and excess of vitamin D, where higher risk of pseudofractures in adult patients with osteomalatia was described. After determining the causal mutation, genetic counselling and eventual prenatal genetic testing are recommended. [ABSTRACT FROM AUTHOR]