ESPE Abstracts

Introduction: Hypophosphatasia (HPP) is a rare, potentially fatal, either autosomal dominant or recessive genetic disorder caused by the loss of function of the tissue-non-specific isoenzyme of the serum alkaline phosphatase, due to pathogenic variants of the ALPL gene. The onset of the deleterious effects on bone metabolism is highly variable, ranging from mild cases with dental abnormalities to severe forms that can be life-threatening in infancy or early childhood. The diagnostic work-up comprises radiographic examinations and laboratory tests that support, but do not confirm the diagnosis- increased urinary phosphoethanolamine (PEA) and inorganic pyrophosphate levels, increased serum pyridoxal 5'-phosphate. Specific treatment with recombinant enzyme replacement therapy, asfotase alfa, substantially improves the outcome of the disease. We present the first case of HPP diagnosed in Romania.

Clinical case: Our patient is a 14-year-old adolescent of consanguineous parents, with a history of septic coxo-femoral osteoarthritis at 3 weeks and significant bone mineralization impairment that drew attention at the age of 6 months, presenting large fontanelles and significant rickets sequelae that required vitamin D supplementation at that time, but then craniosynosthosis occurred at 10 months old. At first, the diagnosis of osteogenesis imperfecta was considered, given the significant bone demineralization of the upper limbs, with “moth-eaten” appearance and cup-shaped metaphysis seen on X-Ray imaging. At the 1y3mo evaluation, the clinical picture showed short stature at -3,18 SD, delayed neuro-motor development, cranial dysmorphism, macrocephaly, loss of temporary teeth, dorsal kyphosis, and a small rib cage. The clinical data and the generalized low bone mineral density raised the suspicion of HPP, supported by high PEA levels in urine and confirmed by the genetic test which identified 2 heterozygous variants: p.Tyr187Cys (exon 6: c.560A>G) and p.Arg450Cys (exon 12: c.1348C>T). The initiation of adequate treatment with asfotase alfa conducted to a favourable clinical and radiological evolution.

Discussions: Because of the similar features to other more common skeletal disorders, HPP can be easily overlooked. Despite its rarity, it is of major importance to consider HPP in order to provide the specific treatment. Patients who present with apparently less severe forms of HPP in childhood and who are misdiagnosed, may present with more severe forms of the disease later in life, given that inappropriate management can exacerbate the clinical consequences of HPP. Our patient’s mutation p.Tyr187Cys (exon 6: c.560A>G) has not been described in the literature before.