Hospital Universitari General de Catalunya , Spain
Dr. Laura Castells is a trained and board certified Pediatrician and Neonatologist. She has a long-running interest in congenital cytomegalovirus infection as well as in genetic and rare diseases. She is currently head of the Neonatal Department of Hospital Universitari General de Catalunya (Barcelona, Spain).
Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). In HPP, loss of function in ALPL-gene leads to high levels of inorganic pyrophosphate and pyridoxal phosphate which inhibits bone matrix calcification. Here, we describe a newborn male with perinatal lethal HPP diagnosed after birth. Prenatal ultrasound at 28 weeks showed femur length shortness. There was no previous family history of bone disease. The patient was delivered by scheduled cesarean section at 37 weeks of gestation, requiring invasive ventilation immediately upon birth due to severe respiratory insufficiency. Diagnosis of HPP was confirmed by low-serum ALP activity <20 UI/L (normal reference range 530-1610 UI/L 0-14dy) and whole body X-ray showing severe bone hypomineralization, and thoracic and pulmonary hypoplasia. Pyridoxal 5’-phosphate (PLP) levels in plasma were >200 nmol/l (normal reference range 23.0-172.5), and phosphoethanolamine in urine was 7567 mcmol/g (normal reference range below 150), both substrates of TNSALP that accumulate endogenously in HPP. Respiratory insufficiency due to the severity of this metabolic systemic disease, led to fatal outcome on day three after birth. Further sequence analysis of ALPL using genomic DNA identified that the patient was heterozygous for two mutations: one in axon 5 of ALPL (p.Arg138Pro), previously unreported, and one in intron 5 of ALPL (c.473-2G>C), previously described. The parent DNA was analyzed being both of them heterozygous carrier.