MON-493 A Unique Case of Severe Osteogenesis Imperfecta Due to a Novel Heterozygous Mutation in COL1A1 Gene with Overlapping Hypophosphatasia Phenotype

Abstract

Background: Osteogenesis imperfecta (OI) is a rare heterogeneous bone fragility disease due to collagen defect most often caused by autosomal dominant (AD) COL1A1 or COL1A2 gene mutations. Severe forms of Hypophosphatasia (HPP) may phenotypically resemble OI, is a distinct disorder of hypomineralization caused by the mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Here in, we present the first case of a neonate with severe perinatal OI caused by a novel AD mutation in COL1A1 gene with HPP phenotype treated with asfotase alfa. Case: A 3-day-old full-term boy born by cesarean section presented with multiple fractures & dislocated hips at birth. On physical exam, he was found to have respiratory distress ultimately requiring intubation, hypoplastic rib-cage, blue sclerae, mesomelia, rhizomelia, left & right dislocated hips. Skeletal survey showed multiple fractures of long bones and ribs of varying ages, characteristic of OI. In addition, he was noted to have generalized hypomineralization, hypoplastic ribs, and some metaphyseal flaring. Interestingly, biochemical evaluation revealed hypercalcemia (corrected calcium of 11.7 mg/dL), low alkaline phosphatase (ALP) 58(80-270 U/L), slightly elevated pyridoxal 5” phosphate 52 (5-50 mg/dL) & high urine phosphoethanolamine 285(83-222 mcmol/g Cr). Due to clinical, radiographic, and biochemical findings concerning for HPP, the patient was started on asfotase alfa. The genetic testing showed a novel likely pathogenic heterozygous variant Chr17: c.1201G>C (p.Gly401Arg) in the COL1A1 gene consistent with AD OI. The ALPL gene sequencing revealed no variants in the coding region with 100% coverage of the region. After 7 wks of treatment, x-rays showed two new long bone fractures, but interval osseous remodeling & healing of the previous fractures with an overall improvement in the tubulation of the long bones. Conclusion: To our knowledge, this is the first report describing low ALP activity with phenotypic features of HPP in a neonate with severe perinatal OI due to a novel AD COL1A1 mutation. The low ALP could be due to osteoblasts dysfunction rather than ALPL gene causing enzyme deficiency & it highlights a potentially important role of osteoblasts in the pathogenesis of OI leading to reduced ALP activity and HPP phenotype. Interestingly, patients with lethal type II OI exhibit hypoplastic ribs and generalized hypomineralization; and, osteoblastic dysfunction has been suggested. It is tempting to speculate that low ALP activity may potentially have an additive effect on the severity and possibly lethality of certain most severe forms of OI contributing to potentially a new phenotype of this heterogeneous disorder. Long-term follow-up is needed to see if the patient will benefit from asfotase alfa treatment. In addition, further studies should be performed to truly understand the pathogenesis of the disease in this patient.