EP115: Two novel NPR2 variants in a patient with acromesomelic dysplasia - Maroteaux type

Abstract

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature (adult height < 120 cm), dolichocephaly, acro- and mesomelic shortening of the limbs, short, broad fingers and flat feet. Radiographic findings include bowed radius with a short ulna, dolichocephaly, platyspondyly and narrowing of the lumbar interpedicular distances. Intelligence is unaffected. The condition is typically diagnosed at birth or in infancy, but features become more apparent over time because of the loss of linear growth. AMDM is caused by biallelic loss of function variants in the NPR2 gene which encodes the natriuretic peptide receptor-B (NPR-B). The NPR2 gene encodes a transmembrane receptor that is critical in endochondral bone formation. Forty four percent of variants in NPR2 occur in the ligand binding domain, 8% in the transmembrane domain, 26% in the protein kinase domain and 21% in the nucleotide cyclase domain. A seven-month-old was seen with clinical findings suggestive of a skeletal dysplasia. She was born at 36 weeks following a pregnancy complicated by maternal polysubstance use and poor prenatal care. Clinical findings were shortening of all limb segments, trident hands, weak grasp, and overlapping second and third toes bilaterally. Radiographic findings were shortening of all the long bones with metaphyseal flaring, short and broad metatarsals, metacarpals and phalanges also with mild metaphyseal widening, platyspondyly with mild anterior vertebral body beaking in the upper lumbar spine. Cervical CT examination revealed platyspondyly of the suboccipital vertebrae and decreased AP diameter of the spinal canal at C1 secondary to anterior bowing of the posterior arch. A multi-gene skeletal dysplasia panel identified twelve variants, including two variants in NPR2. NPR2 c.1699G>T was classified as pathogenic, causing a premature termination at amino acid 567 in the kinase homology domain of the transmembrane protein. While classified as a VUS, the c.1123G>A missense variant was predicted to cause a substitution at amino acid 375 and falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. The patient’s mother tested positive for the pathogenic variant and negative for the VUS in NPR2. Acromesomelic dysplasia, Maroteaux type is a rare skeletal dysplasia with limited published phenotypic and molecular information available. The described patient presented a diagnostic conundrum because only one of the variants had been characterized as pathogenic. The variant of uncertain significance is located in the ligand binding domain of the NPR2 gene, in which the majority of reported variants in this gene are found. In silico algorithms predict this variant to be deleterious to the protein structure and function but these predictions have not been confirmed by functional studies. Furthermore, missense variants within the consensus splice sites commonly cause abnormal splicing. This variant is not found in population databases. While paternal samples are not available to confirm that the variants are in trans, the patient was given the diagnosis of AMDM based on her clinical presentation. Molecular analysis and clinical description of other patients with AMDM will continue to characterize disease causing variants and natural history of this rare disease.