249 - Lethal neonatal NPHP-3 related ciliopathy as a cause for term respiratory failure

Poster Number: 249
Publication Number: 249.339

Jami L. Longo, Phoenix Children's Hospital, Phoenix, AZ, United States; Mohammad Bader, University of Arizona, Phoenix, AZ, United States; Hemananda K. Muniraman, Phoenix Children's Hospital, PHOENIX, AZ, United States; Mohammed Elkhwad, Phoenix Children's Hospital, Scottsdale, AZ, United States; Valerie Blanco, Phoenix Children's Hospital, Phoenix, AZ, United States

Background: The NPHP-3 gene on chromosome 3q22 encodes a protein involved in ciliary development and function. A small number of autosomal recessive NPHP-3 ciliopathies have been described, most commonly in association with nephronophthisis and renal-hepatic-pancreatic dysplasia. This rare gene deletion was found to cause three cases of term pulmonary hypoplasia, multicystic dysplastic kidney disease, and neonatal mortality in a Navajo family.

Objective: To present the first case series of a c.2694-2_2694-1del:p? in intron 19 of the NPHP-3 gene in a Navajo family.

Design/Methods: The medical record was reviewed for phenotypic and genotypic records from the three siblings.

Results: Three siblings were found to have similar phenotypic presentations and the same c.2694-2_2694-1del:p? variant of the NPHP-3 gene. The normal sequence with the bases that are altered is aaac[delag]GGGA. Both mother and father are of Navajo descent and are heterozygous for the same gene variant. The clinical pathology of their first child was early neonatal respiratory failure and death due to pulmonary hypoplasia and multicystic dysplastic kidneys. Their second child was also found on prenatal MRI to have pulmonary hypoplasia, hypoplastic right heart with tricuspid atresia, bilateral multicystic dysplastic kidneys, and anhydramnios. The child died within three hours of life secondary to respiratory failure and right-sided pneumothorax. On autopsy, the lungs were 19% expected volume with pulmonary arteriolar hypoplasia and an extra fissure in the right lower lobe. The heart showed dextrocardia with severe hypoplasia of the right ventricle and tricuspid valve stenosis, right atrial isomerism, and pulmonary artery connecton to the aortic arch (MAPCA). There was a bridging liver with zone 3 congestion and portal fibrosis. There were small bilateral multicystic dysplastic kidneys with bilateral end stage renal disease and club feet. Their third child was found to have pulmonary hypoplasia, pneumothoraces, oligohydramnios, pancreatic head cyst, duodenal duplication cyst, meconium plug syndrome, right inguinal hernia, and multicystic dysplastic kidneys requiring peritoneal dialysis. The infant required intubation at 6 weeks of life and died of respiratory failure at 10 weeks old.

Conclusion(s): This is the first Navajo familial case series of a NPHP-3 gene deletion syndrome and demonstrates a novel gene variant responsible for term hypoplasia, multicystic dysplastic kidney disease, and neonatal mortality.