CLINICAL REPORT Renal-Hepatic-Pancreatic Dysplasia: A Sibship With Skeletal and Central Nervous System Anomalies and NPHP3 Mutation Lawrence Copelovitch, 1 * Maureen M. O’Brien, 2 Marta Guttenberg, 3 Edgar A. Otto, 4 and Bernard S. Kaplan 1 1 Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 2 Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 3 Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 4 Department of Pediatrics, University of Michigan, Ann Arbor, Michigan Manuscript Received: 5 February 2013; Manuscript Accepted: 4 March 2013 We report on five consecutive sibs three with fatal renal-hepatic- pancreatic dysplastic (RHPD) syndrome and two pregnancies ending in early abortion. Three of the fetuses reached term and two survived for 15 and 58 days. They had diffusely cystic kidneys with absence of the distal collecting tubules, hepatic fibrosis, bile duct paucity, and pancreatic fibrosis with irregularly dilated ducts. These findings correspond to many of those reported by Ivemark et al. [Ivemark et al. (1959); Acta Paediat Scand 48: 1–11] as part of the RHPD syndrome. There are several notable differ- ences in this family: one patient had hypocalvaria and a choroid plexus cyst at the right foramen of Luschka, multiple bone abnormalities including widened growth plates and abnormal development of the trabeculae of the ribs, “handle-bar” clavicles, wedge defects of the inferior margin of several thoracic vertebrae; the second patient had hypocalvaria and abnormally developed brain with bilateral exposure of the insulae; and a third patient had anencephaly. Mutational analysis of the two who survived beyond post-delivery demonstrated compound heterozygous novel frameshift mutations in the nephronophthisis type 3 gene (NPHP3). Ó 2013 Wiley Periodicals, Inc. Key words: renal-hepatic-pancreatic dysplasia; nephronophthi- sis; NPHP3; Ivemark syndrome INTRODUCTION Renal-hepatic-pancreatic dysplasia (RHPD) was described in sibs by Ivemark et al. [1959] but is now known to occur as a component of many other well-defined syndromes such as the Zellweger, Meckel, Jeune, Elejalde, and Saldino-Noonan chon- drodysplasias, trisomies 9 and 13, and glutaric aciduria II [Ive- mark et al., 1959; Hunter et al., 1991]. RHPD syndrome is an autosomal recessive trait and many patients present in utero with oligohydramnios. The kidneys may be dysplastic with peripheral cortical cysts, primitive collecting ducts, glomerular cysts, and metaplastic cartilage [Bernstein et al., 1987]. There is fibrosis of liver and pancreas. Most patients die neonatally of respiratory insufficiency. RHPD is also known as Ivemark II syndrome and has been regarded as distinct from Ivemark I syndrome which comprises heterotaxy, poly- or asplenia and congenital cardiac anomalies. Recently, RHPD was determined to be caused by loss of NPHP3 gene function [Bergmann et al., 2008]. Skeletal and central nervous system (CNS) abnor- malities were reported rarely, and anencephaly has not been reported in any documented case of RHPD or NPHP3 muta- tions. The purpose of this report is to broaden known range of RHPD due to NPHP3 mutations to include skeletal anomalies and anencephaly. How to Cite this Article: Copelovitch L, O’Brien MM, Guttenberg M, Otto EA, Kaplan BS. 2013. Renal- hepatic-pancreatic dysplasia: a sibship with skeletal and central nervous system anomalies and nphp3 mutation. Am J Med Genet Part A 161A:1743–1749. Abbreviations: CNS, central nervous system; ASD, atrial septal defect; PDA, patent ductus arteriosis; PFO, patent foramen ovale; RVH, right ventricular hypertrophy Conflict of interest: none. Ã Correspondence to: Lawrence Copelovitch, Division of Genetics, The Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Philadelphia, PA 19104. E-mail: copelovitch@email.chop.edu Article first published online in Wiley Online Library (wileyonlinelibrary.com): 17 May 2013 DOI 10.1002/ajmg.a.35958 Ó 2013 Wiley Periodicals, Inc. 1743