Renal-Hepatic-Pancreatic Dysplasia 1

A number sign (#) is used with this entry because of evidence that renal-hepatic-pancreatic dysplasia-1 (RHPD1) is caused by homozygous or compound heterozygous mutation in the NPHP3 gene (608002) on chromosome 3q22.

Hypomorphic mutations in the NPHP3 gene result in nephronophthisis-3 (NPHP3; 604387), an allelic disorder with a milder phenotype. NPHP3 mutations can also result in the more severe disorder Meckel syndrome-7 (MKS7; 227010).

Genetic Heterogeneity of Renal-Hepatic-Pancreatic Dysplasia

See also RHPD2 (615415), caused by mutation in the NEK8 gene (609799) on chromosome 17q11.

Clinical Features

Ivemark et al. (1959) reported 2 sibs with renal-hepatic-pancreatic dysplasia. Crawfurd (1978) described a brother and sister who both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second infant showed gross renal dysplasia. The pancreas was enlarged, nodular, and cystic in both children. Liver histology of 1 infant showed portal fibrosis with bile duct proliferation. In addition, both had absence or hypoplasia of the spleen, cardiac anomalies, and other situs abnormalities. Crawfurd (1978) noted the phenotypic similarities to the sibs reported by Ivemark et al. (1959), and postulated a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.

Bernstein et al. (1987) reported 5 unrelated affected infants, 3 of whom died neonatally and 2 of whom died in the first year of life. The kidneys showed cystic dysplasia with abnormally differentiated ducts, deficient nephron differentiation, and glomerular cysts. Liver biopsies showed enlarged portal areas containing numerous elongated or dilated biliary ducts and a tendency to perilobular fibrosis. Pancreatic findings included fibrosis and cysts with diminution of parenchymal tissue. The 2 children who survived the neonatal period developed renal insufficiency, chronic jaundice, and insulin-dependent diabetes mellitus. The phenotype was most consistent with that reported by Ivemark et al. (1959). However, Bernstein et al. (1987) noted that similar renal, hepatic, and pancreatic abnormalities appear in other syndromes, including trisomy 9, Meckel syndrome (see 249000), the chondrodysplasias of Jeune syndrome and Saldino and Noonan syndrome (see 613091), and type II glutaric acidemia (231680). The authors concluded that after exclusion of identifiable syndromes, the remaining cases of renal-hepatic-pancreatic dysplasia do not necessarily constitute a homogeneous group.

Torra et al. (1996) reported 2 Spanish brothers who died shortly after birth from cystic malformations of the kidneys, liver, and pancreas. Both pregnancies were complicated by oligohydramnios and both children were born with Potter facies. The parents were unaffected and not known to be related. Postmortem examination of the infants showed multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, dilated pancreatic ducts, and polysplenia, similar to the report of Ivemark et al. (1959) of renal-hepatic-pancreatic dysplasia.

Neuhaus et al. (1996) reported 2 Swiss brothers with renal-hepatic-pancreatic dysplasia. One patient died shortly after birth of lung hypoplasia. The second patient developed end-stage renal failure at age 14 months. The kidneys showed multiple cysts and obliteration of glomeruli. He also had hepatic fibrosis that progressed to cirrhosis and liver failure. Pancreatic function was normal, but showed increased echogenicity on ultrasound. He underwent successful combined liver-kidney transplantation at age 3 years 9 months and was alive at age 17 years with normal neurologic development (Bergmann et al., 2008).

Schrader et al. (2007) reported 2 sibs, born of consanguineous East Indian parents, with renal-hepatic-pancreatic dysplasia. One sib died at age 2 hours, and the other pregnancy was terminated at 18.5 weeks. Both pregnancies were complicated by oligohydramnios. Postmortem examinations showed enlarged cystic kidneys, hepatic ductal plate abnormalities, and pancreatic abnormalities. The mother had 2 pregnancies that resulted in spontaneous abortion. Linkage analysis excluded the PKHD1 gene (606702) on chromosome 6p21.

Fiskerstrand et al. (2010) reported 2 Norwegian sibs, born to remotely consanguineous parents, with a congenital lethal disorder. The first child had intrauterine growth retardation, Potter facies with hypertelorism, beak-like nose, short neck, and short sternum, and died of respiratory insufficiency 1 day after birth. The pregnancy was complicated by oligohydramnios. The lungs and kidneys were hypoplastic, and the kidneys contained multiple small cysts and were dysplastic. The pancreas was enlarged and fibrotic, with irregular ducts and atrophy of acini. There was portal fibrosis and paucity of bile ducts in the liver. The brain was normal. The second pregnancy resulted in elective termination at 16 weeks because of multiple abnormalities in the fetus. The fetus had dysmorphic features consistent with Potter facies and flexion contractures of multiple joints. There was complete situs inversus of the thoracic and abdominal organs. Microscopic studies showed renal dysplasia, hepatic ductal plate malformation, and dysplasia of the pancreas with dilated ductal structures with scarce lobular differentiation. Although the brain was grossly normal, there was evidence of polymicrogyria. The findings were consistent with renal-hepatic-pancreatic dysplasia as reported by Ivemark et al. (1959).

Clinical Variability

Most patients with renal-hepatic-pancreatic dysplasia have died in the perinatal period or in infancy. Bergmann et al. (2008) reported follow-up of 1 of the brothers reported by Neuhaus et al. (1996). He had a liver-kidney transplant at age 3 years and was alive at age 17 years with normal neurologic development. Bergmann et al. (2008) also reported an 8-year-old Vietnamese girl with a phenotype reminiscent of renal-hepatic-pancreatic dysplasia. She had glomerulocystic kidney disease resulting in end-stage renal failure at age 3 months and hepatic cirrhosis with cholestasis necessitating a combined liver-kidney transplant at age 4 years. Although pancreatic exocrine and endocrine function was normal, she had persistently elevated pancreatic amylase levels. Other features included complete situs inversus, postaxial polydactyly of the left foot, and preauricular fistulas. Neurologic and cognitive development was normal.

Molecular Genetics

In the Swiss brothers reported by Neuhaus et al. (1996), Bergmann et al. (2008) identified compound heterozygosity for 2 mutations in the NPHP3 gene (608002.0006; 608002.0007). One sib was alive at age 17 years and had normal neurologic development. Bergmann et al. (2008) also reported a Vietnamese girl with the disorder who had a homozygous truncating NPHP3 mutation (608002.0008). She had a combined kidney-liver transplant at age 4 years, and was alive at age 8 years. Other clinical features included situs inversus totalis, postaxial polydactyly, and preauricular fistulas, illustrating a wide range of early embryonic patterning defects and an expanded phenotype. Neurologic development was normal.

By homozygosity mapping followed by candidate gene sequencing, Fiskerstrand et al. (2010) identified a homozygous truncating mutation in the NPHP3 gene (608002.0004) in 2 sibs with lethal renal-hepatic-pancreatic dysplasia.