Diffuse renal cystic disease in children: morphologic and genetic correlations.

During a 5-year period, we evaluated seven infants and two fetuses who presented with enlarged, hyperechoic kidneys. In each, the initial clinical diagnosis was autosomal recessive polycystic kidney disease (ARPKD). Among the seven unrelated infants were three Caucasian and four African-American infants. No syndromic stigmata were evident in any of these infants. At the time of the initial evaluation, the family data were incomplete for four infants. The two fetuses were presumed to be at-risk for ARPKD based on the diagnosis in previous siblings. Renal histopathology was evaluated in all nine cases and revealed a spectrum of cystic disease ranging from ARPKD to glomerulocystic kidney disease to autosomal dominant polycystic kidney disease to diffuse cystic dysplasia. In the eight cases for whom liver histopathology was available, varying degrees of biliary dysgenesis were evident. We present a detailed analysis of the key histopathological features in each case and discuss the histopathological findings in an embryological context. In addition, we address the current role of molecular genetics in the diagnostic evaluation.

The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: implications for genetic counseling.

Autosomal recessive polycystic kidney disease (ARPKD) is a one of the most common hereditary renal cystic diseases in children. Its clinical spectrum is widely variable with most cases presenting in infancy. Most affected neonates die within the first few hours of life. At present, prenatal diagnosis relies on fetal sonography, which is often imprecise in detecting even the severe form of the disease. Recently, in a cohort of families with mostly milder ARPKD phenotypes, an ARPKD locus was mapped to a 13-cM region of chromosome 6p21-cen. To determine whether severe perinatal ARPKD also maps to chromosome 6p, we have analyzed the segregation of seven microsatellite markers from the ARPKD interval in 22 families with the severe phenotype. In the majority of the affected infants, ARPKD was documented by histopathology. Our data confirm linkage and refine the ARPKD region to a 3.8-cM interval, delimited by the markers D6S465/D6S427/D6S436/D6S272 and D6S466. Taken together, these results suggest that, despite the wide variability in clinical phenotypes, there is a single ARPKD gene. These linkage data and the absence of genetic heterogeneity in all families tested to date have important implications for DNA-based prenatal diagnoses as well as for the isolation of the ARPKD gene.

Mutations in the vasopressin V2 receptor gene in two families with nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (CNDI) is a rare X-linked disorder in which the renal collecting duct is unresponsive to arginine vasopressin, and thus, the urine is consistently hypotonic to plasma. As a result, affected individuals are unable to concentrate urine and suffer from episodes of severe dehydration and hypernatremia. Recently, the association between arginine vasopressin V2 receptor gene mutations and CNDI has been demonstrated. In this report, two additional novel molecular defects of the arginine vasopressin V2 receptor gene in CNDI families are described. In one family, the affected individual demonstrated a G-->T transversion causing a nonsense mutation in codon 231. This mutation results in a glutamic acid becoming a termination codon, causing premature termination and truncation of the encoded receptor protein. This mutation causes a NciI site within the gene to be abolished and a BsaWI site to be created. In the second family, affected individuals showed a 28-basepair duplicating insertion in the very beginning of exon 2 down-stream of the splice acceptor site. It was hypothesized that an insertion mutagenesis mechanism involves the formation of a stem-loop structure within the newly synthesized DNA strand, followed by a slipped mispairing. This may be a general mechanism for the deletion or insertion of repeated sequences within the genome. Recent data show that G-protein-coupled receptors are susceptible to many different mutations that often result in the loss of function, causing a similar clinical phenotype.

Prenatal diagnosis of autosomal recessive polycystic kidney disease: variable outcome within one family.

Autosomal recessive polycystic kidney disease is frequently diagnosed in utero by obstetric ultrasonography. We report a case in which there were varying outcomes of this disorder in three affected fetuses in a family. Recognition of variable expression within one family is important when parents are considering termination of a pregnancy with an affected fetus.

Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies.

We describe a child with circulating anti-epithelial cell antibodies, autoimmune enteropathy with intestinal villous atrophy, and membranous glomerulonephritis. The patient had persistent diarrhea at 6 months of age, and a small bowel biopsy showed active enteritis, villous atrophy, and crypt hyperplasia. When the patient was, 10 months of age, nephrotic syndrome developed because of membranous glomerulonephritis. Results of tests for circulating immune complexes were negative. Indirect immunofluorescence studies revealed a circulating antibody directed against renal epithelial cells. Circulating antibodies directed against normal small intestine epithelial cells were also detected by the immunoperoxidase technique. Western blot and immunoprecipitation identified a 55-kd antigen, in both small bowel and kidney, that reacted with an antibody in the patient's serum. High-dose prednisone therapy induced a clinical remission, resolution of the small bowel injury, and diminished serum anti-epithelial cell antibodies; after dose reduction, clinical relapse occurred with villous atrophy and reappearance of anti-epithelial cell antibodies. When the patient was 45 months of age, persistent diarrhea recurred despite intravenous administration of corticosteroids, cyclosporine, and total parenteral nutrition. Autoantibodies to a 55-kd epithelial cell protein are temporally related to the development of enteropathy and nephropathy. Study of similar patients is needed to determine the role of such antibodies in this disorder.

MRI of disseminated neonatal hemangiomatosis: case report.

A term neonate developed progressive multiple skin hemangiomas with subsequent visceral involvement in the first month of life. MRI was used to evaluate the extent of visceral involvement and to document the response to steroid therapy.

The use of magnesium-containing phosphate binders in patients with end-stage renal disease on maintenance hemodialysis.

We investigated the safety and efficacy of magnesium hydroxide as a phosphate binder in patients with end-stage renal disease on maintenance hemodialysis, 9 volunteers participated in a four-phase study during which each ingested (1) no phosphate binders, (2) magnesium hydroxide (Mg(OH)2) alone, (3) Mg(OH)2 and aluminum hydroxide (A1(OH)3) together and (4) A1(OH)3 alone. Serum magnesium (SMg) concentrations were maintained at less than 4.5 mEq/1 (2.3 mmol/l) in all subjects while they were ingesting 0.75-3 g Mg(OH)2/day and no magnesium toxicity was noted. In individuals taking a constant daily dose, SMg remained stable over 8-12 weeks. Serum phosphorus (SP) decreased from 9.0 mg/dl (2.9 mmol/l)d during the control period to 8.1 mg/dl (2.6 mmol/l) during the Mg(OH)2 period (p less than 0.05) and increased from 6.1 mg/dl (2.0 mmol/l) during the Mg(OH)2 and A1(OH)3 period to 7.0 mg/dl (2.3 mmol/l) during the Al(OH)3 period (p less than 0.05) indicating that Mg(OH)2 could significantly lower SP. However, SP was best controlled (6.1 mg/dl; 2.0 mmol/l) when Al(OH)3 and Mg(OH)2 were used together and all participants preferred the combination therapy to either of the agents alone. These results indicate that Mg(OH)2 is a potentially useful adjunct to A1(OH)3 for managing hyperphosphatemia in patients on maintenance hemodialysis. In this short-term study Mg(OH)3 for managing hyperphosphatemia in patients on maintenance hemodialysis. In this short-term study Mg(OH)2 was well tolerated and with appropriate monitoring did not cause uncontrolled hypermagnesemia. Further studies are clearly required to determine whether long-term therapy with Mg-containing agents is safe in dialysis patients.