Correspondence

Perinatal Deaths in a Family with Autosomal Dominant Polycystic Kidney Disease and a PKD2 Mutation

N Engl J Med 2008; 359:318-319July 17, 2008

Article

To the Editor:

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common mendelian disorders, affecting approximately 12.5 million persons worldwide.1,2 Clinical symptoms usually do not arise until adulthood. ADPKD2 is generally considerably milder than ADPKD1. About 2 to 5% of patients have early-onset ADPKD, which at times is clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD).3 To date, ADPKD with early manifestations has been thought to be strictly confined to persons with ADPKD1.2

We now report on a four-generation family carrying a mutation in the gene for ADPKD2 (PKD2) with previously undetected disease. In the present generation, however, perinatal death due to polycystic kidney disease occurred in the mother's second and third pregnancies, the first having resulted in a healthy girl. The second pregnancy was complicated by oligohydramnios and massively enlarged hyperechogenic fetal kidneys; a boy born at 30 weeks of gestation died shortly after birth from respiratory insufficiency. The third pregnancy was complicated from 20 weeks of gestation forward; a girl born at 34 weeks of gestation died shortly after birth.

Linkage analysis of the gene for ARPKD (PKHD1) revealed identical haplotypes in the healthy daughter and the affected daughter, making ARPKD very unlikely (Figure 1AFigure 1Linkage Analysis for ARPKD in the Unaffected and Affected Daughters of a Family with the PKD2 Mutation, Histologic Findings in a Renal-Biopsy Specimen from the Affected Daughter, the Family Pedigree, and a Sequence Chromatogram Showing the PKD2 Mutation.). Histologic studies unexpectedly showed glomerular cysts that were suspicious for ADPKD (Figure 1B). Abdominal ultrasound studies in the parents revealed no cysts in the 31-year-old mother but two cortical cysts in the left kidney and three cysts in the right kidney in the 32-year-old father. Ultrasound studies in other family members showed bilateral renal cysts in the paternal grandmother and in the 80-year-old paternal great-grandmother (Figure 1C). However, none of these adults had any clinical symptoms. Analysis of the fetal DNA for PKD1 and HNF1β did not show a pathogenic mutation, but PKD2 sequencing revealed a novel frameshift mutation, c.1934_1935del insT (p.Asn645fs), in exon 9 (Figure 1D) that is thought to lead to premature truncation of the encoded polycystin-2 protein and that was not present among 200 ethnically matched control chromosomes. This mutation segregated with the phenotype, further validating its pathogenicity.

These cases emphasize the need for ultrasound studies in the parents and, if the parents are young, the grandparents of a child with polycystic kidney disease of unknown type.4 The high risk of recurrence of ADPKD with early manifestations in affected families suggests a common familial modifying background for early and severe disease expression (e.g., mutations or variants in genes encoding other cystoproteins).5 Definition of the underlying mechanisms might provide further insights into polycystic kidney disease. This family history emphasizes that early manifestations of polycystic kidney disease may occur, even in families with ADPKD2 and that this is information that should be shared with affected persons and their families.

Carsten Bergmann, M.D.
Nadina Ortiz Brüchle, D.V.M.
Valeska Frank, M.Sc.
Rheinisch-Westfälische Technische Hochschule of Aachen University, 52074 Aachen, Germany
cbergmann@ukaachen.de

Helga Rehder, M.D., Ph.D.
Medical University Vienna, 1090 Vienna, Austria

Klaus Zerres, M.D.
Rheinisch-Westfälische Technische Hochschule of Aachen University, 52074 Aachen, Germany

Supported by grants from Deutsche Forschungsgemeinschaft (to Drs. Bergmann and Zerres), the German Kidney Foundation (Deutsche Nierenstiftung, to Dr. Bergmann), and the START program of the medical faculty of the RWTH Aachen University (to Dr. Bergmann).

5 References

1. 1

   Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164
   Full Text | Web of Science | Medline

2. 2

   Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 2007;18:1374-1380
   CrossRef | Web of Science | Medline

3. 3

   Sweeney WE Jr, Avner ED. Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD). Cell Tissue Res 2006;326:671-685
   CrossRef | Web of Science | Medline

4. 4

   Bear JC, McManamon P, Morgan J, et al. Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling. Am J Med Genet 1984;18:45-53
   CrossRef | Web of Science | Medline

5. 5

   Zerres K, Rudnik-Schoneborn S, Deget F. Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. J Med Genet 1993;30:583-588
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   N. Ortiz Brüchle, A. Venghaus, J. von Bothmer, S. Rudnik-Schöneborn, T. Eggermann, C. Bergmann, K. Zerres. (2010) Zystennieren – eine Übersicht. medizinische genetik 22:3, 322-331
   CrossRef

2. 2

   Vicente E Torres, Peter C Harris. (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney International 76:2, 149-168
   CrossRef

3. 3

   Richard N Sandford. (2009) The diversity of PKD1 alleles: implications for disease pathogenesis and genetic counseling. Kidney International 75:8, 765-767
   CrossRef

4. 4

   Sandro Rossetti, Vickie J Kubly, Mark B Consugar, Katharina Hopp, Sushmita Roy, Sharon W Horsley, Dominique Chauveau, Lesley Rees, T Martin Barratt, William G van't Hoff, W Patrick Niaudet, Vicente E Torres, Peter C Harris. (2009) Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney International 75:8, 848-855
   CrossRef