To the Editor: Autosomal dominant polycystic kidney disease(ADPKD) is one of the most common mendelian disorders, affectingapproximately 12.5 million persons worldwide.1,2 Clinical symptomsusually do not arise until adulthood. ADPKD2 is generally considerablymilder than ADPKD1. About 2 to 5% of patients have early-onsetADPKD, which at times is clinically indistinguishable from autosomalrecessive polycystic kidney disease (ARPKD).3 To date, ADPKDwith early manifestations has been thought to be strictly confinedto persons with ADPKD1.2
We now report on a four-generation family carrying a mutationin the gene for ADPKD2 (PKD2) with previously undetected disease.In the present generation, however, perinatal death due to polycystickidney disease occurred in the mother's second and third pregnancies,the first having resulted in a healthy girl. The second pregnancywas complicated by oligohydramnios and massively enlarged hyperechogenicfetal kidneys; a boy born at 30 weeks of gestation died shortlyafter birth from respiratory insufficiency. The third pregnancywas complicated from 20 weeks of gestation forward; a girl bornat 34 weeks of gestation died shortly after birth.
Linkage analysis of the gene for ARPKD (PKHD1) revealed identicalhaplotypes in the healthy daughter and the affected daughter,making ARPKD very unlikely (Figure 1A). Histologic studies unexpectedlyshowed glomerular cysts that were suspicious for ADPKD (Figure 1B).Abdominal ultrasound studies in the parents revealed no cystsin the 31-year-old mother but two cortical cysts in the leftkidney and three cysts in the right kidney in the 32-year-oldfather. Ultrasound studies in other family members showed bilateralrenal cysts in the paternal grandmother and in the 80-year-oldpaternal great-grandmother (Figure 1C). However, none of theseadults had any clinical symptoms. Analysis of the fetal DNAfor PKD1 and HNF1β did not show a pathogenic mutation,but PKD2 sequencing revealed a novel frameshift mutation, c.1934_1935delinsT (p.Asn645fs), in exon 9 (Figure 1D) that is thought tolead to premature truncation of the encoded polycystin-2 proteinand that was not present among 200 ethnically matched controlchromosomes. This mutation segregated with the phenotype, furthervalidating its pathogenicity.
Figure 1. Linkage 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.
Panel A shows the results of linkage analysis for autosomal recessive polycystic kidney disease (ARPKD) in the healthy daughter and the deceased affected daughter, with genetic markers closely flanking the PKHD1 gene on chromosome 6p12. The microsatellite marker D6S465 is located distally to the PKHD1 gene; D6S243 is an intragenic marker, and M182 is located proximally to the PKHD1 gene. Squares denote males, circles females, open symbols unaffected family members, and solid symbols affected family members; the slash indicates the deceased daughter. The recombination rates of the flanking informative markers are about 1.2 cM. Haplotypes are incompatible with linkage to this locus, because the healthy daughter bears the same parental PKHD1 haplotypes as the affected daughter. A DNA sample from the family's first affected child was not available. In Panel B, a renal-biopsy specimen from the deceased affected daughter shows glomerulocystic kidney disease (hematoxylin and eosin), which is suggestive of an early manifestation of ADPKD. Residual glomerular structures can be seen in some of the cysts. Panel C shows the four-generation pedigree of the described family. The sequence chromatogram in Panel D shows the PKD2 mutation c.1934_1935del insT (p.Asn645fs), which segregates with the disease status in this family over four generations. The chromatogram depicts the deletion of two nucleotides (del AC) and a 1-base-pair insertion (ins T) predicted to result in a premature stop. Wild-type and mutant PKD2 sequences are shown below the chromatogram.
These cases emphasize the need for ultrasound studies in theparents and, if the parents are young, the grandparents of achild with polycystic kidney disease of unknown type.4 The highrisk of recurrence of ADPKD with early manifestations in affectedfamilies suggests a common familial modifying background forearly and severe disease expression (e.g., mutations or variantsin genes encoding other cystoproteins).5 Definition of the underlyingmechanisms might provide further insights into polycystic kidneydisease. This family history emphasizes that early manifestationsof polycystic kidney disease may occur, even in families withADPKD2 and that this is information that should be shared withaffected 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{at}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 (toDrs. Bergmann and Zerres), the German Kidney Foundation (DeutscheNierenstiftung, to Dr. Bergmann), and the START program of themedical faculty of the RWTH Aachen University (to Dr. Bergmann).
References
Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164. [Free Full Text]
Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 2007;18:1374-1380. [Free Full Text]
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]
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]
Zerres K, Rudnik-Schöneborn S, Deget F. Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. J Med Genet 1993;30:583-588. [Free Full Text]
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