Nephrology Dialysis Transplantation

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1 Nephrol Dial Transplant ( 1997) 12: Original Article Nephrology Dialysis Transplantation Neonatal presentation of autosomal dominant polycystic kidney disease with a maternal history of tuberous sclerosis M. D. Griffin1, V. Gamble3, D. S. Milliner1, M. R. Gomez2, P. C. Harris3 and V. E. Torres1 1Department of Internal Medicine, Division of Nephrology, 2Department of Pediatric Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA, 3MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK Abstract Background. Childhood presentation of polycystic kidney disease has been reported with tuberous sclerosis complex (TSC). Recently some such cases have been shown to be due to combined deletion of the PKD1 and TSC2 genes, which lie close together on chromosome 16. The phenomenon of anticipation, whereby disease presentation occurs at a progressively earlier age in each generation, has been suggested to occur in autosomal dominant polycystic kidney disease (ADPKD). We have carried out a genetic study of a family in which these issues became clinically relevant. Neonatal presentation of polycystic kidneys occurred in an individual with a maternal family history of epilepsy and features of TSC without renal cystic disease. Methods. Detailed historical and clinical profiles were gathered for three generations of the maternal and paternal families. Both parents underwent renal ultra- sound scanning. Genomic DNA was obtained from affected and unaffected individuals from the maternal family and used for linkage analysis to gene loci for TSC. Results. Renal cysts were not present in the mother by ultrasound. Linkage to TSC2 was found for mem- bers of the maternal family with clinical features of TSC. While a diagnosis of TSC was confirmed in her mother the child was found not to have inherited the disease-related allele. The father was found to have asymptomatic bilateral polycystic kidneys consistent with ADPKD. The presence of ADPKD in other paternal relatives could not be confirmed. Conclusions. The index case was found to have paternally inherited ADPKD with unusually early presenta- tion. While at risk for concomitant maternal inheritance of TSC this diagnosis was ruled out by linkage analysis studies. The ability to clarify the true nature of a complex inherited condition greatly facilitates future management and counselling. The mechan- Correspondence and offprint requests to: Vicente E. Torres MD, Division of Nephrology and Internal Medicine, Mayo Clinic, 200 Second St. SW, Rochester, MN 55905, USA. isms underlying phenotypic heterogeneity in ADPKD remain to be clearly defined and are the subject of ongoing investigation. Key words: hereditary disease; linkage analysis; PKD1, polycystic kidney disease; tuberous sclerosis; TSC2 Introduction The discovery of enlarged, polycystic kidneys in a neonate or child raises an array of potential concerns for both child and family. These pertain to prognosis for early survival, long-term renal function, extrarenal abnormalities and risk to existing family members or future children. When both parents have been previously well the primary diagnostic consideration will usually be that of autosomal recessive polycystic kidney disease (ARPKD). A systematic clinical and genetic study of the family may often provide new information which can be used to better guide management and counselling or may even result in revision of the initial diagnosis. Overlapping features of more than one genetic disease or paraphenomena such as anticipation, genetic imprinting, phenotypic gender differences, and interfamilial heterogeneity have been sources of both dis- covery and controversy in the study of inherited renal cystic disease [1]. No better example exists than the relationship between autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis com- plex (TSC). Coexistence of features of these two diseases in certain pedigrees has been directly responsible for the recent discovery of the gene PKD1 which is mutated in approximately 85% of ADPKD families as well as the recognition of a contiguous gene deletion syndrome in which adjoining copies of PKD1 and TSC2 are deleted from a single chromosome [2,3]. Some studies have suggested that a progressively earlier presentation in each affected generation (genetic anticipation) may occur in ADPKD more often than would be expected by chance alone [4,5]. If such were 1997 European Renal Association European Dialysis and Transplant Association

2 Neonatal polycystic kidneys with maternal tuberous sclerosis 2285 the case it might imply an inherent instability to the examination revealed no developmental or other gene involved. While certain structural features have abnormalities. An abdominal ultrasound examination been linked to this phenomenon in some hereditary demonstrated bilateral symmetrical enlargement of the diseases no such mechanism has emerged to date from kidneys with marked increase in echogenicity (see sequence analysis of PKD1 or the more recently disco- Figure 1, upper panels). The findings were felt to be vered gene PKD2 [3,6 9]. Furthermore the hypothesis typical of infantile polycystic kidney disease. Over of genetic anticipation in ADPKD has been challenged the following 3 months the patient gained weight, by other investigators [10]. reached expected developmental milestones, had no We describe here an index case of neonatal polycystic seizures or other acute illnesses, and the serum kidney disease with a complex family history which creatinine remained normal. has brought all of the above considerations into play and illustrates the value of genetic studies in managing such a case. Methods Index case The patient, a baby girl, was noted to have bulging flanks with bilateral palpable abdominal masses during a routine examination 3 days post-partum. She had been born by normal vaginal delivery at full term with a birth weight of 3.4 kg. She was the first child born to her parents with one prior miscarriage at 10 weeks gestation. Her mother s pregnancy had been uneventful apart from mild hypertension without oedema or pro- teinuria. There was a history of epilepsy in the mother and in a maternal aunt and cousin. The father was in good health. There was no history of renal cystic disease or other renal disease in either family. Physical Both parents underwent physical examination and renal ultrasound. Detailed personal and family histories were recorded for the mother and father with particular attention to renal or neurological disease. Historical details were crosschecked against existing medical records for maternal and paternal family members. Living members of the maternal family underwent physical examination and brain imaging for evidence of TSC. Those with clinical evidence of TSC underwent renal imaging. Gene linkage studies for TSC were carried out on genomic DNA from living members of the maternal family with markers on chromosome 9 (TSC1), Ass and D16S66 [11] and chromosome 16 (TSC2), KG8, SM6, 16AC2.5, and CW2 [12]. These studies were carried out when the patient was 10 years old at a time when the markers for such analysis became available. Fig. 1. Sequential bilateral renal ultrasound images from the index patient. Upper panels ( 4 days post-partum), left and right kidneys are diffusely enlarged with increased echogenicity and loss of corticomedullary differentiation; middle panels (1 year), at least six small- to medium-sized cysts are seen in each kidney with persistent increased echogenicity; lower panels (9 years), the number and size of renal cysts has increased considerably.

3 2286 Results Maternal family Details of the maternal family are represented diagrammatically in Figure 2. The index case is indicated by an arrow. The mother s history was remarkable for tonic clonic seizures with abnormal electroencephalo- gram at age 7 years. Treatment with phenytoin was continued until age 14 and was then withdrawn without subsequent recurrence. Physical examination disclosed several hypomelanotic skin macules and facial angio- fibroma suggestive of TSC. Renal ultrasound and CT scan of the head showed no abnormalities. A maternal cousin (subject IV 2, Figure 2) had been treated for tonic clonic seizures at age 10 years. Findings inclu- ded many hypomelanotic skin macules on physical examination and two non-calcified cortical tubers on magnetic resonance imaging (MRI) of the head characteristic of TSC. Renal ultrasound was negative for cysts or other abnormalities. This child s mother (subject III 3) also had a history of seizures, hypomelanotic skin macules, and negative head MRI. The maternal grandmother (subject II 3,) was found to have several radial migration lines on the head MRI typical of TSC, but no skin lesions or history of seizures. Her sister (subject II 2) had seizures and mental retardation and had died in a state institution where she had lived for many years, being severely handicapped. Linkage analysis using markers close to the chromo- some 9 and chromosome 16 loci for TSC was carried out using genomic DNA from three generations of the maternal family. Only the TSC2 markers demonstrated segregation of a single haplotype with the clinical features of TSC; no individual lacking clinical evidence of TSC inherited this haplotype. The index patient did not inherit the affected maternal chromosome. M. D. Griffin et al. Paternal family The paternal family is also represented in Figure 2. The father (subject III 6) had a normal physical examination but renal ultrasound demonstrated innumerable cysts of varying size in both kidneys character- istic of autosomal dominant polycystic kidney disease. Serum creatinine was 88 mmol/l and creatinine clearance was calculated to be 120 ml/min from a 24-h urine collection. The paternal grandfather (subject II 11) had died at age 49 years of heart disease, but no post-mortem examination had been carried out. Other living members of the paternal family were not known to have renal disease or hypertension and did not wish to undergo renal imaging. The small size of the paternal family and lack of clinical data made it impossible to determine the subtype of ADPKD by linkage analysis. Subsequent clinical follow-up Over a period of 12 years since this patient s initial presentation she has remained healthy without renal impairment or neurological disease and has required therapy with an angiotensin-converting enzyme inhib- itor for blood pressure control. Serial imaging by ultrasound has demonstrated progressive increase in number and size of renal cysts typical of ADPKD (see Figure 1). A younger sibling (subject IV 6) has had epilepsy, behavioural disorder, and hypomelanotic skin patches since the age of 6 months without renal cysts on ultrasound imaging. The diagnosis of TSC made on clinical and MR findings has been supported by linkage analysis in this sibling. The father now has moderate renal impairment, treated hypertension, and evidence of small hepatic cysts on computerized tomo- graphy of the abdomen. Fig. 2. Diagrammatic representation of the maternal and paternal families of the index case (arrow) demonstrating individuals with clinical diagnoses of TSC in the maternal family and polycystic kidney disease in the paternal family. Subject IV 4 represents an early gestation miscarriage of unknown phenotype.

4 Neonatal polycystic kidneys with maternal tuberous sclerosis 2287 Discussion thesis that has yet to be tested experimentally. In the light of this new information the possibility that our This patient and her family illustrate some of the patient had inherited a mutated copy of both genes on different levels of complexity which may be involved opposite chromosomes suggested one explanation for in the assessment of a neonatal or childhood presentaage analysis, that while TSC in the maternal family is her early presentation. It is clear, however, from link- tion of cystic kidney disease. At the time she was born the clinical information available would have suggested caused by a mutation of TSC2, she has not inherited a probable diagnosis of autosomal recessive polycystic the abnormal allele and is not at risk for seizures or kidney disease as well as a possible increased risk of other TSC-related complications. We cannot rule out childhood epilepsy. Following a detailed family history an indirect effect of the maternal TSC or other elements and clinical evaluation of the parents, however, evidof the maternal environment during renal development. ence emerged to support a diagnosis of ADPKD with Even in utero there may be many variables at play in paternal inheritance as well as a 50% risk of TSC the phenotypic expression of an autosomal dominant inherited from the mother. This information has obvituberin and fetal polycystin would seem implausible it disease. While a direct interaction between maternal ous value for the clinician charged with providing immediate and long-term care to the child as well as is possible that the coexistence of TSC could affect the genetic counselling to the parents and extended family. development of ADPKD by some undefined humoral Although signs of TSC were not found on physical mechanism. examination of our patient, it was not possible to Other mechanisms for intrafamilial heterogeneity in ADPKD may well emerge from ongoing studies of the discard this diagnosis by clinical means. mutated genes and their protein products. The striking Early presentation of ADPKD has been well recogage difference at presentation between our patient and nized for some time and follow-up studies would her father represents an extreme example of genetic predict a high likelihood of hypertension and a moderanticipation. This phenomenon, sometimes defined as ate risk of progressive renal impairment before puberty the clinical onset of an inherited disease 10 or more for this patient [13,14]. The risk of future children in years earlier in one generation than the preceding, has this family presenting in childhood with polycystic often been the subject of discussion in regard to kidney disease would also be increased [14]. Paternal ADPKD [1,4,5]. The difficulty lies in distinguishing relatives at risk for ADPKD may be allowed the choice between a single, genetically based mechanism and the of seeking diagnostic clarification and genetic counselcombined results of selection bias and variable environling. Although it was not possible to determine the mental and genetic backgrounds. In some inherited genetic subtype of ADPKD present, the early onset conditions such as myotonic dystrophy and fragile X would strongly favour type 1 (chromosome 16-linked) syndrome a structural explanation for this phenomdisease, which accounts for approximately 85% of enon has been found in the form of trinucleotide families worldwide [15]. In fact no case of type 2 repeats within the gene [1,19]. These inherently (chromosome 4-linked) ADPKD presenting in the unstable elements may propagate during DNA replicaneonatal period has been reported to date. tion in meiosis and become more disruptive to gene More recent discoveries regarding the genetic basis function, resulting in earlier or more severe manifestaof both ADPKD and TSC have allowed genotyping tions of the disease. In the case of PKD1 there have of the maternal family and a further level of under- been no such structural elements identified to date standing of the patient s clinical prognosis. The identi- [5 8] and a stable, nonsense mutation of PKD1 was fication of the genes PKD1 and TSC2 has opened the found in one pedigree with an early onset case of door to defining the pathogenesis of these multisystem ADPKD [20]. In addition the hypothesis of genetic disorders at a molecular level and has also revealed an anticipation in ADPKD has been challenged by other overlap between the two in certain families [3,16]. investigators [10]. These two genes lie tail to tail on the short arm of Recent evidence has also been presented to suggest human chromosome 16 and their coding regions are that somatic mutation of the previously normal allele separated by less than 100 nucleotides [17]. Deletions of this gene within renal tubular epithelial cells may that eliminate part or all of both genes have been be a necessary event for cyst development [21]. Such found to be associated with a variant of TSC which is a two hit model would explain why only a small often characterized by severe polycystic kidney disease number of nephrons undergo cyst formation and might in childhood [2]. The implication is that the ADPKD also offer an explanation for the clinical variability of phenotype in these families may be accelerated by the disease. If this were the case, polymorphisms of additional loss of TSC2 function. This could be the normal copy of the gene or any other genetic or explained by additive but independent defects or by a environmental variables which alter the likelihood true interaction between the two genes or their protein of somatic mutation would greatly influence the patproducts (named polycystin and tuberin respectively). tern of onset and progression of renal impairment. As there is experimental evidence that one function of Regardless of the primary mechanism by which cyst tuberin may relate to gene transcription [18] it is formation is initiated, many other genes inherited from tempting to speculate that expression of PKD1 may both parents may exert an influence on disease progression be under the influence of its close neighbour a hypo- and severity. The identification of these modifier

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