480 Med Genet 1996;33:480-484

A cross sectional study of renal involvement in

J Med Genet: first published as 10.1136/jmg.33.6.480 on 1 June 1996. Downloaded from

J A Cook, K Oliver, R F Mueller, J Sampson

Abstract There are two characteristic types of renal Renal disease is a frequent manifestation involvement in persons with TSC. (1) An- oftuberous sclerosis (TSC) and yet little is giomyolipomas. These are benign neoplasms known about its true prevalence or natural composed of mature adipose tissue, thick history. We reviewed the notes of 139 walled blood vessels, and smooth muscle in people with TSC, who had presented with- varying proportions. In the general population out renal symptoms, but who had been they are a rare finding affecting predominantly investigated by renal ultrasound. In- women (80%) in the third to fifth decade. formation on the frequency, type, and About 50% of people with angiomyolipomas symptomatology of renal involvement was have no stigmata of TSC and usually have retrieved. a large, single angiomyolipoma.6 In TSC the The prevalence ofrenal involvement was angiomyolipomas tend to be small, multiple, 61%. Angiomyolipomas were detected in and bilateral.7 Stillwell et al7 suggested that 49%, renal cysts in 32%, and renal car- there was an increase in the prevalence of cinoma in 2-2%. The prevalence of an- angiomyolipomas with age but only a limited giomyolipoma was positively correlated number of persons with TSC were studied. with age, compatible with a two hit aeti- (2) Renal cysts. These have a characteristic ology. Renal cysts were the commoner histology in TSC. They are lined with a hy- lesion in young children, and their pre- perplastic epithelium consisting ofeosinophilic, valence did not appear to be age related. columnar cells with a "piled up" appearance. Renal investigation in people with TSC This allows them to be differentiated from both had been inconsistent and limited. We sug- autosomal recessive and autosomal dominant gest guidelines for renal investigation in polycystic disease. They can arise from those with TSC. all portions of the nephron and are char- (7Med Genet 1996;33:480-484) acteristically bilateral, multiple, and ofvariable Q size. Key words: tuberous sclerosis; angiomyolipoma; renal A number of reports have also suggested that cyst. there may be an increased incidence of renal http://jmg.bmj.com/ carcinoma in TSC.7 Tuberous sclerosis (TSC) is an inherited auto- somal dominant neurocutaneous syndrome and figures suggested for the incidence of TSC Methods A renal database for TSC was created. In order vary from 1 in 6000 to 1 in 15000.1 The to with clinical manifestations result from hamartomas to be added the renal database, people TSC had to fulfil the following criteria: (1) on September 27, 2021 by guest. Protected copyright. involving multiple organ systems, including the they met the definitive diagnostic criteria for brain, skin, eye, lung, heart, and kidney. The TSC2; (2) the date of birth was known; (3) the involvement in persons with TSC can vary patient had had a renal ultrasound, the results from very mild (a few skin lesions, a specific were accessible, and the date of the scan was of TSC on CT scan, neuroradiological finding known. but no evidence of fits or mental retardation) In an attempt to eliminate possible bias, to severe with fits which are difficult to control, patients who presented because of symptoms mental retardation, and severe skin and visceral owing to renal involvement before the diagnosis involvement.2 Departnent of ofTSC was made were not included. Over 450 Clinical Genetics, TSC exhibits locus heterogeneity with clin- case notes were in the two Ashley Wing, ically indistinguishable disease being caused by sets of reviewed St James' University centres (Leeds and Cardiff) which led to 139 mutations in two different genes. One gene Hospital, Beckett persons with TSC being added to the database. Street, Leeds LS9 7TF, (TSC2) has been identified on chromosome The information that was extracted from the UK 16' and a second gene (TSC1) has been loc- J A Cook notes included the reason for initial referral alised on chromosome 9.4 K Oliver and symptoms and signs of TSC, including Renal disease is the second commonest cause R F Mueller renal symptoms and signs. Results and timing of death in patients with TSC after central Institute of Medical Genetics, University nervous system causes and the commonest Hospital of Wales, cause of death in those over the age of 30.' If Table 1 Reasons for referral Cardiff, UK of com- better management neurological Fit control 50 J Sampson plications through improved imaging, anti- Specialist opinion 41 21 Correspondence to: epileptics, and neurosurgery improves survival, Genetic counselling/family history Dr Cook. New diagnosis of TSC 15 renal involvement might be expected to become General deterioration 8 Received 1 November 1995 a more medical of Behavioural problems 4 Revised version accepted for important complication Total 139 publication 19 January 1996 TSC. A cross sectional study of renal involvement in tuberous sclerosis 481

Table 2 Type andfrequency of complications associated with renal disease secondarily ascertained affected relatives. It had been hoped to compare data from the two Numbers Type of involvement groups, as secondarily ascertained relatives with

Total number of 85/139 Angiomyolipomas only 40/85 TSC often have milder involvement than prob- J Med Genet: first published as 10.1136/jmg.33.6.480 on 1 June 1996. Downloaded from patients with renal Cysts only 17/85 lesions Both lesions 28/85 ands. However, the group was too small for Symptomatic patients 13/85 Angiomyolipomas only 7/13 with renal lesions Cysts only 1/13 meaningful comparison. Both lesions 5/13 Of the 139 patients studied, 85 (61%) had Frank haematuria 9/13 Angiomyolipomas only 4/9 of the males and 63% of Cysts only 1/9 renal lesions, 58% Both lesions 4/9 the females. Of these, 12 had also had renal Abdominal pain 4/13 Angiomyolipomas only 2/4 Cysts only 0/4 CT scans which had confirmed the findings on Both lesions 2/4 ultrasound. Most patients with renal lesions Impaired renal 4/13 Angiomyolipomas only 1/4 were 13 out of 85 function on U&E Cysts only 1/4 asymptomatic. Only patients Both lesions 2/4 (15%) had any symptoms (table 2). The com- Recurrent UTI/pyelonephritis 1/13 Angiomyolipomas only 1/1 was frank haematuria Cysts only 0/1 monest symptom which Both lesions 0/1 occurred in 9/13 symptomatic patients (9.4% of all patients with renal lesions). Haematuria was associated with angiomyolipomas in the majority ofcases (8/9). The incidence ofmicro- Table 3 Type andfrequency of renal lesion scopic haematuria may be much greater than Patients Total Male Female this but, almost invariably, routine urine micro- 139 75 (41%) 82 (59%) scopy was not carried out. Any lesion 61% (85) 58% (33) 63% £52) Other included abdominal Angiomyolipomas 49% (68) 44% (25) 52% (43) symptoms pain Cysts 32% (45) 32% (18) 34% (27) and recurrent urinary tract infections. Ab- Angiomyolipomas only 29% (40) 26% (15) 30% (25) dominal occurred in four all of Cysts only 12% (17) 14% (8) 11% (9) pain patients, Both lesions 20% (28) 18% (10) 22% (18) whom had angiomyolipomas. Blood pressure No lesion 39% (54) 42% (24) 37% (30) was only recorded in one set of notes. Of the 139 patients' notes we examined, only 45 had a documented urea, creatinine, and electrolyte Table 4 Number and distribution of renal lesions result. Only four patients had a serum cre- atinine level outside the normal range and none Angiomyolipomas (68) Renal cysts (45) had reached end stage renal failure. Creatinine Multiple 91% (62/68) 91% (41/45) clearance levels had been performed for two of Single 9% (6/68) 9% (4/45) Bilateral 84% (57/68) 82% (37/45) these patients and were impaired in both. There Unilateral 16% (11/68) 18% (8/45) was an equal distribution of angiomyolipomas and cysts among the four patients with impaired renal function, two had both angiomyolipomas of all renal ultrasounds and the results of renal and cysts, one had angiomyolipomas only, and CT scans if they had been performed were one had cysts only. http://jmg.bmj.com/ entered on the database, as well as the results Two patients had required embolisation of oftests ofrenal function, which were principally bleeding angiomyolipomas and one had re- urea, creatinine, and electrolyte estimations but quired a because of massive included creatinine clearance and nucleotide haemorrhage from an angiomyolipoma leading scans in a few cases. to necrosis of the kidney. A second patient had a nephrectomy because massive kidney

Results enlargement from angiomyolipomas within the on September 27, 2021 by guest. Protected copyright. A total of 139 patients (57 male and 82 female) kidney and in the perirenal fat was thought to were entered on the database. Their ages have led to portal vein obstruction. This case ranged from 1 month to 66 years (mean age is complicated as the patient also has protein 19, median age 19). The reasons for referral C deficiency and it is unclear whether the for these patients are listed in table 1. Of these obstruction was the result of thrombosis or an 139 patients, 116 were probands and 23 were external pressure effect from the angio- myolipomas. We analysed the prevalence and type ofrenal Table 5 Frequency of renal angiomyolipoma according to age and sex involvement by sex (table 3). The proportion Age Total number Total number ofpatients Males Females of males and females with renal lesions did not ofpatients with angiomyolipomas differ significantly. Angiomyolipomas were the <5 26 2 (8%) 0/11 (0%) 2/15 (13%) commonest lesion, occurring in 49% of all 5-10 14 5 (36%) 1/7 (14%) 4/7 (57%) patients. Of those with angiomyolipomas, 91% 10-20 32 15 (47%) 4/12 (33%) 11/20 (55%) 20-30 32 20 (62%) 11/16 (69%) 9/16 (56%) had multiple lesions and 84% had bilateral >30 35 26 (74%) 9/11 (82%) 17/24 (71%) lesions (table 4). Cysts occurred in 32% of all patients, with 91% having multiple cysts and 82% having bilateral cysts (table 4). Angio- myolipomas and cysts occurred together in Table 6 Frequency of renal cysts according to age and sex 20% of all patients. Age Total number Total number ofpatients Males Females The data were also analysed by age at time ofpatients with renal cysts ofradiological examination (tables 5 and 6, figs <5 26 6 (23%) 3/11 (27%) 3/15 (23%) 1 5-10 14 4 (29%) 1/7 (14%) 3/7 (43%) and 2). The incidence of renal angio- 10-20 32 10 (31%) 3/12 (25%) 7/20 (35%) myolipomas increased with age. The product 20-30 32 7 (22%) 5/16 (31%) 2/16 (12%) moment correlation coefficient'0 was 0-91 >30 35 18 (51%) 6/11 (54%) 12/24 (50%) (p<005) indicating significant positive cor- 482 Cook, Oliver, Mueller, Sampson

ot0. Discussion Our study confirmed that renal involvement in tuberous sclerosis is common; 61% of patients

had renal lesions detectable by renal ultrasound J Med Genet: first published as 10.1136/jmg.33.6.480 on 1 June 1996. Downloaded from scan. However, since we did not have a large number of secondarily ascertained patients, this figure may still not be an accurate rep- resentation ofthe true incidence ofrenal disease *~~~--8_ i in TSC. Most patients with renal involvement were asymptomatic. In general, renal symp-

* toms were only recorded in the notes if vo- lunteered by the patient rather than being 4 specifically elicited. The incidence of renal ~~~~~~~~~~~~~~) symptoms may be higher, particularly in the mentally handicapped who may not be aware of symptoms referrable to the renal tract. How- l;taIll IVia e. F . l ever, of 68 patients with angiomyolipomas, eight (12%) had frank hiematuria and two Figure 1 Frequency of angiomyolipomas according to age and sex. required embolisation to control the haem- orrhage. This was performed percutaneously via the femoral artery. Two further patients had .

10 Only a third of the patients in this study had had any investigation ofrenal function. In most ofthese cases, urea, creatinine, and electrolytes had been measured. A large proportion ofrenal 60 function is lost before these indices become abnormal, but more sensitive tests of renal function such as creatinine clearance had not .~~~~~~~~~~~~~~~. 2J been performed in the majority of patients. r) -7 20 Hypertension might also be anticipated in a 20 group of patients with extensive renal disease, _2 but virtually none of the patients had had routine blood pressure measurements. This 0 O ... - rffl ).- may reflect a lack of awareness of renal com- !..5 .. plications in TSC. Angiomyolipomas were the commonest type

of renal lesion, occurring in 49% of patients. http://jmg.bmj.com/ They were usually both multiple and bilateral. Figure 2 Frequency of renal cysts according to age and sex. A study by Stillwell et afi suggested that the prevalence of angiomyolipomas increases with age. Our study has confirmed this finding. relation between age and increasing prevalence Although our data are limited, they indicate of angiomyolipoma. The incidence of renal that females with TSC develop angiomyo- cysts did not show a significant positive cor-

lipomas at a younger age than the males. This on September 27, 2021 by guest. Protected copyright. relation with age (correlation coefficient 0 79, was also suggested by the smaller study ofWebb 0-1

commendations take account of their size and increased risk of renal carcinoma in TSC it the presence or absence of symptoms.'4 Van has been suggested that bilateral nephrectomy Baal et al'5 reported a relationship between should be performed before transplantation. If the size of angiomyolipomas and their risk of this is not done the native kidneys should be J Med Genet: first published as 10.1136/jmg.33.6.480 on 1 June 1996. Downloaded from bleeding. They suggested that small, asymp- routinely evaluated with ultrasound. tomatic tumours should be monitored regularly This study has shown that a majority of and recommended an aggressive approach of patients with TSC develop renal involvement prophylactic selective embolisation for tumours and that in a minority of cases this results in greater than 3 - 5 cm before they bleed. Ifsurgery significant morbidity. However, we have found has to be performed to control bleeding this that comprehensive renal assessment is rarely should be a partial nephrectomy if possible. undertaken. The study highlights the need for The prevalence of renal cysts in our study a large longitudinal study on which recom- was 32% and the prevalence did not show mendations for renal surveillance can be based. a correlation with age, suggesting a different We are now collecting data prospectively and developmental basis to that of angiomyo- are using the following guidelines. We un- lipomas. The incidence of renal cysts did rise dertake a baseline ultrasound of the kidneys in in the over 30 age group, but so does the all patients. In those without evidence of renal incidence of renal cysts in the general popu- involvement, we suggest that renal ultrasound lation"6 and this may be complicating the pic- should be repeated at least every five years. Van ture. Two of the patients in this age group had Baal et all5 have suggested that, in cases with single cysts. renal disease, follow up scans be performed at In children under the age of5 years cysts were six monthly intervals. However, in their study a more common lesion than angiomyolipomas. only 20% of patients with angiomyolipomas Renal cysts in TSC have been reported ante- showed an increase in size of the lesions after natally'7 and in a neonate at birth, when they five years of follow up. We are adopting a more were seen to enlarge over a period of months.'8 conservative regimen and perform follow up Because other features of TSC are frequently scans every one to two years. If there is any absent in infancy some cases have initially and doubt about the nature of a lesion a CT or erroneously been diagnosed as having auto- MRI scan can help to differentiate between somal recessive polycystic kidney disease or angiomyolipoma and carcinoma. infantile presentation of autosomal dominant Regular blood pressure measurements and polycystic kidney disease.'9 More recently, tests of renal function should be performed if some infants with severe polycystic kidneys there is extensive renal involvement. Ifpossible, have been shown to have a contiguous deletion episodes of bleeding should be treated con- of the TSC2 gene and the adjacent autosomal servatively by embolisation ofindividual lesions dominant polycystic kidney disease gene, and, if this is not possible, by partial neph- PKD 1 .20 rectomy rather than total nephrectomy. Yu et al2' and Okada et al22 have suggested Prophylactic embolisation of large angio- http://jmg.bmj.com/ that the major predisposing factor in the de- myolipomas may be considered but more data velopment of renal failure in people with TSC on the risk of haemorrhage are required before is the presence of cystic disease. In our series guidelines can be drawn up. Dialysis and trans- only four patients had recognised renal im- plantation should be considered for patients in pairment. Of these two both had angiomyo- end stage renal failure. lipomas and cysts, one had angiomyolipomas Further work needs to be done to assess

only, and one had cysts only. whether specific subgroups ofTSC patients are on September 27, 2021 by guest. Protected copyright. Three patients in the study developed renal at risk of developing renal insufficiency. Serial cell carcinoma, all three having coexisting an- renal ultrasounds will provide further information giomyolipomas and cysts. The incidence of on the natural history of renal disease in TSC renal cell carcinoma in the general population and this may allow future modification of the is 7-5/100 000. When Washecka et at' reviewed suggested surveillance protocols. Longitudinal published reports on malignant tumours in studies may also provide insights into the aeti- TSC, they noted that halfthe tumours reported ology of renal carcinoma in persons with TSC. were bilateral compared to the population in- cidence of bilateral tumours which is 1-6 to Financial support for this project was provided by the Tuberous 3 - 8%. The median age for development ofrenal Sclerosis Association of Great Britain. carcinoma in the general population is about 60. In our the 1 Webb DW, Osbourne JP. New research in tuberous sclerosis. study patients were aged 27, 35, BMJt 1992;30:1647-8. and 65 years. Although our numbers are small 2 Gomez MR. Tuberous sclerosis. 2nd ed. New York: Raven they would appear to add to the body of evi- Press, 1990. 3 The European Chromosome 16 Tuberous Sclerosis Con- dence suggesting that there is an increased sortium. Identification and characterization of the tuber- incidence of renal cell ous sclerosis gene on chromosome 16. Cell 1993;75: carcinoma in TSC. 1305-15. None ofthe patients in our study had reached 4 Nellist M, Brook-Carter PT, ConnorJM, et al. Identification end stage renal failure, but both dialysis and of markers flanking the tuberous sclerosis locus on chro- mosome 9 (TSC 1). J7 Med Genet 1993;30:224-7. renal transplantation have been undertaken 5 Shepherd CW, Gomez MR, Crowson CS. Causes of death successfully in in patients with tuberous sclerosis. Mayo Clin Proc 1991; patients with TSC."3 Most TSC 66:792-6. patients receiving renal replacement therapy 6 McCullough DL, Scott R, Seybould HM. Renal angio- have had only minor CNS dysfunction, possibly myolipoma (hamartoma): review of the literature and report of 7 cases. J7 Urol 1971;105:32-44. reflecting the unwillingness of doctors to take 7 Stillwell T, Gomez M, Kelalis P. Renal lesions in tuberous on dialysis and transplantation in the mentally sclerosis. J Urol 1987;138:477-81. 8 Stapleton B, Johnson D, Kaplan G, Griswold W. The cystic handicapped patient. In view of the apparent renal lesion in tuberous sclerosis. JPediatr 1980;97:574-9. 484 Cook, Oliver, Mueller, Sampson

9 Washecka R, Hanna M. Malignant tumours in tuberous 17 Blethyn J, Jones A, Sullivan B. Prenatal diagnosis of uni- sclerosis. 1991;37:340-3. lateral renal disease in tuberous sclerosis. BrjRadiol 1990; 10 Altman, D. Practical statistics for medical research. London: 64:161-4. Chapman and Hall, 1991. 18 Moss J, Hendry G. The natural history of renal cysts in an 11 Webb DW, Fryer AE, Osboume JP. On the incidence of fits infant with tuberous sclerosis; evaluation with ultrasound.

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