Pediatr Radiol DOI 10.1007/s00247-014-3147-1
ORIGINAL ARTICLE
Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome Susan J. Back & Savvas Andronikou & Tracy Kilborn & Bernard S. Kaplan & Kassa Darge
Received: 24 March 2014 / Revised: 21 June 2014 / Accepted: 1 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply
S. J. Back (*) : K. Darge Department of Radiology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, USA e-mail: [email protected] S. Andronikou Radiology Department, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa T. Kilborn Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa B. S. Kaplan Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA B. S. Kaplan : K. Darge Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. Objective To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. Materials and methods We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. Results We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with angiomyolipomas (ranging from 0.4 cm to 7.8 cm). Compared to the latest imaging studies, the initial studies only demonstrated 64% of kidneys to be borderline or enlarged; the majority had 10 or more cysts and 0–5 echogenic foci in each kidney, measuring 0.8 cm maximally, which were possible angiomyolipomas. Increased cortical echogenicity was observed in eight kidneys, and decreased corticomedullary differentiation was demonstrated in six kidneys. Cortical thinning varied with size and number of cysts. Conclusion T h e s o n o g r a p h i c r e n a l f i n d i n g s i n TSC2/ADPKD1 contiguous gene syndrome progress over time and demonstrate a specific pattern of renal disease different from typical tuberous sclerosis complex. There are multiple cysts at presentation and there is progressive
Pediatr Radiol
enlargement of the kidneys and of the renal cysts. Because clinical or imaging findings of TSC may not manifest in the young child, the radiologist can be the first to suggest a diagnosis of TSC2/ADPKD1 contiguous gene syndrome and recommend thorough skin examination and imaging in search of TSC findings. The radiologist should be able to suggest the diagnosis of TSC2/ADPKD1 contiguous gene syndrome in children with TSC who have large cysts occupying a large portion of an enlarged kidney. This should not be dismissed as renal cystic disease of TSC or as ADPKD because the diagnosis of TSC2/ADPKD1 contiguous gene syndrome has implications for patient management and prognosis. Keywords Tuberous sclerosis complex . Autosomal-dominant polycystic kidney disease . Contiguous gene syndrome . Ultrasound . Magnetic resonance imaging . Pediatric
Introduction A short segment of chromosome 16 encodes the tumor suppressor gene tuberin (TSC2) as well as the protein polycystin 1 (PKD1), which are responsible for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1, respectively [1]. The TSC2 and PKD1 genes are separated by fewer than 100 base pairs [2]. Deletions involving both genes result in a mixed phenotype of tuberous sclerosis and polycystic renal disease known as the TSC2/ADPKD1 contiguous gene syndrome. Distinct from patients with tuberous sclerosis, those with contiguous deletions involving TSC2 and PKD1 have polycystic kidney disease and renal enlargement in infancy and childhood [2]. Large cysts predominate over angiomyolipomas in the kidneys and they enlarge over time. The diagnosis of TSC2/ADPKD1 contiguous gene syndrome should be considered in these children, who sometimes have phenotypic features of tuberous sclerosis, even in the absence of genetic support. Because TSC, ADPKD and the TSC2/ADPKD1 contiguous gene syndrome can all demonstrate renal cysts on imaging it is important to consider TSC in infants and young children with polycystic kidneys even when there are no other stigmata of TSC [3]. The cutaneous signs of TSC might not develop until after age 4 years and, as a result, TSC has been misdiagnosed as ADPKD in young children [4]. Distinguishing between cysts from TSC and those from TSC2/ADPKD1 contiguous gene syndrome has important implications for the monitoring and management of renal failure and hypertension, which are more common in TSC2/ADPKD1 contiguous gene syndrome than TSC, as well as for the evaluation of coincident lesions and genetic counseling. The potential new therapies for PKD (tolvaptan) and TSC (everolimus) make a more precise diagnosis essential [5, 6].
The radiologic findings of renal cysts with appearances of ADPKD might be the first clues to making a diagnosis of TSC2/ADPKD1 contiguous gene syndrome. Although features of TSC2/ADPKD1 contiguous gene syndrome are well described in the renal, genetic and pathological literature, there is a paucity of discussion in the radiology literature [1, 2, 4, 7, 8]. Radiologists might be the first to identify cystic renal disease and should be able to suggest the diagnosis of TSC2/ADPKD1 contiguous gene syndrome. The purpose of this report is to describe the pediatric renal imaging manifestations in seven children with TSC2/ADPKD1 contiguous gene syndrome.
Materials and methods The seven children and young adults presented in this series were known by members of our group to have imaging manifestations of enlarged and polycystic kidneys at a young age (younger than 4 years). Five were identified by a nephrologist at one institution who follows a cohort of these patients. Two additional children were included from an institution in South Africa by two pediatric radiologist collaborators who had identified similar imaging features in these children under their care. Inclusion of these seven patients is based on a retrospective diagnosis of TSC2/ADPKD1 contiguous gene syndrome. Prior to or following renal imaging, brain and cardiac imaging or physical examination detected lesions considered to be major features of the diagnosis of tuberous sclerosis (Table 1). We reviewed the medical records and imaging studies of these children to characterize the renal imaging findings in this syndrome. The study was performed retrospectively with cross-sectional and longitudinal components. Imaging review included US and MRI when available. We assessed renal size, cyst number, cyst size and presence of angiomyolipomas both at baseline and at follow-up imaging. The percentage of the kidney replaced by cysts was subjectively assessed in increments of 25% as a descriptive assessment of the degree of renal parenchymal involvement. The study was approved by the local institutional review boards.
Results We included seven patients from two referral institutions on two continents (five from the United States and two from South Africa). Patient ages ranged from birth to 21 years over the course of imaging. Initial imaging demonstrating renal cysts was obtained when the patients were 1 day of age to 4 years of age with a mean age of 1 year. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). For patient 6, the earliest renal US images were no
Pediatr Radiol Table 1 Imaging, clinical and genetic findings for each child with TSC2/ADPKD1 contiguous gene syndrome Patient Findings Renal -Renal cyst -Renal AML -Hypertension Neurological -Epilepsy -Cortical tubers -Subependymal nodules -SGCA -Eye disease -Developmental delay Cardiac -Rhabdomyoma Dermatological -Hypomelanotic lesions -Angiofibroma -Shagreen patches -Forehead plaque Genetics
1
2
3
4
5
6
7
x x x
x x
x x x
x x
x x
x x x
x x x
x x x
x x x
x x
x
x
x x x x x x
x x
x x
x x x
x
x x x
x x x
x x
x x
x
Suspected mosaic deletion TSC2
Deletion 194 kb region chromosome 16p13.3
x x x
x
x x Deletion TSC2 exons 32–41
Family declined genetic testing
AML angiomyolipoma, SGCA subependymal giant cell astrocytoma
longer available; for this child we reviewed a report from an examination at the age of 2 years. No patient progressed to end-stage renal disease during this period. Three children were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated creatinine. Although genetic information was not available for every patient, no patient had affected relatives, which suggests de novo deletions. General imaging findings All children developed enlarged, polycystic kidneys. Each patient has two kidneys. On initial studies, 64% of kidneys were borderline or enlarged; the majority had 10 or more cysts and 0-5 echogenic foci in each kidney, measuring 0.8 cm maximally, which were possible angiomyolipomas. Increased cortical echogenicity was observed in eight kidneys and decreased corticomedullary differentiation was demonstrated in six kidneys. Cortical thinning varied with size and number of cysts. The latest available imaging demonstrated that 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning in all but one child. That child had 5–9 cysts in each kidney with 50–75% parenchymal replacement on the right and up to 25% of the
parenchyma replaced on the left. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Multiple echogenic lesions were present in 13 of 14 kidneys, in keeping with angiomyolipomas, ranging in size from 0.4 cm to 7.8 cm (Table 2). Patients 1 and 5 were followed with US from birth. For each of these patients the initial US performed in the first week of age demonstrated multiple sub-centimeter cysts. Patient 1 had more than 15 cysts in each kidney and patient 2 had 5–9 cysts in each kidney. By 1 year of age there was a dramatic increase in the number and size of the cysts (Fig. 1). MRI findings Only three patients were evaluated by abdominal MRI. MRI assessment was undertaken in the setting of known polycystic kidney disease and the presence of solid masses. The large kidney size precluded accurate assessment of all of the renal lesions by sonography. MR images demonstrated the kidneys to be nearly replaced by lesions. Cystic, T2hyperintense and T1-hypointense lesions predominated. In addition, MRI demonstrated solid T2-hypointense and T1hyperintense lesions that suppressed on fat-saturated sequences and enhanced following gadolinium administration.
Pediatr Radiol Table 2 Comparison of first available and most recent renal/bladder sonograms. Right and left kidneys are presented separately as right/left Patient
1
2
3
4
5
Time difference between sonograms (years, months) First vs. last sonogram Number of cysts 0–4=1; 5–9=2; 10–14=3; 15 or more = 4 Largest cyst diameter (cm) Number of AMLs # cyst
Adult Variable Variable
Childhood Many Large AML # Cyst > # AML
AML angiomyolipoma
Pediatr Radiol
to renal failure and hypertension than patients with TSC and may be candidates for novel therapies. Bisceglia et al. [1] noted approximately 20 cases of the TSC2/ADPKD1 contiguous gene syndrome that were defined clinically as the phenotypic findings of TSC and ADPKD. Since their publication, additional cases have been described highlighting the shared phenotypic findings of an intracranial aneurysm in ADPKD in a patient with a clinical diagnosis of TSC [21], patients who had unilateral or delayed presentation of polycystic kidney disease thought to be from mosaicism [22–24] and cases focused on the dermatological manifestations [8]. Some of the families of patients previously published declined molecular analysis and genetic counseling, as was the situation in our study. Genetic confirmation is not considered necessary for the clinical care of these patients. In such cases the diagnosis of TSC2/ADPKD1 contiguous gene syndrome is inferred based on the clinical and imaging manifestations. None of the seven patients in our series has relatives who are affected, suggesting de novo deletions in these patients. Our seven patients not only represent a substantial addition to the number of patients with TSC2/ADPKD1 contiguous gene syndrome but also significantly increase the knowledge base on the imaging findings longitudinally. Unlike cysts in TSC, the renal cysts in the majority of our patients developed in large kidneys and eventually replaced 50% or more of the parenchyma with >15 cysts. The cysts ranged in size from 2.4 cm to 9.3 cm. Initial imaging showed that the majority of children had borderline or enlarged kidneys, 10 or more cysts, increased cortical echogenicity with poor corticomedullary differentiation and many more cysts than angiomyolipomas. Although renal disease in ADPKD usually manifests in adulthood, it can present at any age. Fick et al. [25] observed 140 children at risk for ADPKD and found 62 of them to have renal disease. The mean age of the 37 children with 1–10 cysts was 10 years (±1) and the 25 children with greater than 10 cysts was 13 years (±1). The majority of our patients had 10 or more cysts at the initial imaging, which was performed in the neonatal period of 3 children, in infancy of 2 children and at 2 years and 4 years of age in the remaining 2 children (mean age 1 year). In comparison with TSC2/ADPKD1 contiguous gene syndrome, only those children with ADPKD who have more than 10 cysts have been shown to have renal enlargement [25]. Although cysts can be present in TSC, they are not typically the dominant lesions. The more common renal manifestation is angiomyolipomas. The majority of affected children have renal lesions by their pre-teen years. Henske [17] reported that the minority of lesions is cysts and even fewer have a polycystic appearance. In Casper’s series [26] of 59 patients with TSC ranging in age from 3 days to 36 years, 28 had cysts. Of those, 20 individuals also had angiomyolipomas. The majority of patients with cysts had few in number. Patients who initially did not have cysts (11 patients)
developed them at a mean age of 9 years. Those cysts tended to be small, averaging less than a centimeter in size. In contrast, our patients demonstrated many more cysts than angiomyolipomas. MRI findings when available in our patients were striking and most helpful because the large renal size made follow-up US a challenge for recording changes in individual lesions over time. MRI demonstrated that the kidneys were mostly replaced by lesions of both the cystic and solid variety. Solid lesions had evidence of macro- and microscopic fat and were presumed to represent lipid-rich angiomyolipomas. Because TSC2/ADPKD1 contiguous gene syndrome manifests as a mixed phenotype of TSC and ADPKD, imaging surveillance of lesions is warranted. Recently published recommendations from the TSC consensus conference [27] recommend abdominal and brain MRI to assess for the presence of lesions in the evaluation or diagnosis of TSC. Patients who are asymptomatic and younger than 25 years should undergo brain MRI every 1–3 years; those who are asymptomatic with enlarging ventricles and those with large or growing subependymal giant cell astrocytomas should be imaged more often. Abdominal MRI is recommended every 1–3 years to monitor growth of lesions throughout life [27]. Given the predominance of renal cysts over angiomyolipomas in children with TSC2/ADPKD1 contiguous gene syndrome, US is beneficial for surveillance, especially in younger patients who would require sedation for MRI evaluation. When the limits of US are met with nephromegaly or number of lesions, MRI can be obtained. A limitation of our study is the lack of complete genetic information for each child. Although this information is corroborative, it is not essential to the clinical diagnosis and care of the children. Even though one child had a prenatal diagnosis of a cardiac rhabdomyoma, neither prenatal renal imaging nor report of in utero renal abnormalities was available for this child. Knowledge of the presence or absence of fetal renal abnormalities in our cohort would have been beneficial given the early postnatal and childhood imaging findings.
Conclusion The sonographic renal findings in TSC2/ADPKD1 contiguous gene syndrome progress over time and demonstrate a specific pattern of renal disease different from typical TSC. In comparison with TSC and ADPKD, children with TSC2/ADPKD1 contiguous gene syndrome develop multiple large renal cysts in enlarged kidneys during infancy or early childhood and there is progressive enlargement of the kidneys and renal cysts. In the absence of genetic analysis, TSC2/ADPKD1 contiguous gene syndrome is recognized in the presence of these imaging findings in the kidneys in association with phenotypic manifestations of TSC in the skin,
Pediatr Radiol
brain, heart and other organs. Additionally, in the seven presented patients, each child developed lesions suggestive of angiomyolipomas on follow-up imaging. Although clinical or imaging findings of TSC may not manifest in the young child, the radiologist can be the first to suggest a diagnosis of TSC2/ADPKD1 contiguous gene syndrome and recommend imaging and directed skin examination in search of TSC lesions. Recognition of this constellation of findings by the radiologist may prompt further screening for TSC phenotype (if unknown at the time of renal imaging), and change patient management or counseling.
Conflicts of interest None
References 1. Bisceglia M, Galliani C, Carosi I et al (2008) Tuberous sclerosis complex with polycystic kidney disease of the adult type: the TSC2/ADPKD1 contiguous gene syndrome. Int J Surg Pathol 16:375–385 2. Hartman TR, Liu D, Zilfou JT et al (2009) The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycininsensitive and polycystin 1-independent pathway. Hum Mol Genet 18:151–163 3. Martignoni G, Bonetti F, Pea M et al (2003) Renal pathology in tuberous sclerosis complex. Pathology 35:505–512 4. Brook-Carter PT, Peral B, Ward CJ et al (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease — a contiguous gene syndrome. Nat Genet 8:328–332 5. Steinman TI (2012) Polycystic kidney disease: a 2011 update. Curr Opin Nephrol Hypertens 21:189–194 6. Budde K, Gaedeke J (2012) Tuberous sclerosis complex — associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis 59:276–283 7. Longa L, Scolari F, Brusco A et al (1993) A large TSC2 and PKD1 gene deletion is associated with renal and extrarenal signs of ADPKD. Nephrol Dial Transplant 12:1900–1907 8. Kacerovska D, Vrtel R, Michal M et al (2009) TSC2/PKD1 contiguous gene syndrome: a report of 2 cases with emphasis on dermatopathologic findings. Am J Dermatopathol 31:532–541 9. Han BK, Babcock DS (1985) Sonographic measurements and appearance of normal kidneys in children. AJR Am J Roentgenol 145: 611–616
10. Avni FE, Hall M (2010) Renal cystic diseases in children: new concepts. Pediatr Radiol 40:939–946 11. Avni FE, Garel C, Cassart M et al (2012) Imaging and classification of congenital cystic renal diseases. AJR Am J Roentgenol 198:1004– 1013 12. Sweeney WE, Avner ED (2011) Diagnosis and management of childhood polycystic kidney disease. Pediatr Nephrol 26: 675–692 13. Ravine D, Gibson RN, Waler RG et al (1994) Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease. Lancet 343:824–827 14. Pei Y, Obaji J, Dupuis A et al (2009) Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 20: 205–212 15. Dell KM (2011) The spectrum of polycystic kidney disease in children. Adv Chron Kidney Dis 18:339–347 16. Gabow PA, Kimberling WJ, Strain JD et al (1997) Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 8:105–110 17. Henske EP (2005) Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol 20:854–857 18. Roach ES, Sparagana SP (2004) Diagnosis of tuberous sclerosis complex. J Child Neurol 19:644–649 19. Roach ES, Gomez MR, Northrup MD (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624–628 20. Bernstein J (1993) Renal cystic disease in TSC. Pediatr Nephrol 7: 490–495 21. Chen YL, Luo CB, Hsu SW et al (2001) Tuberous sclerosis complex with an unruptured intracranial aneurysm: manifestations of contiguous gene syndrome. Interv Neuroradiol 7:337– 341 22. Denne C, Gerstl EM, Mayer K et al (2011) Uncommon presentation of tuberous sclerosis in an infant. Arch Pediatr 18:660–664 23. Smulders YM, Eussen BHJ, Verhoef S et al (2003) Large deletion causing the TSC2-PKD1 contiguous gene syndrome without infantile polycystic disease. J Med Genet 40:e17 24. Weber MA, Risdon RA, Malone M et al (2005) Isolated unilateral tuberous sclerosis-associated renal cystic disease in a neonate. Fetal Pediatr Pathol 24:267–275 25. Fick GM, Duley IT, Johnson AM et al (1994) The spectrum of autosomal dominant polycystic kidney disease in children. J Am Soc Nephrol 3:1654–1660 26. Casper KA, Donnelly LF, Chen B et al (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225: 451–456 27. Krueger DA, Northrup H (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255–265
ORIGINAL ARTICLE
Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome Susan J. Back & Savvas Andronikou & Tracy Kilborn & Bernard S. Kaplan & Kassa Darge
Received: 24 March 2014 / Revised: 21 June 2014 / Accepted: 1 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply
S. J. Back (*) : K. Darge Department of Radiology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, USA e-mail: [email protected] S. Andronikou Radiology Department, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa T. Kilborn Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa B. S. Kaplan Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA B. S. Kaplan : K. Darge Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. Objective To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. Materials and methods We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. Results We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with angiomyolipomas (ranging from 0.4 cm to 7.8 cm). Compared to the latest imaging studies, the initial studies only demonstrated 64% of kidneys to be borderline or enlarged; the majority had 10 or more cysts and 0–5 echogenic foci in each kidney, measuring 0.8 cm maximally, which were possible angiomyolipomas. Increased cortical echogenicity was observed in eight kidneys, and decreased corticomedullary differentiation was demonstrated in six kidneys. Cortical thinning varied with size and number of cysts. Conclusion T h e s o n o g r a p h i c r e n a l f i n d i n g s i n TSC2/ADPKD1 contiguous gene syndrome progress over time and demonstrate a specific pattern of renal disease different from typical tuberous sclerosis complex. There are multiple cysts at presentation and there is progressive
Pediatr Radiol
enlargement of the kidneys and of the renal cysts. Because clinical or imaging findings of TSC may not manifest in the young child, the radiologist can be the first to suggest a diagnosis of TSC2/ADPKD1 contiguous gene syndrome and recommend thorough skin examination and imaging in search of TSC findings. The radiologist should be able to suggest the diagnosis of TSC2/ADPKD1 contiguous gene syndrome in children with TSC who have large cysts occupying a large portion of an enlarged kidney. This should not be dismissed as renal cystic disease of TSC or as ADPKD because the diagnosis of TSC2/ADPKD1 contiguous gene syndrome has implications for patient management and prognosis. Keywords Tuberous sclerosis complex . Autosomal-dominant polycystic kidney disease . Contiguous gene syndrome . Ultrasound . Magnetic resonance imaging . Pediatric
Introduction A short segment of chromosome 16 encodes the tumor suppressor gene tuberin (TSC2) as well as the protein polycystin 1 (PKD1), which are responsible for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1, respectively [1]. The TSC2 and PKD1 genes are separated by fewer than 100 base pairs [2]. Deletions involving both genes result in a mixed phenotype of tuberous sclerosis and polycystic renal disease known as the TSC2/ADPKD1 contiguous gene syndrome. Distinct from patients with tuberous sclerosis, those with contiguous deletions involving TSC2 and PKD1 have polycystic kidney disease and renal enlargement in infancy and childhood [2]. Large cysts predominate over angiomyolipomas in the kidneys and they enlarge over time. The diagnosis of TSC2/ADPKD1 contiguous gene syndrome should be considered in these children, who sometimes have phenotypic features of tuberous sclerosis, even in the absence of genetic support. Because TSC, ADPKD and the TSC2/ADPKD1 contiguous gene syndrome can all demonstrate renal cysts on imaging it is important to consider TSC in infants and young children with polycystic kidneys even when there are no other stigmata of TSC [3]. The cutaneous signs of TSC might not develop until after age 4 years and, as a result, TSC has been misdiagnosed as ADPKD in young children [4]. Distinguishing between cysts from TSC and those from TSC2/ADPKD1 contiguous gene syndrome has important implications for the monitoring and management of renal failure and hypertension, which are more common in TSC2/ADPKD1 contiguous gene syndrome than TSC, as well as for the evaluation of coincident lesions and genetic counseling. The potential new therapies for PKD (tolvaptan) and TSC (everolimus) make a more precise diagnosis essential [5, 6].
The radiologic findings of renal cysts with appearances of ADPKD might be the first clues to making a diagnosis of TSC2/ADPKD1 contiguous gene syndrome. Although features of TSC2/ADPKD1 contiguous gene syndrome are well described in the renal, genetic and pathological literature, there is a paucity of discussion in the radiology literature [1, 2, 4, 7, 8]. Radiologists might be the first to identify cystic renal disease and should be able to suggest the diagnosis of TSC2/ADPKD1 contiguous gene syndrome. The purpose of this report is to describe the pediatric renal imaging manifestations in seven children with TSC2/ADPKD1 contiguous gene syndrome.
Materials and methods The seven children and young adults presented in this series were known by members of our group to have imaging manifestations of enlarged and polycystic kidneys at a young age (younger than 4 years). Five were identified by a nephrologist at one institution who follows a cohort of these patients. Two additional children were included from an institution in South Africa by two pediatric radiologist collaborators who had identified similar imaging features in these children under their care. Inclusion of these seven patients is based on a retrospective diagnosis of TSC2/ADPKD1 contiguous gene syndrome. Prior to or following renal imaging, brain and cardiac imaging or physical examination detected lesions considered to be major features of the diagnosis of tuberous sclerosis (Table 1). We reviewed the medical records and imaging studies of these children to characterize the renal imaging findings in this syndrome. The study was performed retrospectively with cross-sectional and longitudinal components. Imaging review included US and MRI when available. We assessed renal size, cyst number, cyst size and presence of angiomyolipomas both at baseline and at follow-up imaging. The percentage of the kidney replaced by cysts was subjectively assessed in increments of 25% as a descriptive assessment of the degree of renal parenchymal involvement. The study was approved by the local institutional review boards.
Results We included seven patients from two referral institutions on two continents (five from the United States and two from South Africa). Patient ages ranged from birth to 21 years over the course of imaging. Initial imaging demonstrating renal cysts was obtained when the patients were 1 day of age to 4 years of age with a mean age of 1 year. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). For patient 6, the earliest renal US images were no
Pediatr Radiol Table 1 Imaging, clinical and genetic findings for each child with TSC2/ADPKD1 contiguous gene syndrome Patient Findings Renal -Renal cyst -Renal AML -Hypertension Neurological -Epilepsy -Cortical tubers -Subependymal nodules -SGCA -Eye disease -Developmental delay Cardiac -Rhabdomyoma Dermatological -Hypomelanotic lesions -Angiofibroma -Shagreen patches -Forehead plaque Genetics
1
2
3
4
5
6
7
x x x
x x
x x x
x x
x x
x x x
x x x
x x x
x x x
x x
x
x
x x x x x x
x x
x x
x x x
x
x x x
x x x
x x
x x
x
Suspected mosaic deletion TSC2
Deletion 194 kb region chromosome 16p13.3
x x x
x
x x Deletion TSC2 exons 32–41
Family declined genetic testing
AML angiomyolipoma, SGCA subependymal giant cell astrocytoma
longer available; for this child we reviewed a report from an examination at the age of 2 years. No patient progressed to end-stage renal disease during this period. Three children were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated creatinine. Although genetic information was not available for every patient, no patient had affected relatives, which suggests de novo deletions. General imaging findings All children developed enlarged, polycystic kidneys. Each patient has two kidneys. On initial studies, 64% of kidneys were borderline or enlarged; the majority had 10 or more cysts and 0-5 echogenic foci in each kidney, measuring 0.8 cm maximally, which were possible angiomyolipomas. Increased cortical echogenicity was observed in eight kidneys and decreased corticomedullary differentiation was demonstrated in six kidneys. Cortical thinning varied with size and number of cysts. The latest available imaging demonstrated that 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning in all but one child. That child had 5–9 cysts in each kidney with 50–75% parenchymal replacement on the right and up to 25% of the
parenchyma replaced on the left. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Multiple echogenic lesions were present in 13 of 14 kidneys, in keeping with angiomyolipomas, ranging in size from 0.4 cm to 7.8 cm (Table 2). Patients 1 and 5 were followed with US from birth. For each of these patients the initial US performed in the first week of age demonstrated multiple sub-centimeter cysts. Patient 1 had more than 15 cysts in each kidney and patient 2 had 5–9 cysts in each kidney. By 1 year of age there was a dramatic increase in the number and size of the cysts (Fig. 1). MRI findings Only three patients were evaluated by abdominal MRI. MRI assessment was undertaken in the setting of known polycystic kidney disease and the presence of solid masses. The large kidney size precluded accurate assessment of all of the renal lesions by sonography. MR images demonstrated the kidneys to be nearly replaced by lesions. Cystic, T2hyperintense and T1-hypointense lesions predominated. In addition, MRI demonstrated solid T2-hypointense and T1hyperintense lesions that suppressed on fat-saturated sequences and enhanced following gadolinium administration.
Pediatr Radiol Table 2 Comparison of first available and most recent renal/bladder sonograms. Right and left kidneys are presented separately as right/left Patient
1
2
3
4
5
Time difference between sonograms (years, months) First vs. last sonogram Number of cysts 0–4=1; 5–9=2; 10–14=3; 15 or more = 4 Largest cyst diameter (cm) Number of AMLs # cyst
Adult Variable Variable
Childhood Many Large AML # Cyst > # AML
AML angiomyolipoma
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to renal failure and hypertension than patients with TSC and may be candidates for novel therapies. Bisceglia et al. [1] noted approximately 20 cases of the TSC2/ADPKD1 contiguous gene syndrome that were defined clinically as the phenotypic findings of TSC and ADPKD. Since their publication, additional cases have been described highlighting the shared phenotypic findings of an intracranial aneurysm in ADPKD in a patient with a clinical diagnosis of TSC [21], patients who had unilateral or delayed presentation of polycystic kidney disease thought to be from mosaicism [22–24] and cases focused on the dermatological manifestations [8]. Some of the families of patients previously published declined molecular analysis and genetic counseling, as was the situation in our study. Genetic confirmation is not considered necessary for the clinical care of these patients. In such cases the diagnosis of TSC2/ADPKD1 contiguous gene syndrome is inferred based on the clinical and imaging manifestations. None of the seven patients in our series has relatives who are affected, suggesting de novo deletions in these patients. Our seven patients not only represent a substantial addition to the number of patients with TSC2/ADPKD1 contiguous gene syndrome but also significantly increase the knowledge base on the imaging findings longitudinally. Unlike cysts in TSC, the renal cysts in the majority of our patients developed in large kidneys and eventually replaced 50% or more of the parenchyma with >15 cysts. The cysts ranged in size from 2.4 cm to 9.3 cm. Initial imaging showed that the majority of children had borderline or enlarged kidneys, 10 or more cysts, increased cortical echogenicity with poor corticomedullary differentiation and many more cysts than angiomyolipomas. Although renal disease in ADPKD usually manifests in adulthood, it can present at any age. Fick et al. [25] observed 140 children at risk for ADPKD and found 62 of them to have renal disease. The mean age of the 37 children with 1–10 cysts was 10 years (±1) and the 25 children with greater than 10 cysts was 13 years (±1). The majority of our patients had 10 or more cysts at the initial imaging, which was performed in the neonatal period of 3 children, in infancy of 2 children and at 2 years and 4 years of age in the remaining 2 children (mean age 1 year). In comparison with TSC2/ADPKD1 contiguous gene syndrome, only those children with ADPKD who have more than 10 cysts have been shown to have renal enlargement [25]. Although cysts can be present in TSC, they are not typically the dominant lesions. The more common renal manifestation is angiomyolipomas. The majority of affected children have renal lesions by their pre-teen years. Henske [17] reported that the minority of lesions is cysts and even fewer have a polycystic appearance. In Casper’s series [26] of 59 patients with TSC ranging in age from 3 days to 36 years, 28 had cysts. Of those, 20 individuals also had angiomyolipomas. The majority of patients with cysts had few in number. Patients who initially did not have cysts (11 patients)
developed them at a mean age of 9 years. Those cysts tended to be small, averaging less than a centimeter in size. In contrast, our patients demonstrated many more cysts than angiomyolipomas. MRI findings when available in our patients were striking and most helpful because the large renal size made follow-up US a challenge for recording changes in individual lesions over time. MRI demonstrated that the kidneys were mostly replaced by lesions of both the cystic and solid variety. Solid lesions had evidence of macro- and microscopic fat and were presumed to represent lipid-rich angiomyolipomas. Because TSC2/ADPKD1 contiguous gene syndrome manifests as a mixed phenotype of TSC and ADPKD, imaging surveillance of lesions is warranted. Recently published recommendations from the TSC consensus conference [27] recommend abdominal and brain MRI to assess for the presence of lesions in the evaluation or diagnosis of TSC. Patients who are asymptomatic and younger than 25 years should undergo brain MRI every 1–3 years; those who are asymptomatic with enlarging ventricles and those with large or growing subependymal giant cell astrocytomas should be imaged more often. Abdominal MRI is recommended every 1–3 years to monitor growth of lesions throughout life [27]. Given the predominance of renal cysts over angiomyolipomas in children with TSC2/ADPKD1 contiguous gene syndrome, US is beneficial for surveillance, especially in younger patients who would require sedation for MRI evaluation. When the limits of US are met with nephromegaly or number of lesions, MRI can be obtained. A limitation of our study is the lack of complete genetic information for each child. Although this information is corroborative, it is not essential to the clinical diagnosis and care of the children. Even though one child had a prenatal diagnosis of a cardiac rhabdomyoma, neither prenatal renal imaging nor report of in utero renal abnormalities was available for this child. Knowledge of the presence or absence of fetal renal abnormalities in our cohort would have been beneficial given the early postnatal and childhood imaging findings.
Conclusion The sonographic renal findings in TSC2/ADPKD1 contiguous gene syndrome progress over time and demonstrate a specific pattern of renal disease different from typical TSC. In comparison with TSC and ADPKD, children with TSC2/ADPKD1 contiguous gene syndrome develop multiple large renal cysts in enlarged kidneys during infancy or early childhood and there is progressive enlargement of the kidneys and renal cysts. In the absence of genetic analysis, TSC2/ADPKD1 contiguous gene syndrome is recognized in the presence of these imaging findings in the kidneys in association with phenotypic manifestations of TSC in the skin,
Pediatr Radiol
brain, heart and other organs. Additionally, in the seven presented patients, each child developed lesions suggestive of angiomyolipomas on follow-up imaging. Although clinical or imaging findings of TSC may not manifest in the young child, the radiologist can be the first to suggest a diagnosis of TSC2/ADPKD1 contiguous gene syndrome and recommend imaging and directed skin examination in search of TSC lesions. Recognition of this constellation of findings by the radiologist may prompt further screening for TSC phenotype (if unknown at the time of renal imaging), and change patient management or counseling.
Conflicts of interest None
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