|Year : 2015 | Volume
| Issue : 1 | Page : 52-55
Gross hematuria in a child with tuberous sclerosis complex
Mairo Adamu Bugaje, Abubakar Yakubu, Rosemund Akuse, Henry Abiodun Aikhionbare
Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State, Nigeria
|Date of Submission||01-Dec-2014|
|Date of Acceptance||30-Jan-2015|
|Date of Web Publication||17-Feb-2015|
Mairo Adamu Bugaje
Department of Paediatrics Ahmadu Bello University Teaching Hospital, Zaria
Tuberous sclerosis is an under diagnosed autosomal dominant neurocutaneous syndrome characterized by the presence of benign congenital tumors in multiple organs expression and a prevalence of 1/6,000-1/12000 newborns. There are varying degrees of renal involvement in tuberous sclerosis complex, which is usually bilateral and asymptomatic. We report a case of Tuberous sclerosis with left sided renal angiomyolipoma and bilateral multiple renal cysts in a 12-year-old boy, who presented with massive hematuria warranting blood transfusion and urosepsis. There was past medical history of repeated seizures. This case highlights the need for a high index of suspicion in a child with un-explained skin lesions, recurrent seizures, mental retardation and symptoms referable to the urinary system.
Keywords: Angiomyolipoma, child, renal cysts, tuberous sclerosis complex
|How to cite this article:|
Bugaje MA, Yakubu A, Akuse R, Aikhionbare HA. Gross hematuria in a child with tuberous sclerosis complex. Sub-Saharan Afr J Med 2015;2:52-5
|How to cite this URL:|
Bugaje MA, Yakubu A, Akuse R, Aikhionbare HA. Gross hematuria in a child with tuberous sclerosis complex. Sub-Saharan Afr J Med [serial online] 2015 [cited 2020 May 28];2:52-5. Available from: http://www.ssajm.org/text.asp?2015/2/1/52/151572
| Introduction|| |
Tuberous sclerosis complex (TSC) is a rare neurocutaneous syndrome characterized by multisystem benign congenital tumors. It is inherited as an autosomal dominant trait with variable expression. The prevalence of TSC ranges from 1/6,000 to 1/12000 newborns. ,, Spontaneous genetic mutations occur in two-thirds of the cases. TSC affects various organ systems, has a wide spectrum of clinical manifestations and a variable degree of severity. ,,
Renal involvement of TSC includes renal angiomyolipoma (AML), renal cysts, and renal cell carcinoma, which may present with hematuria, abdominal pain, and other symptoms in about 87% of cases.  However, symptomatic complications are rare, and when they occur, especially spontaneous bleeding, may prove to be fatal.  We present a 12-year-old boy with TSC with left sided renal AML and bilateral multiple renal cysts who presented with massive hematuria and urosepsis.
| Case report|| |
S. S. was a 12-year-old primary school boy who presented to the emergency pediatric unit, with fever, vomiting, abdominal pain and jaundice of 5 days, total massive hematuria and severe anemia of 2 days duration. This was the first episode of such symptoms in the child. There was no history of acquired body rashes, sore throat, body swelling, headaches, and change in personality or gait. There was no relevant family history of similar or dissimilar illness. Past medical history revealed history of recurrent generalized tonic-clonic convulsions with the occasional coma since the age of 1-year for which he was on anticonvulsant therapy and on follow-up elsewhere. He was noticed at birth to have multiple "birth marks" of varying sizes and color on the face and right thigh. There were hypopigmented flat areas on the trunk and left thigh, which progressively increased in size and number for which he was treated in National Tuberculosis and Leprosy Training Center for the dermal lesions without any improvement. Though he had normal physical growth, he was found to have delayed speech development, blurred vision, and poor school performance. He had no other significant symptoms.
Physical examination revealed severe pallor, mild jaundice, pyrexia of 39°C, and generalized peripheral lymphadenopathy. He had normal weight and height of 36 kg (91% of expected) and 140 cm (94% of expected) respectively. He had numerous angiofibromas on his nose, cheeks and chin with fibrous plaques [Figure 1]; shagreen patch over the thighs, Hypomelanotic macules on the trunk and left thigh [Figure 2] and [Figure 3]. Cardiovascular system examination revealed tachycardia of 130 beats/min and an apical hemic murmur, with a normal blood pressure of 90/60 mmHg. He had hepatomegaly of 6 cm and bilaterally palpable kidneys, but no renal angle tenderness. Fundoscopy revealed hamartomatous lesions on the retina at 9 O'clock and 3 O'clock position in the right and left eyes respectively.
Complete blood count revealed anemia of 6 g/dL and neutrophilia, with the other parameters within normal. Urine examination showed macroscopic hematuria while dipstick revealed positive leukocytes esterase and nitrite tests. A clinical diagnosis of urosepsis in a child with TSC was made for the first time. Additional investigations included abdominal ultrasound, which revealed multiple rounded well marginated echogenic masses consistent with left renal AML with bilateral multiple renal cysts measuring 1.5 cm and 2.1 cm on the right and the left respectively [Figure 4]. A magnetic resonance imaging scan of the brain showed sub-ependymal calcified nodules in the lateral ventricles consistent with the diagnosis of TSC [Figure 5]. Echocardiography was essentially normal, and electroencephalography showed epileptiform discharge at the left fronto-parietal region. Chest X-ray showed radio-opaque strands in the lung parenchyma bilaterally, suggesting multiple fibrosis. Urine and blood cultures were negative.
|Figure 5: Sub-ependymal nodules lateral ventricles on brain magnetic resonance imaging scan|
Click here to view
He was managed conservatively with ceftriaxone, blood transfusion and continued on the anticonvulsant carbamazepine. He improved and was discharged after a hospital stay of 6 days. Child is still on follow-up 24 months after discharge and symptoms of hematuria or urinary tract infection (UTI) have not re-occurred.
| Discussion|| |
This case is worth reporting because of the rarity of occurrence of AML and renal cysts together, as well as the child been undiagnosed for 11 years, perhaps due to the rarity of TSC in our setting.
Tuberous sclerosis complex arises from mutations of either TSC1 (chromosome locus 9q34.3) or TSC2 (16p13.3), which encode hamartin and tuberin, respectively.  These proteins are believed to function as tumor suppressors by forming a complex that regulates cellular proliferation. , Tuberin and hamartin are involved in a key pathway in the cell that regulates protein synthesis and cell size. One of the ways cells regulates their growth is by controlling the rate of protein synthesis. A protein called mammalian target of rapamycin pathway (mTOR) was identified as one of the master regulators of cell growth,  which is controlled by Ras homologue enriched in brain (rheb), a small cytoplasmic GTPase. When rheb is activated, the protein synthesis machinery is turned on, probably via mTOR, and the cell grows in size.
Our patient presented with six major criteria and one minor criterion,  namely hypomelanotic macules, angiofibromas with fibrous plaques, shagreen patch, retinal hamartomas, sub-ependymal nodules, AMLs and multiple renal cysts [Table 1]. Although several physicians saw him elsewhere both general and subspecialists (neurologists and dermatologists), the diagnosis of TSC was not considered until he presented in our facility.
The mental retardation evidenced by poor school performance (in Class 4 at 12 years) could be due to early onset and poorly controlled seizures, and the association of high incidence of mental retardation with AML in patients with TSC as was documented in other reports. 
Almost half of the patients with TSC have an underlying renal pathology, mainly AMLs, cysts and/or renal cell carcinoma.  Our patient had both AML and bilateral renal cysts, although it is considered rare to have both. AMLs and renal cysts account for 50-75% and 17-35% respectively. , AMLs are composed of adiposities, abnormal vasculature, and smooth muscle cells. Symptoms of AML are often absent or minimal, as they tend to grow slowly. Affected patients may present with painless hematuria, flank pain, or a gross retroperitoneal bleed. Spontaneous hemorrhage considered as the most common complication could lead to hemorrhagic shock in 20% of cases. , This was observed in our patient. Although he presented with total hematuria (assumed to be due to spontaneous hemorrhage) and abdominal pain, severe UTI with complications was considered in this child. It is established that UTI could occur in patients with TSC as a complication of renal hamartomas,  due to partial obstruction of the collecting system and spontaneous hemorrhage. Although the presence of features suggesting infection may have compounded the presentation in this child, or could suggest severe urinary infection, it is, however, unlikely to explain the gross hematuria requiring blood transfusion. The risk of bleeding from AML is size dependent, the larger >4 cm the higher the chance. Thus, periodic screening is recommended annually or biannually to monitor the growth. , Embolization, followed by steroid therapy, partial nephrectomy are some modalities for treating bleeding AML. The use of mTOR inhibitor may induce regression of kidney AMLs for asymptomatic AML, as well as improve lung function; facial angiofibromas and seizures. , Pressure effect and malignant transformation are some of the other complications of AML.  The TSC2 gene lies immediately adjacent to PKD1, the major gene for ADPKD raising the possibility that PKD1 plays a role in the etiology of renal cystic disease in tuberous sclerosis. ,
| Conclusion|| |
Renal involvement is common in TSC, but symptomatic complications are rare. A high index of suspicion is required for prompt diagnosis and management of its presenting features. Clinicians should look out for features of TSC and possible renal involvement in children with recurrent seizures especially in resource constrained settings.
| References|| |
Mustafa S. Tuberous sclerosis. In: Robert MK, Bonita FS, Joseph WG, Nina FS, Richard EB, editors. Nelson Textbook of Paediatrics. Philadelphia: Elsevier Saunders; 2011.
Umeoka S, Koyama T, Miki Y, Akai M, Tsutsui K, Togashi K. Pictorial review of tuberous sclerosis in various organs. Radiographics 2008;28:e32.
Mettin RR, Merkenschlager A, Bernhard MK, Elix H, Hirsch W, Kiess W, et al.
Wide spectrum of clinical manifestations in children with tuberous sclerosis complex - Follow-up of 20 children. Brain Dev 2014;36:306-14.
Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:243-54.
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al
. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51.
Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP, Ravine D, et al.
Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1 gene. Am J Hum Genet 1997;61:843-51.
Künzi T, Walther F, Marti HP, Frey FJ, Vogt B. Intrarenal arterial aneurysms with haematuria in a patient with tuberous sclerosis complex. Nephrol Dial Transplant 2005;20:2268-70.
Uzun H. A case of tuberous sclerosis complex with renal angiolipoma who has symptom of gross hematuria. Konuralp Týp Derg 2011;3:35-8.
Goyal S, Agarwal YB, Singla S, Goyal S. Gross hematuria with tuberous sclerosis: Case report and review of literature. Med J DY Patil Univ 2013;6:432-5.
Leung AK, Robson WL. Tuberous sclerosis complex: A review. J Pediatr Health Care 2007;21:108-14.
Dabora SL, Franz DN, Ashwal S, Sagalowsky A, DiMario FJ Jr, Miles D, et al.
Multicenter phase 2 trial of sirolimus for tuberous sclerosis: Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One 2011;6:e23379.
Casper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: Renal imaging findings. Radiology 2002;225:451-6.
Lendvay TS, Marshall FF. The tuberous sclerosis complex and its highly variable manifestations. J Urol 2003;169:1635-42.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]