WBR0278

Author	[[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Will Gibson, Yazan Daaboul, M.D., Alison Leibowitz [2])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Oncology, SubCategory::Renal
Prompt	[[Prompt::A 3-year-old boy is brought to the pediatrician's office by his mother for bloody urine and abdominal pain. His temperature is 37.2 °C (98.96 °F), blood pressure is 144/90 mmHg, and heart rate is 70/min. Physical examination is remarkable for a large abdominal mass. Abdominal ultrasonography confirms the presence of a renal mass. CT scan demonstrates a solid renal mass with normal renal parenchyma towards its rim (claw sign). Which one of the following genetic alterations is responsible for this patient's condition?]]
Answer A	AnswerA::Deletion on chromosome 11
Answer A Explanation	[[AnswerAExp::Nephroblastoma (Wilms or Wilms' tumor) is often caused by WT1 tumor suppressor gene deletion on chromosome 11. WT1 is eponymously named Wilms Tumor 1 gene.]]
Answer B	AnswerB::Mutation of ''TSC2''
Answer B Explanation	[[AnswerBExp::TSC2 is a tumor suppressor gene in the MTOR pathway. Mutations in TSC2 cause tuberous sclerosis, which is characterized by the growth of benign tumors in the brain, skin, kidneys, and other organs.]]
Answer C	AnswerC::Mutation of ''VHL''
Answer C Explanation	[[AnswerCExp::The Von-Hippau-Lindau (VHL) gene encodes a ubiquitin-ligase responsible for increasing the degradation of Hypoxia-Inducible Factor (HIF), a transcription factor involved in a variety of gene products, such as Vascular Endothelial Growth Factor (VEGF). When the VHL gene is inactivated, HIF activity increases uncontrollably and initiates tumor formation in kidney cells. Germline mutations in the VHL tumor suppressor gene are associated with Von-Hippau-Lindau, a cancer-predisposing syndrome.]]
Answer D	AnswerD::Trinucleotide repeats
Answer D Explanation	AnswerDExp::Trinucleotide repeats is not associated with nephroblastoma. Huntington's disease (CAG repeats), myotonic dystrophy (CTG repeats), Fragile X syndrome (GAA repeats), and Friedreich ataxia (GAA repeats) are caused by trinucleotide repeats.
Answer E	AnswerE::Translocation t(2;13)
Answer E Explanation	[[AnswerEExp::Translocation t(2;13) is associated with rhabdomyosarcoma. This translocation fuses the FOXO1 gene from chromosome 13 and the PAX3 gene from chromosome 2.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Nephroblastoma (Wilms tumor) is the most common pediatric kidney cancer. It arises from the pluripotent embryonic renal progenitor cells. Nephroblastoma usually manifests as a palpable abdominal mass that does not cross the midline. In addition, hematuria and high blood pressure may be present in 25% of the cases and suggest invasion of the renal pelvis and compression of the renal arteries, respectively. In advanced cases, metastasis may be present in the abdominal lymph nodes and the lungs. Unlike neuroblastoma, nephroblastoma rarely metastasizes to the bone, and patients rarely have symptoms of bone invasion (bone pain, fractures, or cytopenias). Nephroblastoma may be present in isolation or may be caused by genetic deletions that involve the WT1 tumor suppressor gene in chromosome 11 that result in WAGR syndrome (Wilms tumor, aniridia, genitourinary abnormalities, and retardation). WT1 gene encodes a transcription factor that normally functions in the differentiation of renal and genitourinary tissue. Nephroblastoma has also been associated with Beckwith-Weidemann syndrome (hemihypertrophy of organs). Generally, children with a palpable abdominal mass should first undergo an abdominal ultrasound; suspicious findings warrant an abdominal CT scan. The classical finding of nephroblastoma on abdominal CT scan include a solid renal mass with normal renal parenchyma towards its rim (claw sign), as observed in this patient. In contrast to neuroblastoma, calcifications are rare in nephroblastoma. Nephroblastoma is generally managed surgically followed by chemotherapy. Radiotherapy is reserved for advanced cases with metastasis. Upon resection, microscopic analysis of the tumor typically reveals immature blasts with primitive glomeruli, fibrous cells, and tubules. Educational Objective: Nephroblastoma (Wilms tumor) is associated with WT1 gene deletion on chromosome 11 References: Lee SB, Haber DA. Wilms tumor and the WT1 gene. Exp Cell Res. 2001;264(1):74-99. Nakamura L, Ritchey M. Current management of wilms' tumor. Curr Urol Rep. 2010;11(1):58-65. Friedman AD. Wilms tumor. Pediatr Rev. 2013;34(7):328-30; discussion 330. First Aid 2014 page 541]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Tumor, WBRKeyword::Wilm's tumor, WBRKeyword::Wilms tumor, WBRKeyword::Kidney cancer, WBRKeyword::Beckwith-Weidemann syndrome, WBRKeyword::Childhood cancer, WBRKeyword::Pediatric cancer, WBRKeyword::Nephroblastoma, WBRKeyword::WT1, WBRKeyword::Tumor suppressor gene, WBRKeyword::WAGR syndrome, WBRKeyword::WAGR complex
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