Correspondence

Unilateral Renal Agenesis in a Family with Medullary Thyroid Carcinoma

N Engl J Med 2000; 342:1218-1219April 20, 2000

Article

To the Editor:

Germ-line mutations in the RET proto-oncogene are associated with various disease phenotypes including familial medullary thyroid carcinoma and Hirschsprung's disease.1 Studies have suggested an involvement of RET in the development of the mammalian kidney.2,3 The RET proto-oncogene encodes a receptor tyrosine kinase that is involved in inductive interactions between the epithelium of the ureteric bud and metanephric mesenchyme, leading to the differentiation of a functional kidney. Although mice lacking functional ret may have renal agenesis or dysgenesis, no clinically relevant renal abnormalities have been reported in patients with familial medullary thyroid carcinoma who had RET mutations.4

We studied a family with familial medullary thyroid carcinoma and a RET mutation (TGC →TCC), which led to the substitution of serine for cysteine at position 620.5 The RET mutation was detected in 5 of the 13 family members studied, including Subject IV-3, who had no evidence of medullary thyroid carcinoma (Figure 1AFigure 1Pedigree of a Family with a RET Mutation (Panel A) and an Intravenous Pyelogram in Subject IV-2 (Panel B).). Medullary thyroid carcinoma was diagnosed in five patients, including Subject I-2, who died in 1979 (DNA analysis was not possible in this patient).

One of the patients was a 32-year-old woman (Subject III-1) who was found on ultrasonography and radionuclide imaging to have no left kidney. Her son (Subject IV-2), when only a few months old, had been given a diagnosis of Hirschsprung's disease and had undergone surgical resection of the involved intestinal segment. Subsequently, he was found to have the RET mutation and at the age of 15 years underwent total thyroidectomy, which revealed medullary thyroid carcinoma. Abdominal ultrasonography revealed the absence of the left kidney, which was confirmed by intravenous pyelography (Figure 1B). All other living family members underwent abdominal ultrasonography, which revealed no renal abnormalities. No other family members had a history of Hirschsprung's disease.

The involvement of the RET proto-oncogene in the early growth and differentiation of the kidney is now accepted. It is likely that renal abnormalities have not been diagnosed in patients with familial medullary thyroid carcinoma because abdominal imaging is not routinely performed in such patients. We suggest that noninvasive imaging techniques such as ultrasonography should be used to identify renal abnormalities in patients with RET mutations.

Fausto Loré, M.D.
Giovanni Di Cairano, M.D.
Filotas Talidis, M.D.
University of Siena, 53100 Siena, Italy

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Citing Articles (12)

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   Cornelis JM Lips, Wendy van Veelen, Thera P Links, Jo WM Höppener. (2009) Multiple endocrine neoplasia type 2. Expert Review of Endocrinology & Metabolism 4:5, 443-465
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   Alessio Pini Prato, Marco Musso, Isabella Ceccherini, Girolamo Mattioli, Camilla Giunta, Gian Marco Ghiggeri, Vincenzo Jasonni. (2009) Hirschsprung Disease and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Medicine 88:2, 83-90
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   R. A. Oram, E. L. Edghill, A. S. Woolf, R. C. Hennekam, S. Ellard, A. T. Hattersley, C. Bingham. (2008) RET gene mutations are not a common cause of congenital solitary functioning kidney in adults. NDT Plus 2:2, 183-184
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   Yaoming Yang, Anne-Marie Houle, Julien Letendre, Andrea Richter. (2008) RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec. Human Mutation 29:5, 695-702
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   Michael A. Skinner, Shawn D. Safford, Justin G. Reeves, Margaret E. Jackson, Alex J. Freemerman. (2008) Renal Aplasia in Humans Is Associated with RET Mutations. The American Journal of Human Genetics 82:2, 344-351
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   Julie Blatt, Don Nakayama. (2007) Wilms Tumor Associated With Hirschsprung Disease. Journal of Pediatric Hematology/Oncology 29:12, 858-859
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   Barbara E. Esch, James E. Carr. (2004) Secretin as a Treatment for Autism: A Review of the Evidence. Journal of Autism and Developmental Disorders 34:5, 543-556
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   Irwin M. Best, Gerald McKinney, Chandrika Garg, Andre Scott, Shawn McKinney, William L. Weaver, Harvey L. Bumpers. (2003) Squamous Cell Carcinoma at Herniorrhaphy and Unilateral Renal Agenesis. American Journal of Clinical Oncology 26:3, 297-299
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    Francesca Lombardo, Sebastiano Filetti, Umberto Crocetti, Martin Schlumberger. (2001) Medullary Thyroid Carcinoma and Lack of Renal Agenesis. Thyroid 11:1, 93-93
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    Melissa A. Parisi, Raj P. Kapur. (2000) Genetics of Hirschsprung disease. Current Opinion in Pediatrics 12:6, 610-617
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    Carlton M. Bates. (2000) Kidney Development: Regulatory Molecules Crucial to Both Mice and Men. Molecular Genetics and Metabolism 71:1-2, 391-396
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