Endocrinol Metab.  2013 Dec;28(4):320-325. 10.3803/EnM.2013.28.4.320.

A Novel Mutation in the Von Hippel-Lindau Tumor Suppressor Gene Identified in a Patient Presenting with Gestational Diabetes Mellitus

• Ku YH
• Ahn CH
• Jung CH
• Lee JE
• Kim LK
• Kwak SH
• Jung HS
• Park KS
• Cho YM

• KMID: 2169310
• DOI: http://doi.org/10.3803/EnM.2013.28.4.320

Abstract

BACKGROUND
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene. To date, more than 1,000 germline and somatic mutations of the VHL gene have been reported. We present a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus.
METHODS
A 30-year-old woman presented with gestational diabetes mellitus. She sequentially showed multiple pancreatic cysts, spinal cord hemangioblastoma, cerebellar hemangioblastoma, and clear cell type renal cell carcinomas. Also, her father and brother had brain hemangioblastomas. Each of the three exons of the VHL gene was individually amplified by polymerase chain reaction and direct sequencing was performed using an ABI 3730 DNA analyzer.
RESULTS
DNA sequence analysis to determine the presence of VHL mutation in her family revealed del291C, a novel frameshift mutation.
CONCLUSION
We found a novel mutation in the VHL tumor suppressor gene that presented with gestational diabetes mellitus.

Keyword

von Hippel-Lindau disease; VHL gene; Diabetes, gestational

MeSH Terms

Adult
Brain
Carcinoma, Renal Cell
Diabetes, Gestational*
DNA
Exons
Fathers
Female
Genes, Tumor Suppressor*
Hemangioblastoma
Humans
Pancreatic Cyst
Polymerase Chain Reaction
Pregnancy
Sequence Analysis, DNA
Siblings
Spinal Cord
von Hippel-Lindau Disease
DNA

Figure

• 

  Fig. 1 Radiologic studies revealing the clinical features of the patient. (A) Abdominal computed tomography (CT) scan shows multiple cysts in the pancreas and kidneys. (B) A hemangioblastoma is seen in the spinal cord (arrow). (C) Two hemangioblastomas are seen in the cerebellum (arrows). (D) A follow-up abdominal CT scan shows multiple renal cell carcinomas (arrow).

• 

  Fig. 2 The VHL gene mutation of the patient and her family members. (A) Sequencing analysis reveals a 291C deletion mutation, which produces a frameshift and an early stop codon. The subject's brother (B) showed the same mutation, (C) whereas her clinically unaffected sister and (D) second baby did not.

• 

  Fig. 3 Genogramof the family. The genogram was drawn based on the results of genetic analysis and probable symptoms and signs of von Hippel-Lindau (VHL) syndrome.

Reference

1. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004; 22:4991–5004. PMID: 15611513.

2. Woodward ER, Maher ER. Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. 2006; 13:415–425. PMID: 16728571.

3. Mukhopadhyay B, Sahdev A, Monson JP, Besser GM, Reznek RH, Chew SL. Pancreatic lesions in von Hippel-Lindau disease. Clin Endocrinol (Oxf). 2002; 57:603–608. PMID: 12390333.

4. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O'Toole D, Bernades P, Ruszniewski P, Richard S. Pancreatic involve ment in von Hippel-Lindau disease: the Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau. Gastroenterology. 2000; 119:1087–1095. PMID: 11040195.

5. Richard S, David P, Marsot-Dupuch K, Giraud S, Beroud C, Resche F. Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease. Neurosurg Rev. 2000; 23:1–22. PMID: 10809480.

6. Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Linehan WM, Lerman M. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996; 8:348–357. PMID: 8956040.

7. Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JW, Collins D, Majoor-Krakauer D, Bonner T, Mathew C, Rubenstein A, Halperin J, Mc-Conkie-Rosell A, Green JS, Trofatter JA, Ponder BA, Eierman L, Bowmer MI, Schimke R, Oostra B, Aronin N, Smith DI, Drabkin H, Waziri MH, Hobbs WJ, Martuza RL, Conneally PM, Hsia YE, Gusella JF. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988; 332:268–269. PMID: 2894613.

8. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DS, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov I, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B, Lerman MI. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260:1317–1320. PMID: 8493574.

9. Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore). 1997; 76:381–391. PMID: 9413424.

10. Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010; 31:521–537. PMID: 20151405.

11. Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med. 1976; 136:769–777. PMID: 945722.

12. Lubensky IA, Pack S, Ault D, Vortmeyer AO, Libutti SK, Choyke PL, Walther MM, Linehan WM, Zhuang Z. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. Am J Pathol. 1998; 153:223–231. PMID: 9665483.

13. Libutti SK, Choyke PL, Bartlett DL, Vargas H, Walther M, Lubensky I, Glenn G, Linehan WM, Alexander HR. Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: diagnostic and management recommendations. Surgery. 1998; 124:1153–1159. PMID: 9854597.

14. Tenner S, Roston A, Lichtenstein D, Sica G, Carr-Locke D, Banks PA. Von Hippel-Lindau disease complicated by acute pancreatitis and Evan's syndrome. Int J Pancreatol. 1995; 18:271–275. PMID: 8708400.

15. Beerman MH, Fromkes JJ, Carey LC, Thomas FB. Pancreatic cystadenoma in Von Hippel-Lindau disease: an unusual cause of pancreatic and common bile duct obstruction. J Clin Gastroenterol. 1982; 4:537–540. PMID: 7161467.

16. Kunzli BM, Shrikhande SV, Buchler MW, Friess H. Pancreatic lesions in von Hippel-Lindau syndrome: report of a case. Surg Today. 2004; 34:626–629. PMID: 15221562.

17. Lamiell JM, Salazar FG, Hsia YE. von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore). 1989; 68:1–29. PMID: 2642584.

18. Thompson RK, Peters JI, Sirinek KR, Levine BA. von Hippel-Lindau syndrome presenting as pancreatic endocrine insufficiency: a case report. Surgery. 1989; 105:598–604. PMID: 2650004.

19. Cantley J, Selman C, Shukla D, Abramov AY, Forstreuter F, Esteban MA, Claret M, Lingard SJ, Clements M, Harten SK, Asare-Anane H, Batterham RL, Herrera PL, Persaud SJ, Duchen MR, Maxwell PH, Withers DJ. Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J Clin Invest. 2009; 119:125–135. PMID: 19065050.

20. Puri S, Cano DA, Hebrok M. A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes. 2009; 58:433–441. PMID: 19033400.

21. Kim WT, Ham WS, Ju HJ, Lee JS, Lee JS, Choi YD. Clinical characteristics of renal cell carcinoma in Korean patients with von Hippel-Lindau disease compared to sporadic bilateral or multifocal renal cell carcinoma. J Korean Med Sci. 2009; 24:1145–1149. PMID: 19949673.

22. Na JH, Kim HS, Eoh W, Kim JH, Kim JS, Kim ES. Spinal cord hemangioblastoma: diagnosis and clinical outcome after surgical treatment. J Korean Neurosurg Soc. 2007; 42:436–440. PMID: 19096585.

23. Kang HC, Kim IJ, Park JH, Shin Y, Jang SG, Ahn SA, Park HW, Lim SK, Oh SK, Kim DJ, Lee KW, Choi YS, Park YJ, Lee MR, Kim DW, Park JG. Three novel VHL germline mutations in Korean patients with von Hippel-Lindau disease and pheochromocytomas. Oncol Rep. 2005; 14:879–883. PMID: 16142346.

24. Lee KH, Lee JS, Kim BJ, Lee JK, Kim SH, Kim SH, Lee KT. Pancreatic involvement in Korean patients with von Hippel-Lindau disease. J Gastroenterol. 2009; 44:447–452. PMID: 19333546.