von Hippel-Lindau disease

フォン・ヒッペル・リンドウ病 VHL

WordNet

1. an impairment of health or a condition of abnormal functioning
2. caused by or altered by or manifesting disease or pathology; "diseased tonsils"; "a morbid growth"; "pathologic tissue"; "pathological bodily processes" (同)morbid, pathologic, pathological
3. Swedish soprano who toured the United States under the management of P. T. Barnum (1820-1887) (同)Jenny Lind, Swedish Nightingale

PrepTutorEJDIC

1. (体の)『病気』,疾患 / (精神・道徳などの)病気,病弊
2. 女性の話術芸人 =diseur
3. 病気にかかった / 病的な,不健全な(morbid)
4. verb / verso / 《話》very / velocity / volt[s] / volume / vide
5. …から(from),…の(of)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/08/19 15:41:16」(JST)

wiki en

[Wiki en表示]

Von Hippel–Lindau disease
Typical distribution of hemangioblastomas in von Hippel–Lindau disease.
Classification and external resources
Specialty	medical genetics
ICD-10	Q85.8
ICD-9-CM	759.6
OMIM	193300
DiseasesDB	14000
eMedicine	ped/2417 oph/354
Patient UK	Von Hippel–Lindau disease
MeSH	C10.562.400
GeneReviews	von Hippel-Lindau syndrome
Orphanet	892

Von Hippel–Lindau disease (VHL) is a disease which results from a mutation in the von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.

Classification

VHL disease can be subdivided according to the clinical manifestations, although these groups often correlate with certain types of mutations present in the VHL gene.

Signs and symptoms

Slit lamp photograph showing retinal detachment in Von Hippel-Lindau disease.

Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Conditions associated with VHL disease include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women). Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms. Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%. Spinal hemangioblastomas are found in 13-59% of VHL disease and are specific because 80% are found in VHL disease. Although all of these tumours are common in VHL disease, around half of cases present with only one tumour type.

Pathogenesis

The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in VHL disease.

Von Hippel–Lindau disease is inherited in an autosomal dominant pattern.

Every cell in the body has 2 copies of every gene (bar those found in the sex chromosomes, X and Y). In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours form from only those cells where the second copy of the gene has been mutated. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop.

Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.

30-40% of mutations in the VHL gene consist of 50-250kb deletion mutations that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of VHL disease is caused by the truncation of pVHL by nonsense mutations, indel mutations or splice site mutations.

VHL protein

The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through 2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads to its degradation via the proteasome. During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. HIF1α causes the transcription of genes that contain the hypoxia response element. In VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.

The VHL protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1α (HIF1α). This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognizes and binds to HIF1α only when oxygen is present due to the post translational hydroxylation of 2 proline residues within the HIF1α protein. pVHL is an E3 ligase that ubiquitinates HIF1α and causes its degradation by the proteasome. In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1α. This allows the subunit to dimerise with HIF1β and activate the transcription of a number of genes, including vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin and genes involved in glucose uptake and metabolism. A new novel missense mutation in VHL genes c.194 C>T, c.239 G>A, c.278 G>A, c.319 C>G, c.337 C>G leading to the following variations p.Ala 65 Val, p.Gly 80 Asp, p.Gly 93 Glu, p.Gln 107 Glu, p.Gln 113 Glu in the protein contributed to Renal clear cell carcinoma.

Diagnosis

The detection of tumours specific to VHL disease is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.

Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL, disease techniques such as southern blotting and gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with VHL disease; de novo cases that produce genetic mosaicism are more difficult to detect because mutations are not found in the white blood cells that are used for genetic analysis.

Treatment

There is no way to reverse VHL mutations, but early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life. For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clear-cell renal carcinomas and pheochromocytomas. CNS hemangioblastomas are usually surgically removed if they are symptomatic. Photocoagulation and cryotherapy are usually used for the treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial nephrectomy or other techniques such as radiofrequency ablation.

Epidemiology

VHL disease has an incidence of one in 36,000 births. There is over 90% penetrance by the age of 65. Age at diagnosis varies from infancy to age 60–70 years, with an average patient age at clinical diagnosis of 26 years.

History

Original von Hippel's description of disease.

The German ophthalmologist Eugen von Hippel first described angiomas in the eye in 1904. Arvid Lindau described the angiomas of the cerebellum and spine in 1927. The term von Hippel-Lindau disease was first used in 1936, however its use became common only in the 1970s.

People

Some descendants of the McCoy family (involved in the Hatfield-McCoy feud of Appalachia, USA) are presumed to have VHL. In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield–McCoy feud may have been partly due to the consequences of von Hippel–Lindau disease. The article suggests that the McCoy family was predisposed to bad tempers because many of them had a pheochromocytoma which produced excess adrenaline and a tendency toward explosive tempers.

Nomenclature

Other uncommon names are: angiomatosis retinae, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel–Lindau syndrome, HLS, VHL, Lindau disease or retinocerebellar angiomatosis.

See also

• Haemangioblastoma
• epithelial sodium channel
• Nephron
• proximal convoluted tubule

References

Kumar PS, Venkatesh K, Srikanth L, Sarma PV, Reddy AR, Subramanian S, Phaneendra BV. Novel three missense mutations observed in Von Hippel-Lindau gene in a patient reported with renal cell carcinoma. Indian J Hum Genet. 2013 Jul;19(3):373-6.

External links

• GeneReviews/NCBI/NIH/UW entry on Von Hippel-Lindau Syndrome
• The VHL Handbook
• Von Hippel–Lindau Disease (VHL) at NINDS
• Von Hippel–Lindau syndrome at NLM Genetics Home Reference
• von Hippel–Lindau syndrome at CHORUS

• Hippel–Lindau disease at Who Named It?
• Online 'Mendelian Inheritance in Man' (OMIM) 608537 (VHL gene)
• VHL Family Alliance support group
• Cancer.Net: Von Hippel-Lindau Syndrome

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. フォンヒッペル・リンダウ病の臨床的特徴、診断、およびマネージメント clinical features diagnosis and management of von hippel lindau disease
• 2. フォンヒッペル・リンダウ病の分子生物学および病因 molecular biology and pathogenesis of von hippel lindau disease
• 3. 血管芽細胞腫 hemangioblastoma
• 4. 腎細胞癌の疫学、病理、および病因 epidemiology pathology and pathogenesis of renal cell carcinoma
• 5. 遺伝性腎癌症候群 hereditary kidney cancer syndromes

English Journal

• Tailored imaging of islet cell tumors of the pancreas amidst increasing options.

• Fiebrich HB, van Asselt SJ, Brouwers AH, van Dullemen HM, Pijl ME, Elsinga PH, Links TP, de Vries EG.SourceDepartment of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
• Critical reviews in oncology/hematology.Crit Rev Oncol Hematol.2012 May;82(2):213-26. Epub 2011 Jun 25.
• Pancreatic islet cell tumors are neuroendocrine tumors, which can produce hormones and can arise as part of multiple endocrine neoplasia type 1 or von-Hippel-Lindau-disease, two genetically well-defined hereditary cancer syndromes. Currently, technical innovation improves conventional and specific m
• PMID 21704529

• Von hippel-lindau disease and erythrocytosis.

• Capodimonti S, Teofili L, Martini M, Cenci T, Iachininoto MG, Nuzzolo ER, Bianchi M, Murdolo M, Leone G, Larocca LM.SourceIstituto di Anatomia Patologica, Università Cattolica, Largo Gemelli 8, 00168 Roma, Italy; llarocca@rm.unicatt.it.
• Journal of clinical oncology : official journal of the American Society of Clinical Oncology.J Clin Oncol.2012 May 1;30(13):e137-9. Epub 2012 Mar 5.
• PMID 22393103

Japanese Journal

• Intra-extradural Dumbbell-Shaped Hemangioblastoma Manifesting as Subarachnoid Hemorrhage in the Cauda Equina

• NISHIMURA Yusuke,HARA Masahito,NATSUME Atsushi,TAKEMOTO Masaya,FUKUYAMA Ryuichi,WAKABAYASHI Toshihiko
• Neurologia medico-chirurgica = 神経外科 52(9), 659-665, 2012-09-15
• … A 56-year-old man presented with a rare intra-extradural dumbbell-shaped hemangioblastoma in the lumbar spine associated with von Hippel-Lindau (VHL) disease manifesting as subarachnoid hemorrhage. … Postoperative adhesion must be minimized for second surgery in patients with genetic disease such as VHL, who are likely to suffer recurrence. …
• NAID 10030873100

• Coexistence of Sporadic Cerebellar Hemangioblastoma and Pituitary Null Cell Adenoma : Simultaneous Expression of von Hippel-Lindau Gene Product : Case Report

• SHIMODA Yoshiteru,OGAWA Yoshikazu,ENDO Hidenori,WATANABE Mika,TOMINAGA Teiji
• Neurologia medico-chirurgica = 神経外科 52(8), 591-594, 2012-08-15
• … There was no evident family history of von Hippel-Lindau (VHL) disease, and the systemic investigation failed to detect any other tumors or signs of VHL disease. …
• NAID 10030694759

Related Links

• von Hippel-Lindau Disease: Overview, Physiology, Prognosis

von Hippel-Lindau disease. Clinical picture of the retina, showing a pair of dilated and tortuous feeder vessels coursing on the surface of the retina from the optic nerve head toward the angioma (which is not seen in this ...

• Von Hippel-Lindau Disease: MedlinePlus - National Library of ...

Von Hippel-Lindau disease (VHL) is a rare, genetic disease that causes tumors and cysts to grow in your body. The tumors can be either cancerous or benign. They can grow in your brain and spinal cord, kidneys ...

Related Pictures

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「フォン・ヒッペル・リンドウ病」

　　[★]

英

von Hippel-Lindau disease VHL disease, VHL

同

フォンヒッペル・リンダウ病 VHL病 、リンダウ病、ヒッペル病、フォン・ヒッペル・リンダウン病、フォン・ヒッペル-リンダウ病

網膜血管腫症 retinal angiomatosis

関

血管芽腫、神経皮膚症候群。フォン・ヒッペル病(網膜の血管腫のみの場合(SOP.144))

[show details]

フォン・ヒッペル・リンドウ病 : 約 14,800 件
フォン・ヒッペル・リンダウ病 : 54 件
フォン・ヒッペル・リンダウン病 : nothing

概念

• 癌抑制遺伝子であるVHL遺伝子の変異による常染色体優性遺伝疾患で、中枢神経系の血管芽腫、網膜血管芽腫、腎細胞癌、副腎腫瘍などを発症する疾患である。

頭部の血管芽腫と腎・副腎腫瘍と覚えておこう

病因

• 3p25のVHL遺伝子:癌抑制遺伝子の変異が関与
• 11q13にもマッピングされている。

疫学

• 思春期以降で30歳代の男性に多発。

遺伝形式

• 常染色体優性遺伝

病態

• 多くの臓器に腫瘍や嚢胞を形成(腎(40%に腎細胞癌。腎嚢胞)、中枢神経系の血管芽腫、網膜血管腫、膵腫瘍(膵嚢胞)、肝、副腎(褐色細胞腫)など)
• 眼　：毛細血管レベルで血管腫が発生し、グリアの増殖を伴ってオレンジ色の結節を形成する。血管腫を介したシャントが形成されるために動脈・静脈が拡張蛇行する。進行すれば血管腫から血漿が漏出して漿液性網膜剥離をきたす。また硬性白斑がみられる。

症状

• 眼　：(網膜剥離が起これば)視野障害・視力障害
• 神経：(小脳の血管芽腫により)小脳失調。てんかん(SOP.144)。
• 皮膚：(低頻度)血管腫、カフェオレ斑

合併症

• 赤血球増多症　→　エリスロポエチン産生

検査

• 頭部MRI

• 造影：小脳の血管芽腫は濃染される。嚢胞を伴う場合は均一な低信号領域が認められる。

[show details]

国試

• 096A047、105D030

参考

• 1. [charged] フォンヒッペル・リンダウ病の臨床的特徴、診断、および管理 - uptodate [1]
• 2. [charged] フォンヒッペル・リンダウ病の分子生物学および病因 - uptodate [2]
• 3. VON HIPPEL-LINDAU SYNDROME - OMIM

http://omim.org/entry/193300

メモ

• 混乱していたので、

• フォン・ヒッペル・リンドウ病 von Hippel-Lindau diseaseはVHL遺伝子の変異によるADな疾患で、腎細胞癌、CNSの血管芽腫、網膜血管腫などが特徴的
• ウィップル病 Whipple's diseaseは日本ではまれで、白人の中年男性で見られる全身性細菌感染症による吸収不良症候群の一つ。

「神経皮膚症候群」

　　[★]

英

neurocutaneous syndrome、neurocutaneous disorder

関

母斑症 phakomatosis

• 外胚葉異常により皮膚母斑や神経腫瘍を生じる先天性疾患

• 神経線維腫症1型, neurofibromatosis type 1, NF1, フォン・レックリングハウゼン病 von Recklinghausen disease：NF1の変異による常染色体優性遺伝疾患で多発性のカフェオレ斑、神経線維腫が特徴的。皮膚症状(カフェオレ斑、神経線維腫、黄色腫、貧血母斑、母斑性黄色内皮腫)、眼症状(リッシュ結節)

• 神経線維腫症2型, neurofibromatosis type 2, NF2
• 結節性硬化症, tuberous sclerosis
• ポイツ・イェーガー症候群, Peutz-Jeghers syndrome：顔面片側性の単純血管腫(三叉神経第1枝に沿う(CN V1))、眼の脈絡膜血管腫、脳軟膜の血管腫　→　中枢神経症状(乳幼児期からの痙攣発作、大脳半球萎縮、石灰化、知能障害)、眼症状(脈絡膜の血管腫による眼圧亢進、緑内障　→　牛眼　)
• 色素失調症, incontinentia pigmenti, ブロッホ・ザルツバーガー症候群, Bloch-Sulzberger syndrome
• スタージ・ウェーバー症候群, Sturge-Weber syndrome：遺伝性無し。皮膚症状：顔面片側性の単純血管腫(三叉神経第1枝に沿う(CN V1)) 。中枢神経症状：顔面血管腫が存在する側の特に後頭葉に脳軟膜の血管腫が発生 (NDE.349)。乳幼児期からの血管発作。大脳半球萎縮、石灰化、知能障害。眼症状：緑内障(牛眼)
• クリッペル・トレノーニイ・ウェーバー症候群, Klippel-Trenaunay-Weber syndrome
• 神経皮膚黒色症, neurocutaneous smelanosis
• 汎発性黒子症候群, lentiginosis profusa, LEOPARD症候群
• 基底細胞母斑症候群, basal cell nevus syndrome
• フォン・ヒッペル・リンドウ病, von Hippel-Lindau disease：常染色体優性遺伝。
• 色素血管母斑症, phacomatosis pigmentovascularis, オスラー病, Osler disease
• 遺伝性出血性毛細血管拡張症, hereditary hemorrhagic telangiectasia
• 青色ゴムマリ様母斑症候群, blue rubber-bleb nevus syndrome
• マフッチ症候群, Maffucci's syndrome
• Zinsser-Cole-Engman症候群, Zinsser-Cole-Engman syndrome
• 先天性角化異常症, dyskeratosis congenita
• 表皮母斑症候群, epidermal nervus syndrome
• 先天性血管拡張性大理石様皮斑, cutis marmorata telangiectatica congenita

「常染色体優性遺伝病」

　　[★]

英

autosomal dominant disease, autosomal dominant disorder

同

常染色体優性遺伝疾患

関

常染色体劣性遺伝病

autosomal-dominant diseases (first aid step p.108)

• 成人型嚢胞腎 adult polycystic kidney disease
• 家族性高コレステロール血症 familial hypercholesterolemia (hyperlipidemia type IIA)
• マルファン症候群 Marfan's syndrome
• 神経線維腫症1型 neurofibromatosis type 1(von Recklinghausen's disease)
• 神経線維腫症2型 neurofibromatosis type 2
• 結節性硬化症 tuberous sclerosis
• フォン・ヒッペル・リンドウ病 von Hippel-Lindau disease
• ハンチントン病 Huntington's disease
• 家族性大腸腺腫症 familial adenomatous polyposis
• 遺伝性球状赤血球症 hereditary spherocytosis
• 軟骨無形成症 achondroplasia

男性の年齢と孤発性常染色体優性遺伝病

HIM.2319

• 高齢男性の子供ではsporadic missense mutationにより発生しやすい
• achondroplasia、polyposis coli、Marfan syndrome、Apert's symdrome

「遺伝性神経系腫瘍症候群」

　　[★]

英

hereditary tumor syndrome of the nervous system

関

脳腫瘍

• 神経線維腫症1型
• 神経線維腫症2型
• 結節性硬化症
• von Hippel-Lindau disease
• 網膜芽腫
• Li-Fraumeni症候群

• Turcot症候群

「VHL」

　　[★] フォン・ヒッペル・リンドウ病 von Hippel-Lindau disease

「disease」

　　[★]

• n.

疾患：illnessより厳密な概念。「ある臓器に明確な障害が確認され、それによって症状が出ているとはっきり説明できる場合」 (PSY.9)

特定の原因、病態生理、症状、経過、予後、病理組織所見が全てそろった場合 (PSY.9)

• something that is very wrong with people's attitudes, way of life or with society.

関

ail、ailment、disease entity、disorder、ill、illness、malady、sick、sickness

• 注意

disease ≠ illness ≠ disorder

　 　 　

「Lindau disease」

　　[★] フォン・ヒッペル・リンドウ病

「VON」

　　[★]

同

Vermont Oxford Network