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Cowden syndrome 6(CWS6)

MedGen UID:
767433
Concept ID:
C3554519
Disease or Syndrome
Synonym: CWS6
 
Gene (location): AKT1 (14q32.33)
 
Monarch Initiative: MONDO:0014048
OMIM®: 615109

Definition

The features of Cowden syndrome overlap with those of another disorder called Bannayan-Riley-Ruvalcaba syndrome. People with Bannayan-Riley-Ruvalcaba syndrome also develop hamartomas and other noncancerous tumors.  Some people with Cowden syndrome have relatives diagnosed with Bannayan-Riley-Ruvalcaba syndrome, and other affected individuals have the characteristic features of both conditions. Based on these similarities, researchers have proposed that Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome (named for the genetic cause of the conditions) instead of two distinct conditions.



Some people do not meet the strict criteria for a clinical diagnosis of Cowden syndrome, but they have some of the characteristic features of the condition, particularly the cancers. These individuals are often described as having Cowden-like syndrome. Both Cowden syndrome and Cowden-like syndrome are caused by mutations in the same genes.

Cowden syndrome is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, a gland in the lower neck called the thyroid, and the lining of the uterus (the endometrium). Other cancers that have been identified in people with Cowden syndrome include kidney cancer, colorectal cancer, and an agressive form of skin cancer called melanoma. Compared with the general population, people with Cowden syndrome develop these cancers at younger ages, often beginning in their thirties or forties. People with Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population. Other diseases of the breast, thyroid, and endometrium are also common in Cowden syndrome. Additional signs and symptoms can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development, intellectual disability, or autism spectrum disorder, which can affect communication and social interaction.

Almost everyone with Cowden syndrome develops hamartomas. These growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but they can also occur in the intestine and other parts of the body. The growth of hamartomas on the skin and mucous membranes typically becomes apparent by a person's late twenties.

Cowden syndrome is a genetic disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers. [from MedlinePlus Genetics]

Clinical features

From HPO
Thyroid adenoma
MedGen UID:
56228
Concept ID:
C0151468
Neoplastic Process
The presence of a adenoma of the thyroid gland.
Transitional cell carcinoma of the bladder
MedGen UID:
76013
Concept ID:
C0279680
Neoplastic Process
The presence of a carcinoma of the urinary bladder with origin in a transitional epithelial cell.
Subcutaneous lipoma
MedGen UID:
234674
Concept ID:
C1403035
Neoplastic Process
The presence of subcutaneous lipoma.
Hamartomatous polyposis
MedGen UID:
474435
Concept ID:
C3272802
Disease or Syndrome
Polyp-like protrusions which are histologically hamartomas. These can occur throughout the gastrointestinal tract. Hamartomatous polyps are composed of the normal cellular elements of the gastrointestinal tract, but have a markedly distorted architecture.
Ovarian cyst
MedGen UID:
14540
Concept ID:
C0029927
Disease or Syndrome
The presence of one or more cysts of the ovary.
Varicocele
MedGen UID:
22619
Concept ID:
C0042341
Disease or Syndrome
A varicocele is a widening of the veins along the spermatic cord, leading to enlarged, twisted veins in the scrotum, and manifested clinically by a painless testicle lump, scrotal swelling, or bulge in the scrotum.
Hydrocele testis
MedGen UID:
318568
Concept ID:
C1720771
Congenital Abnormality
Accumulation of clear fluid in the between the layers of membrane (tunica vaginalis) surrounding the testis.
Palmoplantar keratosis
MedGen UID:
44017
Concept ID:
C0022596
Disease or Syndrome
Abnormal thickening of the skin localized to the palm of the hand and the sole of the foot.
Abnormality of the cardiovascular system
MedGen UID:
116727
Concept ID:
C0243050
Congenital Abnormality
Any abnormality of the cardiovascular system.
Colonic diverticula
MedGen UID:
3878
Concept ID:
C0012819
Disease or Syndrome
The presence of multiple diverticula of the colon.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Meningioma
MedGen UID:
7532
Concept ID:
C0025286
Neoplastic Process
The presence of a meningioma, i.e., a benign tumor originating from the dura mater or arachnoid mater.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Intention tremor
MedGen UID:
1642960
Concept ID:
C4551520
Sign or Symptom
A type of kinetic tremor that occurs during target directed movement is called intention tremor. That is, an oscillatory cerebellar ataxia that tends to be absent when the limbs are inactive and during the first part of voluntary movement but worsening as the movement continues and greater precision is required (e.g., in touching a target such as the patient's nose or a physician's finger).
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Hypoplasia of the maxilla
MedGen UID:
66804
Concept ID:
C0240310
Congenital Abnormality
Abnormally small dimension of the Maxilla. Usually creating a malocclusion or malalignment between the upper and lower teeth or resulting in a deficient amount of projection of the base of the nose and lower midface region.
Progressive macrocephaly
MedGen UID:
395368
Concept ID:
C1859896
Finding
The progressive development of an abnormally large skull.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Thyroiditis
MedGen UID:
21548
Concept ID:
C0040147
Disease or Syndrome
Inflammation of the thyroid gland.
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Furrowed tongue
MedGen UID:
21583
Concept ID:
C0040412
Anatomical Abnormality
Accentuation of the grooves on the dorsal surface of the tongue.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Skin tags
MedGen UID:
11452
Concept ID:
C0037293
Neoplastic Process
Cutaneous skin tags also known as acrochorda or fibroepithelial polyps are small benign tumors that may either form secondarily over time primarily in areas where the skin forms creases, such as the neck, armpit or groin or may also be present at birth, in which case they usually occur in the periauricular region.
Goiter
MedGen UID:
42270
Concept ID:
C0018021
Disease or Syndrome
An enlargement of the thyroid gland.
Hyperthyroidism
MedGen UID:
6972
Concept ID:
C0020550
Disease or Syndrome
An abnormality of thyroid physiology characterized by excessive secretion of the thyroid hormones thyroxine (i.e., T4) and/or 3,3',5-triiodo-L-thyronine zwitterion (i.e., triiodothyronine or T3).
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.
Fibroadenoma of the breast
MedGen UID:
64231
Concept ID:
C0178421
Neoplastic Process
A benign biphasic tumor of the breast with epithelial and stromal components.
Breast carcinoma
MedGen UID:
146260
Concept ID:
C0678222
Neoplastic Process
The presence of a carcinoma of the breast.
Angioid streaks
MedGen UID:
1541
Concept ID:
C0002982
Disease or Syndrome
Angioid streaks are irregular tapering linear breaks in the Bruch membrane that typically emanate from the optic disk (summary by Karacorlu et al., 2002).
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Professional guidelines

PubMed

Obstet Gynecol 2019 Dec;134(6):e143-e149. doi: 10.1097/AOG.0000000000003562. PMID: 31764758
Obstet Gynecol 2019 Dec;134(6):1366-1367. doi: 10.1097/AOG.0000000000003563. PMID: 31764755
Castro R, Pimentel-Nunes P, Dinis-Ribeiro M
Best Pract Res Clin Gastroenterol 2017 Aug;31(4):381-387. Epub 2017 Jun 13 doi: 10.1016/j.bpg.2017.06.001. PMID: 28842047

Recent clinical studies

Etiology

Patil P, Pencheva BB, Patil VM, Fangusaro J
Neurotherapeutics 2022 Oct;19(6):1752-1771. Epub 2022 Sep 2 doi: 10.1007/s13311-022-01277-w. PMID: 36056180Free PMC Article
Yehia L, Ni Y, Sesock K, Niazi F, Fletcher B, Chen HJL, LaFramboise T, Eng C
PLoS Genet 2018 Apr;14(4):e1007352. Epub 2018 Apr 23 doi: 10.1371/journal.pgen.1007352. PMID: 29684080Free PMC Article
Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, Baptista AP
An Bras Dermatol 2015 Nov-Dec;90(6):780-96; quiz 797-8. doi: 10.1590/abd1806-4841.20154114. PMID: 26734858Free PMC Article
Bubien V, Bonnet F, Brouste V, Hoppe S, Barouk-Simonet E, David A, Edery P, Bottani A, Layet V, Caron O, Gilbert-Dussardier B, Delnatte C, Dugast C, Fricker JP, Bonneau D, Sevenet N, Longy M, Caux F; French Cowden Disease Network
J Med Genet 2013 Apr;50(4):255-63. Epub 2013 Jan 18 doi: 10.1136/jmedgenet-2012-101339. PMID: 23335809
Arber N, Moshkowitz M
Curr Gastroenterol Rep 2011 Oct;13(5):435-41. doi: 10.1007/s11894-011-0218-4. PMID: 21800071

Diagnosis

Patil P, Pencheva BB, Patil VM, Fangusaro J
Neurotherapeutics 2022 Oct;19(6):1752-1771. Epub 2022 Sep 2 doi: 10.1007/s13311-022-01277-w. PMID: 36056180Free PMC Article
Taghavi A, Mirfazaelian H, Shirian S, Aledavood A, Akhgar A
Br J Hosp Med (Lond) 2018 Jun 2;79(6):352-353. doi: 10.12968/hmed.2018.79.6.352. PMID: 29894252
Brown S, Brennan P, Rajan N
Clin Med (Lond) 2017 Dec;17(6):562-567. doi: 10.7861/clinmedicine.17-6-562. PMID: 29196359Free PMC Article
Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, Baptista AP
An Bras Dermatol 2015 Nov-Dec;90(6):780-96; quiz 797-8. doi: 10.1590/abd1806-4841.20154114. PMID: 26734858Free PMC Article
Arber N, Moshkowitz M
Curr Gastroenterol Rep 2011 Oct;13(5):435-41. doi: 10.1007/s11894-011-0218-4. PMID: 21800071

Therapy

Wollina U, Schönlebe J
Acta Dermatovenerol Croat 2023 Aug;31(1):45-47. PMID: 37843092
Losurdo G, Di Leo M, Rizzi S, Lacavalla I, Celiberto F, Iannone A, Rendina M, Ierardi E, Iabichino G, De Luca L, Di Leo A
Expert Rev Gastroenterol Hepatol 2023 Jul-Dec;17(8):811-816. Epub 2023 Jul 29 doi: 10.1080/17474124.2023.2242240. PMID: 37515779
Parvinian A, Cox CW, Hartman TE
J Thorac Imaging 2018 Nov;33(6):W48-W50. doi: 10.1097/RTI.0000000000000358. PMID: 30142139
Carter J, Pather S
Expert Rev Anticancer Ther 2006 Jan;6(1):33-42. doi: 10.1586/14737140.6.1.33. PMID: 16375642
Alsanea O, Clark OH
Curr Opin Oncol 2001 Jan;13(1):44-51. doi: 10.1097/00001622-200101000-00009. PMID: 11148685

Prognosis

Patil P, Pencheva BB, Patil VM, Fangusaro J
Neurotherapeutics 2022 Oct;19(6):1752-1771. Epub 2022 Sep 2 doi: 10.1007/s13311-022-01277-w. PMID: 36056180Free PMC Article
Abreu Velez AM, Howard MS
Dermatol Ther 2010 Nov-Dec;23(6):662-75. doi: 10.1111/j.1529-8019.2010.01371.x. PMID: 21054710
Gawel J, Schwartz RA, Józwiak S
J Cutan Med Surg 2003 Jan-Feb;7(1):61-5. Epub 2002 Oct 9 doi: 10.1007/s10227-002-1142-x. PMID: 12362260
Alsanea O, Clark OH
Curr Opin Oncol 2001 Jan;13(1):44-51. doi: 10.1097/00001622-200101000-00009. PMID: 11148685
Box JC, Watne AL
Semin Surg Oncol 1995 Nov-Dec;11(6):394-8. doi: 10.1002/ssu.2980110605. PMID: 8607007

Clinical prediction guides

Ours CA, Buser A, Hodges MB, Chen MY, Sapp JC, Gochuico BR, Biesecker LG
Orphanet J Rare Dis 2024 Feb 6;19(1):44. doi: 10.1186/s13023-023-03013-9. PMID: 38321508Free PMC Article
Yehia L, Plitt G, Tushar AM, Joo J, Burke CA, Campbell SC, Heiden K, Jin J, Macaron C, Michener CM, Pederson HJ, Radhakrishnan K, Shin J, Tamburro J, Patil S, Eng C
JAMA Netw Open 2023 Apr 3;6(4):e239705. doi: 10.1001/jamanetworkopen.2023.9705. PMID: 37093598Free PMC Article
Patil P, Pencheva BB, Patil VM, Fangusaro J
Neurotherapeutics 2022 Oct;19(6):1752-1771. Epub 2022 Sep 2 doi: 10.1007/s13311-022-01277-w. PMID: 36056180Free PMC Article
Gilad O, Rosner G, Fliss-Isakov N, Aharon-Kaspi S, Strul H, Gluck N, Kariv R
Clin Transl Gastroenterol 2019 May 22;10(5):1-9. doi: 10.14309/ctg.0000000000000035. PMID: 31107726Free PMC Article
Yasuda H, Yamamoto O, Hirokawa H, Asahi M, Kashimura M, Sakai A
Dermatology 2001;203(2):180-4. doi: 10.1159/000051739. PMID: 11586023

Recent systematic reviews

Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM
World J Gastroenterol 2014 Feb 21;20(7):1833-8. doi: 10.3748/wjg.v20.i7.1833. PMID: 24587660Free PMC Article

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