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Cowden syndrome(CS)

MedGen UID:
5420
Concept ID:
C0018553
Neoplastic Process
Synonyms: Cowden; Cowden disease; Cowden's disease; Cowden's syndrome; CS
SNOMED CT: Cowden's syndrome (58037000); Cowden syndrome (58037000); Multiple hamartoma syndrome (58037000)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Monarch Initiative: MONDO:0016063
OMIM®: 158350; 601728
OMIM® Phenotypic series: PS158350
Orphanet: ORPHA201

Definition

Cowden syndrome-1 is a hamartomatous disorder characterized by macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, and an increased risk for the development of breast, thyroid, and endometrial carcinoma. Bannayan-Riley-Ruvalcaba syndrome (BRRS), previously thought be distinct, shared clinical characteristics with Cowden syndrome, such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms, but had the additional features of developmental delay, macrocephaly, lipomas, hemangiomas, and pigmented speckled macules of the glans penis in males. Because features of BRRS and Cowden syndrome have been found in individuals within the same family with the same PTEN mutation, Cowden syndrome-1 and BRRS are considered to be the same disorder with variable expression and age-related penetrance (summary by Marsh et al., 1999, Lachlan et al., 2007, and Blumenthal and Dennis, 2008). Approximately 80% of patients reported with Cowden syndrome and 60% with BRSS have PTEN mutations (Blumenthal and Dennis, 2008). Some patients with Cowden syndrome may have immune system defects resulting in increased susceptibility to infections (summary by Browning et al., 2015). [from OMIM]

Additional description

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

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.

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.



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.  https://medlineplus.gov/genetics/condition/cowden-syndrome

Clinical features

From HPO
Carcinoma
MedGen UID:
2867
Concept ID:
C0007097
Neoplastic Process
A malignant tumor arising from epithelial cells. Carcinomas that arise from glandular epithelium are called adenocarcinomas, those that arise from squamous epithelium are called squamous cell carcinomas, and those that arise from transitional epithelium are called transitional cell carcinomas (NCI Thesaurus).
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 carcinoma
MedGen UID:
1648335
Concept ID:
C4721610
Neoplastic Process
A malignant neoplasm originating from the surface ovarian epithelium.
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 vasculature
MedGen UID:
66032
Concept ID:
C0241657
Finding
An abnormality of the vasculature.
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.
Lhermitte-Duclos disease
MedGen UID:
140251
Concept ID:
C0391826
Neoplastic Process
It is a rare, slowly growing tumor of the cerebellum, a gangliocytoma sometimes considered to be a hamartoma, characterized by diffuse hypertrophy of the granular layer of the cerebellum.
Hemimegalencephaly
MedGen UID:
140910
Concept ID:
C0431391
Finding
Enlargement of all or parts of one cerebral hemisphere.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Thyroiditis
MedGen UID:
21548
Concept ID:
C0040147
Disease or Syndrome
Inflammation of the thyroid gland.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Decreased circulating antibody concentration
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
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).
Acrokeratosis
MedGen UID:
450988
Concept ID:
C0001202
Disease or Syndrome
Overgrowth of the stratum corneum characterized by flesh-coloured or slightly pigmented smooth or warty papules on the upper surface of hands and feet.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCowden syndrome
Follow this link to review classifications for Cowden syndrome in Orphanet.

Professional guidelines

PubMed

Rebuzzi F, Ulivi P, Tedaldi G
Int J Mol Sci 2023 Jan 21;24(3) doi: 10.3390/ijms24032137. PMID: 36768460Free PMC Article
Mighell TL, Evans-Dutson S, O'Roak BJ
Am J Hum Genet 2018 May 3;102(5):943-955. Epub 2018 Apr 26 doi: 10.1016/j.ajhg.2018.03.018. PMID: 29706350Free PMC Article
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology
Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263. Epub 2015 Feb 3 doi: 10.1038/ajg.2014.435. PMID: 25645574Free PMC Article

Suggested Reading

Recent clinical studies

Etiology

Rebuzzi F, Ulivi P, Tedaldi G
Int J Mol Sci 2023 Jan 21;24(3) doi: 10.3390/ijms24032137. PMID: 36768460Free PMC Article
Huber-Keener KJ
Best Pract Res Clin Obstet Gynaecol 2022 Jun;82:3-11. Epub 2022 Jan 31 doi: 10.1016/j.bpobgyn.2022.01.007. PMID: 35272929
Yehia L, Keel E, Eng C
Annu Rev Med 2020 Jan 27;71:103-116. Epub 2019 Aug 21 doi: 10.1146/annurev-med-052218-125823. PMID: 31433956
Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA
Pathology 2018 Jan;50(1):49-59. Epub 2017 Nov 21 doi: 10.1016/j.pathol.2017.09.004. PMID: 29169633
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology
Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263. Epub 2015 Feb 3 doi: 10.1038/ajg.2014.435. PMID: 25645574Free PMC Article

Diagnosis

Carneiro F
Best Pract Res Clin Gastroenterol 2022 Jun-Aug;58-59:101800. Epub 2022 May 4 doi: 10.1016/j.bpg.2022.101800. PMID: 35988963
Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP
N Engl J Med 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919. PMID: 32459922Free PMC Article
Yehia L, Keel E, Eng C
Annu Rev Med 2020 Jan 27;71:103-116. Epub 2019 Aug 21 doi: 10.1146/annurev-med-052218-125823. PMID: 31433956
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology
Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263. Epub 2015 Feb 3 doi: 10.1038/ajg.2014.435. PMID: 25645574Free PMC Article
Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E
J Natl Cancer Inst 2013 Nov 6;105(21):1607-16. Epub 2013 Oct 17 doi: 10.1093/jnci/djt277. PMID: 24136893

Therapy

Wollina U, Schönlebe J
Acta Dermatovenerol Croat 2023 Aug;31(1):45-47. PMID: 37843092
Parvinian A, Cox CW, Hartman TE
J Thorac Imaging 2018 Nov;33(6):W48-W50. doi: 10.1097/RTI.0000000000000358. PMID: 30142139
Metzger R, Milas M
Curr Opin Oncol 2014 Jan;26(1):51-61. doi: 10.1097/CCO.0000000000000030. PMID: 24300902
Galanopoulou AS, Gorter JA, Cepeda C
Epilepsia 2012 Jul;53(7):1119-30. Epub 2012 May 11 doi: 10.1111/j.1528-1167.2012.03506.x. PMID: 22578218Free PMC Article
Blumenthal GM, Dennis PA
Eur J Hum Genet 2008 Nov;16(11):1289-300. Epub 2008 Sep 10 doi: 10.1038/ejhg.2008.162. PMID: 18781191Free PMC Article

Prognosis

Gorji L, Albrecht P
World J Gastroenterol 2023 Feb 28;29(8):1304-1314. doi: 10.3748/wjg.v29.i8.1304. PMID: 36925460Free PMC Article
Yehia L, Keel E, Eng C
Annu Rev Med 2020 Jan 27;71:103-116. Epub 2019 Aug 21 doi: 10.1146/annurev-med-052218-125823. PMID: 31433956
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology
Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263. Epub 2015 Feb 3 doi: 10.1038/ajg.2014.435. PMID: 25645574Free PMC Article
Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, Milas K, Pederson H, Remzi B, Orloff MS, Eng C
Am J Hum Genet 2011 Jan 7;88(1):42-56. Epub 2010 Dec 30 doi: 10.1016/j.ajhg.2010.11.013. PMID: 21194675Free PMC Article
Farooq A, Walker LJ, Bowling J, Audisio RA
Cancer Treat Rev 2010 Dec;36(8):577-83. Epub 2010 May 23 doi: 10.1016/j.ctrv.2010.04.002. PMID: 20580873

Clinical prediction guides

Carneiro F
Best Pract Res Clin Gastroenterol 2022 Jun-Aug;58-59:101800. Epub 2022 May 4 doi: 10.1016/j.bpg.2022.101800. PMID: 35988963
Mighell TL, Evans-Dutson S, O'Roak BJ
Am J Hum Genet 2018 May 3;102(5):943-955. Epub 2018 Apr 26 doi: 10.1016/j.ajhg.2018.03.018. PMID: 29706350Free PMC Article
Leachman SA, Lucero OM, Sampson JE, Cassidy P, Bruno W, Queirolo P, Ghiorzo P
Cancer Metastasis Rev 2017 Mar;36(1):77-90. doi: 10.1007/s10555-017-9661-5. PMID: 28283772Free PMC Article
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology
Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263. Epub 2015 Feb 3 doi: 10.1038/ajg.2014.435. PMID: 25645574Free PMC Article
Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, Milas K, Pederson H, Remzi B, Orloff MS, Eng C
Am J Hum Genet 2011 Jan 7;88(1):42-56. Epub 2010 Dec 30 doi: 10.1016/j.ajhg.2010.11.013. PMID: 21194675Free PMC Article

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
Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E
J Natl Cancer Inst 2013 Nov 6;105(21):1607-16. Epub 2013 Oct 17 doi: 10.1093/jnci/djt277. PMID: 24136893

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