Rare Hematology News

Disease Profile

Cowden syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

All ages

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ICD-10

Q85.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Cowden disease; CD; Cowden's disease;

Categories

Congenital and Genetic Diseases; Digestive Diseases; Hereditary Cancer Syndromes;

Summary

Cowden syndrome is an inherited condition that is characterized primarily by multiple, noncancerous growths (called hamartomas) on various parts of the body. People with the syndrome usually have large head (macrocephaly), benign tumors of the hair follicle (trichilemmomas), and white papules with a smooth surface in the mouth (papillomatous papules), starting by the late 20s. It is considered part of the PTEN Hamartoma Tumor Syndrome spectrum which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome. People who have Cowden syndrome are at an increased risk of developing certain types of cancer, such as breast, thyroid, and endometrial (lining of the uterus) cancer. Most cases are caused by mutations in the PTEN gene and are inherited in an autosomal dominant manner.[8504][1] Management typically includes screening for associated tumors and/or prophylactic surgeries.[2]

Symptoms

Cowden syndrome is characterized primarily by multiple, noncancerous growths (called hamartomas) on various parts of the body. Approximately 99% of people who have Cowden syndrome will have benign growths on the skin and/or in the mouth by the end of their 20s. A majority of people with Cowden syndrome will also develop growths (called hamartomatous polyps) along the inner lining of the gastrointestinal tract.[8504][1]

People affected by Cowden syndrome also have an increased risk of developing certain types of cancer. Breast, thyroid, and endometrial (the lining of the uterus) cancers are among the most commonly reported tumorsThe lifetime risk of developing breast cancer is 85%; for thyroid cancer the risk is approximately 35%; and the risk for endometrial cancer is about 28%.[8504] Other associated cancers include colorectal cancer, kidney cancer, and melanoma. People with Cowden syndrome often develop cancers at earlier ages (before age 50) than people without a hereditary predisposition to cancer.[2][8504][3]

Other signs and symptoms of Cowden syndrome may include benign diseases of the breast, thyroid, and endometrium; a rare, noncancerous brain tumor called Lhermitte-Duclos disease; an enlarged head (macrocephaly); autism spectrum disorder; intellectual disability; and vascular (the body's network of blood vessels) abnormalities.[2][8504]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Breast carcinoma
Breast cancer
0003002
Colorectal polyposis
0200063
Conjunctival hamartoma
0100780
Generalized hyperkeratosis
0005595
Goiter
Enlarged thyroid gland in neck
0000853
Macule
Flat, discolored area of skin
0012733
Palmoplantar keratoderma
Thickening of palms and soles
0000982
Papilloma
0012740
Papule
0200034
30%-79% of people have these symptoms
Abnormality of the penis
0000036
Adenoma sebaceum
0009720
Ataxia
0001251
Cavernous hemangioma
Collection of dilated blood vessels that forms mass
0001048
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment

[ more ]

0100543
Furrowed tongue
Grooved tongue
0000221
Global developmental delay
0001263
Hamartomatous polyposis
0004390
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Lipoma
Fatty lump
Noncancerous fatty lump

[ more ]

0012032
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Macroglossia
Abnormally large tongue
Increased size of tongue
Large tongue

[ more ]

0000158
Melanocytic nevus
Beauty mark
0000995
Meningioma
0002858
Mucosal telangiectasiae
0100579
Subcutaneous nodule
Firm lump under the skin
Growth of abnormal tissue under the skin

[ more ]

0001482
5%-29% of people have these symptoms
Abnormal cerebellum morphology
Abnormality of the cerebellum
Cerebellar abnormalities
Cerebellar abnormality
Cerebellar anomaly

[ more ]

0001317
Autism
0000717
Bone cyst
Bone cysts
0012062
Brachydactyly
Short fingers or toes
0001156
Cataract
Clouding of the lens of the eye
Cloudy lens

[ more ]

0000518
Cellular immunodeficiency
0005374
Endometrial carcinoma
0012114
Enlarged polycystic ovaries
Enlarged ovaries with cysts
0008675
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Follicular thyroid carcinoma
0006731
Gynecomastia
Enlarged male breast
0000771
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
High palate
Elevated palate
Increased palatal height

[ more ]

0000218
Hypopigmented skin patches
Patchy loss of skin color
0001053
Increased intracranial pressure
Rise in pressure inside skull
0002516
Kyphosis
Hunched back
Round back

[ more ]

0002808
Melanoma
0002861
Multiple cafe-au-lait spots
0007565
Myopia
Close sighted
Near sighted
Near sightedness
Nearsightedness

[ more ]

0000545
Pectus excavatum
Funnel chest
0000767
Renal cell carcinoma
Cancer starting in small tubes in kidneys
0005584
Scoliosis
0002650
Seizure
0001250
Short stature
Decreased body height
Small stature

[ more ]

0004322
1%-4% of people have these symptoms
Decreased circulating antibody level
0004313
Lymphopenia
Decreased blood lymphocyte number
Low lymphocyte number

[ more ]

0001888
Recurrent infections
Frequent infections
Frequent, severe infections
Increased frequency of infection
infections, recurrent
Predisposition to infections
Susceptibility to infection

[ more ]

0002719
Percent of people who have these symptoms is not available through HPO
Abnormality of the vasculature
Abnormality

Cause

Most cases of Cowden syndrome are caused by mutations in the PTEN gene. PTEN is a tumor suppressor gene. Mutations in PTEN result in a defective protein that is unable to carry out its normal role. This leads to the development of the various tumors and cancers associated with Cowden syndrome.[8504]

Rarely, Cowden syndrome is caused by mutations in another gene like KLLN, SDHB, SDHC, SDHD, PIK3CA or AKT1. Some affected families have no identifiable mutation in any of the genes associated with Cowden syndrome; in these families, the exact underlying cause is unknown.[8504][4][5]

Diagnosis

A diagnosis of Cowden syndrome is based on the presence of characteristic signs and symptoms. Genetic testing for a mutation in the PTEN gene can then be ordered to confirm the diagnosis. If a mutation in PTEN is not found, genetic testing for the other genes known to cause Cowden syndrome can be considered.[8504]

The National Comprehensive Cancer Network [] consensus clinical diagnostic criteria have been divided into three categories:[3][8504] 

  • Pathognomonic criteria (criteria that is characteristic for a particular disease): mucosal and skin lesions
  • Major criteriabreast cancer, macrocephaly, thyroid cancer and endometrial cancer
  • Minor criteria: thyroid lesions, intellectual disability, hamartomatous intestinal polyps, fibrocystic disease of the breast, lipomas, fibromas, genital and urinary tumors or malformations, uterine fibroids

A diagnosis is given if a patient has the "pathognomonic" skin lesions, two or more major criteria, one major and 3 or more minor criteria, or 4 or more minor criteria. The diagnostic criteria for adults and children have some differences.[3] The PTEN Cleveland Clinic Risk Calculator can be used to estimate the chance of finding a PTEN mutation in children and adults with signs and symptoms of Cowden syndrome.

Finding mutations in the PTEN gene or other causal genes confirms diagnosis.

GeneReviews offers more detailed information regarding the diagnosis of Cowden syndrome including the clinical diagnostic criteria.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Because Cowden syndrome is associated with an increased risk for certain types of cancer, management is typically focused on high-risk cancer screening. According to the National Comprehensive Cancer Network 2014, the recommended screening protocol for Cowden syndrome includes:[2]

    Cancer Screening for Women

    • Breast self exams beginning at age 18
    • Clinical breast exams every 6-12 months beginning at age 25**
    • Annual mammogram and breast MRI beginning at age 30-35**
    • Annual screening for endometrial cancer with ultrasound and/or random biopsy may be considered beginning at age 30-35
    • Prophylactic surgeries may be considered as a preventative option for some forms of cancer

    Cancer Screening for Men and Women

    • Annual physical examination beginning at age 18**
    • Annual thyroid ultrasound beginning at age 18**
    • Baseline colonoscopy at age 35 with follow-up every 5 years (more frequent if polyps identified)
    • Consider renal (kidney) ultrasound every 1-2 years beginning at age 40

    **or individualized based on the earliest diagnosis of cancer in the family.

    Pediatric (age <18 years)

    • Yearly thyroid ultrasound examination** (on identification of a PTEN pathogenic variant)
    • Yearly skin check with physical examination
    • Neurodevelopmental evaluation

    If there are not any symptoms, observation alone is prudent. Cutaneous lesions should be removed only if malignancy is suspected or symptoms (e.g., pain, deformity, increased scarring) are serious. When symptomatic, topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may offer temporary relief. [Hildenbrand et al 2001].

    GeneReviews offers more specific information on the treatment and management of Cowden syndrome.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • PTEN World is an online discussion forum where members dealing with Cowden syndrome can share advice and support with other patients and caregivers.

        Organizations Providing General Support

          Learn more

          These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

          Where to Start

          • DermNet NZ is an online resource about skin diseases developed by the New Zealand Dermatological Society Incorporated. DermNet NZ provides information about this condition.
          • Medline Plus Genetics contains information on Cowden syndrome. This website is maintained by the National Library of Medicine.
          • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

            In-Depth Information

            • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
            • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
            • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
            • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
            • PubMed is a searchable database of medical literature and lists journal articles that discuss Cowden syndrome. Click on the link to view a sample search on this topic.

              References

              1. Fiala KH. Cowden Disease (Multiple Hamartoma Syndrome). Medscape Reference. 2018; https://emedicine.medscape.com/article/1093383-overview.
              2. Daly MB & cols. Genetic/Familial High-Risk Assessment: Breast and Ovarian. National Comprehensive Cancer Network. 2015; https://www.tri-kobe.org/nccn/guideline/gynecological/english/genetic_familial.pdf.
              3. Cowden syndrome. Orphanet. 2013; https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=243.
              4. Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. January 2012; 21(2):300-310.
              5. Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. January 2013; 92(1):76-80.

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