Cowden syndrome (also known as Cowden's disease) is an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inherited condition characterized by benign overgrowths called
hamartoma
A hamartoma is a mostly benign, local malformation of cells that resembles a neoplasm of local tissue but is usually due to an overgrowth of multiple aberrant cells, with a basis in a systemic genetic condition, rather than a growth descended fr ...
s as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers.
It is also known as multiple hamartoma syndrome, a name shared by
a more general syndrome of the same name. It is often underdiagnosed due to variability in disease presentation, but 99% of patients report mucocutaneous symptoms by age 20–29. Despite some considering it a primarily dermatologic condition, Cowden's syndrome is a multi-system disorder that also includes neurodevelopmental disorders such as
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...
.
The incidence of Cowden's disease is about 1 in 200,000, making it quite rare.
Furthermore, early and continuous screening is essential in the management of this disorder to prevent malignancies.
It is associated with mutations in ''
PTEN'' on 10q23.3, a
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
gene otherwise known as phosphatase and tensin homolog, that results in dysregulation of the
mTOR
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
pathway leading to errors in cell proliferation, cell cycling, and apoptosis. The most common malignancies associated with the syndrome are adenocarcinoma of the breast (20%), followed by adenocarcinoma of the thyroid (7%),
squamous cell carcinomas of the skin (4%), and the remaining from the colon, uterus, or others (1%).
Signs and symptoms

As Cowden's disease is a multi-system disorder, the physical manifestations are broken down by organ system:
Skin
Adolescent patients affected with Cowden syndrome develop characteristic lesions called
trichilemmomas, which typically develop on the face, and verrucous papules around the mouth and on the ears.
Oral
papilloma
A papilloma (plural papillomas or papillomata) ('' papillo-'' + '' -oma'') is a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like and often finger-like fronds. In this context, papilla refers to the projection cr ...
s are also common.
Furthermore, shiny
palmar keratoses with central dells are also present.
At birth or in childhood, classic features of Cowden's include pigmented genital lesions,
lipoma
A lipoma is a benign tumor made of adipose tissue, fat tissue. They are generally soft to the touch, movable, and painless. They usually occur just under the skin, but occasionally may be deeper. Most are less than in size. Common locations inc ...
s, epidermal
nevi
The Infrastructure Investment and Jobs Act (IIJA), also known as the Bipartisan Infrastructure Law (BIL),H.R. 3684 is a United States federal statute enacted by the 117th United States Congress and signed into law by President Joe Biden on Nove ...
, and
cafe-au-lait spots.
Squamous cell carcinomas of the skin may also occur.
Thyroid
Two thirds of patients have thyroid disorders, and these typically include benign
follicular adenoma
A thyroid adenoma is a benign tumor of the Thyroid, thyroid gland, that may be inactive or active (functioning autonomously) as a toxic adenoma.
Signs and symptoms
A thyroid adenoma may be clinically silent ("cold" adenoma), or it may be a functi ...
s or
multinodular goiter
A goitre (British English), or goiter (American English), is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.
Worldwide, over 90% of goitre cases are ca ...
of the thyroid.
Additionally, Cowden's patients are more susceptible to developing thyroid cancer than the general population. It is estimated that less than 10 percent of individuals with Cowden syndrome may develop
follicular thyroid cancer
Follicular thyroid cancer accounts for 15% of thyroid cancer and occurs more commonly in women over 50 years of age. Thyroglobulin (Tg) can be used as a tumor marker for well-differentiated follicular thyroid cancer. Thyroid follicular cells are ...
.
Cases of
papillary thyroid cancer
Papillary thyroid cancer (papillary thyroid carcinoma,
PTC) is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases.Chapter 20 in: 8th edition. It occurs more frequently in women and presents ...
have been reported as well.
Female and male genitourinary
Females have an elevated risk of developing
endometrial cancer
Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...
s, which is highest for those under the age of 50.
Currently, it is not clear whether
uterine leiomyomata (fibroids) or congenital genitourinary abnormalities occur at an increased rate in Cowden syndrome patients as compared to the general population.
The occurrence of multiple testicular lipomas, or testicular lipomatosis, is a characteristic finding in male patients with Cowden syndrome.
Gastrointestinal
Polyps are extremely common as they are found in about 95% of Cowden syndrome patients undergoing a colonoscopy.
They are numerous ranging from a few to hundreds, usually of the hamartomatous subtype, and distributed across the colon as well as other areas within the gastrointestinal tract.
Other types of polyps that may be encountered less frequently include ganglioneuromatous, adenomatous, and lymphoid polyps.
Diffuse
glycogenic acanthosis of the esophagus is another gastrointestinal manifestation associated with Cowden syndrome.
Breast
Females are at an increased risk of developing breast cancer, which is the most common malignancy observed in Cowden's patients.
Although some cases have been reported, there is not enough evidence to indicate an association between Cowden syndrome and the development of male breast cancer.
Up to 75% demonstrate benign breast conditions such as
intraductal papilloma
Intraductal papillomas of the breast are benign lesions with an incidence of approximately 2-3% in humans. They result from abnormal proliferation of the epithelial cells lining the breast ducts.
Two types of intraductal papillomas are generally ...
tosis,
fibroadenoma
Fibroadenomas are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules (milk producing glands) and ducts (tubes that carry the milk to the nipple). These are surrounded by glandular, ...
s, and
fibrocystic changes.
However, there is currently not enough evidence to determine if benign breast disease occurs more frequently in Cowden's patients as compared to individuals without a hereditary cancer syndrome.
Central nervous system
Macrocephaly is observed in 84% of patients with Cowden syndrome.
It typically occurs due to an abnormally enlarged brain, or
megalencephaly
Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general populati ...
.
Patients may also exhibit
dolichocephaly
Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a term used to describe a head that is longer than average relative to its width. In humans, scaphocephaly is a form of dolichocephaly.
Dolichoceph ...
.
Varying degrees of
autism spectrum disorder
Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
and
intellectual disability
Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
have been reported as well.
Lhermitte-Duclos disease is a benign cerebellar tumor that typically does not manifest until adulthood in patients with Cowden syndrome.
Genetics
Cowden syndrome is inherited in an autosomal dominant fashion.
Germline mutation
A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...
s in ''PTEN'' (phosphatase and tensin homolog), a tumor suppressor gene, are found in up to 80% of Cowden's patients.
Several other hereditary cancer syndromes, such as
Bannayan–Riley–Ruvalcaba syndrome, have been associated with mutations in the ''PTEN'' gene as well. PTEN negatively regulates the cytoplasmic
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
pathway, which is responsible for cell growth and survival, and also functions to repair errors in
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
.
Thus, in the absence of this protein, cancerous cells are more likely to develop, survive, and proliferate.
Recently, it was discovered that germline heterozygous mutations in SEC23B, a component of coat protein complex II vesicles secreted from the endoplasmic reticulum, are associated with Cowden syndrome. A possible interplay between PTEN and SEC23B has recently been suggested, given emerging evidence of each having a role in ribosome biogenesis, but this has not been conclusively determined.
Diagnosis
The revised clinical criteria for the diagnosis of Cowden's syndrome for an individual is dependent on either one of the following: 1) 3 major criteria are met or more that must include macrocephaly, Lhermitte-Duclos, or GI hamartomas 2) two major and three minor criteria.
The major and minor criteria are listed below:
Screening
The management of Cowden syndrome centers on the early detection and prevention of cancer types that are known to occur as part of this syndrome.
Specific screening guidelines for Cowden syndrome patients have been published by the
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) is an alliance of 33 cancer centers in the United States, most of which are designated by the National Cancer Institute (one of the U.S. National Institutes of Health) as comprehensive cancer cent ...
(NCCN).
Surveillance focuses on the early detection of breast, endometrial, thyroid, colorectal, renal, and skin cancer.
See below for a complete list of recommendations from the NCCN:
Treatment
Malignancies that occur in Cowden syndrome are usually treated in the same fashion as those that occur sporadically in patients without a hereditary cancer syndrome.
Two notable exceptions are breast and thyroid cancer.
In Cowden syndrome patients with a first-time diagnosis of breast cancer, treatment with
mastectomy
Mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. A mastectomy is usually carried out to treat breast cancer. In some cases, women believed to be at high risk of breast cancer choose to have ...
of the involved breast as well as prophylactic mastectomy of the uninvolved contralateral breast should be considered.
In the setting of
thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck, ...
or a
follicular adenoma
A thyroid adenoma is a benign tumor of the Thyroid, thyroid gland, that may be inactive or active (functioning autonomously) as a toxic adenoma.
Signs and symptoms
A thyroid adenoma may be clinically silent ("cold" adenoma), or it may be a functi ...
, a ''total''
thyroidectomy
A thyroidectomy is an operation that involves the surgery, surgical removal of all or part of the thyroid gland. In general surgery, endocrine or head and neck surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other ...
(as opposed to a ''hemi''thyroidectomy, in which only one lobe of the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
would be removed) is recommended even in cases where it appears that only one lobe of the thyroid is affected.
This is due to the high likelihood of recurrence as well as the difficulty in distinguishing a benign from malignant growth with a hemithyroidectomy alone.
The benign mucocutaneous lesions observed in Cowden syndrome are typically not treated unless they become symptomatic or disfiguring, as these lesions have little to no risk of
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
.
If the benign lesions do cause symptoms, numerous treatment options, including topical agents,
cryosurgery
Cryosurgery (with ''cryo'' from the Ancient Greek ) is the use of extreme cold in surgery to destroy abnormal or diseased tissue; thus, it is the surgical application of cryoablation.
Cryosurgery has been historically used to treat a number o ...
,
curettage
Curettage ( or ), in medical procedures, is the use of a curette (French, meaning "scoop" Mosby's Medical, Nursing & Allied Health Dictionary, Fourth Edition, Mosby-Year Book 1994, p. 422) to remove tissue by scraping or scooping.
Curettages ...
, laser ablation, and excision, may be utilized.
History
Cowden Syndrome was described in 1963, when Lloyd and Dennis described a novel inherited disease that predisposed to cancer. It was named after the Cowden family, in which it was discovered. They described the various clinical features including "adenoid facies; hypoplasia of the mandible and maxilla; a high-arch palate; hypoplasia of the soft palate and uvula; microstomia; papillomatosis of the lips and oral pharynx; scrotal tongue;
ndmultiple thyroid adenomas."
The genetic basis of Cowden Syndrome was revealed in 1997, when germline mutations in a locus at 10q23 were associated to the novel
PTEN tumor suppressor.
See also
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References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
{{DEFAULTSORT:Cowden Syndrome
Deficiencies of intracellular signaling peptides and proteins
Hereditary cancers
Rare syndromes
Epidermal nevi, neoplasms, and cysts
Syndromes affecting the breast
Syndromes affecting the gastrointestinal tract