Cowden syndrome | |
---|---|
Other names | Cowden's disease, multiple hamartoma syndrome |
Cumulative risk for the development of cancer in males and females with Cowden syndrome from birth to age 70. | |
Specialty | Oncology, Dermatology, Gastroenterology, Neurology |
Frequency | 1 in 200,000 individuals |
Cowden syndrome (also known as Cowden's disease and multiple hamartoma syndrome) is an autosomal dominant inherited condition characterized by benign overgrowths called hamartomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers. [1] It is often underdiagnosed due to variability in disease presentation, but 99% of patients report mucocutaneous symptoms by age 20–29. [2] Despite some considering it a primarily dermatologic condition, Cowden's syndrome is a multi-system disorder that also includes neurodevelopmental disorders such as macrocephaly. [3]
The incidence of Cowden's disease is about 1 in 200,000, making it quite rare. [4] Furthermore, early and continuous screening is essential in the management of this disorder to prevent malignancies. [4] It is associated with mutations in PTEN on 10q23.3, a tumor suppressor gene otherwise known as phosphatase and tensin homolog, that results in dysregulation of the mTOR pathway leading to errors in cell proliferation, cell cycling, and apoptosis. [5] 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%). [6]
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. [7] Oral papillomas are also common. [7] Furthermore, shiny palmar keratoses with central dells are also present. [7] At birth or in childhood, classic features of Cowden's include pigmented genital lesions, lipomas, epidermal nevi, and cafe-au-lait spots. [7] Squamous cell carcinomas of the skin may also occur. [6]
Thyroid
Two thirds of patients have thyroid disorders, and these typically include benign follicular adenomas or multinodular goiter of the thyroid. [8] Additionally, Cowden's patients are more susceptible to developing thyroid cancer than the general population. [9] It is estimated that less than 10 percent of individuals with Cowden syndrome may develop follicular thyroid cancer. [8] Cases of papillary thyroid cancer have been reported as well. [3]
Female and Male Genitourinary
Females have an elevated risk of developing endometrial cancers, which is highest for those under the age of 50. [3] 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. [3] The occurrence of multiple testicular lipomas, or testicular lipomatosis, is a characteristic finding in male patients with Cowden syndrome. [3]
Gastrointestinal
Polyps are extremely common as they are found in about 95% of Cowden syndrome patients undergoing a colonoscopy. [3] 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. [3] [10] Other types of polyps that may be encountered less frequently include ganglioneuromatous, adenomatous, and lymphoid polyps. [10] Diffuse glycogenic acanthosis of the esophagus is another gastrointestinal manifestation associated with Cowden syndrome. [3]
Breast
Females are at an increased risk of developing breast cancer, which is the most common malignancy observed in Cowden's patients. [3] 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. [3] Up to 75% demonstrate benign breast conditions such as intraductal papillomatosis, fibroadenomas, and fibrocystic changes. [3] 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. [3]
Central Nervous System
Macrocephaly is observed in 84% of patients with Cowden syndrome. [11] It typically occurs due to an abnormally enlarged brain, or megalencephaly. [12] Patients may also exhibit dolichocephaly. [12] Varying degrees of autism spectrum disorder and intellectual disability have been reported as well. [11] Lhermitte-Duclos disease is a benign cerebellar tumor that typically does not manifest until adulthood in patients with Cowden syndrome. [13]
Cowden syndrome is inherited in an autosomal dominant fashion. [14] Germline mutations in PTEN (phosphatase and tensin homolog), a tumor suppressor gene, are found in up to 80% of Cowden's patients. [10] Several other hereditary cancer syndromes, such as Bannayan-Riley-Ruvalcaba syndrome, have been associated with mutations in the PTEN gene as well. [15] PTEN negatively regulates the cytoplasmic receptor tyrosine kinase pathway, which is responsible for cell growth and survival, and also functions to repair errors in DNA. [14] [10] Thus, in the absence of this protein, cancerous cells are more likely to develop, survive, and proliferate. [10]
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. [16] 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. [17]
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. [3] The major and minor criteria are listed below:
Major criteria |
Breast cancer |
Endometrial cancer (epithelial) |
Thyroid cancer (follicular) |
Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3) |
Lhermitte-Duclos disease (adult) |
Macrocephaly (≥97 percentile: 58 cm for females, 60 cm for males) |
Macular pigmentation of the glans penis |
Multiple mucocutaneous lesions (any of the following): |
Multiple trichilemmomas (≥3, at least one biopsy proven) |
Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules) |
Mucocutaneous neuromas (≥3) |
Oral papillomas (particularly on tongue and gingiva), multiple (≥3) OR biopsy proven OR dermatologist diagnosed |
Minor criteria |
Autism spectrum disorder |
Colon cancer |
Esophageal glycogenic acanthosis (≥3) |
Lipomas (≥ 3) |
intellectual disability (i.e., IQ ≤ 75) |
Renal cell carcinoma |
Testicular lipomatosis |
Thyroid cancer (papillary or follicular variant of papillary) |
Thyroid structural lesions (e.g., adenoma, multinodular goiter) |
Vascular anomalies (including multiple intracranial developmental venous anomalies) |
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. [1] Specific screening guidelines for Cowden syndrome patients have been published by the National Comprehensive Cancer Network (NCCN). [11] Surveillance focuses on the early detection of breast, endometrial, thyroid, colorectal, renal, and skin cancer. [11] See below for a complete list of recommendations from the NCCN:
Women | Men and Women |
---|---|
Breast awareness starting at age 18 years of age | Annual comprehensive physical exam starting at 18 years of age or 5 years before the youngest age of diagnosis of a component cancer in the family (whichever comes first), with particular attention to breast and thyroid exam |
Clinical breast exam, every 6–12 month, starting at age 25 y or 5–10 y before the earliest known breast cancer in the family | Annual thyroid starting at age 18 y or 5–10 y before the earliest known thyroid cancer in the family, whichever is earlier |
Annual mammography and breast MRI screening starting at age 30–35 y or individualized based on earliest age of onset in family | Colonoscopy, starting at age 35 y, then every 5 y or more frequently if patient is symptomatic or polyps found |
For endometrial cancer screening, encourage patient education and prompt response to symptoms and participation in a clinical trial to determine the effectiveness or necessity of screening modalities | Consider renal ultrasound starting at age 40 y, then every 1–2 y |
Discuss risk-reducing mastectomy and hysterectomy and counsel regarding degree of protection, extent of cancer risk and reconstruction options | Dermatological management may be indicated for some patients |
Address psychosocial, social, and quality-of-life aspects of undergoing risk-reducing mastectomy and/or hysterectomy | Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms |
Education regarding the signs and symptoms of cancer |
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. [12] Two notable exceptions are breast and thyroid cancer. [12] In Cowden syndrome patients with a first-time diagnosis of breast cancer, treatment with mastectomy of the involved breast as well as prophylactic mastectomy of the uninvolved contralateral breast should be considered. [1] In the setting of thyroid cancer or a follicular adenoma, a total thyroidectomy is recommended even in cases where it appears that only one lobe of the thyroid is affected. [12] 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. [12]
The benign mucocutaneous lesions observed in Cowden syndrome are typically not treated unless they become symptomatic or disfiguring. [12] If this occurs, numerous treatment options, including topical agents, cryosurgery, curettage, laser ablation, and excision, may be utilized. [12]
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; [and] multiple thyroid adenomas." [18]
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. [19]
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.
Multiple endocrine neoplasia is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.
Proteus syndrome is a rare disorder with a genetic background that can cause tissue overgrowth involving all three embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development. The clinical and radiographic symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations.
Peutz–Jeghers syndrome is an autosomal dominant genetic disorder characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa (melanosis). This syndrome can be classed as one of various hereditary intestinal polyposis syndromes and one of various hamartomatous polyposis syndromes. It has an incidence of approximately 1 in 25,000 to 300,000 births.
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Because patients with Lynch syndrome can have polyps, the term HNPCC has fallen out of favor.
A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize. Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have relatively well differentiated cells. They are often surrounded by an outer surface or stay contained within the epithelium. Common examples of benign tumors include moles and uterine fibroids.
Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the SDHD gene. Names previously used for SDHD were PGL and PGL1. Succinate dehydrogenase is an important enzyme in both the citric acid cycle and the electron transport chain. Hereditary PGL-PCC syndrome is caused by a parental imprint of the SDHD gene. Screening can begin by 6 years of age.
Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human, adult onset, autosomal dominant genetic disorder caused by the FLCN gene. It can cause susceptibility to kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles, called fibrofolliculomas. The symptoms seen in each family are unique, and can include any combination of the three symptoms. Fibrofolliculomas are the most common manifestation, found on the face and upper trunk in over 80% of people with BHD over the age of 40. Pulmonary cysts are equally common (84%), but only 24% of people with BHD eventually experience a collapsed lung. Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors.
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 from a single mutated cell (monoclonality), as would typically define a benign neoplasm/tumor. Despite this, many hamartomas are found to have clonal chromosomal aberrations that are acquired through somatic mutations, and on this basis the term hamartoma is sometimes considered synonymous with neoplasm. Hamartomas are by definition benign, slow-growing or self-limiting, though the underlying condition may still predispose the individual towards malignancies.
Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.
Carney complex and its subsets LAMB syndrome and NAME syndrome are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. It is distinct from Carney's triad. Approximately 7% of all cardiac myxomas are associated with Carney complex.
Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth syndrome and hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. The disease is inherited in an autosomal dominant manner. The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz–Jeghers syndrome, juvenile polyposis and Cowden syndrome. Mutation of the PTEN gene underlies this syndrome, as well as Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, these four syndromes are referred to as PTEN Hamartoma-Tumor Syndromes.
Endometrial intraepithelial neoplasia (EIN) is a premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. It is composed of a collection of abnormal endometrial cells, arising from the glands that line the uterus, which have a tendency over time to progress to the most common form of uterine cancer—endometrial adenocarcinoma, endometrioid type.
Juvenile polyposis syndrome is an autosomal dominant genetic condition characterized by the appearance of multiple juvenile polyps in the gastrointestinal tract. Polyps are abnormal growths arising from a mucous membrane. These usually begin appearing before age 20, but the term juvenile refers to the type of polyp, not to the age of the affected person. While the majority of the polyps found in juvenile polyposis syndrome are non-neoplastic, hamartomatous, self-limiting and benign, there is an increased risk of adenocarcinoma.
Hereditary breast–ovarian cancer syndromes (HBOC) are cancer syndromes that produce higher than normal levels of breast cancer, ovarian cancer and additional cancers in genetically related families. It accounts for 90% of the hereditary cancers. The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family. The name HBOC may be misleading because it implies that this genetic susceptibility to cancer is mainly in women. In reality, both sexes have the same rates of gene mutations and HBOC can predispose to other cancers including prostate cancer and pancreatic cancer. For this reason, the term "King syndrome" has recently come into use. The new name references Mary-Claire King who identified the genes BRCA1 and BRCA2.
Lhermitte–Duclos disease (LDD), also called dysplastic gangliocytoma of the cerebellum, 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. It is often associated with Cowden syndrome. It was described by Jacques Jean Lhermitte and P. Duclos in 1920.
Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation, body asymmetry, polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.
The Genomic Medicine Institute at the Cleveland Clinic is an inter-disciplinary institute and department that focuses on patient care, patient-oriented research, and outreach and education in personalized healthcare guided by genetics and genomics. It is located in the Center for Genomics Research Building in the Cleveland Clinic, in Cleveland, Ohio, United States of America.
A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.
Charis Eng is a Singapore-born physician-scientist and geneticist at the Cleveland Clinic, notable for identifying the PTEN gene. She is the Chairwoman and founding Director of the Genomic Medicine Institute of the Cleveland Clinic, founding Director and attending clinical cancer geneticist of the institute’s clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairwoman of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine.
{{cite book}}
: CS1 maint: location missing publisher (link){{cite book}}
: CS1 maint: location missing publisher (link){{cite book}}
: CS1 maint: location missing publisher (link){{cite book}}
: CS1 maint: location missing publisher (link)