Cowden Syndrome

Cowden syndrome, also known as multiple hamartoma syndrome, is an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inherited condition that presents with multiple, noncancerous growths on various parts of the body. The syndrome is classified as a phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome that is caused by mutations in the PTEN gene. Patients usually have macrocephaly, trichilemmomas (hair follicle tumors), and papillomatous papules in the mouth. Cowden syndrome is associated with an increased risk of developing breast, thyroid, colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix, and endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer. Management includes surveillance for associated tumors and prophylactic surgeries.

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Overview

Definition

Cowden syndrome is an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance genodermatosis caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the PTEN gene and characterized by multiple benign hamartomas in any location of the body, mucocutaneous lesions, and macrocephaly.

Epidemiology

  • 1 in 200,000 people are affected.
  • Most common phenotype of the PTEN gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations spectrum
  • Some studies suggest that women are more commonly affected. 
  • Most patients are white.

Etiology

  • Autosomal dominant inherited mutations in a tumor suppressor gene
  • Mutation is in the PTEN gene on arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm 10q23.
  • PTEN is a lipid phosphatase that removes phosphate groups from signaling molecules.
  • When PTEN is mutated, cells are allowed to proliferate.

Pathophysiology

  • The PTEN protein:
    • Promotes cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death by restricting growth and survival signals, allowing for normal cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
    • Negatively controls the pathway for regulating cell growth and survival (phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway)
  • The PTEN gene is lost by a “2nd hit” mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of MutationsPTEN is not expressed
  • Normal downregulation of the mTOR pathway is lost →  loss of control of apoptosis → overproliferation of cells occurs → hamartomatous growths → neoplasms develop
Pten protein pathophysiology of cowden syndrome

PTEN protein function:
The PTEN protein works in different ways to suppress the formation and spread of tumors.

Image: “PTEN protein” by Front Oncol Feb 2015. doi: 10.3389/fonc.2015.00024. License: CC BY 4.0

Clinical Presentation

History

  • Usually presents in patients’ 20s
  • Patients report appearance of lesions on the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucous membranes first.
  • Women may complain of menstrual abnormalities due to uterine leiomyomas.
  • Hamartomatous polyps in the GI tract can cause pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and bleeding.

Physical examination

  • Head: macrocephaly
  • Oral cavity: papillomas
  • Skin: trichilemmoma (yellow-brown, warty papules), multiple seborrheic keratoses
  • Soft tissue: hamartomas, lipomas, or angiolipomas
  • Neck: goiter Goiter A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Goiter, thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
  • Breast (in both women and men): breast masses, breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Rectal exam: positive hemoccult

Diagnosis

Diagnostic criteria

  • Diagnosis depends on the fulfillment of 1 of 4 sets of criteria: 
    1. Pathognomonic criteria
    2. At least 2 major criteria
    3. 1 major and 3 minor criteria
    4. 4 minor criteria
  • Pathognomonic criteria: mucosal and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
  • Major criteria:
    • Macrocephaly
    • Thyroid cancer
    • Breast cancer
    • Endometrial cancer
  • Minor criteria:
    • Genitourinary tumors or malformations
    • Lipomas
    • Fibromas
    • Intellectual disability
    • Fibrocystic disease of the breast
    • GI hamartomas
    • Thyroid lesion (i.e., goiter Goiter A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Goiter)
    • Uterine fibroids

Laboratory tests

  • CBC
  • Thyroid function test (thyroid-stimulating hormone (TSH), FT4)
  • Stool for occult blood
  • Urinalysis
  • PTEN gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations testing

Diagnostic imaging

  • Based on complaint
  • Abdominal CT scan
  • Abdominal MRI
  • Ultrasound of uterus for leiomyomas
  • Mammography
Colonoscopy showing tumor of the descending colon

Hamartoma of the descending colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix in a patient with Cowden syndrome

Image: “Preoperative colonoscopic views” by Pistorius et al. License: CC BY 4.0, cropped by Lecturio.

Management

Surveillance

  • Management is centered around more frequent cancer screenings.
  • Education regarding the signs and symptoms of cancer
  • Monthly breast self-exams for women
  • Annual history and physical examinations including:
    • Thyroid ultrasound
    • Uterine screening for women
    • Skin checks
    • Kidney screening (urinalysis)
  • Colonoscopy starting at age 35 years:
    • Colonoscopy every 5 years
    • More frequently if symptomatic or polyps found
  • Mammogram, starting at age 30 for women

Complications

  • Neoplasms:
    • Skin (in 90%–100% of cases)
    • Mucosa
    • GI tract
    • Bones
    • CNS
    • Eyes
    • Genitourinary tract
    • Thyroid (in 66% of cases)
  • Gastric polyps
  • Desmoid tumors 
  • Thyroid tumors and disorders

Prognosis

  • Patients may have close-to-normal life expectancies.
  • Frequent cancer screening and prompt diagnosis improve outcomes. 
  • Morbidity and mortality are associated with ↑ frequency of malignant tumors
  • Benign tumors can cause significant morbidity.
  • At least 40% of patients have a minimum of 1 malignant primary tumor.

Differential Diagnosis

  • Hereditary nonpolyposis colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancer ( HNPCC HNPCC Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome): also known as Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome, an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder caused by mutations in the mismatch repair (MMR) genes, which ultimately leads to the development of colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer in 1st-degree relatives. Management is with prophylactic colectomy and frequent endoscopy for surveillance. 
  • Juvenile polyposis: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance condition characterized by the growth of hyperplastic, hamartomatous polyps in the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix. The condition is commonly associated with mutations in the SMAD4 and BMPR1A genes. Diagnosis is made by visualizing > 5 polyps on colonoscopy, or any number plus a positive family history. Management is surgical in order to reduce the likelihood of GI bleeding and obstruction. 
  • Colorectal cancer (CRC): the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease, arising from genetic and epigenetic abnormalities, with influence from environmental factors. Almost all cases of CRC are adenocarcinoma. Most cases are asymptomatic, so screening is important. Diagnosis is by colonoscopy. Management is primarily surgical.
  • Thyroid cancer: malignancy of the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland cells, which can arise from the thyroid follicular cells or the calcitonin-producing C cells. Exposure to ionizing radiation and iodine deficiency are also considered risk factors. Diagnostic is with TSH, ultrasound, and biopsy. Management is mainly surgical.
  • Uterine leiomyomas: also known as uterine fibroids; benign tumors arising from smooth muscle cells in the uterine myometrium. Uterine leiomyomas present with abnormal bleeding and pelvic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Fibroids are hypoechoic, well-circumscribed, round masses on pelvic ultrasound. Depending on patient symptoms and preference, treatment for leiomyomas may include surgical resection or medical options to reduce bleeding or bulk.

References

  1. Kumar V, Abbas A, Aster J, Perkins J. (2018). Robbins basic pathology. Philadelphia, Pennsylvania: Elsevier.
  2. Patraquim C, et al. (2017). A Pediatric Case of Cowden Syndrome with Graves’ Disease. Case reports in pediatrics, 2017, 2750523. 
  3. Garofola C, Jamal Z, Gross GP. (2021). Cowden disease. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved June 15, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK525984/
  4. Stanich PP. (2020) PTEN hamartoma tumor syndromes, including Cowden syndrome. UpToDate. Retrieved June 15, 2021, from https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome
  5. Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). 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.
  6. 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.
  7. Fiala, K. (2018). Cowden Disease (Multiple Hamartoma Syndrome) Treatment & Management. Retrieved June 15, 2021, from https://emedicine.medscape.com/article/1093383-treatment#d8

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