Cowden syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Cowden syndrome is an inherited disorder which follows autosomal dominant pattern. Cowden syndrome is characterized by multiple tumor-like growths called hamartomas. Most of the patients with cowden syndrome condition presents with hamartomas. These small, noncancerous growths are most commonly found on the skin and mucous membranes, but can also occur in the gastrointestinal tract and other parts of the body. People with Cowden syndrome are more prone to risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus. Women with Cowden syndrome have as much as a 25-50% lifetime risk of developing breast cancer.

Cowden syndrome/ Cowden’s disease/ multiple hamartoma syndrome follows autosomal dominant fashion of inheritance. Cowden syndrome was first described in 1940 by Salem and Steck.

There is no established system for the classification of cowden syndrome.

It is thought that cowden syndrome is the result caused by phosphatase and tensin homolog (PTEN) gene mutations. Cowden syndrome follows autosomal dominant pattern of inheritance.

The most common cause of cowden syndrome is PTEN gene mutations.

Cowden syndrome must be differentiated from the following Familial Adenomatous Polyposis, Peutz–Jeghers syndrome, Carney Syndrome and Hereditary Non–Polyposis Colon Cancer.

The incidence of rare disease cowden syndrome is approximately 1 in 250,000 individuals. The prevalence of cowden syndrome is unknown. The incidence of cowden syndrome increases with age. Cowden syndrome affects men and women equally.

There are no established risk factors for cowden syndrome.

According to the National Comprehensive Cancer Network (NCCN) Guidelines, screening for cowden syndrome patients is recommended for women who are at risk for breast cancer, uterine cancer and colon cancer.

Cowden syndrome follows an autosomal dominant pattern of inheritance. If left untreated, patients with cowden syndrome may prone to develop manu cancers.Common complications of cowden syndrome include breast, colon cancer and endometrial cancer. Prognosis is generally ranges from excellent to poor.

Biopsy is the gold standard and definitive test for diagnosis of cowden syndrome. The diagnostic criteria of cowden syndrome is based on the Cowden syndrome/PHTS criteria which include Pilarski et al diagnostic criteria.

The hallmark of cowden syndrome is Trichilemmomas. A positive history of PTEN gene mutation is suggestive of cowden syndrome. The most common symptoms of cowden syndrome includetrichilemmomas, oral papillomas and acral keratoses is suggestive of cowden syndrome.

Common physical examination findings of cowden syndrome include trichilemmomas, acral keratoses, and facial papules. The presence of trichilemmomas on physical examination is highly suggestive of cowden syndrome.

Laboratory findings consistent with the diagnosis of cowden syndrome include skin biopsy, chemistry panels, urinalysis, thyroid function tests and cbc count.

There are no ECG findings associated with Cowden syndrome.

There are no x-ray findings associated with cowden syndrome.

There are ultrasound findings associated with cowden syndrome. Ultrasound may be helpful in the diagnosis of complications of cowden syndrome, which include testicular swelling, hydrocele, and hyperechoic masses of the testes.

Head and neck CT scan may be helpful in the diagnosis of cowden syndrome. Findings on CT scan suggestive of cowden syndrome include enlarged thyroid lobes and calcifications.

Spine MRI may be helpful in the diagnosis of cowden syndrome. Findings on MRI suggestive of cowden syndrome include thoracolumbar scoliosis and disc disease.

There are no other imaging findings associated with cowden syndrome.

There are no other diagnostic studies associated with cowden syndrome.

Due to different phenotypes cowden syndrome is likely to be an underdiagnosed condition. Pharmacologic medical therapy is recommended among patients with cutaneous manifestations in cowden syndrome.

Surgery is not the first-line treatment option for patients with cowden syndrome. Surgery is usually reserved for patients with gastrointestinal polyps, Dysplastic Gangliocytoma and facial papules.

There are no established measures for the primary prevention of cowden syndrome.

There are no established measures for the secondary prevention of cowden syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Cowden syndrome/ Cowden’s disease/ multiple hamartoma syndrome follows autosomal dominant fashion of inheritance. Cowden syndrome was first described in 1940 by Salem and Steck.

• Cowden syndrome was first described in 1940 by Salem and Steck.^[1]

• Cowden syndrome was first discovered by Lloyd and Dennis, in 1963.^[2]

• The association between autosomal dominant pattern of inheritance and Cowden syndrome was made in 1972.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Cowden syndrome is one of the syndrome which belong to PTEN hamartoma tumor syndromes (PHTS).

Cowden syndrome is one of the syndrome which belong to PTEN hamartoma tumor syndromes (PHTS). These syndrome has been due to somatic mutation in phosphatase and tensin homolog (PTEN) gene. All PTEN hamartoma tumor syndromes (PHTS) follow autosomal dominant pattern of inheritance. PTEN hamartoma tumor syndromes (PHTS) include the following:^[1][2][3]

• Cowden syndrome
• Bannayan-Riley-Ruvalcaba syndrome
• Adult Lhermitte-Duclos disease
• Proteus syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

It is thought that cowden syndrome is the result caused by phosphatase and tensin homolog (PTEN) gene mutations. Cowden syndrome follows autosomal dominant pattern of inheritance.

The normal physiology of PTEN gene can be understood as follows:

• Location of PTEN gene tracks back to 10q22-23 chromosome.^[1]
• PTEN gene is an tumor suppressor gene.
• PTEN gene whose function affects in the following:^[2]
  • Cell cycle progression
  • Cell proliferation
  • Chemotaxis
  • Apoptosis
  • Aging
  • Muscle contractility
  • DNA damage response
  • Angiogenesis and
  • Cell polarity

• Cowden syndrome is transmitted in autosomal dominant pattern.^[3]
• Genes involved in the pathogenesis of cowden syndrome include:^[4]
• Mutations in the PTEN gene leads to oncogenesis, and somatic mutations
• Phosphatase and tensin homolog (PTEN) gene plays an important role in the following:^[5][6][7]
  • Phosphoinositide-3-kinase (PI3K)-AKT pathway and
  • Rapamycin (mTOR) signaling pathways
• PTEN track backs to 10q23 which encodes and plays a significant role in the following:^[8][9][10]
  • Effects G1 cell cycle arrest and apoptosis
  • Cellular proliferation and
  • Migration
  • Apoptosis
• Other gene mutations involved in the pathogenesis of cowden syndrome include:
  • KLLN (KILLIN) gene hypermethylation of the promoter region ^[11][12]
  • Succinate dehydrogenase (SDH) gene mutation^[13]
  • PIK3CA gene mutation^[14]
  • AKT1 gene mutation
  • SEC23B gene mutation^[15]
  • Epidermal growth factor receptor (EGFR) gene mutation^[16]

Conditions associated with cowden syndrome include:^[17][18][19]

• Breast cancer– 85% increases the risk
• Thyroid cancer– 35% increases the risk
• Endometrial cancer– 28% increases the risk
• Colorectal cancer– 9% increases the risk
• Kidney cancer– 35% increases the risk
• Melanoma– 6% increases the risk
• Bannayan-Riley-Ruvalcaba syndrome

On gross pathology, thyroid in cowden syndrome shows the following features: ^[20]

• Scattered foci of adipose tissue
• Lymphocytic thyroiditis

• On microscopic histopathological analysis, non dysplastic epithelium, dilated glands, expanded stroma are characteristic findings of colon polyps in cowden syndrome.^[21][22]
• On microscopic histopathological analysis, C-cell hyperplasia, yellow-tan, lack gelatinous colloid, small follicles and positivity in the endothelial cells found in thyroid pathology in cowden syndrome.^[23][24][25]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The most common cause of cowden syndrome is PTEN gene mutations. PTEN hamartoma tumor syndrome (PHTS) which includes a group of many disorders Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Proteus and Proteus-like syndrome (PS).

Common causes of cowden syndrome may include:^[1][2]

• PTEN gene mutations in a gene on chromosome 10
• Allelic heterogeneity is positive in cowden syndrome

Less common causes of cowden syndrome include:^[3][4]

• KLLN (KILLIN) gene mutation
• Succinate dehydrogenase (SDH) gene mutation^[5]
• SEC23B gene mutation^[6]
• EGFR gene mutation^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Cowden syndrome must be differentiated from the following Familial Adenomatous Polyposis, Peutz–Jeghers syndrome, Carney Syndrome and Hereditary Non–Polyposis Colon Cancer.

Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
				Parathyroid	Pitutary	Pancreas
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis,  Hemangioblastomas, Pheochromocytoma,  Renal cell carcinoma, Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor, Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	–	–	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)	–	–	–	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features” are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner’s syndrome	APC	5q21	Multiple polyps in the colon  Osteomas of the skull Thyroid cancer, Epidermoid cysts, Fibromas Desmoid tumors	–	–	–	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	– Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1   SDHB  SDHD	–	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone. Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013

Diseases	History and Symptoms			Physical Examination			Laboratory Findings			Other Findings
	Abdominal Pain	Rectal Bleeding	Fatigue	Abdominal Tenderness	Hyperpigmentation	Anemia	Gene(s)	Gastrointestinal Tumors	Cancers
Cowden Syndrome[1]	–	–	–	–	Axillary+ Inguinal+ Facial+	–	PTEN	Adenoma+  Hamartoma+++	Breast Thyroid Endometrium	Trichilemmoma Skin hamartoma Hyperplastic polyp Macrocephaly Breast fibrosis
Familial Adenomatous Polyposis	+	+	+	+/–	–	+	APC gene MUTYH gene	Adenoma+++	Colon Brain Thyroid	Desmoid tumor Osteoma
Peutz–Jeghers syndrome	+	+	+	+	+	+	STK11 (LBK1) gene	Adenoma+ Hamartoma+++	Breast Lung Pancreas Ovaries Sertoli cells Uterine
Juvenile Polyposis Syndrome	+		+	–	–	–	SMAD4 BMPR1A	Adenoma+  Hamartoma+++	Colon
Carney Syndrome	–	–	–	–	Facial+ Mucosal+	–	PRKAR1A		Thyroid Sertoli Cell	Myxoma of skin Myxoma of heart
Hereditary Non–Polyposis Colon Cancer	–	+	+	+/–	–	+	MLH1 MSH2 MSH3 MSH6 PMS1 PMS2	Adenoma+	Endometrium Stomach Kidneys Ureter Ovaries	Sebaceous adenoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The incidence of rare disease cowden syndrome is approximately 1 in 250,000 individuals. The prevalence of cowden syndrome is unknown. The incidence of cowden syndrome increases with age. Cowden syndrome affects men and women equally.

• The incidence of cowden syndrome is approximately 1 per 200,000 to 250,000 individuals worldwide.^[1][2]
• Before the PTEN gene mutation identification the incidence of cowden syndrome is approximately 1 per 1,000,000 individuals worldwide.^[3]

• The prevalence of cowden syndrome is unknown.^[4]
• The prevalence of breast cancer in cowden syndrome increases by 3 fold.^[5]
• The prevalence of renal cell carcinomas in cowden syndrome increases by 2 fold.^[6]
• The prevalence of non-medullary follicular thyroid cancer in cowden syndrome increases by 70 fold.^[7][8]

• The incidence of cowden syndrome increases with age.^[9]
• Based on Surveillance Epidemiology and End Results (SEER) data the median age at diagnosis is before 35 years.^[10]

• There is racial predilection to cowden syndrome.
• Cowden syndrome usually affects individuals of the caucasians race more than other races.^[11]

• Cowden syndrome affects men and women equally.^[12][13]
• Females are little more commonly affected by cowden syndrome than males.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

There are no established risk factors for cowden syndrome.

There are no established risk factors for cowden syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

According to the National Comprehensive Cancer Network (NCCN) Guidelines, screening for cowden syndrome patients is recommended for women who are at risk for breast cancer, uterine cancer and colon cancer.

According to the National Comprehensive Cancer Network (NCCN) Guidelines, screening for cowden syndrome patients is recommended for women who are at risk for:^[1]

• Breast cancer
  • Starting at the age of 25 years, breast exam should be considered for every 6-12 months^[2].^[3][4][5][6]
  • Starting at the age of 30-35 years, patients should consider magnetic resonance imaging (MRI) and and mammogram.
  • Patients who are at risk for breast cancer also should consider 3D mammography.
• Uterine cancer
  • Starting at the age of 30-35 years, annual uterine biopsies should be considered.^[7]
• Endometrial cancer
  • Starting at the age of 30-35 years, annual uterine biopsies or ultrasound should be considered.
• Colon cancer
  • Starting at the age of 35 years, for every 5 years colonoscopy should be considered.^[8][9][10]
• Thyroid cancer
  • Patients at all ages should consider an annual thyroid examination with an ultrasound scan is recommended.^{[11][12][13][14][15]}
• Renal cancer
  • Starting at the age of 40 years, for every 1-2 years ultrasound of should kidney should be considered.
• Skin cancer
  • Dermatologic screening should be considered when needed.^[16]
  • Trichilemmomas and mucocutaneous papillomatous papules are one of the early dermatological manifestations of the cowden syndrome and helps in early detection of the disease.^[17]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Cowden syndrome follows an autosomal dominant pattern of inheritance. If left untreated, patients with cowden syndrome may prone to develop manu cancers.Common complications of cowden syndrome include breast, colon cancer and endometrial cancer. Prognosis is generally ranges from excellent to poor.

• The symptoms of cowden syndrome usually tend to develop in second decade of life but varies and develops in ranging from 4 to 75 years.^[1][2]
• If left untreated, patients with cowden syndrome may prone to develop many cancers.^[3]

• Common complications of cowden syndrome include:^[4][5][6]
  • Breast cancer
  • Colon cancer
  • Endometrial cancer
  • Bladder cancer (transitional cell carcinoma)
  • Renal cell carcinoma
  • Non-Hodgkin lymphoma
  • Acute myelogenous leukemia
  • Osteosarcoma

• Prognosis is generally ranges from excellent to poor, and the mortality rate of patients with cowden syndrome is based on malignant tumors associated with it.
• The presence of benign tumours is associated with a particularly poor prognosis among patients with cowden syndrome.

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