Cowden syndrome

Cowden syndrome
ICD-9	759.6
OMIM	158350
DiseasesDB	31336
MeSH	D006223

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Cowden syndrome is an inherited disorder characterized by multiple tumor-like growths called hamartomas and an increased risk of certain forms of cancer. Almost everyone with this condition has hamartomas. These small, noncancerous growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but can also occur in the intestinal tract and other parts of the body. People with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus. Indeed, women with Cowden syndrome have as much as a 25-50% lifetime risk of developing breast cancer. (Robbins & Cotran (2004). Pathological Basis of Disease, 7th Edition. Elsevier. p. 1134.) Noncancerous breast and thyroid diseases are also common. Other signs and symptoms of Cowden syndrome can include an enlarged head, a rare noncancerous brain tumor called Lhermitte-Duclos disease and mental retardation.

Epidemiology

Because Cowden syndrome can be difficult to diagnose, the exact prevalence is unknown; however, it probably occurs in at least 1 in 200,000 people.

Genetics

Mutations in the PTEN gene cause Cowden syndrome. PTEN is a tumor suppressor gene, which means it helps control the growth and division of cells. Inherited mutations in the PTEN gene have been found in about 80 percent of people with Cowden syndrome. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors. Cowden syndrome is one of several inherited diseases caused by mutations in the PTEN gene.

In the other 20 percent of Cowden syndrome cases, the cause is not yet known. Some of these cases may be caused by mutations in a region of DNA that regulates the activity of the PTEN gene.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. It is characterized by numerous hamartomas, among other symptoms.

Differentiating Cowden syndrome from other diseases

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

Differentiating from other diseases causing multiple polyps

Diseases	History and Symptoms			Physical Examination			Laboratory Findings			Other Findings
	Abdominal Pain	Rectal Bleeding	Fatigue	Abdominal Tenderness	Hyperpigmentation	Anemia	Gene(s)	Gastrointestinal Tumors	Cancers
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
Cowden Syndrome	–	–	–	–	Axillary+ Inguinal+ Facial+	–	PTEN	Adenoma+  Hamartoma+++	Breast Thyroid Endometrium	Trichilemmoma Skin hamartoma Hyperplastic polyp Macrocephaly Breast fibrosis
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

References

• de Jong MM, Nolte IM, te Meerman GJ, van der Graaf WT, Oosterwijk JC, Kleibeuker JH, Schaapveld M, de Vries EG (2002). "Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility". J Med Genet. 39 (4): 225–42. PMID 11950848.CS1 maint: Multiple names: authors list (link)
• Eng C (2000). "Will the real Cowden syndrome please stand up: revised diagnostic criteria". J Med Genet. 37 (11): 828–30. PMID 11073535.
• Kelly P (2003). "Hereditary breast cancer considering Cowden syndrome: a case study". Cancer Nurs. 26 (5): 370–5. PMID 14710798.
• Pilarski R, Eng C (2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". J Med Genet. 41 (5): 323–6. PMID 15121767.
• Waite KA, Eng C (2002). "Protean PTEN: form and function". Am J Hum Genet. 70 (4): 829–44. PMID 11875759.
• Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C (2003). "Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway". Am J Hum Genet. 73 (2): 404–11. PMID 12844284.CS1 maint: Multiple names: authors list (link)