Cowden Syndrome

A rare syndrome characterized by multiple hamartomas (small flesh-colored nodules on the skin made up by hair follicles and small wart-like growths) and a risk of breast, thyroid, and uterine neoplasias.

Multiple Hamartoma Syndrome.

Named after Rachel Cowden, the first patient described.

More than 200 cases have been described in the medical literature. Males and females are equally affected, however, thyroid cancer is the most common cancer in males, whereas breast cancer is the most common in affected women.

Autosomal dominant with interfamilial and intrafamilial variance.

Cowden syndrome results from a mutation in the PTEN (phosphatase and tensin homologue) tumor suppressor gene. (Synonym: MMAC1 [mutated in multiple advanced cancers-1] gene), which has been mapped to 10q23. PTEN encodes a phosphatase involved in regulation of growth, survival, and death of cells. The lack of PTEN functionality appears to be responsible for the uncontrolled proliferation of certain cells and the formation of hamartomas (and neoplasias).

Based on the clinical findings. Usually Cowden syndrome is diagnosed only after the first year of life. Mucocutaneous signs are most pathognomonic but least obvious. Signs include acral keratosis, facial trichilemmomas, oral papillomas, and scrotal tongue. The International Cowden Syndrome Consortium summarized the diagnostic features into major criteria (macrocephaly, thyroid cancer, breast cancer, and Lhermitte-Duclos disease [see Other Conditions to Be Considered]) and minor criteria (mental retardation, nonmalignant thyroid changes, nonmalignant breast tumors, gastrointestinal hamartomas, lipomas, fibromas, urogenital tumors). Mucocutaneous lesions alone can meet the criteria under certain circumstances (depending on the number and type of lesions). The diagnosis is considered very likely when one major and three minor criteria, two major criteria (but only if either macrocephaly or Lhermitte-Duclos disease is present), or four minor criteria are met.

Macrocephaly, not secondary to hydrocephalus, may be present in up to 39% of patients and usually becomes evident only after the first year of life. It is often accompanied by frontal bossing, adenoid facies, hypoplastic maxilla and mandible, and high arched palate. Mild mental retardation with seizures and cerebellar signs (tremor) is present in 12% of patients. Kyphosis, kyphoscoliosis, and anomalies of the thyroid gland are reported in approximately two thirds of patients and may include multinodular goiter, adenomas, and follicular adenocarcinoma. Patients should undergo regular checkups for signs of thyroid cancer (especially men). The most serious malignancy in females is (early-onset) breast cancer, which may affect up to one third of female patients and often occurs bilaterally. Gastrointestinal adenomas, hamartomatous and hyperplastic polyps, lymphangiomas, and ganglioneurofibromas may occur in almost three fourths of patients and can be localized anywhere between the esophagus and the anus (including gallbladder) but are most common in the colon. Malignant transformation is a possible risk. Urogenital lesions include carcinomas of the kidneys, urethra, and uterine cervix, ovarian cysts, leiomyomas, and teratomas, vaginal and vulvar cysts, and testicular hamartomas. Mucocutaneous lesions are present in more than 90% of patients and may appear in different forms. In more than three fourths of patients, small, white, oral papules representing fibromas with a diameter up to 3 mm can be detected on the lips, palate, gingiva, and tonsillar fossae. Involvement of the tongue can result in scrotal tongue (lingua scrotalis), with thickening and deep furrowing giving it the appearance of scrotal skin. Verruciform, flesh-colored papules (most often trichilemmomas) with a diameter of up to 5 mm are often located in periorificial areas and exhibit a keratin-plugged center. About two thirds of patients manifest acral keratosis characterized by verruciform papules on the dorsum of the hands and the feet, while approximately one third of patients have signs of keratosis palmoplantaris. Additional skin lesions may include subcutaneous lipomas, hemangiomas, and neuromas.

Assessment of the upper airway is crucial because hypoplasia of maxilla and mandible have been described, and potential obstruction by tumors is possible. Be aware of other relevant problems, such as thyroid dysfunction (obtain laboratory results of thyroid function free T4, T3 and TSH). It may be wise to obtain a complete blood count preoperatively because anemia may result from intestinal polyps or malignancies. Mental retardation may affect patient cooperation. Sedative and/or anxiolytic premedication and/or the presence of the primary caregiver during induction of anesthesia may be helpful.

Patients may present for multiple surgical procedures because of multiple tumors. Airway management may be difficult because of macrocephaly, hypoplastic maxilla with high arched palate, hypoplastic mandible, thyroid tumors, and papillomatosis of the base of the tongue, pharynx, and larynx. In one case laryngeal and hypopharyngeal papillomas resulted in difficult airway management complicated with bleeding and acute airway obstruction requiring emergency tracheostomy. Maintenance of spontaneous ventilation until the airway has been secured and availability of alternative airway management options (e.g., fiberoptic bronchoscope, laryngeal mask airway) is recommended. However, if gastrointestinal obstruction results from tumors, a rapid-sequence technique is recommended or should at least be weighed against maintenance of spontaneous ventilation because of expected airway problems.

Hepatic or renal involvement is unlikely unless these organs are affected by tumors. Avoid neuromuscular blockers until the airway has been secured (except for rapid sequence induction). One case of postoperative delirium was proposed to be related to abnormal metabolism of buprenorphine. Consider interactions between antiepileptic treatment and anesthetic drugs.

Bannayan-Zonana Syndrome: This inherited disorder is characterized by excessive growth prenatally and postnatally, manifesting with macrocephaly and scaphocephaly with normal intelligence or mild mental retardation and multiple hamartomas (lipomas, intestinal polyps). As affected infants age, the growth rate slows down and commonly results in normal adult height.

Carney Complex consists of spotty skin pigmentation in association with multiple neoplasias (mainly cardiac and endocrine tumors).

Proteus Syndrome: A rare congenital hamartomatous disorder characterized by multiple, diverse, somatic manifestations: partial bilateral gigantism of hands and feet, nevi, hemihypertrophy, subcutaneous tumors, and macrocephaly with cranial hyperostoses. It is named after the Greek god Proteus, “the polymorphous,” who could change his shape at will to avoid capture.

Riley-Smith Syndrome: A rare syndrome very similar to the Bannayan-Zonana syndrome characterized by macrocephaly, pseudopapillomata, hemangiomas, and multiple lipomas. Subcutaneous hemangiomas may be present at birth or appear later in childhood.

Lhermitte-Duclos Syndrome (Dysplastic Gangliocytoma of the Cerebellum; Benign Hypertrophy of the Cerebellum; Diffuse Ganglioneuroma of the Cerebellar Cortex; Neurocystic Blastoma; Hamartoblastoma; Cerebellar Hamartoma; Cerebellar Gangliomatosis; Neurocytoma Myelinicum; Gangliocytoma Myelinicum Diffusum; Purkinjeoma): Approximately 100 cases have been described. Patients present in young adult age with symptoms of cerebellar dysfunction (absent or only minimal signs in 50%), occlusive hydrocephalus with signs of increased intracranial pressure. However, symptoms may already be present shortly after birth. In approximately 60% of patients, Lhermitte-Duclos syndrome occurs sporadically, in the remaining 40%, an association with Cowden syndrome can be diagnosed. Magnetic resonance imaging usually confirms the clinical diagnosis. Macroscopically, the cerebellar folia and cortex are enlarged. Histologic examination reveals replacement of the cerebellar internal granular cell layer by large dysplastic neuronal cell bodies resembling Purkinje cells. Prominent myelinated tracts with axonal enlargement in the outer molecular layer of the cerebellar cortex are considered typical.