Cowden Syndrome 1

A number sign (#) is used with this entry because of evidence that Cowden syndrome-1 (CWS1) is caused by heterozygous germline mutation in the PTEN gene (601728) on chromosome 10q23.

Description

Cowden syndrome-1 is a hamartomatous disorder characterized by macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, and an increased risk for the development of breast, thyroid, and endometrial carcinoma. Bannayan-Riley-Ruvalcaba syndrome (BRRS), previously thought be distinct, shared clinical characteristics with Cowden syndrome, such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms, but had the additional features of developmental delay, macrocephaly, lipomas, hemangiomas, and pigmented speckled macules of the glans penis in males. Because features of BRRS and Cowden syndrome have been found in individuals within the same family with the same PTEN mutation, Cowden syndrome-1 and BRRS are considered to be the same disorder with variable expression and age-related penetrance (summary by Marsh et al., 1999, Lachlan et al., 2007, and Blumenthal and Dennis, 2008).

Approximately 80% of patients reported with Cowden syndrome and 60% with BRSS have PTEN mutations (Blumenthal and Dennis, 2008).

Some patients with Cowden syndrome may have immune system defects resulting in increased susceptibility to infections (summary by Browning et al., 2015).

Nomenclature

Marsh et al. (1999) suggested that the spectrum of disorders caused by mutation in the PTEN gene be referred to as PTEN hamartoma tumor syndrome (PHTS).

Lachlan et al. (2007) concluded that the Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome represent a single condition with variable expression and age-related penetrance, which is common in tumor-suppressor disorders, and suggested that it is not helpful to split PTEN-related disorders into separate clinical syndromes.

Genetic Heterogeneity of Cowden Syndrome

Also see CWS4 (615107), caused by hypermethylation of the promoter of the KLLN gene (612105), which shares the same transcription site as the PTEN gene, on chromosome 10q23; CWS5 (615108), caused by mutation in the PIK3CA gene (171834) on chromosome 3q26; CWS6 (615109), caused by mutation in the AKT1 gene (164730) on chromosome 14q32; and CWS7 (616858), caused by mutation in the SEC23B gene (610512) on chromosome 20p11.

Two previously designated forms of Cowden syndromes, CWS2 and CWS3, reported to be caused by mutations in the SDHB (185470) and SDHD (602690) genes, respectively, have been called into question based on the frequency of the reported variants in the ExAC and gnomAD databases; see Associations Pending Confirmation in the MOLECULAR GENETICS section.

Clinical Features

Riley and Smith (1960) described a mother and 2 of 7 children with macrocephaly, pseudopapilledema, and multiple hemangiomata. Two other sibs had macrocephaly and pseudopapilledema. Intellect and vision were unimpaired.

Bannayan (1971) first described the triad of macrocephaly, lipomatosis, and angiomatosis in a single child observed at autopsy at the Johns Hopkins Hospital. Zonana et al. (1975, 1976) described the triad in a father and 2 sons, suggesting autosomal dominant inheritance. One son had overgrowth of the right index finger and involvement of the small bowel mesentery by hamartoma with angiomatous, lipomatous, and lymphangiomatous components.

Miles et al. (1981) and Miles et al. (1984) documented Bannayan-Zonana syndrome in 11 persons in 4 additional families. Clinical features included high palate, scaphocephaly, lipomas of the anterior abdominal wall, thigh, perineum, scapula area, etc., hemangiomas of the anterior abdominal wall, wrist, knee, and foot, bleeding from intracranial hemangioma, and arteriovenous malformation leading to leg amputation. Some children had pectus excavatum. Most of the lipomas spontaneously regressed with age. In some patients, seizures resulted from intracranial hemorrhage. Despite macrocephaly, computerized axial tomography showed no enlargement of the cerebral ventricles, and there was no pseudopapilledema. Affected persons had increased birth weight and length, but growth leveled off at age 6 or 7 years. There was delayed motor development with incoordination, delayed speech development, and mild mental retardation. Drooling was a problem in children. The disorder appeared to be autosomal dominant, but the authors noted that about 80% of affected persons have been male. In 1 instance, the disorder was transmitted by a man with a head of normal size.

Ruvalcaba et al. (1980) described 2 unrelated patients with macrocephaly, intestinal polyposis, and pigmented macules of the penis, and suggested that they had Sotos syndrome (117550). However, Smith (1982) subsequently suggested that these patients had a disorder different from Sotos syndrome.

Higginbottom and Schultz (1982) described Bannayan syndrome in 3 generations of an American black kindred. They concluded that affected persons may have an increased risk of intracranial tumors: a woman in their family had meningothelial meningioma removed at age 28.

DiLiberti et al. (1983) described a 7.5-year-old boy with macrocephaly, hamartomatous intestinal polyps, and cafe-au-lait spots on the penis, and referred to the disorder as 'Ruvalcaba-Myhre-Smith syndrome.' The patient's mother had macrocephaly, a facial appearance similar to the son's, and a hamartomatous intestinal polyp. DiLiberti et al. (1983) also identified prominent Schwalbe lines, which are a frequent normal finding but a consistent feature of 'anterior chamber cleavage syndromes,' prominent corneal nerves, and lipid storage myopathy as features of the disorder.

DiLiberti et al. (1984) reported an association of a lipid storage myopathy with Ruvalcaba-Myhre-Smith syndrome, based on 4 patients with the disorder. The patients had delayed psychomotor development and/or hypotonia in childhood. Electromyography in 3 patients showed evidence of a myopathic process. Muscle biopsy in all 4 showed a lipid storage myopathy with increased numbers of neutral lipid droplets, predominantly in type 1 fibers. Type 2 fibers were consistently smaller than expected.

In the sporadic cases of Bannayan (1971) and of Okumura et al. (1986), death occurred as a result of severe visceral lipomatosis at ages 3.5 years and 5.75 years, respectively.

Dvir et al. (1988) reported a 4.5-year-old boy with macrocephaly, pseudopapilledema, enlarged penis, lipoangiomatosis, and spotted pigmentation of the glans penis. The patient's father and a brother had macrocephaly; the father had enlarged penis. Dvir et al. (1988) noted that the findings were consistent with features reported by Riley and Smith (1960), Bannayan (1971), and Ruvalcaba et al. (1980), and concluded that they all referred to the same syndrome. Dvir et al. (1988) proposed to unify the main features into 1 hereditary syndrome and name it 'macrocephaly-hamartomas-papilledema.'

Gorlin (1988) also suggested that Ruvalcaba-Myhre-Smith syndrome was the same as the Bannayan-Zonana syndrome. He referred to the case of an 8-year-old male who had 50 or more hamartomas of the bowel through which he lost serum protein. The diagnosis of BZS had been made, but Gorlin found that the patient also had speckled penis, consistent with RMSS.

In a 38-year-old man with macrocephaly, multiple lipomas, and vascular anomalies, Pyeritz (1988) observed 'unstable angina,' dilated aortic root, and ascending aorta.

Halal and Silver (1989) described an 8.5-year-old boy with slowly progressive macrocephaly, psychomotor retardation, multiple subcutaneous angiolipomas, hypertelorism, exotropia, prolonged drooling to age 5 years, cutis marmorata, telangiectases over the shoulders, atrial septal defect repaired at age 4 years, broad thumbs and great toes, and muscle wasting. The angiolipomas were bluish subcutaneous nodules scattered all over his body. The parents were second cousins. The father was thought to have minor manifestations of the disorder, i.e., mild hypertelorism and broad thumbs and great toes, as well as mild cutis marmorata over the inner aspect of the forearms and a cluster of telangiectases and dilated vessels on the anterior aspect of both legs. Halal and Silver (1989) concluded that the proband and his father may have had the Bannayan-Zonana syndrome, with previously undescribed additional anomalies, overlapping with the syndrome of cutis marmorata telangiectatica congenita (CMTC; 219250). Alternatively, the disorder in the father and son may have represented a new syndrome of macrocephaly and hamartomas with overlapping manifestations with BZS and CMTC.

Moretti-Ferreira et al. (1989) commented on the variability of severity in Bannayan-Zonana syndrome, which may represent different allelic mutations or genetic heterogeneity.

DiLiberti (1992) examined the muscle biopsy results from 14 children with macrocephaly and hypotonia/weakness and correlated them with clinical findings. Of the 14, 13 had evidence of lipid storage myopathy, either generalized or focal. All 13 had examinations consistent with benign familial macrocephaly, Ruvalcaba-Myhre-Smith syndrome, or Bannayan-Zonana syndrome.

Gorlin et al. (1992) reported a kindred in which 12 members had Bannayan-Riley-Ruvalcaba syndrome. The clinical features showed overlap between Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome. Seven of the patients had Hashimoto thyroiditis.

Powell et al. (1993) reported 27 children, aged 14 months to 9 years, who had megalencephaly, hypotonia, proximal muscle weakness, speech and motor delay, and increased intracellular lipid (myoliposis) in needle muscle biopsy specimens. The patients had many features of the Ruvalcaba-Myhre-Smith syndrome, and in 17 families the authors confirmed the autosomal dominant inheritance pattern previously suggested. Muscle carnitine content was low in all 11 patients and all 4 affected relatives tested. All 27 probands were treated with oral L-carnitine; a clinical response was noted in 17. Powell et al. (1993) speculated that myoliposis may be found in other disorders with megalencephaly and muscle symptoms. Fryburg et al. (1994) suggested that a defect in long-chain fatty acid oxidation resulting from deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (LCHAD; 143450) may be responsible for the lipid myopathy in the Bannayan-Riley-Ruvalcaba syndrome. Their patient had macrocephaly with prominent frontal bossing and low-set ears, hypertelorism, and hemangiomas.

Boccone et al. (2006) reported a Sardinian boy with BRRS confirmed by genetic analysis. In addition to the classic features of macrocephaly, downslanting palpebral fissures, joint hypermobility, and pigmented macules on the penis, the boy also had autism and reactive nodular lymphoid hyperplasia of the small and large intestinal mucosa. Boccone et al. (2006) recommended screening for lymphomas as well as other malignancies in patients with BRRS.

In Cowden syndrome, multiple hamartomatous lesions, especially of the skin, mucous membranes, breast, and thyroid, are encountered. Verrucous skin lesions of the face and limbs, cobblestone-like papules of the gingiva and buccal mucosa, and multiple facial trichilemmomas are leading findings (Brownstein et al., 1977). Hamartomatous polyps of the colon and other intestines occur also. Only 1 case had been reported before the report of Weary et al. (1972). Weary et al. (1972) proposed the designation multiple hamartoma syndrome and identified an autosomal dominant pattern of inheritance in the family of Rachel Cowden, for whom Lloyd and Dennis (1963) had named the disorder. Affected brother and sister were observed by Gentry et al. (1974). Gentry et al. (1974) observed affected persons in 4 generations, with father-to-son transmission. Brownstein et al. (1979) reported on the dermatopathology in 19 patients with Cowden syndrome. Twenty-nine of 53 facial lesions biopsied were trichilemmomas. All oral mucosal lesions were fibromas. Biopsies from the hands and feet showed benign keratosis.

Ruschak et al. (1981) described a patient who at the age of 18 years, after experiencing several years of recurrent diarrhea, underwent colectomy and ileostomy for multiple colonic polyposis. Several lipomas on the trunk were also removed. The patient was unique in having deficiency of T-lymphocyte function with recurrent cellulitis and abscess formation and the eventual development of acute myelogenous leukemia.

Elston et al. (1986) described a 70-year-old woman in whom the diagnosis of Cowden syndrome had been made on the basis of facial trichilemmomas at age 63. Adenoid facies, high-arched palate, thickened, furrowed tongue, pectus excavatum, and scoliosis were described. Trichilemmomas were found in the sacral area. The need for close surveillance for malignancy was emphasized by the development of 3 different malignant neoplasms in this patient in a 16-year period.

Starink et al. (1986) analyzed 21 cases of Cowden syndrome in 7 families, with multiple cases in 4 of the families. They reconfirmed autosomal dominant inheritance with high penetrance in both sexes and high frequency of breast cancer in females. Craniomegaly was the most frequent extracutaneous finding. About 60% of patients had gastrointestinal polyps and 76% had cutaneous fibromas.

Breast cancer in CS is an indication for prophylactic mastectomy in the view of Walton et al. (1986).

Williard et al. (1992) described the case of a woman who presented at age 32 with breast cancer. Her mother had died of breast cancer at age 42, and 2 maternal aunts had had premenopausal breast cancer. She had multiple soft, fleshy, 3- to 5-mm papillomatous lesions consistent with acrochordons in the axillae, inframammary folds, groins, and posterior neck. She also had nodular and papillomatous lesions of the tongue and frenulum.

Schrager et al. (1998) analyzed the clinical and pathologic features of breast disease in 19 women with Cowden disease. The 19 women showed a spectrum of benign histopathologic findings, including ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic change. Features suggestive of a breast hamartoma were found in 17 (89%). Malignant disease, most of which was ductal carcinoma, was found in 14 women (74%): ductal carcinoma in situ in 12, and infiltrating ductal carcinoma in 12. A common benign breast lesion in CD is a densely fibrotic hyalinized nodule.

Hanssen et al. (1993) described Cowden syndrome in a large 4-generation family. Anticipation was demonstrated with greater severity and earlier onset of signs and symptoms in successive generations. Macrocephaly was present in all affected individuals, was markedly progressive in 3 of 6 affected children in the fourth generation, and was associated with slight to moderate delay in psychomotor development. There was 1 instance of male-to-male transmission. In a survey of 87 reported patients, Hanssen et al. (1993) found a marked excess of affected females; the male-to-female ratio was 26 to 61.

In 4 affected members in a 3-generation family with Cowden syndrome, Carlson et al. (1986) found that measurements of epidermal growth factor (EGF; 131530) in body fluids yielded normal findings.

Haibach et al. (1992) reported renal cell adenocarcinoma and primary neuroendocrine carcinoma of the skin in association with Cowden syndrome. They searched for abnormalities in the EGFR gene (131550) in kidney, liver and thyroid as well as in the tissue of the primary neuroendocrine carcinoma, but found none. Primary neuroendocrine carcinoma of the skin (PNECS) is also known as trabecular carcinoma or Merkel cell carcinoma. First described by Tang and Toker (1978), it originates from the Merkel cell, a pluripotential basal epidermal cell.

Lyons et al. (1993) observed meningioma in a 41-year-old woman known to have Cowden disease. In addition to many skin lesions, she had a history of follicular adenoma of the thyroid and breast carcinoma as well as a family history of carcinoma of the colon affecting 2 previous generations.

Hanssen and Fryns (1995) indicated that progressive macrocephaly, scrotal tongue, and mild to moderate mental retardation are important signs of Cowden syndrome in young children. Trichilemmomas in the nasolabial folds and palmar and plantar hyperkeratotic pits usually become evident later in childhood. They are often accompanied by the appearance of subcutaneous lipomas and cutaneous hemangiomas.

Omote et al. (1999) reported a patient with airway obstruction that occurred during induction of general anesthesia caused by the presence of extended multiple papillomas on the lingual tonsils, epiglottis, and the surrounding structure, in whom the diagnosis of Cowden disease was made postoperatively. The patient was a 55-year-old woman undergoing mastectomy for cancer of the right breast. At the age of 27 years, she had undergone partial thyroidectomy for benign adenomatous changes in the right lobe of the thyroid gland.

Fackenthal et al. (2001) reported 2 males with Cowden syndrome and germline mutations in the PTEN gene who developed breast cancer. One developed breast cancer at the age of 41 years and the second at the age of 43 years.

By a review of available imaging studies, Tan et al. (2007) identified vascular anomalies in 14 (54%) of 26 patients with BRRS or Cowden syndrome. The anomalies presented clinically as cutaneous discoloration, swelling, or pain. Eight (57%) of 14 patients had multiple lesions, and 11 (85%) of 13 with cross-sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12 (86%) of 14 were fast-flow vascular anomalies with focal segmental dilatation of draining veins. Excessive ectopic fat was present in 11 (92%) of 12 patients examined by MRI. Intracranial developmental venous anomalies were found in 8 (89%) of 9 patients who had brain MRI with contrast. Histology of some cases showed disordered growth of blood vessels, adipose, and fibrous tissue, with a low level of proliferation.

Lachlan et al. (2007) were unable to find a genotype/phenotype correlation among 42 patients from 26 families with PTEN mutations and clinical features of either Cowden syndrome or BRRS. The earliest features of the PTEN-related phenotype were macrocephaly and hamartomas, with mucocutaneous features and sometimes malignancies developing over time in the same patients.

Busch et al. (2013) studied 23 individuals with PTEN mutations and 2 with PTEN-negative Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, respectively. The mean IQ was in the average range and the range of intellectual functioning was very wide, from extremely low to very superior. However, in a large subset of patients, scores were lower than expected in motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. Busch et al. (2013) concluded that contrary to previous reports suggesting an association with intellectual disability, the mean intellectual intelligence quotient was average, with a broad range of function. They suggested that specific evidence of disrupted frontal circuits may have implications for treatment compliance and cancer surveillance.

Lhermitte-Duclos Disease

Padberg et al. (1991) suggested that the disorder previously referred to as cerebelloparenchymal disorder VI (Lhermitte-Duclos disease) is merely part of the multiple hamartoma syndrome. Mental dullness and in some cases signs of increased intracranial pressure are features; the latter is the result of herniation of the cerebellar tonsils. The condition was first described by Lhermitte and Duclos (1920). Ambler et al. (1969), who described the disorder in mother and son, stated that a total of 35 cases had been reported. Padberg et al. (1991) observed 2 unrelated patients who had macrocephaly, seizures and mild cerebellar signs resulting from dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Both had autosomal dominant Cowden disease evidenced by facial, oral, and acral papules. In the 2 families, 9 sibs demonstrated the mucocutaneous lesions, thyroid disease, breast tumors, and ovarian tumors compatible with the diagnosis of Cowden disease. Some of them also showed various degrees of neurologic signs such as macrocephaly, mental retardation, seizures, tremors, and dysdiadochokinesia. Padberg et al. (1991) suggested that the combination of Lhermitte-Duclos disease and Cowden disease represents a new phakomatosis.

Albrecht et al. (1992) described 2 patients who had both Cowden syndrome and Lhermitte-Duclos disease and concluded that these are the same entity, a hamartoma-neoplasia syndrome. The skin lesions were described as multiple trichilemmomas, a type of benign skin appendage tumor. Oral papillomatosis and cutaneous keratoses also occurred. Trichilemmomas covering the pinna and around the mouth were pictured as well as papillomatosis of the tongue and keratoses of the sole.

Eng et al. (1994) described a 3-generation family with Cowden disease and Lhermitte-Duclos disease. Lhermitte-Duclos disease is believed to be a hamartomatous overgrowth of hypertrophic ganglion cells which replace the granular cell layer and Purkinje cells of the cerebellum. In the grandfather of the proband in the family reported by Eng et al. (1994), the diagnosis of Lhermitte-Duclos disease had been made by cerebellar biopsy. Eng et al. (1994) found no chromosomal abnormality in the peripheral lymphocytes of the proposita and her affected mother and by single-strand conformation polymorphism analysis found no evidence of mutation in the p53 gene.

Wells et al. (1994) found reports of 7 cases of Lhermitte-Duclos syndrome occurring in adults with Cowden syndrome and reported this association in a 16-year-old girl with craniomegaly, choroidal hamartoma, right conjunctival papilloma, and a history of bilateral multinodular adenomatous goiter and cystic hygroma. Although Cowden syndrome has traditionally been defined by mucocutaneous criteria, it typically also involves hamartomas and neoplasms of internal organs, most commonly in the thyroid, breast, and female genitourinary tract. Because the mucocutaneous features may develop several decades after birth, the patient reported by Wells et al. (1994) highlighted the need for long-term follow-up of a pediatric patient with Lhermitte-Duclos syndrome because of the risk of malignancies associated with Cowden syndrome. The characteristic pathologic features of Lhermitte-Duclos syndrome are global hypertrophy of the cerebellum, coarse gyri, and the typical 'inverted cortex' pattern.

Vinchon et al. (1994) described an affected woman who was first seen at the age of 16 for ataxia and symptoms of raised intracranial pressure. A ventriculoatrial shunting relieved the symptoms. A nodule in her left breast was removed at the age of 18. At the age of 24, the symptoms of raised intracranial pressure recurred, CT scan disclosed a trigonoseptal tumor, and partial resection of the lesion showed it to be a benign astrocytoma. Hypothalamic hyperprolactinemia and goiter due to microinvasive vesicular carcinoma were other complications. Dermatologic examinations showed several trichilemmomas over the nose, subclavian area, and right elbow. Vinchon et al. (1994) found 72 reported cases of Lhermitte-Duclos disease; 26 had conditions suggesting Cowden disease and 7 were definite cases of Cowden disease.

Cowden Syndrome With Immunodeficiency

Browning et al. (2015) reported 2 unrelated boys with genetically confirmed Cowden syndrome associated with primary immunodeficiency resulting in recurrent infections. However, the immune defect differed between the 2 patients: 1 had hypogammaglobulinemia with a functional antibody deficiency, whereas the other had persistent CD4+ T-cell lymphopenia with normal antibody production. T cells from the patient with hypogammaglobulinemia showed a reduced level of PTEN protein expression and an increase in Akt (164730) and S6 (see 608938) phosphorylation following stimulation.

Driessen et al. (2016) studied peripheral B-cell development in 9 patients with heterozygous mutations in the PTEN gene. Only 3 of the patients had recurrent infections associated with hypogammaglobulinemia, fulfilling the diagnostic criteria for common variable immunodeficiency (CVID): a mother and daughter diagnosed with Cowden syndrome, and an unrelated boy with macrocephaly and hypogammaglobulinemia (case 2 in Cogulu et al., 2007). The remaining 6 patients did not have a clinically apparent antibody deficiency. Compared to controls, individuals with PTEN mutations had decreased absolute counts of class-switched memory B cells, with a more severe reduction observed in those with hypogammaglobulinemia. These findings suggested a T-cell-dependent B-cell defect. Those with PTEN mutations showed a decrease in class-switch recombination and in somatic hypermutation frequency. Driessen et al. (2016) hypothesized that increased PI3K (see 171834)/Akt signaling, resulting from PTEN defects, deregulates the humoral immune response, similar to the case in patients with IMD14 (615513), who have activating mutations in the PIK3CD gene (602839).

Biochemical Features

Hobert et al. (2012) evaluated plasma succinate levels in patients with mutations in PTEN, SDHB, and SDHD. Among 15 PTEN mutation-positive individuals who met Cowden syndrome criteria, 1 SDHB mutation-positive individual, and 5 SDHD mutation-positive individuals, elevated plasma succinate was observed in 13 of these 21 (62%) individuals as compared with 5 of 32 (16%) controls (p less than 0.001). Elevated plasma succinate in 10 of the 15 (67%) individuals with pathogenic germline PTEN mutations but in less than 20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%). Urine succinate was elevated in a smaller percentage of the patients. Hobert et al. (2012) concluded that their data suggested that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identified a common biochemical alteration in these 2 patient populations (PTEN and SDHx mutation-positive individuals) that provided a plausible link for the shared phenotypic findings across these groups.

Diagnosis

Pilarski and Eng (2004) reviewed the International Cowden Consortium operational criteria for the diagnosis of Cowden syndrome (2000 version) and the PTEN mutation spectrum in this and related disorders.

Pilarski et al. (2011) reported the clinical features of 172 patients, including 90 females and 82 males, with PTEN mutations. These patients were identified from a larger cohort of 802 patients referred for PTEN analysis. However, only 79 (34%) of 230 patients who met the diagnostic criteria for Cowden syndrome were found to carry a PTEN mutation. Of those meeting criteria for BRRS, 23 (55%) of 42 patients had a mutation, and 7 (78%) of 9 patients with an overlap syndrome carried a mutation. Logistic regression analysis suggested that in women, the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal lesions predicted a mutation. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign gastrointestinal lesions, and benign thyroid disease. However, the incidence of benign breast disease and uterine fibroids were not higher in women with mutations than in the general population, and the rate of benign skin lesions in both sexes was less than commonly reported in association with PTEN mutations.

Tan et al. (2011) developed a clinical scoring system for selection of patients for PTEN mutation testing based on a prospective study of 3,042 probands satisfying relaxed Cowden syndrome clinical criteria. For adults, a semiquantitative score resulted in a well-calibrated estimation of pretest probability of PTEN status. For pediatric individuals, macrocephaly (present in 100% of patients) was a necessary criterion for PTEN testing when present with one of the following: autism or developmental delay (present in 82%); dermatologic features, including lipomas, trichilemmomas, oral papillomas, and penile freckling (present in 60%); vascular features, such as arteriovenous malformations or hemangiomas (present in 29%); or gastrointestinal polyps (present in 14%). Tan et al. (2011) noted that in addition, pediatric-onset thyroid cancer and germ cell tumors (testicular cancer and dysgerminoma) are recognized associations of Cowden syndrome and should provoke consideration of PTEN testing.

Population Genetics

Nelen et al. (1999) estimated that the prevalence of Cowden disease is 1 in 200,000 to 250,000 in the Dutch population.

Mapping

To localize the gene for Cowden disease, Nelen et al. (1996) performed an autosomal genome scan using DNA markers. They examined a total of 12 families, and obtained a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on 10q22-q23. The authors stated that the neurologic and neoplastic features of Cowden disease are consistent with the possibility that the Cowden gene is a tumor suppressor gene. The high frequency of breast cancer in female Cowden patients (approximately 30%) made it a strong candidate for a breast cancer susceptibility gene. It should also be considered in connection with nonmedullary thyroid cancer.

Cytogenetics

Zigman et al. (1997) localized the gene for the Bannayan-Riley-Ruvalcaba syndrome to chromosome 10q23 by study of 2 patients with intestinal juvenile polyposis and karyotypic abnormalities involving 10q. Patient 1 was a boy who displayed cognitive and developmental delay, macrocephaly, subcutaneous hamartoma, and hypotonia, in addition to multiple intestinal juvenile polyps. He ultimately underwent a total abdominal colectomy for refractory anemia and failure to thrive. Patient 2 was a girl who had features consistent with Bannayan-Riley-Ruvalcaba syndrome, including hypotonia, cognitive and developmental delay, and multiple intestinal juvenile polyps. This patient also had additional features not typical of BRRS, including atrial and ventricular septal defects, dysplastic pulmonic valve, left superior vena cava draining into a dilated coronary sinus, and bilateral clubfoot. Patient 1 had an unbalanced translocation between chromosomes 10 and 9; patient 2 has an interstitial deletion of 10q23.1-q24.2. In each case, DNA markers allowed localization of the defect to 10q23. Three other unrelated patients with the diagnosis of BRRS but without karyotypic abnormalities were also studied; 2 of the 3 patients had pigmentary changes of the penis.

Arch et al. (1997) described an 18-month-old patient originally thought to have BRRS. She had an interstitial deletion of chromosome 10q23.2-q24.1, the region to which Cowden disease and the PTEN gene had been mapped. Because of the considerable phenotypic overlap between the BRRS and Cowden disease and because of a demonstration in their patient that the PTEN gene was deleted on chromosome 10, Arch et al. (1997) suggested that these are allelic disorders. The 18-month-old patient had macrocephaly, facial dysmorphism with prominent forehead and hypertelorism, a lipoma on the right abdomen and on the right thumb, 2 small hemangiomas on the back and shoulder, and 2 skin tags at the base of the spine and in the groin area. Psychomotor development was delayed. Ophthalmologic examination showed pseudopapilledema bilaterally. Neither parent had any features of either Cowden disease or BRR syndrome. Hematochezia prompted upper and lower gastrointestinal endoscopy, which showed multiple sessile polyps throughout the duodenum and large intestine. Histology showed that these were hamartomatous.

Tsuchiya et al. (1998) described a 6-year-old African American boy with mental retardation, dysmorphic features, and juvenile polyposis coli. A cytogenetically visible interstitial deletion of 10q23 was identified and characterized by fluorescence in situ hybridization. Five YACs that span an 11- to 15-cM region within the deletion were identified. The patient's deletion contained the putative locus for Cowden syndrome and the PTEN gene. The patient first had rectal bleeding at 2 years of age. Polyps were identified extending from the duodenum to the rectum. Dysmorphic features included macrocephaly with a head circumference of 53.6 cm, frontal bossing, hypertelorism, flat nasal bridge, hyperpigmentation at the corners of the mouth, thickened gingiva, bilateral preauricular pits, and a flat midface. He had a large penis with a hyperpigmented macule on the dorsal shaft. Multiple other hyperpigmented macules as well as a large area of hypopigmentation were identified. The distal phalanges of all fingers and toes were strikingly bulbous and nail clubbing was noted.

Ahmed et al. (1999) reported a boy with features consistent with BRR who had a novel de novo balanced translocation, 46,XY, t(10;13)(q23.2;q33), and a malignant intracranial hCG-secreting tumor, resulting in precocious puberty. The pathology of such tumors can vary, but none had yet been associated with the Cowden disease or BRRS phenotype or with PTEN mutations. Although previous reports provided evidence that germline intragenic mutations and gross deletion of PTEN can lead to BRRS, the authors postulated that a germline balanced translocation incorporating PTEN could also lead to the BRRS phenotype.

Molecular Genetics

The chromosomal region containing the Cowden syndrome locus was known to contain the tumor suppressor gene PTEN, which had been found to be mutated in sporadic brain, breast, and prostate cancer. Liaw et al. (1997) found germline mutations in the PTEN gene in 4 of 5 families with Cowden syndrome. Missense (601728.0001) and nonsense mutations were predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of the protein. All affected individuals of the 5 families studied manifested trichilemmomas, regardless of whether their mutation was a missense or nonsense mutation. Nonsense mutations were associated with macrocephaly in 2 families. In 1 of these families, a premature stop codon at position 157 (601728.0003) was also associated with Lhermitte-Duclos disease (LDD), manifested by ataxia and dysplastic cerebellar gangliocytomatosis. In the other family, a stop codon at position 233 (601728.0002) was not associated with cerebellar manifestation. Liaw et al. (1997) speculated that the larger N-terminal truncation may be responsible for the more severe LDD phenotype. Their data indicated that PTEN is a tumor suppressor gene in the germline and that it plays a role in organizing the relationship of different cell types within an organ during development. Because germline mutations of PTEN predispose to a breast and thyroid cancer syndrome (Cowden syndrome) and somatic mutations are found in sporadic breast cancer, PTEN was an obvious candidate for predisposition to non-CS breast cancer.

Nelen et al. (1997) confirmed that the PTEN gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN gene, and by mutation analysis in 8 unrelated familial and 11 sporadic patients with Cowden disease. They detected 8 different mutations in various regions of the PTEN gene (e.g., 601728.0005). One mutation was detected twice (601728.0007). All detected changes in the gene were predicted to have a deleterious effect on the putative protein. They found no indications of a correlation between genotype and phenotype. In 10 patients, no mutation could be detected. These were patients who showed linkage to the same region, 10q22-q23; no evidence emerged from the phenotype of these patients to suggest genetic heterogeneity. Nelen et al. (1999) identified PTEN mutations in an additional 13 patients with Cowden disease. The mutations were dispersed throughout the gene, with a clustering in exon 5.

Arch et al. (1997) described an 18-month-old boy with macrocephaly, pseudopapilledema, 2 small lipomas, hamartomatous neoplasms, and polyps of the duodenum and colon who had an interstitial deletion of 10q23.2-q24.1. The initial diagnosis had been Bannayan-Riley-Ruvalcaba syndrome. Cowden disease is relatively poorly described in young children. The overlap of clinical features of Cowden disease and BBRS, the demonstration of an interstitial deletion of the region of chromosome 10 containing the Cowden disease locus, and the specific demonstration that the PTEN gene was missing from the deleted chromosome 10 in their patient led Arch et al. (1997) to suggest that these 2 disorders are allelic.

Marsh et al. (1997) identified germline mutations in the PTEN gene in patients with Bannayan-Zonana syndrome. One of the mutations that Marsh et al. (1997) identified, R233X (601728.0002), had previously been reported in patients with Cowden disease. The identical mutation occurred in 2 unrelated families on 2 different 10q22-q23 haplotypes, arguing against a common ancestor or a founder effect.

Marsh et al. (1998) carried out mutation analysis in the PTEN gene in 64 unrelated Cowden syndrome-like families. These families were defined as having some features of Cowden syndrome but did not meet the diagnostic criteria of the International Cowden Consortium. Minimally, these Cowden syndrome-like families contained at least 1 member with both nonmedullary thyroid cancer and at least 1 other related member with breast cancer diagnosed at any age. They could also comprise subjects with both breast cancer and nonmedullary thyroid cancer. Alternatively, families could be made up of either breast or nonmedullary thyroid cancer and other features of Cowden syndrome, such as trichilemmomas, without meeting diagnostic criteria. Mutation analysis identified only 1 mutation, leu70 to pro (601728.0012), in a male with follicular thyroid carcinoma. Marsh et al. (1998) concluded that germline PTEN mutations play a relatively minor role in Cowden syndrome-like families.

Longy et al. (1998) identified 4 mutations in the PTEN gene in 6 patients from 4 unrelated families with Bannayan-Riley-Ruvalcaba syndrome. In 1 family, 1 individual had features more suggestive of Cowden disease, whereas the overall family phenotype was that of Bannayan-Riley-Ruvalcaba syndrome. Celebi et al. (1999) reported a further family with a single PTEN mutation (601728.0021) in which 2 female members had phenotypic findings of Cowden syndrome and 2 males had phenotypic findings of BZS.

Olschwang et al. (1998) identified mutations in the PTEN gene (601728.0009-601728.0011) in 3 unrelated patients reported to have juvenile polyposis coli (174900). One of them was a 14-year-old boy who underwent colonoscopy that revealed juvenile polyposis; the second patient was a 74-year-old man with anemia and hypoalbuminemia in whom gastroscopy and colonoscopy showed polyps throughout the digestive tract; and the third patient was found to have juvenile polyps throughout the stomach, duodenum, and colon when gastroscopy and colonoscopy were performed at the age of 7 years, after a 3-year history of intermittent rectal bleeding. However, Eng and Peacocke (1998) and Eng and Ji (1998) questioned the role of PTEN mutations in the juvenile polyposis syndrome, and suggested further that the 3 patients found by Olschwang et al. (1998) had either Cowden disease or Bannayan-Zonana syndrome; the 74-year-old man had manifestations they interpreted as suggestive of Cowden disease, and the 2 children may not have yet demonstrated features of Cowden disease, which has a penetrance well below 10% under 15 years of age (Nelen et al., 1996). Similarly, Lynch et al. (1997) referred to germline PTEN mutations in individuals with juvenile polyposis, but it was obvious to Waite and Eng (2002), from the text, that all of the individuals had Cowden syndrome. Kurose et al. (1999) reported 1 individual with juvenile polyposis syndrome who had a germline PTEN mutation. However, on reexamination, classic cutaneous features of Cowden syndrome were found. Waite and Eng (2002) concluded that discovery of a germline PTEN mutation in an individual considered to have JPS should raise a suspicion that the clinical diagnosis is incorrect.

Marsh et al. (1999) screened for PTEN mutations in constitutive DNA samples from 43 Bannayan-Riley-Ruvalcaba syndrome individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both Cowden disease and BRRS. Mutations were identified in 26 of 43 (60%) BRRS cases. Genotype-phenotype analyses within the BRRS group suggested a number of correlations, including the association of PTEN mutations and cancer or breast fibroadenoma in any given CS, BRRS, or BRRS/CS overlap family (p = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (p = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRRS patients (p = 0.028). In contrast to the report of Carethers et al. (1998), in which no PTEN mutations or deletions were found in sporadic cases of BRRS, Marsh et al. (1999) found that identification of germline PTEN mutations was equally likely in sporadic and familial BRRS (p = 0.113). Comparisons between BRRS and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRRS when compared with BRRS alone (p = 0.002). Among CS, BRRS, and BRRS/CS overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CS and BRRS may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Agrawal and Eng (2006) identified 8 novel naturally occurring PTEN splice variants that result in different downstream signaling effects. Sarquis et al. (2006) studied these and previously described naturally occurring splice variants in 85 (65 female and 20 male) patients with CS/BRRS (with or without PTEN mutations) compared with 27 controls. There appeared to be a splice variant genotype-phenotype correlation in which the splice variant expression profiles were distinct among CS, CS-like, and BRRS.

Pal et al. (2012) measured insulin sensitivity and beta-cell function as well as anthropometric indices in 15 patients diagnosed with Cowden disease who carried mutations in the PTEN gene as well as 15 age-, sex-, and body mass index (BMI)-matched controls. Measures of insulin resistance were lower in patients with PTEN mutations than in controls (p = 0.001), which was confirmed by hyperinsulinemic euglycemic clamping studies. Increased AKT phosphorylation was observed in patients versus controls, suggesting that the patients' increased insulin sensitivity might be explained by enhanced insulin signaling through the PI3K/AKT pathway (see 164730). In addition, PTEN mutation carriers were obese compared to population-based controls (p less than 0.001); the increased body mass was due to augmented adiposity without corresponding changes in fat distribution. Pal et al. (2012) concluded that PTEN haploinsufficiency appears to result in an increased risk of obesity and cancer but a decreased risk of type 2 diabetes (125853), owing to enhanced insulin sensitivity.

Mester and Eng (2012) studied 187 pathogenic PTEN-mutation positive families and confirmed 20 (10.7%) to be de novo mutations in the probands. De novo status was suspected based on family history in 36 (19.3%) probands. Inherited mutations showed no preference for maternal or paternal lineage. Mester and Eng (2012) concluded that the frequency of de novo PTEN mutation is at minimum 10.7% and at best 47.6%, and concluded that absence of PTEN hamartoma tumor syndrome features within a family history should not preclude consideration of this diagnosis for patients with relevant personal history.

Orloff et al. (2013) reported that, while PTEN mutations are found in 85% of Cowden syndrome patients accrued from tertiary epidemic centers, prospective accrual from the community over the aforegoing 12 years revealed a 25% PTEN mutation frequency.

'Proteus-like' Syndrome

Zhou et al. (2000) reported a boy with congenital hemihypertrophy, epidermoid nevi, macrocephaly, lipomas, arteriovenous malformations, and normal intellect. He was given the clinical diagnosis of 'Proteus