PROTEUS-LIKE SYNDROME, INCLUDED
MULTIPLE HAMARTOMA SYNDROME
LHERMITTE-DUCLOS DISEASE, INCLUDED
LDD, INCLUDED
CEREBELLAR GRANULE CELL HYPERTROPHY AND MEGALENCEPHALY, INCLUDED
CEREBELLOPARENCHYMAL DISORDER VI, INCLUDED
MHAM DYSPLASTIC GANGLIOCYTOMA OF THE CEREBELLUM, INCLUDED
CPD6, INCLUDED
CWS1
CD
CS
Cohen-Hayden syndrome
Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome (BRRS; 153480) share clinical characteristics such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms. Furthermore, both conditions and several other distinctive phenotypes are caused by mutations ... Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome (BRRS; 153480) share clinical characteristics such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms. Furthermore, both conditions and several other distinctive phenotypes are caused by mutations in the PTEN gene. For this reason Marsh et al. (1999) suggested that the spectrum of disorders be referred to as PTEN hamartoma tumor syndrome (PHTS). Approximately 80% of CS patients have PTEN mutations (Blumenthal and Dennis, 2008). Blumenthal and Dennis (2008) provided a detailed review of PTEN hamartoma tumor syndromes. - Genetic Heterogeneity of Cowden Syndrome Mutations in the SDHB gene (185470) on chromosome 1p36.1-p35 cause Cowden syndrome-2 (CWD2; 612359). Mutations in the SDHD gene (602690) on chromosome 11q23 cause Cowden syndrome-3 (CWD3; 615106). Hypermethylation of the promoter of the KLLN gene (612105), which shares the same transcription site as the PTEN gene on 10q23, results in Cowden syndrome-4 (CWD4; 615107). Mutations in PIK3CA (171834) on 3q26.3 cause Cowden syndrome-5 (CWD5; 615108). Mutations in AKT1 (164730) on 14q32.3 cause Cowden syndrome-6 (CWD6; 615109).
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 ... 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.
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 ... 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. 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. Breast cancer is an indication for prophylactic mastectomy in the view of Walton et al. (1986). 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. 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. Carlson et al. (1986) could demonstrate no linkage with any of a battery of markers in a family with 4 affected in 3 generations. Furthermore, measurements of epidermal growth factor (131530) in body fluids yielded normal findings. 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. 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. 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. 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.
The chromosomal region containing the Cowden disease gene was known to contain a tumor suppressor gene (PTEN; 601728) that had been found to be mutated in sporadic brain, breast, and prostate cancer. Liaw et al. (1997) found germline ... The chromosomal region containing the Cowden disease gene was known to contain a tumor suppressor gene (PTEN; 601728) that 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 disease) and somatic mutations are found in sporadic breast cancer, PTEN was an obvious candidate for predisposition to non-CD 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 CD. 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. (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. 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 CD, BRRS, or BRRS/CD 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 CD families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CD alone or both CD and BRRS when compared with BRRS alone (P = 0.002). Among CD, BRRS, and BRRS/CD overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CD 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 expressional genotype-phenotype correlation in which the splice variant expressional 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-like' syndrome because of phenotypic similarities to Proteus syndrome (176920). Sequence analysis of DNA from peripheral blood revealed heterozygosity for a single base transversion resulting in an arg335-to-ter substitution in the PTEN gene product (601728.0021), whereas analysis of DNA from a nevus, lipoma, and arteriovenous mass also revealed heterozygosity for a somatic R130X (601728.0007) mutation. The former mutation had been reported in patients with Cowden syndrome, whereas the latter mutation had been reported in patients with Bannayan-Zonana syndrome. Zhou et al. (2000) postulated that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in 'Proteus-like' syndrome with its implications for cancer development in the future. Smith et al. (2002) described a 16-month-old male with a de novo 1-bp deletion in the cDNA of the PTEN gene, 507delC (601728.0032), and classic features of Proteus syndrome, including a left-sided epidermal nevus following the lines of Blaschko, widespread capillary venous malformation on his chest and abdomen, multiple lipoblastomata, disproportionate overgrowth of the right leg, and a progressive course. Cohen et al. (2003) disputed the diagnosis of Proteus syndrome in the cases reported by Zhou et al. (2000) and Smith et al. (2002). Cohen et al. (2003) noted that the patient reported by Zhou et al. (2000) had a 'Proteus-like' syndrome, an unhelpful and confounding term, and did not meet the classic diagnostic criteria, whereas 5 additional patients with classic Proteus syndrome had no PTEN mutations. An additional study by Zhou et al. (2001) failed to provide sufficient clinical data for a diagnosis of Proteus syndrome. Cohen et al. (2003) also stated that the patient reported by Smith et al. (2002) did not have classic clinical features of Proteus syndrome but rather had features more consistent with PTEN hamartoma-tumor syndrome. Based on a review of the literature and personal referrals, Cohen et al. (2003) concluded that many physicians misdiagnose Proteus syndrome and that no patient with a PTEN mutation has Proteus syndrome. Loffeld et al. (2006) reported a 3-year-old boy with a germline PTEN missense mutation inherited from his mother who had Cowden syndrome. The boy showed extensive epidermal nevus, macrocephaly, vascular malformations, asymmetric hypertrophy of 1 leg, localized macrodactyly, and abdominal lipoma. They identified loss of heterozygosity for the missense mutation in an epidermal nevus from the boy, suggesting wildtype PTEN allele loss. Caux et al. (2007) reported 2 unrelated families in which multiple members had typical Cowden syndrome confirmed by genetic analysis. The female proband of 1 family had an atypical phenotype of segmental overgrowth, lipomas, vascular malformations, and epidermal nevi, and molecular analysis revealed loss of the wildtype allele in several atypical lesions, including a cutaneous fibroma, an epidermal nevus, and a lipoma. The female proband of the other family also had an atypical presentation but lacked epidermal nevus, and molecular analysis of a single biopsy of her affected skin did not show loss of the wildtype PTEN allele. The findings suggested that heterozygous germline PTEN mutations associated with a mosaic inactivation of the wildtype allele may underlie multiple atypical dysmorphisms suggestive of other diseases, including Proteus syndrome (176920). These atypical lesions could be explained by biallelic inactivation and complete loss of PTEN function, resulting in segmental exacerbations of the disease. To clinically distinguish between Proteus syndrome and segmental exacerbation of Cowden disease, Caux et al. (2007) suggested 'SOLAMEN syndrome' as an acronym for segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus.