May 2006

Mucocutaneous NeuromasAn Underrecognized Manifestation of PTEN Hamartoma-Tumor Syndrome

Author Affiliations

Author Affiliations: Ronald O. Perelman Department of Dermatology (Drs Schaffer, Kamino, Witkiewicz, and Orlow) and Departments of Pathology (Drs Kamino and Witkiewicz) and Pediatrics (Drs Schaffer and Orlow), New York University School of Medicine, New York; and Departments of Dermatology and Pathology, Yale University School of Medicine, New Haven, Conn (Dr McNiff).


Copyright 2006 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2006

Arch Dermatol. 2006;142(5):625-632. doi:10.1001/archderm.142.5.625

Background  The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed.

Observations  We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS.

Conclusions  This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites.

The spectrum of clinical findings associated with germline mutations in the PTEN tumor suppressor gene, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and some cases of Proteuslike syndrome.14 Cowden syndrome and BRRS are clinically overlapping autosomal dominant genodermatoses characterized by different hamartomatous lesions involving tissues of ectodermal, mesodermal, and endodermal origin (ie, overgrowth of mature cells of types appropriate to the affected tissue).5 Cowden syndrome and BRRS share several mucocutaneous features, including the tricholemmomas, oral papillomas, and acral keratoses that were initially described in patients with CS; the lipomas and vascular malformations that typify BRRS; as well as findings such as acrochordons, acanthosis nigricans, and cafe au lait macules.1,6,7 Sclerotic fibromas represent another skin manifestation of CS,8 while pigmented macules of the genitalia have a particular association with BRRS.911 Hamartomatous gastrointestinal tract polyps are commonly found in both disorders. However, an increased incidence of benign and malignant neoplasms (particularly of the thyroid gland, breast, and uterus) is primarily seen in CS,4 and macrosomia at birth, hypotonia, and lipoid storage myopathy have thus far been limited to patients with BRRS.10

Although the skin is the ectodermal structure most consistently affected by PHTS, abnormalities of neural tissues are also frequently observed. Macrocephaly (more specifically termed megalencephaly, as the brain itself is enlarged) is seen in one third of individuals with CS and in virtually all of those with BRRS.1015 Clinical manifestations of central nervous system involvement in PHTS range from developmental delay to seizures.10,12,1518 Lhermitte-Duclos disease (LDD), a dysplastic gangliocytoma of the cerebellum thought to represent a hamartoma rather than a true neoplasm, is another occasional component of CS.1922 In addition, patients with PHTS have an increased risk of developing meningiomas,5,20,2224 and pseudopapilledema and amblyopia have been described in individuals with BRRS.10

Abnormalities of the peripheral nervous system have not yet been firmly established as components of PHTS. However, some authors have proposed that a closer examination of the peripheral nervous system in patients with PHTS is warranted.25 A review of the world literature (including a search of the MEDLINE database from January 1, 1966, to March 31, 2005, case series, reviews, textbooks, editorials, and the reference lists of all articles identified) revealed that cutaneous neuromas have previously been described in at least 11 patients with PHTS, 8 of whom had CS (Table 1).5,16,2633 These lesions had a predilection for the extremities and face, and mucosal neuromas were noted in 2 patients.28,32 Despite these observations, neuromas are not mentioned as a manifestation of CS in the diagnostic criteria for the disorder,2,34 in databases such as the Online Mendelian Inheritance in Man,35 or in several recent review articles.4,36,37

Table 1. 
Image not available
Mucocutaneous Neuromas in Patients With PTEN Hamartoma-Tumor Syndrome (PHTS)

In addition to mucocutaneous neuromas, there are a few reports of solitary neurofibromas,17,31,38,39 neurilemmomas,40 and ganglions10 in association with PHTS. Hypertrophy of cutaneous nerves is also a common incidental observation in skin biopsy specimens from patients with CS.13 Furthermore, the presence of gastrointestinal tract ganglioneuromas has been documented in more than 15 individuals with PHTS.5,23,32,4149 Last, corneal nerve hypertrophy (a finding stated by some to be pathognomonic for multiple endocrine neoplasia type 2B [MEN2B])50,51 has been noted in approximately one third of patients with BRRS.9,10,12

The patient described herein developed multiple mucocutaneous neuromas as a consequence of a novel heterozygous germline nonsense mutation in PTEN. This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain.


A 5-year-old boy was initially seen with a 6-month history of the progressive development of multiple painful papules on the vermilion portion of the upper lip, fingers, palms, and shins. The patient had been born at 36 weeks’ gestational age, the product of an uncomplicated twin pregnancy. His birth weight was 3300 g (95th percentile), and his occipitofrontal head circumference was 40 cm (>99th percentile). Magnetic resonance imaging studies performed during the neonatal period to evaluate the marked macrocephaly revealed no abnormalities other than a small arachnoid cyst of the left anterior middle cranial fossa, which was stable in repeated studies at ages 6 months and 2 years. The patient’s occipitofrontal head circumference remained above the 99th percentile for his age, while his height and weight were at the 50th percentile. His cognitive and motor development was normal, and he had no other significant medical problems. The patient’s parents and fraternal twin were normocephalic, with no history of mucocutaneous lesions, gastrointestinal tract polyps, thyroid disorders, pheochromocytoma, or other benign or malignant neoplasms. Family history was significant for renal cancer in the patient’s maternal grandfather at age 59 years and for pancreatic cancer in his maternal aunt at age 65 years.

On physical examination, the patient was macrocephalic (occipitofrontal head circumference, 60 cm [>99th percentile]) with dolichocephaly and mild frontal bossing. Approximately 15 dome-shaped, smooth, translucent pink to skin-colored papules measuring 2 to 6 mm in diameter were noted on the vermilion portion of the upper lip, fingers (sides and palmar surface), palms, and shins (Figure 1). The patient reported pain on palpation of the lesions. No verrucous papules, oral mucosal papillomas, thickening of the lips or tongue, acral or palmoplantar keratoses, pigmented macules of the penis or perioral area, cafe au lait macules, acanthosis nigricans, acrochordons, lipomas, vascular malformations, or other significant mucocutaneous lesions were present. Muscle strength and tone were normal, joints were not hyperextensible, and no additional skeletal anomalies (eg, a high-arched palate or marfanoid habitus) were evident. The thyroid gland was not palpable.

Figure 1.
Image not available

Dome-shaped, smooth, translucent skin-colored papules on the vermilion portion of the upper lip (A) and on the thumb (B).

A biopsy specimen from a papule on the thumb demonstrated a dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath (Figure 2). These findings were diagnostic of a nonencapsulated neuroma.

Figure 2.
Image not available

Photomicrographs of a biopsy specimen from a papule on the thumb. A, Several discrete tumor nodules in the upper dermis are demonstrated (hematoxylin-eosin, original magnification ×10). B, The compact fascicles are composed of cytologically bland Schwann cells (hematoxylin-eosin, original magnification ×20). C, The Schwann cells show immunoreactivity for S100 protein (original magnification ×40). D, Numerous axons are present within the Schwann cell fascicles (neurofilament stain, original magnification ×40). E, Epithelial membrane antigen stain highlights perineurial cells (arrow) surrounding individual nerve fascicles (original magnification ×20). F, Abundant mucin is evident within the tumor stroma (colloidal iron stain, original magnification ×20).

An ophthalmologic examination showed prominent corneal nerves bilaterally but normal Schwalbe lines. Results of laboratory studies, including a complete blood cell count, thyroid function tests, serum calcium and calcitonin levels, and urinalysis, were within normal limits.

Because cutaneous neuromas have been reported in patients with CS, prominent corneal nerves have been described as a feature of BRRS, and macrocephaly represents a frequent manifestation of both of these conditions, we considered the possibility that our patient had a form of PHTS affecting predominantly neural tissues. Genetic analysis by direct sequencing of the 9 exons of PTEN was performed and revealed a novel heterozygous germline nonsense mutation (Trp111X) in exon 5, expected to result in a truncated PTEN protein. No mutations were detected on sequencing of exons 15 and 16 of the RET gene, excluding the possibility of an atypical form of MEN2B.

The patient subsequently experienced several episodes of crampy abdominal pain during a 2-week period. An abdominal ultrasonogram revealed enlarged pericolonic lymph nodes, the results of an examination of the stool for occult blood was negative, and the pain resolved spontaneously. A baseline colonoscopy and thyroid ultrasonography were planned. PTEN gene analysis for the patient’s parents revealed no mutations.


Recognition of the mucocutaneous manifestations of PHTS is important to establish the diagnosis and to facilitate early detection of associated systemic disease in patients and their family members. Characteristic skin findings develop in 99% of individuals with CS and in most individuals with BRRS.13,52 In early series of patients with CS, neuromas were described in as many as 5% to 10% of affected individuals.5,13,16,23,2630 More than half of the PHTS-associated neuromas reported to date first appeared during childhood (Table 1). In contrast, the classic mucocutaneous manifestations of CS often do not develop until late adolescence or early adulthood.23 Therefore, as seen in our case, neuromas may represent the initial cutaneous sign of PHTS in a subset of patients.

The involvement of neural tissues in PHTS should not come as a surprise, as levels of PTEN expression throughout embryological development and during adult life are higher in the central and peripheral nervous systems than in any other organs.25 Furthermore, the initial identification of PTEN in 1997 was based on the high frequency of somatic deletions involving chromosome 10q23 in glioblastomas,53,54 and somatic PTEN mutations are frequently found in different tumors of glioneural lineage.5557 Recently, Pten conditional knockout mouse models provided additional insight into the role of this tumor suppressor gene in the central nervous system. Homozygous deletion of Pten in neural progenitor cells during murine embryogenesis led to enlarged, histoarchitecturally disordered brains with increased cell proliferation, decreased cell death, and increased cell size.58 Postnatal deletion of Pten in neuronal populations resulted in progressive macrocephaly, seizures, and ataxia associated with dramatic increases in neuronal soma size but normal proliferation; in particular, cerebellar abnormalities that closely resembled LDD histologically were identified.59,60 All of these observations highlight the importance of PTEN as a “master regulator” in developing and mature neural tissues.61

To our knowledge, this is the first reported case of multiple neuromas as the sole mucocutaneous manifestation of PHTS. The presence of macrocephaly and corneal nerve hypertrophy provided additional clues to the diagnosis. Thus far, our patient’s PHTS has been found to involve only neural tissues and does not meet diagnostic criteria for CS or BRRS.1,2,10,34

The histologic features of the nonencapsulated neuromas observed in our patient and in previously reported cases of PHTS are strikingly similar to those of the neuromas seen in MEN2B, with a compact arrangement of well-delineated hypertrophic nerve bundles surrounded by a distinct perineural sheath.26,62 These findings resemble those of the solitary circumscribed neuroma (also known as palisaded encapsulated neuroma), although palisaded encapsulated neuromas typically show intersecting fascicles of spindle cells forming larger nodules, with less obvious mucin than was evident in our case.62,63

The novel nonsense germline mutation detected in our patient (Trp111X) is located in exon 5 of PTEN, which encodes the phosphatase core motif (discussed in the penultimate paragraph of this section) and represents the site of 40% of all CS mutations reported to date.4 Although our patient’s mutation has not been previously described, a nearby Gln110X mutation has been observed in individuals with phenotypic features of LDD, CS, and BRRS.4,64 Perhaps the truncated proteins that result from such mutations lead to the preferential loss of a PTEN function that is especially critical in regulating the growth of neural cells. Staal et al65 recently described a man with a germline mutation (Arg234Gln) in the 3′-encoded C2 domain of PTEN who developed brain tumors of multiple lineages (meningioma and glioma) but no other stigmata of PHTS. However, previous studies1,4,7,31,46,66 failed to correlate particular germline PTEN mutations with specific phenotypic characteristics; clinical features often vary considerably within affected kindreds, and identical mutations have been described in individuals with CS and BRRS phenotypes. It is likely that modifying genes or cell type–specific RNA regulators have important effects on the types of tissues involved and the degree of severity of the manifestations (eg, hamartomas vs malignant neoplasms).67

Most cases of multiple mucocutaneous neuromas reported in the literature occurred in patients with MEN2B. Multiple mucosal neuromas represent a cardinal feature of MEN2B and have been previously considered a pathognomonic finding.51,68,69 Their appearance in early childhood provides an important clue to the diagnosis of this uncommon autosomal dominant cancer predisposition syndrome. Multiple endocrine neoplasia type 2B is caused by mutations in the RET proto-oncogene (particularly Met918Thr) that lead to activation and altered substrate specificity of the RET tyrosine kinase receptor.70,71 In addition to mucosal neuromas (typically involving the lips, tongue, and eyelids), MEN2B is characterized by aggressive medullary thyroid carcinomas, pheochromocytomas, gastrointestinal tract ganglioneuromatosis, corneal nerve hypertrophy, and a marfanoid body habitus.72 Patients with MEN2B occasionally develop cutaneous neuromas, most often located in periorificial areas of the face.73 However, cutaneous neuromas in acral sites or occurring in the absence of mucosal lesions have not yet been described in individuals with MEN2B.

Multiple mucosal neuromas have also been observed outside the setting of MEN2B (Table 2).50,69,7483 At least 6 patients had cutaneous and mucosal lesions,50,74,76,77,81,82 and 11 patients were noted to have prominent corneal nerves.50,74,7780,82 In 4 affected families, genetic analysis confirmed the absence of mutations in the RET proto-oncogene.69,7981 We postulate that some of these patients may have actually had PHTS.

Table 2. 
Image not available
Mucocutaneous Neuromas in Patients Without PTEN Hamartoma-Tumor Syndrome or Multiple Endocrine Neoplasia Type 2B (MEN2B)*

PTEN hamartoma-tumor syndrome and MEN2B share several clinical features, including mucocutaneous neuromas, hypertrophy of cutaneous nerves, prominent corneal nerves, gastrointestinal tract ganglioneuromatosis, thyroid C-cell hyperplasia, a high-arched palate, pectus excavatum, and joint hyperextensibility.10,14,15,32,44,72,84,85 On a molecular level, there is also considerable overlap in the signaling pathways regulated by PTEN and RET (Figure 3), especially those with important functions in controlling the growth and development of neural and neural crest–derived tissues. PTEN is a lipid phosphatase that serves as a central negative regulator of the phosphatidylinositol 3-kinase/Akt pathway, and proper PTEN signaling leads to G1 cell cycle arrest, apoptosis, or both.86,87 In contrast, RET represents a positive regulator of the phosphatidylinositol 3-kinase/Akt pathway. Recently, loss-of-function PTEN mutations in patients with LDD and the gain-of-function Met918Thr RET mutation responsible for MEN2B have been associated with a highly activated phosphatidylinositol 3-kinase/Akt pathway in neural tissues (including the “dysplastic gangliocytoma” cells of LDD), implicating enhanced phosphatidylinositol 3-kinase signaling in the pathogenesis of the overlapping clinical phenotypes of these disorders.64,88,89

Figure 3.
Image not available

Overlap in the signaling pathways regulated by PTEN and RET. The phosphatidylinositol 3-kinase (PI3K)/Akt cascade is negatively regulated by PTEN (a lipid phosphatase) and positively regulated by RET (a tyrosine kinase receptor that is normally activated by dimerization on the binding of soluble ligands [green pentagons] to cell surface–bound coreceptors of the glial cell line–derived neurotrophic factor receptor α family [light blue squares and rectangles]). Loss-of-function PTEN mutations and gain-of-function RET mutations are associated with a highly activated PI3K pathway. The Met918Thr RET mutation responsible for multiple endocrine neoplasia type 2B not only results in constitutive activation of RET but also causes a change in its substrate specificity; the change in substrate specificity leads to markedly increased phosphorylation of Tyr1062, which specifically activates the PI3K cascade. PDK1 indicates phosphoinositide-dependent kinase 1. The asterisk indicates altered substrate specificity (with hyperactivation on ligand binding and dimerization); P, phosphate group; +, activation of PI3K cascade; ++, excess activation; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent kinase 1; and S6K, ribosomal protein S6 kinase 1.

Because MEN2B is a potentially deadly disease with an effective intervention available (prophylactic thyroidectomy during early childhood), analysis of the RET gene is recommended in any patient with multiple mucosal neuromas.90 We propose that PHTS also be considered in the differential diagnosis for patients with multiple mucocutaneous neuromas. Since multiple neuromas are rare in the general population and involve primarily mucosa and periorificial skin in individuals with MEN2B, their occurrence in extrafacial sites is particularly suggestive of PHTS. The presence of multiple neuromas (especially involving acral sites) may prove to be more specific for PHTS than other cutaneous findings that serve as diagnostic criteria (eg, lipomas, fibromas, and acral keratoses).2,34,91 Because the exact risk of malignancy associated with forms of PHTS other than CS has not yet been determined, it is recommended that patients with PHTS be monitored following the CS guidelines.34

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Article Information

Correspondence: Julie V. Schaffer, MD, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 560 First Ave, Room H-100, New York, NY 10016 (schafj04@med.nyu.edu).

Financial Disclosure: None.

Accepted for Publication: June 3, 2005.

Author Contributions: Dr Schaffer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schaffer and Orlow. Acquisition of data: Schaffer, Kamino, Witkiewicz, and Orlow. Analysis and interpretation of data: Schaffer, Kamino, Witkiewicz, McNiff, and Orlow. Drafting of the manuscript: Schaffer, Kamino, and Orlow. Critical revision of the manuscript for important intellectual content: Schaffer, Kamino, Witkiewicz, McNiff, and Orlow. Administrative, technical, and material support: Schaffer, Witkiewicz, and Orlow. Study supervision: Schaffer, Kamino, McNiff, and Orlow.

Marsh  DJKum  JBLunetta  KL  et al.  PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999;81461- 1472
Eng  C Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37828- 838
Zhou  XPMarsh  DJHampel  HMulliken  JBGimm  OEng  C Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet 2000;9765- 768
Eng  C PTEN: one gene, many syndromes. Hum Mutat 2003;22183- 198
Weary  PEGorlin  RJGentry  WC  JrComer  JEGreer  KE Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1972;106682- 690
Fargnoli  MCOrlow  SJSemel-Concepcion  JBolognia  JL Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba syndrome. Arch Dermatol 1996;1321214- 1217
Marsh  DJCoulon  VLunetta  KL  et al.  Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998;7507- 515
Requena  LGutierrez  JSanchez Yus  E Multiple sclerotic fibromas of the skin: a cutaneous marker of Cowden’s disease. J Cutan Pathol 1992;19346- 351
Gretzula  JCHevia  OSchachner  LS  et al.  Ruvalcaba-Myhre-Smith syndrome. Pediatr Dermatol 1988;528- 32
Gorlin  RJCohen  MM  JrCondon  LMBurke  BA Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 1992;44307- 314
Hendriks  YMVerhaller  JTvan der Smagt  JJ  et al.  Bannayan-Riley-Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation–positive cases. Fam Cancer 2003;279- 85
DiLiberti  JHWeleber  RGBudden  S Ruvalcaba-Myhre-Smith syndrome: a case with probable autosomal-dominant inheritance and additional manifestations. Am J Med Genet 1983;15491- 495
Starink  TMvan der Veen  JPArwert  F  et al.  The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986;29222- 233
Hanssen  AMFryns  JP Cowden syndrome. J Med Genet 1995;32117- 119
Longy  MLacombe  D Cowden disease: report of a family and review. Ann Genet 1996;3935- 42
Nuss  DDAeling  JLClemons  DEWeber  WN Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1978;114743- 746
Salem  OSSteck  WD Cowden’s disease (multiple hamartoma and neoplasia syndrome): a case report and review of the English literature. J Am Acad Dermatol 1983;8686- 696
Miles  JHZonana  JMcfarlane  JAleck  KABawle  E Macrocephaly with hamartomas: Bannayan-Zonana syndrome. Am J Med Genet 1984;19225- 234
Padberg  GWSchot  JDVielvoye  GJBots  GTde Beer  FC Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. Ann Neurol 1991;29517- 523
Albrecht  SHaber  RMGoodman  JCDuvic  M Cowden syndrome and Lhermitte-Duclos disease. Cancer 1992;70869- 876
Koch  RScholz  MNelen  MRSchwechheimer  KEpplen  JTHarders  AG Lhermitte-Duclos disease as a component of Cowden’s syndrome: case report and review of the literature. J Neurosurg 1999;90776- 779
Derrey  SProust  FDebono  B  et al.  Association between Cowden syndrome and Lhermitte-Duclos disease: report of two cases and review of the literature. Surg Neurol 2004;61447- 454
Starink  TM Cowden’s disease: analysis of fourteen new cases. J Am Acad Dermatol 1984;111127- 1141
Lyons  CJWilson  CBHorton  JC Association between meningioma and Cowden’s disease. Neurology 1993;431436- 1437
Gimm  OAttie-Bitach  TLees  JAVekemans  MEng  C Expression of the PTEN tumour suppressor protein during human development. Hum Mol Genet 2000;91633- 1639
Gentry  WC  JrEskritt  NRGorlin  RJ Multiple hamartoma syndrome (Cowden disease). Arch Dermatol 1974;109521- 525
Weinstock  JVKawanishi  H Gastrointestinal polyposis with orocutaneous hamartomas (Cowden’s disease). Gastroenterology 1978;74890- 895
Laugier  PKuffer  ROlmos  LHunziker  NRougier  MFiore-Donno  G Cowden disease: report of 8 cases in 2 families [in French]. Ann Dermatol Venereol 1979;106453- 463
Hoshino  A Megalencephaly: a report of 4 children including a previously undescribed congenital syndrome and review of the literature [in Japanese]. No To Shinkei 1981;33377- 384
Barax  CNLebwohl  MPhelps  RG Multiple hamartoma syndrome. J Am Acad Dermatol 1987;17342- 346
Bussaglia  EPujol  RMGil  MJ  et al.  PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome. J Invest Dermatol 2002;118639- 644
Zambrano  EHolm  IGlickman  J  et al.  Abnormal distribution and hyperplasia of thyroid C-cells in PTEN-associated tumor syndromes. Endocr Pathol 2004;1555- 64
Mascaro  JMKuffer  R Mucous myelinic neuromas [in French]. Bull Soc Fr Dermatol Syphiligr 1966;73231- 234
Pilarski  REng  C Will the real Cowden syndrome please stand up (again)? expanding the mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2004;41323- 326
Online Mendelian Inheritance in Man, Web site. MIM 158350. Last edited June11 2004;Available at:http://www.ncbi.nlm.nih.gov/omim/Accessed March 31, 2005
Perriard  JSaurat  JHHarms  M An overlap of Cowden’s disease and Bannayan-Riley-Ruvalcaba syndrome in the same family. J Am Acad Dermatol 2000;42348- 350
Tsao  H Update on familial cancer syndromes and the skin. J Am Acad Dermatol 2000;42939- 969
Civatte  JLaufer  JDelort  JMorel  P Cowden’s disease: recent French case [in French]. Ann Dermatol Venereol 1977;104645- 647
Elton  RStroud  JWagenberg  HGreki  JSchwartz  O Cowden’s syndrome [letter]. Int J Dermatol 1981;20617- 618
Starink  TMMeijer  CJBrownstein  MH The cutaneous pathology of Cowden’s disease: new findings. J Cutan Pathol 1985;1283- 93
Lashner  BARiddell  HWinans  CS Ganglioneuromatosis of the colon and extensive glycogenic acanthosis in Cowden’s disease. Dig Dis Sci 1986;31213- 216
Hizawa  KIida  MMatsumoto  T  et al.  Gastrointestinal manifestations of Cowden’s disease: report of four cases. J Clin Gastroenterol 1994;1813- 18
Lacambra  CGallego  M Intestinal ganglioneuromatosis as presenting form of Cowden's syndrome in 2 brothers [in Spanish]. Rev Clin Esp 1998;198404- 405
Longy  MCoulon  VDuboue  B  et al.  Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype. J Med Genet 1998;35886- 889
Kubo  YUrano  YHida  Y  et al.  A novel PTEN mutation in a Japanese patient with Cowden disease. Br J Dermatol 2000;1421100- 1105
Wanner  MCelebi  JTPeacocke  M Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome. J Am Acad Dermatol 2001;44183- 187
Chambonnière  MLPorcheron  JScoazec  JYAudigier  JCMosnier  JF Intestinal ganglioneuromatosis diagnosed in adult patients [in French]. Gastroenterol Clin Biol 2003;27219- 224
Harada  NSugimura  TYoshimura  R  et al.  Novel germline mutation of the PTEN gene in a Japanese family with Cowden disease. J Gastroenterol 2003;3887- 91
McGarrity  TJWagner Baker  MJRuggiero  F  et al.  GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol 2003;981429- 1434
Guillet  GGauthier  YTamisier  JM  et al.  Linear cutaneous neuromas (dermatoneurie en stries): a limited phakomatosis with striated pigmentation corresponding to cutaneous hyperneury (featuring multiple endocrine neoplasia syndrome?). J Cutan Pathol 1987;1443- 48
Delius  REThompson  NW Early total thyroidectomy in patients with multiple endocrine neoplasia IIb syndrome. Surg Gynecol Obstet 1989;169442- 444
Hildenbrand  CBurgdorf  WHLautenschlager  S Cowden syndrome: diagnostic skin signs. Dermatology 2001;202362- 366
Li  JYen  CLiaw  D  et al.  PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;2751943- 1947Article
Steck  PAPershouse  MAJasser  SA  et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15356- 362
Wang  SIPuc  JLi  J  et al.  Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 1997;574183- 4186
Smith  JSTachibana  IPasse  SM  et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 2001;931246- 1256
Knobbe  CBMerlo  AReifenberger  G Pten signaling in gliomas. Neuro-oncol 2002;4196- 211
Groszer  MErickson  RScripture-Adams  DD  et al.  Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 2001;2942186- 2189
Backman  SStambolic  VSuzuki  A Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 2001;29396- 403
Kwon  C-HZhu  XZhang  J  et al.  Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 2001;29404- 411
Li  LLiu  FRoss  AH PTEN regulation of neural development and CNS stem cells. J Cell Biochem 2003;8824- 28
Reed  RJFine  RMMeltzer  HD Palisaded, encapsulated neuromas of the skin. Arch Dermatol 1972;106865- 870
Argenyi  ZBCruz  DS Comparative light-microscopic and immunohistochemical study of traumatic and palisaded encapsulated neuromas of the skin. Am J Dermatopathol 1992;14504- 510
Zhou  XPMarsh  DJMorrison  CD  et al.  Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet 2003;731191- 1198
Staal  FJvan der Luijt  RBBaert  MR  et al.  A novel germline mutation of PTEN associated with brain tumours of multiple lineages. Br J Cancer 2002;861586- 1591
Celebi  JTTsou  HCChen  FF  et al.  Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN. J Med Genet 1999;36360- 364
Bignold  LP The cell-type-specificity of inherited predispositions to tumours: review and hypothesis. Cancer Lett 2004;216127- 146
Jones  BASisson  JC Early diagnosis and thyroidectomy in multiple endocrine neoplasia, type 2b. J Pediatr 1983;102219- 223
Pujol  RMMatias-Guiu  XMiralles  JColomer  Ade Moragas  JM Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity? J Am Acad Dermatol 1997;37349- 352
Ichihara  MMurakumo  YTakahashi  M RET and neuroendocrine tumors. Cancer Lett 2004;204197- 211
Santoro  MCarlomagno  FRomano  A  et al.  Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2BScience 1995;267381- 383
Holloway  KBFlowers  FP Multiple endocrine neoplasia 2B (MEN 2B)/MEN 3. Dermatol Clin 1995;1399- 103
Bazex  ABoulard  CDesol  G  et al.  Hereditary Sipple syndrome [in French]. Ann Dermatol Venereol 1977;104103- 114
Thies  W Multiple true fibrillary neuroma (plexiform neuroma) of the skin and mucous membrane [in German]. Arch Klin Exp Dermatol 1964;218561- 573
Holm  TWPrawer  SESahl  WJBart  BJ Multiple cutaneous neuromas. Arch Dermatol 1973;107608- 610
Schnitzler  LSimard  CBaudoux  CLefranc  M Cutaneous and mucosal neuromas, with a histopathologic and ultrastructural study [in French]. Ann Dermatol Syphiligr (Paris) 1973;100241- 260
Altmeyer  PMerkel  KH Multiple systemic neuromas of the skin and mucous membranes [in German]. Hautarzt 1981;32240- 244
Valentines  JMarigo  MQuintana  MGomez  JM Familial mucosal neuromatosis: a minor form of the MEN-2b syndrome [in French]. J Fr Ophtalmol 1984;7479- 484
Dennehy  PJFeldman  GLKambouris  MO’Malley  ERSanders  CYJackson  CE Relationship of familial prominent corneal nerves and lesions of the tongue resembling neuromas to multiple endocrine neoplasia type 2B. Am J Ophthalmol 1995;120456- 461
Gomez  JMBiarnes  JVolpini  VMarti  T Neuromas and prominent corneal nerves without MEN 2B. Ann Endocrinol (Paris) 1998;59492- 494
Truchot  FGrezard  PWolf  F  et al.  Multiple idiopathic mucocutaneous neuromas: a new entity? Br J Dermatol 2001;145826- 829
Jashnani  KDBahal  NKDhume  VMAbhyankar  SV Mucosal neuromas and prominent corneal nerves without MEN IIB. Indian J Pathol Microbiol 2003;46668- 670
Shimazaki  TYoshida  YIzumaru  SNakashima  T Laryngeal solitary multiple mucosal neuromas without multiple endocrine neoplasia (MEN) type 2B. Auris Nasus Larynx 2003;30191- 195
Carney  JAHayles  ABPearse  AGPerry  HOSizemore  GW Abnormal cutaneous innervation in multiple endocrine neoplasia, type 2b. Ann Intern Med 1981;94362- 363
Winkelmann  RKCarney  JA Cutaneous neuropathology in multiple endocrine neoplasia, type 2b. J Invest Dermatol 1982;79307- 312
Sulis  MLParsons  R PTEN: from pathology to biology. Trends Cell Biol 2003;13478- 483
Sansal  ISellers  WR The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004;222954- 2963
Murakami  HIwashita  TAsai  N  et al.  Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signaling molecules mediated by Ret with the MEN 2B mutation. Biochem Biophys Res Commun 1999;26268- 75Article
Salvatore  DMelillo  RMMonaco  C  et al.  Increased in vivo phosphorylation of Ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Cancer Res 2001;611426- 1431
Brandi  MLGagel  RFAngeli  A  et al.  Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;865658- 5671
High  WAStewart  DEssary  LRKageyama  NPHoang  MPCockerell  CJ Sclerotic fibroma-like change in various neoplastic and inflammatory skin lesions: is sclerotic fibroma a distinct entity? J Cutan Pathol 2004;31373- 378