Skin abnormalities in individuals with macrocephaly: Cowden disease from a dermatologist's point of view

Cowden disease is a rare autosomal dominant disorder characterized by multiple hamartomas and (malignant) tumors affecting major organs including the breast, thyroid, endometrium, brain, skin and mucosa. Diagnostic criteria as formulated by the International Cowden Consortium serve as a guideline to clinically identify patients in which Cowden disease is suspected. However, the spectrum of abnormalities associated with PTEN mutations is very broad, such that the term PTEN hamartoma tumor syndrome (PTHS) is often used. The diagnostic criteria for Cowden disease do not always serve to reliably identify patients who fall within the PTHS spectrum. Therefore, it is important that clinicians are aware of features that should raise the suspicion of such a syndrome. To illustrate this point, we present three patients with clinical features of the PTEN hamartoma tumor syndrome spectrum. These patients have macrocephaly in common. Two of them meet the criteria for Cowden disease; one patient refused mutation analysis, while mutation analysis in the other patient revealed no PTEN mutation. The third patient does not meet the criteria for Cowden disease; however, genetic analysis showed a pathogenic mutation in the PTEN gene. Dermatologists regularly encounter the (muco-)cutaneous abnormalities that can be seen in PTEN hamartoma tumor syndrome. These findings combined with a (family) history of internal malignancy or a macrocephaly should raise the suspicion of PTHS, even in the absence of classical Cowden criteria.     

Identification of PTEN mutations in five families with Bannayan-Zonana syndrome

Germline mutations in PTEN, a putative tumor suppressor gene, has been identified in 2 autosomal dominant inherited hamartoma syndromes, Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS). While both diseases exhibit distinct phenotypic features, there seems to be a partial clinical overlap between the 2 diseases. To date, 9 families with BZS have been screened for PTEN mutations, of which 5 were found to exhibit mutations in this gene. We report 5 novel germline mutations in the PTEN coding sequence from 5 unrelated families with the BZS phenotype. While all the mutations we identified are novel in BZS, 1003C-->T (nonsense mutation) and 209+5G-->A (putative splice site mutation) have been previously reported in unrelated families with CS and Lhermitte Duclos disease. Interestingly, 1 of the families has an individual with BZS and 1 with CS phenotype, associated with a single PTEN mutation, 885insA. These data support the notion that CS and BZS may be within the spectrum of the same primary disorder.     

Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome

Linear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, first described in 2007, which is seen in patients with PTEN hamartoma tumor syndrome. It is considered to be a type 2 form of segmental mosaicism, and we suggest that it has certain clinical features that distinguish it from epidermal nevi seen in similar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus in a 4-year-old boy and review the literature.     

A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease

Cowden disease, also known as multiple hamartoma syndrome, is a rare disease inherited in an autosomal dominant pattern, which confers a high risk of developing breast and thyroid carcinomas. Mutations in PTEN, a tumor suppressor gene located on chromosome 10q23, have been identified in patients with Cowden disease. In this work, the direct sequencing of all coding regions of the PTEN gene led us to the identification of N48K, a new germline PTEN missense mutation, in a patient suffering from Cowden disease. The genetic analysis of 200 chromosomes from healthy individuals revealed that the variant was not common in our population. Moreover, by functional analysis we found that the ability of PTEN N48K mutant protein to inhibit the activation of the proto-oncogene PKB/Akt was impaired, supporting the involvement of N48K mutation in Cowden disease. Loss of heterozygosity using three microsatellites (D10S215, D10S541, and D10S564) and the complete sequence analysis of PTEN exons in breast and endometrial tumor samples from the same patient were also carried out in an attempt to identify additional PTEN somatic mutations. The lack of loss of heterozygosity or additional mutations in tumor samples suggests that abnormalities of the regulatory regions of the PTEN gene or haplo-insufficiency might occur in tumors from Cowden disease patients.     

Rapidly growing collagenomas in multiple endocrine neoplasia type I

Patients with multiple endocrine neoplasia type I (MEN-I) frequently develop skin lesions including collagenomas, angiofibromas, and lipomas. We report a patient with MEN-I who exhibited rapid growth of multiple collagenomas after pancreatic enucleation of a vasoactive intestinal peptide-secreting tumor (VIPoma) and excision of multiple pancreatic masses. Five of the collagenomas were protuberant, with the bulk of the lesion protruding above the skin. Histologic analysis of the collagenomas revealed broad collagen bundles in a haphazard arrangement and decreased elastic fibers. Rapid growth of protuberant collagenomas appears to be unusual in MEN-I, but we suggest that MEN-I be considered in patients with apparent eruptive collagenoma.     

PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome

Cowden syndrome is an autosomal dominant genodermatosis, characterized by the presence of multiple hamartomas in the skin, breast, thyroid, gastrointestinal tract, central nervous system, and an increased risk in developing breast and thyroid carcinomas. Over 80 germline mutations of the tumor suppressor gene PTEN, on chromosome 10q23, have been reported in more than 100 unrelated patients and families; however, questions regarding distribution of the mutations in populations from different geographic areas, and phenotypic expression are still unclear. In this study the results are reported of mutation analysis of PTEN in 13 families from Spain and one family of Brazilian origin with Cowden syndrome. PTEN germline mutations were detected in nine of them (64%). Five mutations were located in exon 5, one in exon 6, two in exon 7, and one in exon 8. Four of the mutations were novel. In another case, an identical change had been previously reported as a somatic mutation in an endometrial carcinoma. In one family, the patient presented a de novo mutation, which was not detected in his parents. In five patients, the detection of the PTEN germline mutation confirmed their condition, even in the absence of sufficient criteria to make the clinical diagnosis of Cowden syndrome.     

以泛发性雀斑样痣为皮肤表现的临床综合征

雀斑样痣临床表现为分布境界清楚的棕黑色斑点,可以仅有皮肤受累,也可表现为系统疾病的一部分.临床上以雀斑样痣为皮肤表现的综合征呈常染色体显性遗传,皮肤受累表现为特征性的多发性雀斑样痣,同时伴有不同的系统如心血管系统、内分泌系统、神经系统和骨骼的受累.主要探讨Carney综合征、Leopard综合征、Peutz?Jeghers综合征、Laugier?Hunziker综合征、PTEN相关的错构瘤综合征、雀斑样痣伴动脉夹层综合征和家族性泛发性雀斑样痣共7种以雀斑样痣为皮肤表现的综合征的临床表现和致病基因,并对其发病的分子学机制进行探讨,以加深对该疾病的认识.     

Congenital Myxoid and Pigmented Dermatofibrosarcoma Protuberans: A Case Report

Dermatofibrosarcoma protuberans (DFSP) is a low‐grade, mesenchymal, spindle cell tumor. In addition to the classical form characterized by a storiform pattern of tumor cells, pigmented (Bednar's tumor) and myxoid variants can be observed. Classical DFSP and Bednar's tumor are easily diagnosed. The myxoid variant represents a diagnostic challenge. Pigmented and myxoid variants are rare and thus far have never been reported in association in congenital DFSP. We came across a unique DFSP that was, at the same time, congenital, pigmented, and myxoid. The tumor was surgically excised with broad free margins and no recurrence. The differential diagnosis with other entities such as giant cell fibroblastoma, CD34‐positive plaque‐like dermal fibroma, superficial plaque‐like CD34 DFSP, and neurocristic hamartoma is discussed. The recognition of this hybrid variant of congenital DFSP is important to avoid under‐ or overtreatment.     

Linear Cowden nevus: a new distinct epidermal nevus

Within the group of epidermal nevi, a so far nameless disorder is described under the term "linear Cowden nevus". This non-organoid epidermal nevus is caused by loss of heterozygosity, occurring at an early developmental stage in an embryo with a germline PTEN mutation, giving rise to Cowden disease. Hence, linear Cowden nevus can be categorized as a characteristic feature of type 2 segmental Cowden disease. Until now, several authors had mistaken this epidermal nevus as a manifestation of Proteus syndrome. The concept of linear Cowden nevus implies that Proteus syndrome is by no means caused by PTEN mutations. As a clinical difference, linear Cowden nevus is markedly papillomatous and thick, whereas linear Proteus nevus tends to be rather flat. Moreover, the spectrum of possibly associated cutaneous or extracutaneous anomalies differs in the two types of nevi. In conclusion, linear Cowden nevus, that may also be called "linear PTEN nevus", represents a distinct clinicogenetic entity.     

Familial Blau syndrome without uveitis caused by a novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene with good response to infliximab

The proband in this study was a 4‐year‐old Mexican girl with Blau syndrome. She and her affected family members had skin rash and arthritis but no uveitis. Exome sequencing and DNA direct sequencing from blood samples revealed a novel nucleotide‐binding oligomerization domain‐containing protein 2 gene mutation in the affected family members. This study is the first report of a Mexican family with Blau syndrome showing good infliximab treatment response. The novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene (c.1808A>G) enriches the mutation spectrum in Blau syndrome. This family represents one of the few cases of autosomal Blau syndrome with no uveitis; because of phenotype variability, it is important to recognize Blau syndrome's clinical spectrum and recommend genetic consultation.     

Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome

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.     

Molecular evidence of type 2 mosaicism in Gorlin syndrome

We present a 12‐year‐old girl with a family history of Gorlin syndrome who had unilateral, segmentally arranged basaloid skin tumours present since birth, ipsilateral, palmoplantar pits of rather large size distributed along Blaschko lines, and an ipsilateral odontogenic keratocyst. The patient and her father were heterozygous for a germline mutation in the form of a single‐base substitution in exon 18 of the PTCH1 gene. In the patient's lesional skin, a microdeletion in exon 3 of PTCH1 was detected, giving rise to a truncated protein. This additional mutation was ruled out in the contralateral skin and in blood lymphocytes, thus confirming its mosaic state. In this way we provide for the first time molecular proof of a type 2 segmental involvement of this autosomal dominant trait.     

Familiäres Auftreten einer segmentalen Typ‐2‐Manifestation der kutanen Leiomyomatose

Background: There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild‐type allele. This phenomenon can be regarded as a precondition for tumor growth. In type‐2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area. Patients and Methods: A 74‐year‐old female patient and her 52‐year‐old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother. Results: Based on their typical clinical appearance, these cases represent the rare familial occurrence of type‐2 manifestation of leiomyomas which indicates a postzygotic loss of the wild‐type allele. Conclusion: Very unusual is the familial occurrence in mother and son of this type‐2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.     

Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome

Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two inherited hamartoma syndromes characterized by distinct phenotypic features. Mutations in the PTEN gene have been identified in patients with CS and BZS, suggesting the presence of a common genetic basis. We describe a single kindred with individuals manifesting both CS and BZS phenotypes (CS/BZS overlap family) in which we have identified a novel mutation in PTEN by DNA sequencing. We have confirmed these results by means of restriction enzyme analysis. The presence of individuals with CS and BZS within the same family, and moreover the identification of identical PTEN gene mutations in these individuals, suggest that these two syndromes represent different phenotypic expressions of one disease. Furthermore, these findings imply that, like patients with CS, individuals with BZS should be monitored for the onset of malignancy.     

Pacinian collagenoma: A distinct form of sclerotic fibroma

Sclerotic fibroma (storiform collagenoma) is a rare benign skin tumor. A solitary tumor, as well as multifocal lesions, are found either sporadically, or associated with Cowden syndrome. The tumor usually presents as clinically asymptomatic, slowly growing papule or nodule on the skin of the head, neck, and upper extremities. Microscopically the lesion is sharply demarcated, composed of hyalinized bands of collagen with low cellularity and a distinctive irregularly whorled or storiform pattern. We describe a case of a unique variant of this tumor in the scalp of a 33-year-old male. The tumor was microscopically composed of concentrically arranged collagen bundles with prevailing type III collagen, which resembled an enlarged Vater-Pacini corpuscle, with low density of CD34-positive and glucose transporter 1-negative spindle shaped cells. The specific microscopic appearance is suggestive of the term “Pacinian collagenoma” for this unique benign tumor.     

Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors

Background: Trichilemmoma (TL) can occur as a solitary sporadic lesion usually on the face or as multiple facial lesions almost invariably associated with Cowden syndrome (CS). CS is a multisystem disorder caused by a germline inactivating mutation in PTEN (10q23.31), a tumor suppressor gene. We sought to identify PTEN loss by immunohistochemistry (IHC) in sporadic and CS‐associated TL to determine whether IHC is a useful tool to assess an individual for CS. Methods: Six TL biopsies associated with CS and 33 biopsies without CS were retrieved. IHC for PTEN was performed. Results were scored as positive (reactivity in TL cells) or negative (no reactivity in TL cells); normal squamous epithelium and vascular endothelium served as internal positive controls. Results: Complete PTEN loss was noted in 5/6 (83%) CS‐associated TL and 1/33 (3%) sporadic (non‐CS) TL. Conclusion: Demonstration of complete PTEN loss in TL by IHC is strongly suggestive of association with CS, but retention of PTEN staining does not entirely exclude CS. Therefore, PTEN IHC in TLs may be helpful in screening TL for association with CS, but should be used in context with other established clinical criteria, and possibly germline PTEN genotyping to confirm a diagnosis of CS. Al‐Zaid T, Ditelberg JS, Prieto VG, Lev D, Luthra R, Davies MA, Diwan AH, Wang W‐L, Lazar AJ. Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors.     

Proliferative lesion of anogenital mammary‐like glands in the setting of Cowden syndrome: case report and review of the literature

Mammary‐like glands are normal appendages of anogenital skin and can give rise to epithelial and stromal tumors that closely resemble breast tumors. Cowden syndrome is an autosomal‐dominant cancer‐predisposition syndrome that is associated with increased risk of various benign and malignant tumors including breast cancers. Here, we report the first case of a proliferative lesion of mammary‐like glands in the setting of Cowden syndrome. A 27‐year‐old female with Cowden syndrome (R130Q‐PTEN mutation) presented with a 1‐cm tender, polypoid perianal lesion. An excisional biopsy revealed a circumscribed, lobulated lesion with fibromyxoid stroma and epithelial hyperplasia with apocrine and columnar cell changes that was arranged in papillary, micropapillary and focal cribriform architecture. The features strikingly resembled proliferative changes commonly seen in the breast. Interestingly, the patient subsequently developed an atypical complex sclerosing lesion of the breast. Given the increased risk of breast neoplasia in Cowden syndrome, and the morphologic relationship between breast glands and mammary‐like glands, this case raises the possibility of an increased risk of neoplasia arising in mammary‐like glands in the setting of Cowden syndrome.     

In situ assessment of PI3K and PTEN alterations in mycosis fungoides: correlation with clinicopathological features

Deregulated signalling through phosphatidylinositol 3‐kinase (PI3K) pathway plays a critical role in tumour initiation and progression. We have already shown that AKT is activated in skin lesions in Mycosis Fungoides (MF) and we herein further investigate the frequency and clinical significance of PTEN and PI3K at the protein and at the DNA level as well as the presence of AKT1 mutations in skin lesions from 50 patients with MF clinical stages I‐IV in relation to clinicopathological features. Increased p‐AKT expression correlated with poor prognosis in plaques (P = 0.0198), whereas p‐AKT was an independent predictor of poor survival in the entire cohort (P = 0.017, HR = 1.012). PTEN cytoplasmic expression was found low or absent in all 77.3% of cases and inversely correlated with advanced clinical stages (P = 0.0744). Molecular analysis showed no AKT1 mutation, no PI3KCA copy number gain, only 1 case with PI3KCA mutation in exon 9 and 3 cases with PTEN mutations (7%) in exons 7, 8 and 5. The latter correlated with disease (P = 0.0253) and progression (P < 0.0001) free survival in tumour stage. Although activation of PI3K/AKT signalling pathway due to PTEN alterations is rarely attributed to abnormalities in PTEN, PI3K, and AKT1 genes, PTEN mutations exert a negative effect on patients’ prognosis with tumours.