KRAS, HRAS and EGFR Mutations in Sporadic Sebaceous Gland Hyperplasia.

Sporadic sebaceous gland hyperplasia (SGH) is a benign skin lesion, with a high prevalence in the general population. Although SGH has been attributed to both extrinsic and intrinsic factors, the underlying genetic changes have not yet been characterized. Recently, HRAS and KRAS mutations have been identified in sebaceous naevus, a hamartoma sharing histological characteristics with SGH. Therefore we screened 43 SGH for activating mutations in RAS genes and other oncogenes. We identified a wide spectrum of mutually exclusive activating HRAS (8/43), KRAS (11/43) and EGFR mutations (7/31) in altogether 60% of the lesions investigated. A RAS and EGFR wildtype status was found in 15 normal sebaceous glands in the head and neck area. Our findings indicate that activating HRAS, KRAS and EGFR mutations play a major role in the pathogenesis of sporadic SGH. These results support the concept that SGH is a true benign neoplasm rather than a reactive hyperplasia.

Naevus sebaceus: a mosaic RASopathy.

Epidermal naevi are common cutaneous mosaic disorders that occur in 0.1-0.3% of live births. They are subdivided into keratinocytic and organoid naevi, the latter including naevus sebaceus (NS). Typically, NS develops as a yellowish-orange plaque on the scalp, and represents a hamartoma containing epidermal, sebaceous and apocrine elements. The histological features of NS sampled in childhood include hyperkeratosis, acanthosis, increased sebaceous lobules, and primitive hair follicles. During puberty, most lesions develop more prominent sebaceous and apocrine components. Subsequently, secondary tumours may occur in around 25% of NS; most lesions are benign (e.g. trichoblastomas, syringocystadenoma papilliferum or other basaloid proliferations), although malignant tumours arising within NS can occur (< 1%). Recently, somatic mosaicism has been shown, with activating Ras mutations in HRAS or KRAS in NS lesional keratinocytes (but not in adjacent nonlesional skin or dermal fibroblasts). These mutations lead to constitutive activation of the RAF-MEK-ERK and phosphoinositide 3-kinase signalling pathways, and result in increased cellular proliferation. Similar but more extensive mosaicism underlies Schimmelpenning-Feuerstein-Mims syndrome. The most common mutation is c.37G>C (p.Gly13Arg) in HRAS, which is present in > 90% of NS. This mutation also seems to be present in NS cases that develop secondary tumours, although no additional mutations (second hit) or other genetic events have yet been identified. Treatment of NS often involves prophylactic surgical excision, but the recent identification of key epidermal signalling abnormalities underlying the cell proliferation means that future development of new medical treatments for NS that target the aberrant signalling pathways may also be feasible.

Genetic characterization of healthy and sebaceous adenitis affected Standard Poodles from the United States and the United Kingdom.

The degree of heterogeneity associated with geographic origin and sebaceous adenitis (SA) status in Standard Poodles from the United States (US) and the United Kingdom (UK) was assessed. Healthy and SA-affected Standard Poodles from the US and the UK shared a major mitochondrial DNA (mtDNA) haplotype and a single Y chromosome haplotype. However, minor mtDNA haplotypes and frequencies were somewhat different between US and UK dogs and were significantly less associated with SA than major haplotypes across both populations. The US and UK populations exhibited recent divergence from a common gene pool, based on allele frequencies of 24 highly polymorphic short tandem repeats and principle coordinates and cluster analyses of genotype frequencies. However, there was no differentiation between SA affected and unaffected dogs. Over 90% of US and UK Poodles shared a common dog leukocyte antigen (DLA) class II haplotype, but showed some differentiation in minor haplotype frequency. No difference was observed in haplotype heterozygosity between SA affected and unaffected dogs from the same country and no disease association for SA was found within the DLA region by a high density single nucleotide polymorphism (SNP) scan. Zygosity mapping in the DLA region of Poodles indicated much lower site-specific diversity than in an outbred population of street dogs from Bali, Indonesia, reflecting the degree that breed associated historical bottlenecks have reduced diversity in a polymorphic region of the genome. This study shows possible pitfalls in more extensive genome-wide association studies, such as case and control numbers, population stratification, the involvement of multiple genes, and/or the possibility that SA susceptibility is fixed or nearly fixed within the breed, which can reduce power to detect genetic associations.

Sebaceous lesions and their associated syndromes: part II.

Sebaceous lesions are associated with two syndromes with widespread multisystem disorders and tumors. Linear sebaceous nevus syndrome has been traditionally known as the triad of sebaceous nevus of Jadassohn, seizures, and mental retardation. This syndrome encompasses a much broader spectrum of multisystem disorders, which is explored below. Muir-Torre syndrome is described as the presence of sebaceous tumors or keratoacanthomas with an underlying visceral malignancy. It is caused by mutations in DNA mismatch repair genes. We discuss its relationship with Lynch syndrome and suggest a comprehensive algorithm on how to screen patients with sebaceous neoplasms for Muire-Torre syndrome. We also provide suggested intensive cancer screening guidelines based on recommendations for patients with Lynch syndrome that may also be of value for patients with Muir-Torre syndrome.

Pruritic bluish-black subcutaneous papules on the chest.

Steatocystoma multiplex (SM) is characterized by multiple dermal cysts involving the pilosebaceous glands. Although most presenting cases are sporadic, there is a rare familial syndrome involving a mutation in keratin 17 (K17) that is inherited in an autosomal dominant fashion. SM often presents concomitantly with eruptive vellus hair cysts (EHVS) and pachyonychia congenital type 2 (PC-2). We report a sporadic case of SM in a 21-year-old man.

BRAF mutations in multiple sebaceous hyperplasias of patients belonging to MYH-associated polyposis pedigrees.

The characteristics of sebaceous gland hyperplasia (SGH) consist of yellowish or skin-colored papules and nodules. Chronic sun exposure and immunosuppressed conditions are the main environmental risk factors, whereas chronological aging regulated by hormones and molecular changes are the intrinsic risk factors. We have evaluated the contribution of BRAF, K-Ras, and N-Ras mutations to the pathogenesis of SGHs in four patients belonging to three MYH-associated polyposis (MAP) pedigrees. MAP is an autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. Immunohistochemistry of mismatch repair and APC proteins was performed. DNA isolated from blood lymphocytes and formalin-fixed or paraffin-embedded SGHs was PCR amplified and sequenced. In the SGH patients, we detected T1796A heterozygous substitution (V600E) in the BRAF gene. Compound biallelic germline MYH mutations (Y165C/G382D, R168H/379delC, and Y90X/delGGA464) were detected in the MAP patients. In contrast to the majority of melanocytic lesions, activating hotspot mutations in BRAF have not been involved so far in the pathogenesis of SGH. BRAF mutation is not a specific marker of melanocytic cancerogenesis, and it can also be involved in SGHs. In both melanocytic and non-melanocytic skin tumors, BRAF mutation is linked to early tumorigenesis events.

Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity.

Pachyonychia congenita type 2 (PC-2) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, focal keratoderma, multiple pilosebaceous cysts, and other features of ectodermal dysplasia. It has been demonstrated that PC-2 is caused by mutations in the keratin 17 and keratin 6b genes. In this report, we describe a missense mutation in the keratin 17 gene, M88T, in a Korean patient whose phenotype included early onset steatocystoma multiplex and Hutchinson-like tooth deformities along with other typical features of PC-2 such as hypertrophic nails, natal teeth and follicular hyperkeratosis.

Expression, candidate gene, and population studies of the melanocortin 5 receptor.

In mouse the melanocortin 5 receptor is known to regulate sebaceous gland function. To clarify its role in man, we have studied melanocortin 5 receptor expression in skin, and allelic variation at the melanocortin 5 receptor locus in diverse human populations and candidate disease groups. Melanocortin 5 receptor protein and mRNA expression were studied by immunohistochemistry and reverse transcriptase polymerase chain reaction. Melanocortin 5 receptor mRNA was detected in normal skin and cultured keratinocytes but not in cultured fibroblasts or melanocytes. Immunohistochemistry revealed melanocortin 5 receptor immunoreactivity in the epithelium and appendages, including the sebaceous gland, eccrine glands, and apocrine glands, as well as low level expression in the interfollciular epidermis. In order to screen for genetic diversity in the melanocortin 5 receptor that might be useful for allelic association studies we sequenced the entire melanocortin 5 receptor coding region in a range of human populations. One nonsynonymous change (Phe209Leu) and four synonymous changes (Ala81Ala, Asp108Asp, Ser125Ser, and Thr248Thr) were identified. Similar results were found in each of the populations except for the Inuit in which only the Asp108Asp variant was seen. The apparent "global distribution" of melanocortin 5 receptor variants may indicate that they are old in evolutionary terms. Variation of melanocortin 5 receptor was examined in patients with acne (n = 21), hidradenitis supprativa (n = 4), and sebaceous gland lesions comprising sebaceous nevi, adenomas, and hyperplasia (n = 13). No additional mutations were found. In order to determine the functional status of the Phe209Leu change, increase in cAMP in response to stimulation with alpha-melanocyte-stimulating hormone was measured in HEK-293 cells transfected with either wild-type or the Phe209Leu variant. The variant melanocortin 5 receptor was shown to act in a concentration-dependent manner, which did not differ from that of wild type. We have therefore found no evidence of a causative role for melanocortin 5 receptor in sebaceous gland dysfunction, and in the absence of any association between variation at the locus and disease group, the pathophysiologic role of the melanocortin 5 receptor in man requires further study.

Familial nevoid sebaceous gland hyperplasia affecting three generations of a family.

Familial sebaceous gland hyperplasia is a benign entity with onset at puberty and a tendency to worsen with age. It is characterized by a nevoid symmetric pattern in the sebaceous areas of the face sparing the orbital, perinasal, preauricular and perioral areas showing prominent follicular openings and interfollicular dermal yellowish or white prominent skin. Usually, the face is affected, with the neck, column and thorax affected in a milder pattern. We describe a family with familial nevoid sebaceous gland hyperplasia in three consecutive generations. All the patients were successfully treated with oral isotretinoin. The pedigree suggests autosomal dominant inheritance with incomplete penetrance.