Generalized Epidermal Nevus and Acanthosis Nigricans Due to a Postzygotic FGFR3 Variant

FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia), benign skin tumors (epidermal nevi, seborrhaeic keratosis, and acanthosis nigricans), and epithelial malignancies (multiple myeloma and prostate and bladder carcinoma). Hypochondroplasia is the most common type of short-limb dwarfism in children resulting from fibroblast growth factor receptor 3 (FGFR3) mutation. Acanthosis nigricans might be seen in severe skeletal dysplasia, including thanatophoric dysplasia and SADDAN syndrome, without a biochemical evidence of hyperinsulinemia. Insulin insensitivity and acanthosis nigricans are uncommonly seen in hypochondroplasia patients with FGFR3 mutations which may represent a new association. We aim to describe the association of hypochondroplasia, acanthosis nigricans, and insulin resistance in a child harboring FGFR3 mutation. To our knowledge, this is the first case report associating the p.N540 with acanthosis nigricans and the second to describe hyperinsulinemia in hypochondroplasia. This finding demonstrates the possible coexistence of insulin insensitivity and acanthosis nigricans in hypochondroplasia patients.

Garcia-Hafner-Happle syndrome, also known as Fibroblast growth factor receptor 3 epidermal nevus syndrome, is a new neurocutaneous phenotype, which has been identified in 2008 by Garcı’a-Vargas et al. The disorder is caused by a mosaic R248C mutation of the FGFR3 gene, which is characterized by a keratinocytic epidermal nevus, acanthosis nigricans, and neurological abnormalities like seizures, intellectual impairment, cortical atrophy, and underdevelopment of corpus callosum. The epidermal nevus syndromes represent a group of distinct disorders in which an epidermal nevus is associated with abnormalities in other organ systems like central nervous system, cardiovascular system, genitourinary system, eyes, and bone. Recently, nine well-defined different epidermal nevus syndromes (ENSs) have been identified on clinical, histopathologic, and molecular basis. We present here the details of a patient with the clinical features and skin biopsy findings suggestive of Garcia-Hafner-Happle syndrome.

Acanthosis nigricans nævoïde ou « RAVEN » (rounded and velvety epidermal nevus) : trois cas

Dear Editor: A 48-year-old Korean female patient complained of brownish papules with verrucous surface, and a linear distribution. She had recognized cutaneous lesions about 15 years previously, and these lesions became more remarkable in coloration and linear distribution for the past year. The skin lesions seemed as a linear pattern following the lines of Blaschko, involving the right leg, which were extended to same side of her sole manifest as linear distributed, verrucous, and hyperkeratotic plaques (Fig. 1). She had no past medical history and family history. Histopathological examination from the right calf showed hyperkeratosis, acanthosis and hyperpigmentation of the basal layer (Fig. 2A). The histopathology from her ipsilateral sole showed verrucous surfaced epidermal alterations which were represented by definite hyperkeratosis, epidermal acanthosis, parakeratosis, and rete ridge elongations (Fig. 2B). She was diagnosed with nevus unius lateris. She had a surgical excision of the plantar lesion subsequently reconstruction with a skin graft. Alternatively, topical treatment with retinoic acid and topical corticosteroid were applied on her right leg lesions. Fig. 1 (A, B, C) The skin lesions appeared in a linear fashion, following the lines of Blaschko, involving primarily the right leg, which were extended to ipsilateral sole. Right sole manifest as yellowish, thick, linear distributed, verrucous, and hyperkeratotic ... Fig. 2 (A) A biopsy specimen from the right calf shows hyperkeratosis, acanthosis and hyperpigmentation of the basal layer (H&E stain, ×100). (B) Histology performed on a biopsy specimen from a keratotic lesion on the sole reveals verruciform ... Epidermal nevus is a mosaic disorder as a result of somatic mutations that have occurred during fetal life1. Epidermal nevus has a tendency to follow the Blaschko lines. Eighty percent of lesions appear within the first year of life, with the majority of lesions appearing by age 14 years. Our patient recognized her leg and sole lesions in her thirties. Such late-developing epidermal nevi probably represent lesions that have always been present sub-clinically, but recent growth resulted in clinical recognition. Congenital lesions tend not to expand significantly, and the majority of epidermal nevi remain quiescent after adolescence. But, in our patient, her lesions were progressed, and became more remarkable in coloration and linear distribution. The histopathologic features of epidermal nevi are described as acanthosis, hyperkeratosis, and papillomatosis. The rete ridges are elongated, and focal thickening of the granular layer and parakeratotic columns are seen2. Frequently, hyperpigmentation in the basal cell layer is evident. This corresponds with the brownish skin lesions. In addition, the margins of skin lesions are sharply demarcated from the surrounding normal skin on microscopy3. This correlates with well-described papules with distinct demarcations. Linear epidermal nevus that is clinically indistinguishable from inflammatory linear verrucous epidermal nevus (ILVEN) may have different histologic appearances. ILVEN has distinguishing histopathology which are hyperkeratosis, parakeratosis (parakeratotic areas alternate with orthokeratotic), slight spongiosis and lymphocytic exocytosis4. Treatment of linear epidermal nevus depends on surgical excision, extending into the deep dermis to prevent a recurrence. Unfortunately, this is not always possible in some cases of extensive involvement. In these instances, other treatment modalities are available to treat these lesions. Laser ablation, cryotherapy, electrofulguration and variable degree of chemical peels may offer partial or full destruction of lesions. Although topical corticosteroids, topical retinoids, and calcipotriene offer little improvement, these medications can be used as an adjunctive treatment to increase the efficacy of the surgical intervention5. Our patient has no recurrence after excision of plantar lesion. And her leg lesions remain quiescent with topical corticosteroids and topical retinoids.

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome

Before discussing the spectrum of cutaneous melanocytic naevi and melanomas, it is useful to discuss briefly the large variety of cutaneous pigmented lesions unrelated to these entities. We shall restrict ourselves largely to lesions in which increased melanin production is an essential and sometimes striking feature; the large variety of cutaneous lesions which may show only slight increase in pigmentation of the epidermal basal layer, or which may be pigmented macroscopically for other reasons, will not be discussed. Other lesions, which appear pigmented clinically largely because of epidermal hyperkeratosis, often associated with papillomatosis, such as linear epidermal naevus, acanthosis nigricans and hypertrophic solar keratosis, will be referred to briefly.

“Ectopic acanthosis nigricans” in inguinal skin grafted to the hands of a child

Conflict of interest: none declared. Inflammatory linear verrucous epidermal naevus (ILVEN) is a rare skin disorder characterized by hyperkeratotic, erythematous and verrucous lesions that follow Blaschko’s lines. Inflammatory episodes often occur. Histologically, epidermal acanthosis is seen. A characteristic pattern of orthokeratosis with broadened granular layer alternating with parakeratosis overlying hypogranulosis may be observed. ILVEN occurs sporadically, familial forms being rarely reported in the literature.1–6 We report here a new family with ILVEN. A 3‐year‐old‐girl presented with linear, erythematous, pruritic, verrucous and keratotic lesions following Blaschko’s lines, which had been present since birth. She was the first child born to nonconsanguineous parents. There was no family history of psoriasis or eczema. The lesions were localized at the right side of the lower lip and on the right axilla (Fig. 1a). Her 27‐year‐old father had a similar lesion on the right side of the scrotum that had been present since childhood (Fig. 1b). The child’s younger brother and mother were both unaffected. Inflammatory episodes were reported for both the father and daughter.

Unilateral nevoid acanthosis nigricans (UNAN) is a rare, benign, autosomal dominant form of acanthosis nigricans (AN) that can manifest at birth or during childhood or puberty. A 6-year-old boy presented with asymptomatic, brownish-black raised lesions on the left side of the back extending to the left arm 4 years ago. It started as a small dark-colored asymptomatic papule over the left side of the chest. It progressed over 4 years to the present size and remained stable. On examination, there were multiple well-to-ill-defined brownish-black velvety plaques with soft ridges and ill-defined irregular margins, with scaly surface. Dermoscopy showed multiple crista cutis and sulcus cutis with hyperpigmented dots in crista cutis. The clinical differentials considered were linear epidermal nevus (EN) and linear AN. Histopathology revealed hyperkeratosis, mild papillomatosis, and lymphocytic infiltrate. The interpapillary spaces were filled with keratotic material. In accordance with the clinical, dermoscopic, and histopathological findings, the final diagnosis of UNAN was made. UNAN is a rare and benign form of AN inherited as an autosomal dominant. It is not associated with any endocrinopathy, drugs, or internal malignancy. Linear verrucous EN can resemble nevoid AN clinically and histopathologically. The differential diagnoses which can be kept include the EN, confluent and reticulated papillomatosis, Dowling–Degos disease, and seborrheic keratosis.

Adult-onset verrucous epidermal nevus overlying an implanted cardioverter-defibrillator

Somatic HRAS p.G12S Mutation Causes Woolly Hair and Epidermal Nevi

Dermatologically, FGFR3 mutations can lead to acanthosis nigricans (AN), epidermal nevi, and seborrheic keratosis. A recent case report found that topical rapamycin (sirolimus) can improve FGFR3-induced epidermal nevi with AN features in children, specifically with Fitzpatrick skin type (FST) I/II, and we would like to expand these findings to skin plaques with extensive AN-like features in the FST IV/V adolescent population. An 18-year-old female with FST IV/V and FGFR3-induced hypochondroplasia presented to our clinic with extensive AN-like plaques. Significant improvement with lightening and thinning of the plaques was observed after applying 1% topical rapamycin cream twice daily. Topical rapamycin should be considered as a treatment option for AN, particularly in FST IV/V adolescents with FGFR3-induced AN.

There are rare reports of epidermal nevi with exaggerate hyperkeratosis and papillomatosis (3) on the axillary region that are reminiscent of acanthosis migricans (2). Even a rounded and velvety axillary epidermal nevus has been identified as a separate entity (4). We believe that the particular environmental conditions of the folds can explainthe greater evidence at this level of epidermal nevus and also of other diseases such as seborrhoeic warts, pemphigus vegetans, acanthosis nigricans and granular parakerotosis (1). The histologic absence of epidermolytic hyperkeratosis eliminates the possibility of epidermolytic ichthyosis in the offspring. However, we believe that other inherited skin disorders, such as erythrokeratoderma variabilis, may manifest themselves as epidermal nevus when they are due to a post-zygotic mutation and as generalized disease in the offspring in case of concomitant gonadal mosaicism.

Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi.

Nevoid acanthosis nigricans is a rare, benign form of acanthosis nigricans. Of the 24 cases documented in the literature, only two are exclusively localized to the umbilicus. We present four cases of nevoid acanthosis nigricans localized to the umbilicus; in patients less than 25 years of age, with no known co-morbidities, three of whom were females. Two of the cases received, with good response, treatment based on topical calcipotriol, a medication not previously reported to be used for this indication. Contrary to other types of acanthosis nigricans, the nevoid acanthosis nigricans is not associated with any syndrome, endocrinopathy, obesity, medication, or neoplasia and it can be confused with other pathologies such as epidermal nevus or dermatosis neglecta.