Late onset epidermal nevus with hypertrichosis and facial hemihypertrophy.

Epidermal nevus syndromes are rare conditions, characterized by different types of keratinocytic or organoid epidermal nevi in association with ocular, neurological, and skeletal manifestations. We present a case of late onset epidermal nevus with hypertrichosis and hemihypertrophy of face. Genetic analysis did not reveal presence of FGFR3 or PIK3CA mutations. The patient has features that cannot be categorized into the present well-known syndromes.

What was known?

Epidermal nevus with hemifacial hypertrophy can occur in Schimmelpenning syndrome, phakomatoses pigmentokeratotica, Proteus syndrome and type 2 segmental Cowden disease.

Introduction

The epidermal nevus syndromes are a group of congenital syndromes comprising epidermal nevi in conjunction with central nervous system (CNS), ocular, musculoskeletal, and other organ anomalies.[1] Most epidermal nevi are noticed at birth or develop during the first year of life.[2] Reports of associated hemi hypertrophy of the face are multiple and almost always noticed at birth.[3] We herewith report a patient having an epidermal nevus at 25 years of age with onset of gradually progressing hemihypertrophy of face associated with overlying hypertrichosis. Genetic analysis done from the skin did not reveal fibrobalst growth factor receptor 3 (FGFR3) mutations. This patient could represent a variant of the syndrome described by Gobello et al.[4]

Report

A 26-year-old man reported to skin outpatient department with dark warty growth on left side of cheek for past 6 years. It progressed insidiously to involve the cheek and neck. He noticed gradual disproportionate enlargement of the left side of face after the onset of the growth. He had no history of seizures, headaches or any other CNS events. On examination, there were linear hyperpigmented verrucous papules with overlying hypertrichosis on left side of cheek extending on to the neck [Figure 1a]. The left side of the face looked larger than the right [Figure 1b]. There were no other skin lesions. Ophthalmological examination gave normal results. X-ray skull was suggestive of mandible condylar hyperplasia. However, orthopantogram revealed slight widening of ramus; no other bony abnormality was observed. Computed axial tomography of the cranium and brain showed thickening of the frontal bone on the left side [Figure 2]. Skin biopsy of the representative skin lesion (face) showed hyperkeratosis with papillomatosis [Figure 3]. It did not show epidermolytic hyperkeratosis. Genetic analysis was done from the skin in the area affected by the nevus. On genetic analysis of skin samples taken from the nevus, only wild type alleles were revealed for the hotspot loci on FGFR3 and p110α subunit of phosphatidyl inositol-3 - kinase (PIK3CA). Patient's epidermal nevus was treated with carbon dioxide laser with moderate results.

Figure 1

(a) Verrucous epidermal nevus with overlying hypertrichosis on left side of face and neck, (b)- Hemihypertrophy of left side of face and scalp

Figure 2

CT scan showing thickening of frontal bone on left side

Figure 3

Section of skin biopsy showing hyperkeratosis, acanthosis, and papillomatosis. (H and E, ×40)

Discussion

Keratinocytic nevi and sebaceous nevi can be associated with epidermal nevus syndromes (ENSs). The epidermal nevus syndrome refers to a sporadic neurocutaneous disorder characterized by epidermal nevi, ophthalmological and neurological manifestations. Happle has described multiple phenotypes associated with cutaneous mosaicism and made a strong case for avoiding umbrella terms like epidermal nevus syndrome and organoid nevus syndrome when describing a specific ENS.[56] The well-defined syndromes are Schimmelpenning syndrome, phakomatoses pigmentokeratotica, nevus comedonicus syndrome, angora hair nevus syndrome, Becker's nevus syndrome, Type 2 segmental Cowden disease, FGFR3 segmental nevus syndrome, and CHILD (congenital hemidysplasia with icthyosiform erythroderma and limb defects) syndrome.[5]

Of these, Schimmelpenning syndrome, phakomatoses pigmentokeratotica, Proteus syndrome, and type 2 segmental Cowden disease may be associated with hemi hypertrophy of face or limbs.[5] However, our patient did not have the other characteristic features of the above disorders. Mild facial dysmorphism has been described in a case with FGFR3 mutation.[7] Patients with hemihypertrophy of face usually are reported to have cortical defects like hemimegalencephaly, focal cortical dysplasia, and neuronal migration defects like pachygyria and polymicrogyria heterotopias in the affected hemisphere.[3] Our patient had an epidermal nevus with hemihypertrophy of face with no other abnormalities. Onset is usually in infancy, rarely in childhood.[3] Our patient had relatively late onset of epidermal nevus associated with left-sided progressive hemihypertrophy of the face and hypertrichosis.

Hypertrichosis confined to the area of epidermal nevus is described in angora hair nevus syndrome[6] and in a case of epidermal nevus with bony abnormalities described by Gobello et al.[4] Gobello et al.[4] described a 16-year-old boy with non-epidermolytic epidermal nevus, hypertrichosis and follicular hyperkeratosis in addition to hemihypoplasia of limbs, brachydactyly, clinodactyly, and onychodystrophy. Genetic analysis done from the affected skin in this case did not reveal mutations in FGFR3.[6] In our patient too, only wild type alleles for FGFR3 were seen in affected skin. Our patient had hypertrichosis overlying an epidermal nevus with hemihypertrophy of face. While the features do not exactly match those described by Gobello et al., hypertrichosis confined to the epidermal nevus is unique to both cases. Follicular hyperkeratosis was not seen in our patient though.

Genetic analysis done from lesional skin showed only wild-type alleles of both FGFR3 and PIK3CA genes. Somatic mosaicism for FGFR3 mutations involving skin and other organ systems have been described in patients.[89] If the mutation involves the gonads, such patients are said to be at risk for thanatophoric dysplasia.[9] In many other patients with epidermal nevi, somatic mutations resulting in mosaicism confined to keratinocytes of the affected area have been demonstrated in the FGFR3 gene,[10] specifically at the R248C hotspot, and in the PIK3CA gene.[11] Keratin 1 and 10 mutations are described in nevi showing granular degeneration. CHILD syndrome is caused by NSDHL (NAD (P) H steroid dehydrogenase-like) gene mutations; Type 2 Cowden disease by PTEN (phosphatase and tensin homolog) mutations.[5] No other loci are currently known or implicated in the causation of epidermal nevi.

We report this unique case of late onset epidermal nevus with hypertrichosis and hemihypertrophy as it does not belong to any of the classical epidermal syndromes. A possible association to “Gobello syndrome” cannot be confirmed until more molecular diagnostic techniques are developed and employed.

What is new?

Hemifacial hypertrophy and hypertrichosis can occur in association with epidermal nevus in the absence of FGFR3 mutations. This does not fit into any of the known ENS and could be a new entity.