Linear and segmental verrucous epidermal naevus with ipsilateral breast hypoplasia

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Verrucous epidermal naevus (VEN), a subtype of keratinocytic epidermal naevus, manifests at birth or presents in the infantile period. Ipsilateral breast hypoplasia is the commonest component of Becker’s naevus syndrome (BNS), which is a part of epidermal naevus syndrome (ENS); however, it has not been reported with linear and segmental VEN. We report a similar case in a young female.

A 16-year-old girl presented with darkly pigmented verrucous plaques arranged in a Blaschko-linear and Blaschko-segmental pattern involving the left body region, including the left upper extremity, extending to the left side of the back, with brown to black coloured thick papules over the left breast [Figures 1a-b]. The lesions had been present since birth and had progressively become more verrucous and pigmented. There were no neurological, ocular, or skeletal abnormalities. She also had ipsilateral breast hypoplasia with decreased fibrofatty tissue and nipple retraction [Figure 1c]. Polarised dermoscopy (Dermlite DL4, 3 Gen, CA, USA, 10x) from the pigmented plaque showed cerebriform pattern, thick white scales, and large brown circles [Figure 2a]. Skin biopsy of the plaque from the left breast revealed hyperkeratotic and acanthotic epidermis, papillomatosis with elongated rete ridges, and basal layer hyperpigmentation without the features of epidermolytic hyperkeratosis [Figures 2b-c]. Clinical and histopathological findings were confirmatory for the diagnosis of VEN, which was present in a blashkoid distribution. To evaluate the pathogenesis of ipsilateral breast hypoplasia, immunohistochemical (IHC) markers were performed on skin biopsy, which showed positive androgen receptors (AR) in the nucleus of keratinocytes as well as in the adnexal glands and hair follicles, and negative estrogen receptors (ER) [Figures 3a-c]. Whole genome sequencing identified two heterozygous missense variants in the PIK3CA gene: c.481A>G (p.Ser161Gly) in exon 3 and c.1465A>T (p.Met489Leu) in exon 9. Both genetic variants were interpreted as being of uncertain clinical significance (VUS) [Figure 3d].

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Figure 1a: Hyperpigmented verrucous plaque in linear distribution over the left upper limb.

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Figure 1b: Close-up of hyperkeratotic hyperpigmented cerebriform plaque.

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Figure 1c: Reduced size of the left breast with overlying hyperpigmented plaque.

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Figure 2a: Dermoscopy showing cerebriform pattern, thick white scales (blue arrow), and brown circles (red arrow) (DermLite DL4, CA USA, polarised, 10x). Inset: clinical image showing verrucous hyperpigmented papules

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Figure 2b: Scanner view of skin biopsy specimen showing hyperkeratosis (black arrow), acanthosis (blue arrow), papillomatosis (red arrow) (Haematoxylin & eosin, 40x).

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Figure 2c: Histopathology showing increased pigmentation of the basal cell layer (black arrow) (Haematoxylin and eosin, 400x).

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Figure 3a: Androgen receptor (AR) positivity in the nucleus of keratinocytes (Immunohistochemistry, 100x).

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Figure 3b: Androgen receptor (AR) positivity in hair follicle (black arrow) and adnexal gland (blue arrow) (Immunohistochemistry, 100x).

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Figure 3c: Estrogen receptor negativity (Immunohistochemistry, 100x).

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Figure 3d: Whole genome sequencing showing mutation in PIK3CA gene (black arrow).

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Linear VEN is a keratinocytic type of epidermal naevus. It may manifest alone or be associated with other developmental anomalies like neurological, ocular, or skeletal, constituting ENS. BNS manifests as Becker’s naevus (BN) associated with ipsilateral musculoskeletal or breast abnormalities, lacking the neurological involvement seen in ENS. Clinically, epidermal naevi manifest as warty, verrucous plaques that follow a Blaschko-linear or segmental distribution, consistent with somatic mosaicism from postzygotic genetic mutation. Somatic activating mutations in genes regulating epidermal growth and differentiation have been implicated in the pathogenesis of VEN. Approximately 40% of cases carry mosaic gain-of-function mutational changes in RAS gene family members, most frequently HRAS, with less frequent involvement of KRAS and NRAS.¹ Additional pathogenic variants have been identified in FGFR3 and PIK3CA, both of which influence epidermal proliferation through the RAS/Mitogen-activated protein kinase pathway (RAS-MAPK) and Phosphatidylinositol 3-kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K-AKT-mTOR) signalling network pathways.² The PIK3CA gene encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), a key component of the PI3K-AKT-mTOR signalling cascade that regulates cell growth, proliferation, and survival. Gain-of-function mutational changes in PIK3CA are responsible for a combined group collectively known as PIK3CA-related overgrowth spectrum (PROS), which includes congenital or childhood onset cellular overgrowth without dysplastic change. Within this spectrum, linear epidermal naevi arise due to mosaic PIK3CA mutations confined to the epidermal lineage, often presenting in a blaschkoid distribution. In the present case, two heterozygous missense variants were identified in the PIK3CA gene. Although both are currently classified as VUS, they are positioned within evolutionarily conserved regions and were predicted to be deleterious by multiple computer-based testing tools (LRT, MutationTaster2). The p.Met489Leu variant lies proximally to the known mutational hotspot residues E542 and E545 within the helical domain of PIK3CA, which we hypothesise to be responsible for the likely pathogenicity in the index case.³ Breast hypoplasia is a well-documented feature of BN, attributed to increased AR sensitivity. A detailed literature search revealed sparse data regarding AR expression patterns in VEN; however, reports describing AR expression patterns in BN have been published. To date, only a single case of VEN associated with ipsilateral breast hypoplasia has been reported; however, no underlying genetic mutation was identified in that case.⁴ While mutations in PIK3CA are frequently implicated in breast carcinogenesis, reports of nipple or breast tissue atrophy in patients with PIK3CA-related overgrowth syndromes are exceedingly rare, with only one such case documented.⁵ In the present case, IHC revealed AR positivity within the affected skin. We therefore hypothesise that a mechanism analogous to that implicated in BN-associated breast hypoplasia may be involved. This observation is particularly unexpected in the context of a possible PIK3CA mutation.

In conclusion, given the currently undefined aetiology of VEN associated with ipsilateral breast hypoplasia, future studies employing whole genome sequencing and IHC analysis may provide further insight into the underlying pathogenic mechanisms of such entities. We also want to emphasise that studies on AR expression pattern in various adnexal tissues in normal skin, as well as in different epidermal naevi, would be helpful for the detailed understanding of such similar entities.