Lewandowsky and lutz dysplasia: report of two cases in a family.

Lewandowsky and Lutz dysplasia, also known as epidermodysplasia verruciformis (EV), is an inherited disorder in which there is widespread and persistent infection with human papilloma virus, defect in cell-mediated immunity and propensity for malignant transformation. Differential clinical and histopathologic evolutions of lesions in two cases of familial EV are compared and discussed in detail. Cases were followed up for 7 years. Detailed history, clinical features and investigations, including skin biopsy from different sites at different times, were examined. Generalized pityriasis versicolor like hypopigmented lesions in both the cases, together with variable pigmented nodular actinic keratosis like lesions on sun-exposed areas, were present. Multiple skin biopsies done from various sites on different occasions revealed features typical of EV along with lesions, i.e., actinic keratosis, Bowen's disease, basal and squamous cell carcinoma, in the elder sibling. However, skin biopsy of the other sibling showed features of EV and seborrheic keratosis only till date. This study reveals that the disease progression is variable among two individuals of the same family. Malignant lesions were seen only on sun-exposed areas and may be associated with other skin lesions or infections such as angiokeratoma of Fordyce and tinea cruris, as seen in this report.

Introduction

Lewandowsky and Lutz dysplasia or epidermodysplasia verruciformis (EV) is an extremely rare genetic disorder first documented by Felix Lewandowsky and William Lutz in 1922.

It begins in childhood and is characterized by generalized infections with human papilloma virus (HPV), frequent association with cutaneous carcinomas and abnormalities of cell-mediated immunity.

Here we compare clinical and histopathologic features of two cases of EV in a family, with 7 years of follow up, and discuss differential clinical and histopathologic evolutions of lesions in detail.

Case Report

Detailed history was taken. A pedigree analysis was done. Clinical features were noted. Dermatologic examination was done in detail. Investigations included routine hemogram, biochemical examination, chest X-ray, skin scrapping for KOH examination and biopsy examination of skin lesions from multiple sites at different times in both the cases.

Two brothers [Figures 1 and 2], first presented at 16 and 18 years of age, respectively, came with a history of multiple, discreet, hypopigmented lesions all over the body since 8 years of age. Elder brother was also asthmatic since childhood. They gave history of consanguineous parentage (uncle–niece). Pedigree chart is shown in Figure 3. None of the living family members (total 18) had this disease.

Figure 1

Photograph of elder sibling showing hypopigmented lesions all over the body, along with hyperpigmented, black colored plaques over chest, abdomen, arms. Scars of previous operations are seen over chest wall and right nasolabial fold

Figure 2

Photograph of younger sibling showing hypopigmented lesions all over the body and two scaly erythematous lesions over the chest wall

Figure 3

Pedigree chart showing the diseased individuals

On examination, multiple discreet and confluent hypopigmented plaques were present, some were slight erythematous with surface scaling and polycyclic borders over upper torso. Some on dorsa of the hands were slightly elevated. Genitalia and scalp were spared in both cases. In addition, the elder brother also showed a scaly pigmented nodular lesion of approximately 1 cm in diameter on the chest wall over the sternum.

Biopsy from the lesions showed hyperkeratosis, hypergranulosis, irregular acanthosis, vacuolated cells in upper stratum malphigi and enlarged cells with gray blue cytoplasm. Some nuclei appeared large, round, and empty owing to marginal distribution of the chromatin. The features were consistent with diagnosis of EV [Figure 4]. Histopathologic examination of chest wall lesion revealed morphology of actinic keratosis.

Figure 4

Histopathologic appearance of skin biopsy displaying typical lesion of EV showing swollen keratinocytes with gray blue cytoplasm (H and E, ×40)

Both were advised to avoid sunlight and to visit regularly for any change or if new lesions appear. However, so they could not follow the advice stringently.

Subsequently, 3 years later, the elder brother again presented to the department. On examination, the plaques had increased in number and were more confluent. In addition, there were hyperpigmented, black colored plaques over chest, back, abdomen, nose, right nasolabial fold and right cheek. Over the right scrotum, multiple angiomatous papules arranged in a linear pattern, suggestive of angiokeratoma of Fordyce were seen [Figure 5]. Also present were circinate patches over the groin.

Figure 5

Photograph of elder sibling showing angiokeratoma of Fordyce with EV

KOH smears from axilla were positive for fungal elements. Electro-fulguration of angiokeratoma of Fordyce was done. Multiple excision biopsies were taken from hyperpigmented, keratotic and warty lesions. Histopathological examination revealed variable morphology ranging from seborrheic keratosis, actinic keratosis [Figure 6], Bowen's disease (back), moderately differentiated squamous cell carcinoma (chest wall) and basi-squamous carcinoma with seborrheic differentiation (on face).

Figure 6

Microphotograph of actinic keratosis showing epidermal hyperplasia with hyperkeratosis and atypical keratinocytes confined to lower aspect of epidermis (H and E, ×40)

Younger brother presented 5 years after initial presentation with two notable scaly erythematous lesions of 1 and 0.5 cm over the chest wall. Biopsy from larger lesion revealed features of seborrheic keratosis.

After 3 years, the elder brother again presented with multiple small flat and raised erythematous and hyperpigmented lesions. One enlarged nodular lesion over the chest wall near the site of previous scar was excised, which on histopathology showed features of Bowen's disease [Figure 7]. Both the patients are presently under regular follow up.

Figure 7

Microphotograph of Bowen's disease where dysplastic keratinocytes are involving the entire thickness of epidermis (H and E, ×100)

The grandfather who also had similar disease died early without any biopsy examination.

Discussion

EV is an inherited disorder in which there are widespread and persistent infections with HPV, defect in cell-mediated immunity and propensity for malignant transformation.

Although most common form of EV is sporadic,[1] there have been few reports of familial EV.[2] A total of 12 reports of EV in Indian patients have been published so far,[3-13] out of which only three were of familial cases.[348] Largest number of cases includes 14 members of a family reported from India.[3] Herein, we report three more cases of EV in a family of 18 individuals spread among three generations.

Etiopathogenesis of the disease includes genetic factors, immunologic factors and persistent HPV infections.

There are inactivating mutations of EVER1 and EVER2 genes located on chromosome 17.[14] HPV infection in EV patients leads to widespread benign lesions of skin. About 20 HPV types have been characterized in these lesions and patients are usually infected with more than one genotype.[15]

But many of the EV patients show an abnormal susceptibility to specific group of HPVs only, including the oncogenic HPV type 5 (HPV5). Infection results in pathognomonic pityriasis versicolor-like lesions, red plaques, and flat wart-like lesions. A specific cytopathic effect is linked to the high level of viral replication in differentiating keratinocytes.[16]

Although most patients of EV have impaired cell-mediated immunity, it is still not known whether impairment of immune response is primary or secondary to massive HPV infection. It has been thought that basic immunologic defect might be the inability to recognize EV specific HPVs in such patients.[17]

The persistence of HPV infection is possibly the result of an immunogenetic defect which determines the generation of several cytokines capable of downregulating cell-mediated immunity.[18]

Malignant transformation of lesions occurs on sun-exposed areas in 25–30% of the patients at a relatively young age (third or fourth decade).[4] Syn-carcinogenic role of HPV5 and ultraviolet rays is supported by frequent mutations of p53 gene in premalignant and malignant EV tumors.[19]

Both of our patients are farmers by profession and prone to sun exposure. However, propensity for malignant transformation was more in elder brother.

While the younger brother required three biopsy examinations and only showed features of seborrhoic keratosis, the elder brother needed more than seven biopsy examinations from lesions over face and chest wall showing features of seborrhoic keratosis, actinic keratosis, Bowen's disease, squamous cell carcinoma and basisquamous carcinoma.

Associated diseases reported in EV are NF-1,[20] thymoma,[21] Hansen's disease, herpes simplex labialis and eccrine poroma,[5] celiac disease and porokerotosis of Mibelli[22] and Systemic Lupus Erythematosus.[23] In the present study, one of the patients had EV with angiokeratoma of Fordyce, tinea cruris and asthma.

It has been stated that EV patients are not prone to bacterial, fungal, or viral infections with the exception of HPVs associated with plane warts.[24] However, Padmawathy et al. reported a case of EV with Hansen's disease and herpes simplex labialis.[5] Similarly, in our case, the patient suffered from tinea cruris.

Conclusions

It is therefore concluded that the disease progression is variable among individuals of the same family. Malignant lesions were seen only on sun-exposed areas. Proclivity for malignant transformation is due to syn-carcinogenic affect of ultraviolet rays and HPV infection, which in turn depends on individual genetic susceptibility. May be associated with other skin lesions or infections such as angiokeratoma of Fordyce and tinea cruris, as in the present case.