Effect of phenytoin sodium in reducing blistering of epidermolysis bullosa report of four cases

Introduction

Epidermolysis bullosa (EB) is a genetic disorder which follows simple mendelian inheritance pattern with exception of EB acquisita, the exact inheritance pattern of which is not clear.[1],[2],[4] Defects in any one of the genes that codes for critical skin proteins like collagen and keratin are thought to be responsible for this condition.[1],[2] Some in vitro studies have demonstrated that phenytoin inhibits synthesis or secretion of collagenase, when it was added to human skin explant and fibroblast cultures.[7]

Subjects and Methods

Four neonates were studied after thorough clinical evaluation including detailed history and relevant investigations.

Case 1

A 2-day-old male baby, appropriate for gestational age was admitted with history of bullous lesions noted on second day of life over both lower limbs. Baby was born by normal labour to a primigravida of non consanguineous marriage who had no significant illness either before or during pregnancy. There was no family history of similar illness. Within two days, there was involvement of upper limbs and trunk and three days later nails also were affected. [Figure - 1], [Figure - 2]

Case 2 and 3

These babies were twins, both being low birth weight born by normal labour to a third gravida of non-consanguineous marriage. Mother had no significant illness, except for the fact that the second pregnancy was aborted at two months. Both babies were admitted on third day of life with bullae noted on the upper and lower limbs as well as on the trunk. Later there was involvement of face as well as nails.

Case 4

This male baby was fifth of second degree consanguineous parents and was term AGA bay born normally. Third pregnancy of mother was aborted at two and a half month and fourth baby died at first month of life due to epidermolysis bullosa. This baby had bullae over trunk and limbs with involvement of nails.

All these babies had blisters over areas of skin which are vulnerable to pressure and Nikilsky′s sign was positive. Serological test (Blood VDRL) of mothers for syphilis was negative. Tzanck smear from lesions were taken but was negative. Babies didn′t have any clinical or serological evidence of intrauterine infection. Biopsy from lesions showed that blisters were subepidermal with cleavage beneath the PAS positive basement membrane on light microscopy.

All babies were put on oral phenytoin in a dose of 5mg/Kg/day. Precautions were taken to avoid trauma to skin by keeping babies on plantain leaves. Antibiotics were given prophylactically and local antibiotic cream was also applied. Babies were kept in isolation in newborn nursery. They were periodically evaluated including photographs to document decrease in percentage of blistering. They were specifically followed up for development of anemia, hypoproteinemia and super added infections. Peripheral smear was evaluated periodically to rule our thrombocytopenia. Regular weight recording was done to assess nutritional status.

All the babies had significant reduction in the number of lesions. When the already present lesions were healed, new lesions did not appear even when we subjected the skin to trauma by rubbing the skin. Objective assessment was done by counting the number of blisters over a two square cm surface area before initiation of treatment and after two weeks of treatment.

Discussion

Epidermolysis bullosa is a rare genetic disorder. There are three main types-simplex, junctional and dystrophic.[1],[4] Most are inherited as autosomal recessive and some dominant.[4] In EB simplex, blister cleavage is intraepidermal, in junctional EB it is intra lamina densa and in dystrophic type, below lamina densa ie sublamina densa.[1],[2],[4] There are 25-30 subtypes of EB and of these only two are considered lethal ie the junctional Herlits which is deadly to the newborn and recessive dystrophic EB-Ha Ilopean-Siemens (Gravis) type.[1],[2],[3] [Figure - 3]

One variety (subtype) of EB simplex, Dowling Meara variant, is often confused with recessive dystrophic type because clinical manifestations are similar. Milia, nail involvement, oral blistering are seen in both.[4],[5] All the four babies which we studied had clinical features suggestive of either of these two forms of EB and biopsy confirmed the diagnosis of dystrophic EB. [Figure - 4]

Phenytoin is a commonly used antiepi-leptic given in maintenance dose of 5mg/Kg/day after a loading dose of 1020mg/Kg/day.[6] Common side effects of the drug are-hirsutism, gum hyperplasia, ataxia, skin rashes and Stevens Johnson syndrome, megaloblastic anemia, polyneuropathy and rickets.[6] Gum hyperplasia appears to be due to altered collagen metabolism. The metabolite of phenytoin 5(p-HPPH) has been implicated.[6] In vitro studies have demonstrated that phenytoin inhibits synthesis or secretion of collagenase.[7] This ability may be responsible for the beneficial effect of phenytoin in patients with EB.

Eventhough only four cases were studied, our study shows that phenytoin if used judiciously is safe and effective in reducing blistering and thereby improving outcome in lethal forms of EB like dystrophic EB.