Newborn girl with blistering rash

A full-term, infant girl is noted to have blistering on the abdomen shortly after birth. She is otherwise well appearing without other obvious anomalies. She subsequently develops more blisters and erosions and is shown here at 17 days of age. She was born via normal spontaneous vaginal delivery to a healthy 25-year-old primigravid mother. The pregnancy was uneventful, and there was no history of herpes simplex infection.

Rupture of membranes occurred spontaneously, and she delivered four hours later. There is no history of blistering in any family members. On exam, the patient was afebrile with normal vital signs. There were discrete bullae and erosions on her abdomen and buttocks. Her oral, conjuctival, and vaginal mucosae appear normal.

What is your diagnosis?

Diagnosis: Epidermolysis Bullosa

Epidermolysis bullosa (EB) describes a group of inherited blistering disorders in infants and children.

Blisters develop spontaneously or following friction or trauma. The incidence of EB is one in 50,000 births.

Classification of EB is divided into four broad sub-types based on the level of the blistering seen on electron microscopy. More specifically, epidermolysis bullosa simplex (EBS) occurs at the level of the basal keratinocytes in the epidermis, junctional epidermolysis bullosa (JEB) occurs at the level of the basement membrane zone, dystrophic epidermolysis bullosa (DEB) refers to blistering in the superficial dermis, and the rare Kindler syndrome refers to blistering at several layers of the skin.

EBS is the most common type and is usually autosomal dominant with gene defects in keratin 5 and 14. These keratins are expressed in all basal keratinocytes and provide structural integrity to these cells. Healing occurs without scarring because the blister formation occurs at the level of the epidermis. Clinical expression ranges from bullae confined to the hands and feet to generalized blistering and mucosal involvement. It is generally considered milder than the other sub-types. A rare form with deficiency of plectin may be associated with muscular dystrophy.

JEB occurs at the epidermal-dermal junction known as the basement membrane zone and includes gene mutations in several key proteins integral to the structural integrity of the skin. There are several types of JEB ranging from life-threatening to mild disease, and all types of JEB have autosomal recessive inheritance. The most severe form is known as Herlitz type due to a laminin 332 mutation with about half of patients dying by the age of 2. The buttocks and perioral areas are common sites of blistering, and laryngeal involvement presents with hoarseness. Patients with non-Herlitz JEB due to mutations in the genes for collagen 17 or alpha 6 beta 4 integrin present similarly to patients with Herlitz type but are generally less severe and live into adulthood. Rarely, JEB may present with pyloric atresia.

DEB occurs in the superficial dermis and is due to collagen 7 mutations. Collagen 7 constitutes the dermal anchoring fibrils that are important in epidermal-dermal cohesion. Bullae formation result in scarring and milia. DEB is divided into dominant and recessive types with dominant disease being generally less severe. Recessive DEB most commonly demonstrates widespread severe blistering leading to scarring, contractures, pseudosyndactyly, esophageal strictures, frequent caries, alopecia, nutritional deficiencies, anemia, squamous cell carcinoma and frequent infections. Patients with RDEB tend to have shorter life spans.

Clues that a patient may have epidermolysis bullosa include congenital absence of skin (aplasia cutis congenita) on the extremities. This used to be referred to as Bart’s syndrome. Other clues include the formation of milia at sites of blistering, nail dystrophy, mucosal involvement, blistering at sites of adhesive or trauma, a hoarse cry, and natal teeth. A family history of blistering, nail dystrophy, or dental anomalies is very helpful but is often not recognized by families initially. Consanguinity also suggests the possibility one of the autosomal recessive types of EB.

Diagnosis is made by skin biopsy following induction of a fresh blister. Specimens are processed for electron microscopy and immunofluorescence mapping studies at special laboratories to assess the level of the blister and presence or absence of the cutaneous proteins discussed above. Definitive diagnosis can be confirmed by genetic mutation analysis. It is impossible to clinically diagnose the type of EB in the newborn period without laboratory studies as all newborns look quite similar. The patient presented here was found to have Herlitz type of JEB and died at 2 years of age.

Treatment is currently supportive and is beyond the scope of this article. Gene therapy and stem cell transplantation are now underway and may provide a cure in the future.

The differential diagnosis of blistering disorders in the neonate is extensive. Common infections include cutaneous neonatal herpes simplex virus (HSV) and neonatal varicella-zoster virus (VZV) as well as Staphylococcal scalded skin syndrome and bullous impetigo. Other inherited disorders that may present with blistering include incontinentia pigmenti, ectodermal dysplasia and congenital bullous ichythosiform erythroderma, a type of severe ichythosis. Autoimmune blistering disorders include neonatal pemphigus vulgaris and infants born to mothers with pemphigus gestationis (a form of bullous pemphigoid that develops in pregnancy or post-partum). Langerhans cell histiocytosis may also present with vesicles and bullae.

Marissa J. Perman, MD, is a second-year dermatology resident at the University of Cincinnati.

For more information:

• Fine JD. The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008; 58:931-50.
• Paller, AS. Clinical Pediatric Dermatology. A Textbook of Skin Disorders of Childhood and Adolescence. Philadelphia: Elsevier, 2006; 345-355.
• Pfendner EG. Basic science of epidermolysis bullosa and diagnostic and molecular characterization: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol. 2007;46:781-94.