Dermatology MCQ - Genetic Disorders - Epidermolysis Bullosa

A newborn infant presents with extensive blistering and erosions of the skin and mucous membranes following a normal vaginal delivery. Nikolsky's sign is positive. A skin biopsy for immunofluorescence mapping shows cleavage within the lamina lucida of the basement membrane zone, with staining for collagen IV on the floor of the blister and laminin 332 on the roof. What is the most likely diagnosis and its associated extracutaneous complication?

A. Epidermolysis Bullosa Simplex (KRT5/KRT14 mutation); risk of milia and scarring.
B. Junctional Epidermolysis Bullosa (LAMA3/LAMB3/LAMC2 mutation); high risk of failure to thrive and severe, often fatal, laryngeal and tracheobronchial involvement.
C. Dystrophic Epidermolysis Bullosa (COL7A1 mutation); high risk of aggressive squamous cell carcinoma in chronic wounds.
D. Kindler Syndrome (FERMT1 mutation); poikiloderma and photosensitivity.
E. Epidermolysis Bullosa Acquisita (autoantibody to type VII collagen); onset in adulthood.

Correct Answer: B. Junctional Epidermolysis Bullosa (LAMA3/LAMB3/LAMC2 mutation); high risk of failure to thrive and severe, often fatal, laryngeal and tracheobronchial involvement.

Answer and Explanation

The correct answer is B. This question describes a severe, life-threatening presentation of Junctional Epidermolysis Bullosa (JEB), specifically a major subtype. The key clues are the onset at birth with widespread blistering from minor trauma (delivery), the positive Nikolsky sign (indicating fragile skin), and the critical diagnostic finding on immunofluorescence mapping. The cleavage plane within the lamina lucida, with collagen IV on the floor (from the lamina densa) and laminin 332 (formerly laminin 5) on the roof (from the hemidesmosome/lamina lucida), is pathognomonic for JEB. Mutations in the genes encoding laminin 332 (LAMA3, LAMB3, LAMC2) are the most common cause of severe JEB. The associated lethal extracutaneous complication in severe JEB is progressive stenosis and blistering of the upper airway (larynx, trachea) and bronchi, leading to respiratory failure, which is a major cause of death in infancy.

Why the Other Options are Incorrect:

• A. Epidermolysis Bullosa Simplex (EBS): The cleavage plane in EBS is intraepidermal (within basal keratinocytes), not within the lamina lucida. It is generally less severe at birth and not typically associated with the same degree of mucosal involvement or fatal respiratory complications.

• C. Dystrophic Epidermolysis Bullosa (DEB): The cleavage plane in DEB is sublamina densa, within the superficial dermis. Immunofluorescence would show collagen IV and laminin 332 on the roof of the blister. While DEB carries a high risk of SCC, the blister mapping findings are inconsistent.

• D. Kindler Syndrome: This is a mixed cleavage pattern disorder with photosensitivity and poikiloderma, not the classic lamina lucida cleavage described.

• E. Epidermolysis Bullosa Acquisita (EBA): This is an autoimmune blistering disease, not congenital. It has a sublamina densa cleavage plane (like DEB) due to autoantibodies against type VII collagen.

Additional High-Yield Information for Exams:

• Classification by Cleavage Plane (Key to Diagnosis):

  • Simplex (EBS): Intraepidermal (basal keratinocyte cytolysis). Mutations in KRT5/KRT14.

  • Junctional (JEB): Lamina lucida. Mutations in laminin 332 genes or integrins (*ITGA6/ITGB4*).

  • Dystrophic (DEB): Sublamina densa. Mutations in COL7A1 (type VII collagen).

• Specific Subtypes & Complications:

  • Severe JEB (formerly Herlitz): Caused by null mutations in laminin 332. Features include granulation tissue around mouth/nares, severe failure to thrive, anemia, and the life-threatening laryngotracheal stenosis mentioned.

  • Recessive DEB (RDEB-severe): The most severe form of DEB. Characterized by mitten deformities (pseudosyndactyly) of hands/feet, microstomia, esophageal strictures, and an extremely high risk of aggressive squamous cell carcinoma arising in chronic wounds after adolescence.

  • Dominant DEB (DDEB): Milder, often localized, with dystrophic (atrophic) scarring and milia.

• Differential Diagnosis: Other causes of neonatal blistering include staphylococcal scalded skin syndrome (cleavage in granular layer, periorificial crusting), congenital erosive and vesicular dermatosis, and bullous mastocytosis.

• Prognosis: Varies from normal lifespan in mild EBS to high mortality in infancy for severe JEB, and significant morbidity and reduced lifespan in severe RDEB due to sepsis, malnutrition, and SCC.

• Management & Rationale:

  • Rationale: Management is intensive, supportive, and multidisciplinary, focusing on wound care, pain control, nutrition, and prevention/treatment of complications.

  • First-line/Wound Care: Meticulous, gentle daily wound care with non-adherent dressings to promote healing and prevent infection. Pain management is critical.

  • Nutrition: Early gastrostomy tube placement is often necessary in severe forms to ensure adequate nutrition and growth.

  • Monitoring/Prevention: In RDEB, regular surveillance for SCC in chronic wounds via biopsy of suspicious areas. In JEB, regular otolaryngology evaluation for airway stenosis. Physical/occupational therapy to maintain mobility and prevent contractures.

  • Advanced Therapies: Stem cell therapy, bone marrow transplantation, and gene therapy are under investigation, particularly for RDEB.