Dermatology MCQ - Genetic Disorders - Ichthyosis Vulgaris

A 10-year-old boy presents with fine, white to gray scales on his extensor surfaces, particularly noticeable on his shins and forearms. The scaling is worse in the winter and improves in warm, humid weather. The skin on his flexures is spared. He also has mild hyperlinear palms and a personal history of atopic dermatitis. What is the most likely underlying genetic defect and the associated structural finding in the epidermis?

A. Mutation in the filaggrin (FLG) gene; a reduced or absent granular layer on histology.
B. Mutation in the transglutaminase 1 (TGM1) gene; a thickened stratum corneum with retention of the nucleus.
C. Mutation in the steroid sulfatase (STS) gene; an absent or reduced stratum corneum.
D. Defect in lamellar body secretion; a basket-weave hyperkeratosis on histology.
E. Mutation in the keratin 1 (KRT1) gene; epidermolytic hyperkeratosis on histology.

Correct Answer: A. Mutation in the filaggrin (FLG) gene; a reduced or absent granular layer on histology.

Answer and Explanation

The correct answer is A. This question describes the classic presentation of ichthyosis vulgaris (IV). The key clues are the fine, white, "pasted-on" scales on extensor surfaces with flexural sparing, worsening in dry/cold weather, and the strong association with atopic dermatitis and hyperlinear palms. IV is a disorder of keratinization caused by loss-of-function mutations in the filaggrin (FLG) gene. Filaggrin is a key protein in the granular layer that aggregates keratin filaments and is later broken down into natural moisturizing factors. Its deficiency leads to a defective skin barrier. Histologically, this manifests as a thin or absent granular layer and compact hyperkeratosis.

Why the Other Options are Incorrect:

• B. Mutation in the transglutaminase 1 (TGM1) gene: This causes lamellar ichthyosis or congenital ichthyosiform erythroderma, which are severe, autosomal recessive disorders presenting as collodion babies with large, plate-like or fine white scales over the entire body, not the localized, seasonal pattern of IV.

• C. Mutation in the steroid sulfatase (STS) gene: This causes X-linked recessive ichthyosis. It presents with large, dark brown, adherent scales that often spare the flexures but involve the neck and pre-auricular area ("dirty neck" appearance). It is not associated with atopy or hyperlinear palms, and improves less with age than IV.

• D. Defect in lamellar body secretion: This is a feature of harlequin ichthyosis and some forms of lamellar ichthyosis, not the mild, common IV.

• E. Mutation in the keratin 1 (KRT1) gene: This causes epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma), characterized by widespread blistering at birth that evolves into a warty, hyperkeratotic pattern, not fine, white scaling.

Additional High-Yield Information for Exams:

• Genetics & Pathogenesis: Autosomal semi-dominant. Heterozygotes (one mutated FLG allele) have mild disease; homozygotes or compound heterozygotes (two mutations) have moderate to severe disease. Filaggrin deficiency leads to:

  • Impaired keratin filament aggregation.

  • Reduced production of natural moisturizing factors (e.g., urocanic acid, pyrrolidone carboxylic acid).

  • A defective epidermal barrier, allowing increased transepidermal water loss and penetration of allergens, explaining the link to atopic dermatitis, asthma, and allergic rhinitis (the "atopic march").

• Clinical Features:

  • Onset: Usually after 3 months of age, not congenital.

  • Scale: Fine, white, "pasted-on" or powdery. Most prominent on extensor surfaces of limbs (shins) and trunk.

  • Keratosis pilaris: Very commonly associated (rough, follicular papules on upper arms, thighs, cheeks).

  • Hyperlinear palms and soles: A very common and diagnostic finding.

• Histopathology: The hallmark is a reduced or absent granular layer with overlying compact hyperkeratosis. The remainder of the epidermis is normal.

• Differential Diagnosis: The main differential is X-linked recessive ichthyosis (XLI). Key differences:

  • IV: Fine white scale, improves with age, hyperlinear palms, strong atopy association.

  • XLI: Large, dark brown scale, does not improve with age, no atopy/hyperlinear palms, corneal opacities (on slit-lamp), delayed labor in mother of affected male.

• Associated Conditions & Prognosis:

  • Prognosis: Often improves with age, especially after puberty. It is a lifelong condition but is manageable.

  • Atopy: Up to 50% of patients with moderate-severe IV have atopic dermatitis. FLG mutations are the strongest known genetic risk factor for atopic dermatitis.

• Management & Rationale:

  • Rationale: The goal is to hydrate the skin and reduce scale by replacing the missing natural moisturizing factors and providing occlusion.

  • First-line Therapy: Daily, aggressive moisturization with emollients containing humectants (urea, lactic acid, glycerol) and occlusives (petrolatum).

  • Topical Keratolytics: For thicker scaling, alpha-hydroxy acids (lactic acid, glycolic acid) or urea-containing creams (10-40%) are effective to gently remove scale.

  • Lifestyle: Use of humidifiers in dry climates, short, lukewarm showers, and avoidance of harsh soaps.

  • Systemic Therapy: Rarely needed. Oral retinoids (acitretin) may be considered for severe, refractory cases.