Ichthyosis

Ichthyoses are a heterogeneous group of disorders of cornification characterised by generalised scaling, dryness and thickening of the skin. They are classified as common (ichthyosis vulgaris, X-linked recessive ichthyosis) and rare syndromic or non-syndromic forms, hereditary or acquired.

Common hereditary forms

• Ichthyosis vulgaris: the commonest (1 in 250). Loss-of-function mutations in FLG (filaggrin), semidominant. Reduced or absent keratohyalin granules. Onset after 3 months of age. Strong association with atopic dermatitis, asthma and hay fever.
• X-linked recessive ichthyosis (XLI): steroid sulfatase (STS) deficiency (Xp22.31 deletion in 90%), affecting 1 in 2,000-6,000 males. Accumulation of cholesterol sulfate. Onset at birth to first months.

Autosomal recessive congenital ichthyoses (ARCI)

• Lamellar ichthyosis (TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, ABCA12, others): collodion baby at birth.
• Congenital ichthyosiform erythroderma.
• Harlequin ichthyosis (ABCA12 null mutations): most severe, with thick armour-like plates, ectropion, eclabium, and high neonatal mortality (now improved with intensive care and retinoids).

Keratinopathic ichthyoses

• Epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma): KRT1/KRT10, autosomal dominant. Blistering in infancy, hyperkeratosis with corrugated, ridged scales.
• Superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens): KRT2.
• Ichthyosis Curth-Macklin (KRT1).

Syndromic ichthyoses

• Netherton syndrome: SPINK5, trio of ichthyosis linearis circumflexa, bamboo hair (trichorrhexis invaginata), and atopic diathesis with raised IgE. Neonatal erythroderma and failure to thrive.
• Sjögren-Larsson syndrome: ALDH3A2, ichthyosis, spastic diplegia/tetraplegia, intellectual disability, glistening macular dots.
• Refsum disease: PHYH, retinitis pigmentosa, neuropathy, cerebellar ataxia, ichthyosis, raised phytanic acid.
• Chanarin-Dorfman syndrome: ABHD5, neutral lipid storage with myopathy.
• KID syndrome (keratitis, ichthyosis, deafness; GJB2), CHILD syndrome (NSDHL, X-linked dominant), Conradi-Hünermann-Happle (EBP), IBIDS/trichothiodystrophy (ERCC2/3), Gaucher type 2, multiple sulfatase deficiency, neutral lipid storage disease.
• Acquired ichthyosis: associated with malignancy (Hodgkin lymphoma, other lymphomas, solid tumours), HIV, hypothyroidism, sarcoidosis, leprosy, chronic kidney disease, malabsorption and drugs (nicotinic acid, hydroxyurea, clofazimine, statins, kinase inhibitors).
• Pathophysiology: impaired barrier function with defective lipid processing, increased transepidermal water loss, retention hyperkeratosis (cohesion defects) or accelerated epidermal turnover. Consequences include infection risk, heat intolerance, hypohidrosis, and psychosocial burden.

• Ichthyosis vulgaris: fine white-grey scales on extensor limbs and trunk, sparing flexures (antecubital, popliteal), palmar hyperlinearity ("palmar hyperlinearity"), keratosis pilaris, and worse in winter.
• XLI: large dark brown "dirty" polygonal adherent scales on neck, trunk, extensor limbs, with flexural involvement, sparing palms and soles, corneal opacities (asymptomatic, deep, in 50% of males and carriers), cryptorchidism, and maternal obstetric problems (prolonged labour due to placental sulfatase deficiency). Associated with attention deficit and Kallmann syndrome contiguous gene deletion (anosmia, hypogonadotropic hypogonadism).
• Collodion baby: tight translucent membrane enveloping the newborn, with ectropion and eclabium, fissuring, and desquamation over 2-4 weeks. 70-90% develop ARCI (lamellar ichthyosis or CIE), 10% resolve (self-healing collodion baby, bathing suit ichthyosis, ALOX12B/TGM1).
• Lamellar ichthyosis: large dark plate-like scales over the entire body, ectropion, eclabium, palmoplantar keratoderma, scarring alopecia, and nail dystrophy.
• CIE: fine white scales with background erythema.
• Harlequin ichthyosis: thick plates separated by deep red fissures, severe ectropion and eclabium, flattened ears, restricted breathing and feeding, sepsis, hypothermia, and dehydration. Survivors have erythrodermic ichthyosis.
• Epidermolytic ichthyosis: neonatal blistering and erythroderma, evolving into verrucous hyperkeratosis in flexures and malodorous scale.
• Netherton: neonatal erythroderma, failure to thrive, hypernatraemic dehydration, recurrent infections, food allergy, serpiginous scaly migratory plaques, brittle hair.
• Complications: heat intolerance, decreased sweating, recurrent skin infection (bacterial, fungal), fissures and pain, eczema, hearing loss from ear canal debris, ectropion and exposure keratitis, contractures, short stature (severe), impaired quality of life, and psychological distress.
• Differential diagnosis: atopic dermatitis, xerosis, psoriasis, pityriasis rubra pilaris, erythrokeratodermia, acquired causes (malignancy), pellagra, nutritional deficiency, and exfoliative dermatitis.

• Clinical diagnosis based on morphology, age at onset, distribution, family history and associated features.
• Skin biopsy: hyperkeratosis with decreased/absent granular layer (ichthyosis vulgaris), normal or thickened granular layer with orthokeratosis (XLI, lamellar), granular degeneration and epidermolytic hyperkeratosis (keratinopathic).
• Genetic testing: next-generation sequencing multigene ichthyosis panel and chromosomal microarray (STS deletion), confirming the subtype, enabling prognosis, genetic counselling and prenatal diagnosis.
• Biochemical tests: serum cholesterol sulfate (XLI), lipoprotein electrophoresis (XLI shows increased beta mobility), steroid sulfatase activity in leukocytes or fibroblasts, plasma phytanic acid (Refsum), very long chain fatty acids, immunoglobulin E, hair microscopy for Netherton (bamboo hair), LEKTI immunostaining, and electron microscopy for ultrastructure.
• Evaluation of complications: infections, ophthalmology (ectropion, keratitis), audiology, growth, nutritional status (iron, zinc, protein, vitamin D), renal function (for systemic retinoids), neurological assessment, and monitoring of plasma sodium in neonates.
• Acquired ichthyosis: investigate for underlying disease (CBC, ESR, LDH, chest radiograph, lymph node examination, thyroid tests, HIV, renal function, CT chest/abdomen).

There is no cure for hereditary forms. Therapy is symptomatic, aiming to hydrate, remove scales, and reduce complications. Gene therapy and targeted treatments are being developed.

Skin care (cornerstone)

• Daily lukewarm baths or showers (10-20 minutes) to soften scale, followed within minutes by thick emollients (white soft paraffin, emulsifying ointment, urea 5-10% cream, lactic acid cream 5%, glycerol-containing products) applied 2-4 times daily. Soap substitutes, avoiding irritants.
• Keratolytics: urea 10-40% creams (or 10% for children), salicylic acid 2-5% in emollient base (caution in children and extensive areas due to salicylism), lactic acid 5-12%, propylene glycol 20-50% in water (under occlusion at night), alpha-hydroxy acids. Calcipotriol or tazarotene occasionally. Ammonium lactate 12% lotion.
• Mechanical: gentle exfoliation with pumice or sponge, and nail care.
• Topical retinoids (tazarotene 0.05%, tretinoin 0.025%) for localised areas, with irritation risk.
• Topical corticosteroids briefly for inflammation (not for long-term use) and tacrolimus is avoided in Netherton (systemic absorption).

Systemic retinoids (severe, disabling forms: lamellar ichthyosis, CIE, epidermolytic, harlequin survivors)

• Acitretin 0.25-1 mg/kg/day (adults), 0.5 mg/kg in children (lowest effective dose), or isotretinoin 0.5-1 mg/kg/day. They reduce scaling and hyperkeratosis dramatically but cause mucocutaneous dryness, hepatotoxicity, hypertriglyceridaemia, bone changes (premature epiphyseal closure, hyperostosis in long-term children), and teratogenicity (women of childbearing age need contraception for 3 years after acitretin, avoid alcohol). Monitor liver function, lipids, bone radiographs. Epidermolytic ichthyosis may blister more at higher doses, so use low dose. Not for Netherton (may worsen) or XLI (rarely needed).
• Alitretinoin has been used for palmoplantar keratoderma.

Neonatal care (collodion baby and harlequin ichthyosis)

NICU: humidified incubator (humidity 70-90%), temperature regulation, aseptic care, thick petrolatum or ointments, avoidance of occlusive adhesives, fluid and electrolyte monitoring (hypernatraemic dehydration), nutrition (increased calories, nasogastric feeding), antibiotic therapy for sepsis, eye care (lubricants), respiratory support, and analgesia. Systemic acitretin 0.5-1 mg/kg/day in harlequin ichthyosis hastens shedding of plates and improves survival. Surgical release of tight skin (ectropion, contractures) when needed.

Specific subtypes

• Ichthyosis vulgaris: emollients, urea or lactic acid, and treat associated atopic dermatitis.
• XLI: emollients, keratolytics, ophthalmological review (corneal opacities), testicular examination, genetic counselling, and screening for contiguous gene deletion features.
• Epidermolytic ichthyosis: emollients, antiseptic baths (dilute bleach, chlorhexidine) for odour/infection, topical and oral antibiotics, low-dose retinoids.
• Netherton syndrome: emollients, topical steroids carefully (risk of absorption), antibiotics, nutritional support, immunoglobulin replacement, allergy management, and biologics (dupilumab 300 mg every 2 weeks, secukinumab, ixekizumab, infliximab, IVIG) with promising results.
• Sjögren-Larsson syndrome: keratolytics, neurological care, zileuton (5-lipoxygenase inhibitor) under investigation.
• Refsum disease: low phytanic acid diet and plasmapheresis.
• Acquired ichthyosis: treat the underlying cause, stop causative drugs.

Management of complications

• Infections: topical or oral antibiotics (cefalexin 500 mg, flucloxacillin), antifungals (topical terbinafine, itraconazole), antiseptic baths, and prevention by good skin care.
• Heat intolerance: cool environment, hydration, cooling vests and sprays, avoidance of overheating.
• Ectropion: eye lubricants, nocturnal ointment, surgical correction.
• Ear canal: regular cleaning by ENT, hearing aids.
• Pain from fissures: occlusive dressings, topical analgesics.
• Vitamin D deficiency: supplementation 800-2000 IU daily, with calcium.
• Bone health monitoring on retinoids.
• Psychosocial: counselling, school liaison, patient organisations, and career guidance.

Genetic counselling and prevention

Autosomal recessive (25% recurrence), autosomal dominant (50%), X-linked (carrier mothers), prenatal diagnosis by chorionic villus sampling or amniocentesis, and preimplantation genetic testing.

Follow-up

Dermatology review every 3-6 months, annually for stable mild forms. Monitor growth, nutrition, retinoid toxicity, infection, and psychosocial wellbeing. Multidisciplinary care in complex cases.