Ichthyosis vulgaris is the most common and mildest form of nonsyndromic ichthyosis, having an incidence of 1:250 to 1:1000.⁵ It is characterized by xerosis, scaling, pruritus, and eczema, and it is strongly associated with atopic manifestations.⁵ The most commonly affected sites are the extensor surfaces of the lower legs and the back. Other cutaneous features include palmoplantar hyperlinearity and keratosis pilaris (dry, rough patches, and tiny bumps), usually on the upper arms, thighs, cheeks, or buttocks. Trichomegaly with elongated eyelashes has been reported as a cutaneous marker for this disease seen in 13% of patients.¹⁰ The causative genetic mutation is in the FLG gene that encodes profilaggrin,¹¹ a precursor protein of filaggrin, a protein that
facilitates terminal differentiation of the epidermis, and the formation of the protective skin barrier.¹² In terminal differentiation, filaggrin is cross-linked to the cornified cell envelope, which constitutes an insoluble barrier in the stratum corneum to protect the organism against environmental agents and to prevent epidermal water loss.¹³

Recessive X-linked ichthyosis is the second most common ichthyosis. It affects males and is more severe than ichthyosis vulgaris, with a prevalence of 1:2000 to 1:6000. It is clinically characterized by generalized dark brown, polygonal scales and dryness on the back of the scalp, ears, neck, back, and legs with sparing of the face that appears shortly after birth. Symptoms begin at birth, and by childhood or adolescence patients become severely affected. The skin is often exacerbated in cold weather but dramatically improves during the summer.¹⁴ It is caused by a deficiency of the enzyme steroid sulfatase.⁸ Approximately 90% of patients have large deletions involving the STS (steroid sulfatase) gene and adjacent DNA.⁷

Autosomal recessive congenital ichthyosis is uncommon with a prevalence of 1:100,000. It presents at birth with erythrodermic, scaly skin over almost the entire body.⁵ Clinical presentation and severity of presentation can vary significantly and fall on a continuum. Takeichi and Akiyama⁷ clinically divided this group into three major and three minor subtypes. Harlequin ichthyosis, also known as alligator baby or malignant keratosis,¹⁵ is the most severe form of nonsyndromic inherited ichthyosis. Clinically, these babies are usually born prematurely with thick, platelike scales that severely restrict movement, severe eyelid ectropion, eclabium (out-turned lips) flattening of the ears, and scarring alopecia of the scalp and eyebrows.¹⁶ Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection.¹⁷ The disease is associated with mutations in any one of more than 12 genes involved in the biosynthesis that regulate epidermal lipid synthesis and cornified lipid envelopes.⁶ These include ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, TGM1, and SLC27A4, but 15% of affected families do not have pathogenic variants in any of the known genes.¹⁷

Lamellar ichthyosis is another phenotype of autosomal recessive ichthyosis that is less severe than harlequin ichthyosis. The severity of the hyperkeratosis and scales varies from patient to patient. The scales covering most of the body are large, thickened, and dark gray or brown. Other signs may include eyelid ectropion, hair loss, palmoplantar hyperkeratosis, abnormally formed fingernails and toenails, lips that are turned outward, hypohidrosis, increased sensitivity to heat, dehydration, and respiratory difficulties.¹⁸ Less frequently, affected individuals may have joint abnormalities and rickets.¹⁹ In a series of 13 patients with lamellar ichthyosis and ectropion, 2 cases (15.4%) resulted in corneal scarring.²⁰,²¹ In another series of 10 patients, corneal leukoma was seen in 30%.²² Cruz et al²² postulate that the corneal damage is not directly linked to lower ectropion but is multifactorial. Cicatricial ectropion can involve both upper and lower eyelids with lagophthalmos exacerbating evaporative dry eye disease and decreased tear breakup time.²³ The risk of corneal scarring increases especially in cases where Bell phenomenon is absent. A rare case of spontaneous subconjunctival abscess was described in a child with lamellar ichthyosis.²⁴ Eight causative genes have been identified associated with lamellar ichthyosis: ABCA12 (adenosine triphosphate-binding cassette subfamily A member 12); ALOXE3 (lipoxygenase 3); ALOX12B (12R-lipoxygenase); CERS3 (ceramide synthase 3); CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22); NIPAL4/ICHTHYIN (NIPA-like domain containing 4); PNPLA1 (patatin-like phospholipase domain-containing protein 1); and TGM1 (transglutaminase 1).⁷

Congenital ichthyosiform erythroderma, also known as collodion baby, is a form of autosomal recessive congenital ichthyosis characterized by generalized, red, dry, pruritic, and rough skin with large coarse and fine white scales.⁷ Erythroderma and scaling appear after several weeks when the collodion membrane is shed. The scales are typically fine and white or light gray. Systemic erythroderma is present, but this may improve in infancy.¹⁸,²⁵ Mutations have been identified in several causative genes including ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4/ICHTHYIN, PNPLA1, and TGM1.²⁶

Self-healing collodion baby is a minor variant of autosomal recessive congenital ichthyosis accounting for approximately 10% of all cases. It is characterized by nearly complete resolution of scaling within the first 3 months of life.⁵,²⁷ It is associated with TGM1, ALOX12B, and ALOXE3 mutations,²⁸ and two cases were described associated with homozygous mutations in the gene CYP4F22.

Acral self-healing collodion baby is a very rare variant of autosomal recessive congenital ichthyosis where the patients are born with the typical membrane but limited to the hands and feet only, and after it sheds, the skin appears completely normal.²⁹ This variant is associated with a novel mutation in the TGM1 gene.³⁰

Bathing suit ichthyosis is another minor variant of autosomal recessive congenital ichthyosis characterized by a unique distribution of lesions on the trunk, the proximal parts of the upper limbs, the scalp, and the neck. The central face and extremities are not involved.⁵,³¹,³² Twenty missense mutations of TGM1 have been reported, nine of which occurred only in patients with this phenotype.

Keratinopathic ichthyosis was proposed as a general term for another group of rare phenotypes that include epidermolytic ichthyosis, superficial epidermolytic ichthyosis, annular epidermolytic ichthyosis, ichthyosis Curth-Macklin, autosomal recessive epidermolytic ichthyosis, epidermolytic nevi, and congenital reticular ichthyosiform erythroderma. They are all associated with mutations in the keratin family genes, KRT1, KRT2, and KRT10. Epidermolytic ichthyosis is the most prevalent form of the keratinopathic ichthyoses characterized by generalized erythroderma and blistering at birth,
followed by hyperkeratosis later in life.⁵,⁷,³³ The blistering and erythema diminish with age. Superficial epidermolytic ichthyosis is characterized by mild epidermal hyperkeratosis over flexural areas and blister formation with a more superficial pattern than epidermolytic ichthyosis. It is caused by mutations in KRT2, rather than KRT1 or KRT10.⁵ Annular epidermolytic ichthyosis is another rare distinct phenotypic variant of epidermolytic ichthyosis characterized by the intermittent development of annular, polycyclic, erythematous, scaly plaques over the proximal extremities and the trunk.³⁴ It is associated with a unique mutation in KRT10. Ichthyosis Curth-Macklin is an autosomal dominant disorder characterized by spiky or verrucous hyperkeratosis affecting the large joints and the trunk.³⁵,³⁶ Mutations of KRT1 have been identified in patients with this disorder.³⁷ Autosomal recessive epidermolytic ichthyosis is a phenotype where babies are born with collodion skin and generalized erythroderma. The collodion membrane is shed early. In the first months after birth, infants develop skin erosions after mild mechanical trauma and progressive ichthyosis with generalized hyperkeratosis most pronounced on the big joints, elbows, and knee bends and show phenotypic variability from mild to lethal forms.³⁸ The condition is caused by autosomal recessive mutations in KRT10 leading to a complete absence of the protein.³⁹,⁴⁰ Epidermolytic nevus is characterized by single or multiple circumscribed verrucous lesions frequently presenting following Blaschko lines.⁴¹,⁴² Mutations in KRT1 and KRT10 have been reported. Congenital reticular ichthyosiform erythroderma (also referred to as ichthyosis with confetti) is a very rare skin disease in which babies are born with erythroderma, prominent scales, and palmoplantar keratoderma.⁴³,⁴⁴ Hundreds to thousands of pale confetti-like spots appear on body surfaces and increase in number and size with advancing age. Mutations in KRT10 and CRIE have been described.⁴⁵

Among the syndromic forms of ichthyosis, several uncommon syndromes have been described.⁸ Netherton syndrome is a rare autosomal recessive disorder that mostly affects females with an incidence of 1 in 200,000 individuals.⁴⁶ The syndrome is caused by mutations of the SPINK5 gene and includes congenital ichthyosis with double-edged scales, bamboo hair, and atopic predisposition. Hair is short, sparse, and dry.⁸,⁴⁷,⁴⁸ The syndrome also includes a predisposition to allergies, asthma, and eczema, with hypereosinophilia, trichorrhexis invaginata, and elevated serum IgE levels.

Sjögren-Larsson syndrome is an autosomal recessive error of lipid metabolism due to biallelic mutations in the ALDH3A2 gene that result in a deficiency of fatty aldehyde dehydrogenase. Premature birth is common, seen in 73% of cases.⁴⁹,⁵⁰,⁵¹,⁵² Affected patients show a classical triad of congenital ichthyosis, mental retardation, and spastic paralysis of the limbs.⁵⁰ A collodion membrane is not seen. The skin has an erythematous and hyperkeratotic appearance that transforms over days to the dry scaly appearance of ichthyosis. They may also show alopecia, eclabion, and eyelid ectropion.⁵¹ Patients display sparse to florid perifoveal crystalline inclusions (glistening white dots) located in the inner retina and may show retinal thinning, cystic macular degeneration, retinal pigment epithelium atrophy, and deficiency of macular pigment.

Refsum syndrome is an autosomal recessive disease that develops from age 7 months to older than 50 years, and patients are usually normal at birth. It is characterized by ichthyosis, retinitis pigmentosa, progressive panretinal degeneration, cataract, sensorineural deafness, peripheral neuropathy, cerebellar ataxia, anosmia, hemeralopia, muscular atrophy, cardiomyopathy, progressive myelin degeneration, functional disorders of the nervous system, cochlear hearing loss, and renal failure, and an increase in the cerebrospinal fluid level of protein.⁵³,⁵⁴,⁵⁵ It is caused by biallelic pathogenic variants in either PHYH (encoding phytanoyl-CoA hydroxylase), which accounts for more than 90% of Refsum disease, or PEX7 (encoding the PTS2 receptor), which accounts for less than 10% of the disease.⁵⁶