Ichthyosis

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According to the latest consensus on ichthyosis, it is classified into two main forms: non-syndromic types, which only exhibit skin manifestations, and syndromic types, which involve manifestations in other organs as well (Table 1). In non-syndromic types, there are four groups: Common ichthyosis, Autosomal Recessive Congenital Ichthyosis (ARCI), Keratinopathic ichthyosis, and other less common forms of ichthyosis(sources from therapeutique-dermatologique.org).

Autosomal Recessive Congenital Ichthyosis (ARCI) encompasses various forms of non-syndromic ichthyosis. According to the 2009 International Consensus Conference on Ichthyosis, it is primarily classified into three major types:

“Harlequin ichthyosis”

“Lamellar ichthyosis (LI)” observed in collodion babies, which can be further categorized into non-bullous erythroderma skin with large brown or white scales.

“(Non-bullous) Congenital ichthyosiform erythroderma (CIE)” is used to distinguish the erythrodermic type of ARCI with small white scales from the lamellar non-erythrodermic type.

Note: “Bullous congenital ichthyosiform erythroderma” refers to a type of autosomal dominant ichthyosis, also known as “Epidermolytic ichthyosis” (EI) or “Epidermolytic hyperkeratosis” (EHK), which does not present in the form of collodion babies.

In addition to these main types of non-syndromic ichthyosis, some rare subtypes have been identified, such as swimsuit ichthyosis, self-healing collodion baby ichthyosis, and ichthyosis prematurity syndrome.

Epidemiology: According to data from the Ichthyosis and Related Skin Types Foundation, ARCI affects approximately 1 in 200,000 individuals in the United States, with the harlequin ichthyosis phenotype being extremely rare.

Clinical Presentation: Although most newborns with ARCI are collodion babies, the clinical presentation and severity of ARCI can vary widely, including the most severe and lethal harlequin ichthyosis, lamellar ichthyosis (LI), and (non-bullous) congenital ichthyosiform erythroderma (CIE) in older individuals.

Harlequin Ichthyosis: Newborns are covered with thick, hard, armor-like cornified skin at birth, leading to facial and cranial deformities. Infants may experience life-threatening complications such as respiratory distress, dehydration, electrolyte imbalance, feeding difficulties, and bacterial infections. The reported survival rate is 56%, and with advancements in neonatal intensive care and treatment options, the survival rate is expected to improve further.

Lamellar Ichthyosis (LI): Newborns with LI typically present with a collodion membrane. The membrane subsequently dries and peels off, replaced by white and later brown, lamellar scales covering the entire body. Severely affected infants may exhibit ectropion, eclabium, scarred alopecia of the scalp and eyebrows, and excessive keratosis of the palms and soles. Erythroderma may be present but is usually mild and not a primary feature.

Congenital Ichthyosiform Erythroderma (CIE): Up to 90% of CIE children will have a collodion membrane at birth. They subsequently develop erythroderma (widespread red skin) and fine, white scales. They also experience palmoplantar keratosis, often accompanied by painful fissures and finger contractures. Severely affected newborns may have ectropion, eclabium, scalp involvement, and eyebrow loss.

Intermediate Phenotype: Many affected individuals fall within some stage of the LI-CIE spectrum, classified as mild LI or mild CIE or displaying fine/mild scales characteristic of non-LI/non-CIE features, termed Congenital Ichthyosis with Fine Scales (CIFS).

Other Rare Subtypes:

Swimsuit Ichthyosis: Mainly observed in individuals of South African descent, caused by pathogenic variations in TGM1, presenting with brown or dark gray scales on the trunk (swimsuit area) while limbs and central face are almost entirely unaffected.

Self-Healing Collodion Baby Ichthyosis: Ichthyosis largely disappears in infancy, with only dryness, mild residual, or localized desquamation, linear keratosis of palms, cheek erythema, or anhidrosis.

Ichthyosis Prematurity Syndrome (IPS): Babies are born prematurely between weeks 29-35. Typically associated with a history of polyhydramnios during pregnancy, the skin at birth is erythrodermic, edematous, and massively thickened, resembling fetal lamellar ichthyosis. Newborns experience severe respiratory distress due to intrauterine aspiration of amniotic fluid, leading to poor Apgar scores, requiring intensive care and prolonged hospitalization. However, the prognosis for IPS is generally favorable.

Genotype-Phenotype Correlation:

ABCA12: Detected in nearly all children with harlequin ichthyosis across different racial backgrounds, mostly involving nonsense mutations and small indels causing premature protein translation termination. Splice mutations and missense mutations are less common, and partial gene deletions spanning exons 1 to 35 have been reported.

Note: While pathogenic variations in ABCA12 account for most cases of harlequin ichthyosis, pathogenic variations in ABCA12 have also been reported in 10 LI families (mostly from North Africa) and 8 CIE families.

ALOX12B, ALOXE3: Typically associated with individuals having either CIE or intermediate phenotypes, though self-healing collodion baby ichthyosis has been reported in other individuals.

CERS3: Consistent skin manifestations, including collodion membrane at birth, facial and trunk erythema with fine scales, large brown scales on lower limbs, and premature skin aging with keratotic mottled plaques.

CYP4F22: Pathogenic variations have been reported in LI-prone families, associated with linear keratosis of palms and soles, but without collodion-like appearance at birth. Also reported in individuals with self-healing collodion baby ichthyosis.

LIPN: Presents as generalized fine, white scales and minimal erythema in late childhood.

NIPAL4: Presents as CIE or intermediate phenotype.

PNPLA1: Typically presents with a collodion membrane at birth, transitioning to CIE phenotype with scalp involvement, linear keratosis of palms and soles. However, cases with widespread dark brown scales, associated with hypohidrosis or mild disease with generalized fine epidermal desquamation and knee hyperkeratosis, have also been observed.

SLC27A4: Associated with ichthyosis prematurity syndrome (IPS) phenotype.

TGM1: The vast majority have typical LI phenotypes; many have milder non-erythrodermic phenotypes. Additionally, reported in a few individuals with “swimsuit ichthyosis” and self-healing collodion baby ichthyosis(quotes from therapeutique).

This comprehensive overview covers the classification, epidemiology, clinical presentation, and genotype-phenotype correlations of ichthyosis, shedding light on the complexity and diversity within this group of inherited skin disorders.

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