Lamellar Ichthyosis/non-Bullous Ichthyosiform Erythroderma

DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME Lamellar ichthyosis/Non-bullous ichthyosiform erythroderma
Synonymous ARCI, autosomal recessive congenital ichthyosis, ichthyosis congenita, non-bullous congenital ichthyosiform erythroderma
Estimated prevalence 1:200,000-300,000
OMIM 242100, 242300, 601277, 604777, 604781, 606545
Inheritance Autosomal recessive
Gene (s) ABCA12 (607800), ALOX12B (603741), ALOXE3 (607206), CYP4F22 611495), ichthyin (609383), TGM1 (190195)

Definition

Lamellar ichthyosis (LI), also referred to as non-bullous congenital ichthyosiform erythroderma (NCIE), comprises different types of non-syndromic autosomal recessive congenital ichthyoses (ARCI). The cornification disorder is characterised by generalized hyperkeratosis and scaling ranging from mild to very severe.

Clinical Description

Most patients are born encased in a tight shiny covering, called collodion membrane, and often show a certain skin inflammation/erythroderma. The membranes are gradually replaced during the first weeks of life, and patients develop large, dark or plate-like scales. In contrast, individuals with the NCIE phenotype show a pronounced erythroderma with fine, white scaling. Approximately 10% of all collodion babies heal completely, a condition called self-healing collodion baby (SHCB). Bathing suit ichthyosis (BSI) is regarded another special variant of lamellar ichthyosis, in which patients are born with generalized ichthyosis, which only heals on the extremities and face. Non-erythrodermic, non-lamellar ARCI is regarded a very mild intermediate phenotype within the spectrum of LI situated at one end of the pole and NCIE at the other.

Pathogenesis

In about 35-40% of cases, LI/NCIE is caused by homozygous or compound heterozygous mutations in the TGM1 gene (LI/NCIE type 1) leading to a deficiency of keratinocyte transglutaminase. Transglutaminases are Ca2+-dependent enzymes involved in the assembly of the cornified cell envelope. This resilient sheath of e-(g-glutamyl)lysine cross-linked proteins is deposited subjacent to the plasma membrane in terminally differentiating keratinocytes. The covalent g-amide bonds between various proteins or peptides are formed by transglutaminase-1, -3 and -5. An important specific function of transglutaminase-1 is the cross-linking of w-hydroxyceramides to the cornified cell envelope.

The LI/NCIE locus on chromosome 17p13 (LI/NCIE type 5), which is more often associated with the NCIE phenotype, revealed missense mutations or deletions in ALOXE3 or ALOX12B. These genes encode epidermal lipoxygenase-3 (eLOX3) and 12R-lipoxygenase (12R-LOX). Lipoxygenases are iron-containing dioxygenases, which metabolise essential fatty acids, phospholipids or triglycerids. In the epidermis, eLOX3 and 12R-LOX participate in the same metabolic pathway, which converts arachidonic acid into specific epoxyalcohol products. Loss of function in one of these enzymes probably impairs the epidermal lipid formation. The so called ichthyin gene (LI/NCIE type 6) encodes a putative transmembrane protein, which might be a receptor for products of the epoxyalcohol/lipoxygenase pathway.

Patients with IL/NCIE type 2 (2q34) were all born with collodion membrane and presented a generalised pure lamellar ichthyosis with palmoplantar keratoderma. This phenotype is associated with missense mutations in the ABCA12 gene, the same gene, in which large intragenic deletions and frameshift deletions cause Harlequin ichthyosis. The ATP-binding cassette (ABC) transporter family encompasses a variety of membrane proteins involved in the energy-dependent transport across membranes. In the epidermis, ABCA12 has an important function for the lamellar granules, which traffic lipids, proteases and various functional proteins across the apical keratinocyte membrane into the interstitial space.

Most recently, the molecular basis of LI/NCIE type 3 (19p12-q12) has been established. This subtype is due to autosomal recessive mutations in FLJ39501, a gene encoding an enzyme of the cytochrome P450 family. The former LI/NCIE type 4 (19p13) actually belongs to type 3.

Attempts to refine the classification of LI and NCIE phenotypes by the use of clinical, biochemical and ultrastructural observations have so far failed to yield a consistent scheme. TGM1 mutations can give rise to either LI or NCIE. The distinct Self-healing-collodion baby (SHCB) phenotype as well as Bathing suit ichthyosis (BSI) is due to particular missense mutations in TGM1. Increased intrauterine water pressure or increased local skin temperature play an important pathophysiological role in the two latter special conditions of transglutaminase-1 deficiency.

Diagnosis

The patient’s history includes a detailed family history. Clinical main criteria are the presence of ichthyosis since birth (excluding ichthyosis vulgaris or X-linked recessive ichthyosis) and the isolated phenotype of non-bullous, generalised hyperkeratosis.

A very severe collodion baby with maximal ectropion/eclabium and extreme hyperkeratosis constricting the thorax and/or extremities is suggestive of Harlequin ichthyosis. Symptoms of other organ systems such as severe failure to thrive, frequent superinfections, neurological symptoms, limb defects, hair/nail anomalies etc. indicate a syndrome with associated congenital ichthyosis.

First of all, the laboratory procedure includes a skin biopsy for histological analysis (e.g. to screen for epidermolytic hyperkeratosis), for electron microscopy (ultrastructural subclassification of LI/NCIE), and for immunhistochemical analysis (e.g. for the transglutaminase activity test). DNA sequencing analysis (from EDTA blood) often establishes the specific molecular diagnosis, which is important for genetic counselling.

Treatment

To date, there is no causative therapy available. Taking into account the daily effort of the patients, which is especially necessary for the removal of the hyperkeratosis and scaling, the symptomatic topical treatment can improve the phenotype to a very large extent.

This therapy includes a regular bath (e.g. with sodium bicarbonate or oil) and the daily use of ointments with a scaling effect (urea, propylene glycol, lactic acid, etc.). Special attention must be given to the potentially life threatening increased transepidermal water loss and temperature deregulation of the neonates. Therefore, they must often be kept in an incubator during the first week(s) of life.

Systemic retinoids in a low dosage are often very efficient in reducing the scaling, but difficult (if not impossible) to apply in children or fertile women. Many affected individuals as well as their families benefit from a contact with the self support group.