Harlequin Type Ichthyosis Congenita
DISEASE CARD
| Disease group | Keratinization Disorder |
|---|---|
| DISEASE NAME | Harlequin Type Ichthyosis Congenita |
| Synonymous | Harlequin Fetus, Harlequin Ichthyosis |
| Estimated prevalence | - |
| OMIM | 242500 |
| Inheritance | Autosomal Recessive |
| Gene (s) | ABCA12 (607800) |
Definition
Harlequin ichthyosis (HI) is the most severe form of keratinizing disorders (autosomal recessive congenital ichthyosis), often lethal in the neonatal period due to sepsis and respiratory failure. It is characterized by a profound thickening of the keratin skin layer, resulting in a dense “armor”-like skin that covers the body with deep fissures, and contraction abnormalities of the eyes, ears, and mouth. HI is caused by mutations in ABCA12, leading to defective lipid transport that significantly impairs normal development of the skin barrier.1, 2
Clinical Description
Affected newborns with HI are encased in a very thick “coat of armor” i.e. large yellowish plaques/plates of stratum corneum covering the entire body. Soon after birth, numerous erythematous skin fissures arise within the covering, reaching deep into the dermis and giving the appearance of a harlequin’s costume. The skin is pulled tight such that the face changes its normal appearance, with eversion of the eyelids (ectropion), lips (eclabion) and flattening of the ears and nose. The extremities are swollen due to constriction by massive skin thickening and around 10% of patients develop autoamputation of digits. Liveborn infants usually die within the first days of life from respiratory, infectious, and/or dehydration-related complications, unless early systemic retinoid treatment is given.
In children, surviving the initial critical phase of the disease, the thickening of the stratum corneum decreases and large, lamellar scales develop on a diffusely erythematous skin.
Pathogenesis
As a consequence of impaired ABCA12 function, Akiyama et al. observed that lamellar granules do not properly form and therefore the lipids and proteases (such as glucosylceramide) essential for stratum corneum formation were abnormally processed, diffusely distributed, and abnormally secreted or not secreted at all. The lack of lipid lamellae formation in the intercellular space results in abnormal barrier formation and extraordinary thickening of the stratum corneum. Likewise, absence of interstitial proteases reduces digestion of corneodesmosomes, holding the superficial keratinocytes together, which results in the accumulation of stratum corneum.2-5
Diagnosis
The main clinical criteria are the presence of ectropion, eclabium and extreme hyperkeratosis constricting the thorax and/or extremities. Diagnosis can be confirmed by identifying a loss/reduction of ABCA12 expression in the granular layer of the epidermis. Electron microscopy in HI patients shows abnormal, vacuolated lamellar granules in the upper intermediate cells and a large number of lipid droplets in the cytoplasm of incompletely keratinized keratinocytes. Molecular analysis is recommended (sequencing of the ABCA12 gene) for genetic counselling and prenatal diagnosis, as the risk of recurrence is 25%. Prenatal diagnosis is usually feasible with 2D ultrasound combined with 3D imaging.6
Treatment
Treatment with systemic retinoids (preferred compound acitretin) as early as possible after delivery facilitates desquamation of the hyperkeratotic membrane and has improved the prognosis. In the early phase, a humidified incubator is essential to counteract the profound transcutaneous losses of water and heat. A strict temperature regulation and nutrition management is required. Further, physiotherapy, pain and infection control as well as skin and eye care are relevant. Emollients should be applied multiple times a day to the skin and bathing can be recommended. Keratinolytics (e.g. salicylic acid, urea) in the neonatal period are contraindicated due to the high cutaneous absorption that may result in systemic toxicity.7