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)


Harlequin ichthyosis (HI) is the most severe form of keratinizing disorders, often lethal in the neonatal period. It is characterized by a profound thickening of the keratin skin layer, resulting in a dense “armor”-like scale 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 impacts normal development of the skin barrier.

Clinical Description

Harlequin ichthyosis (HI) is inherited in an autosomal-recessive manner. Affected newborn infants are encased in a very thick “coat of armor” made of large yellowish plaques covering the entire body. Soon after birth, red and deep fissures occur giving the appearance of a harlequin’s costume. The skin is pulled tight such that the face loses its normal appearance and appears frog-like, with eversion of the eyelids (ectropion) and lips (eclabion) and flattening of the ears and nose. The extremities are swollen due to constriction by massive thickening of the skin. 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.


As a consequence of impaired ABCA12 function,Akiyama et al. found that lamellar granules were not properly formed and therefore the lipids essential for stratum corneum formation (such as glucosylceramide) were abnormally processed, diffusely distributed, and abnormally secreted or not secreted at all. The lack of lipid lamellae formation in the intercellular space resulted in abnormal barrier formation and extraordinary thickening of the stratum corneum.


Clinical main criteria are the presence of ectropion and eclabium and extreme hyperkeratosis constricting the thorax and/or extremities. Diagnosis is confirmed by 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 diagnosis is performed by sequencing of the ABCA12 gene, the specific identification of the causative mutations being essential for genetic counselling and prenatal diagnosis.


Treatment with systemic retinoids (synthetic derivatives of vitamin A) during the newborn period can facilitate desquamation of the hyperkeratotic membrane. Several babies treated with retinoids, have survived and subsequently developed a severe phenotype of congenital ichthyosis.