Cause

Cause....

Harlequine Ichthyosis is caused by the mutation in a gene known as ABCA12 (Adenosine Triphosphate [ATP]-binding Cassette Transporter, subfamily A, member 12) in chromosome region 2q34. Patients with Harlequin Ichthyosis are usually homozygous for this mutation consistent with autosomal recessive inheritance.

The ABCA12 gene provides instruction for making a protein known as an ATP-binding Cassette (ABC) Transporter. The ABC transporter proteins carry many types of molecules across the cell membranes. In particular, the ABCA12 protein plays a major role in transporting fats (lipids) from the cytosol of the corneocyte into lamellar granules. Lamellar granules are intracellular granules that originate from the Golgi apparatus of keratinocyte in the stratum corneum. These granules are responsible for secreting lipids that maintain the skin barrier at the interface between the granular cell layer and cornified layers. The extruded lipids are arranged into lamellae in the intracellular space with the help of concomitantly released hydrolytic enzymes. The lamellae from the skin’s hydrophobic sphingolipid seal.

In HI the ABCA12-mediated transfer of lipid to lamellar granules is absent. The lamellar granules themselves are morphologically abnormal or absent. Normal extrusion of lipid from these granules into the intracellular space cannot occur, and lipid lamellae are not formed. This defective lipid ‘mortar’ between corneocyte ‘bricks’ results in aberrant skin permeability and lack of normal corneocyte desquamation.

The exact mechanism of this transport abnormality has yet to be elucidated. One hypothesis involves abnormal calcium-mediated signalling by means of calpains. Calpains are calcium-activated neutral proteases that are essential to normal epidermal differentiation. Calpains are consistently underexpressed in patients with harlequin ichthyosis compared with the general population.

The pivotal role of ABCA12 in harlequin ichthyosis is supported by in vitro data. Studies have demonstrated normalization of lipid transport when the wild-typeABCA12 gene is transferred to keratinocytes of patients with harlequin ichthyosis.

A milder form of ichthyosis, lamellar ichthyosis type 2, also involves mutations in the ABCA12 gene. The phenotypic difference between these two disorders has been explained on the basis of differing genotypic variants. Nonsense mutations inABCA12 are seen in harlequin ichthyosis, whereas missense mutations underlie lamellar ichthyosis type 2.

Histopathologic, Ultrastructural & Biochemical Factors

Histopathologic, ultrastructural and biochemical studies have identified several characteristic abnormalities in the skin of patients with harlequin ichthyosis (HI).

The 2 main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. The pathophysiology of the other abnormalities is yet to be elucidated.

Abnormal Lamellar Granule Structure and Function

All patients with harlequin ichthyosis have absent or defective lamellar granules and no intercellular lipid lamellae. The lipid abnormality is believed to allow excessive transepidermal water loss. Lack of released hydrolases prevents desquamation, resulting in a severe retention hyperkeratosis.

Abnormal conversion of Profilaggrin to Filaggrin

Profilaggrin is a phosphorylated poly-protein residing in keratohyalin granules in keratinocytes in the granular cell layer. During the evolution to the corneal layer, profilaggrin converts to filaggrin by means of dephosphorylation. Filaggrin allows dense packing of keratin filaments. Its subsequent breakdown into amino acids occurs prior to desquamation of the stratum corneum.

Abnormal Expression of Keratin

Keratinocyte cell cultures have yielded interesting and heterogeneous findings among patients with harlequin ichthyosis.

Keratin filament density is low in most patients. Expression of certain keratins is abnormal in some patients and normal in others. How this altered expression of structural proteins influences desquamation is uncertain.

Abnormal Keratohyalin Granules

Keratohyalin granules are identified by antifilaggrin antibodies and can be abnormal in some patients with harlequin ichthyosis. They can be large and stellate, small and rounded or absent.