Harlequin Ichthyosis Clinical Presentation

Harlequin ichthyosis manifests at birth. Harlequin ichthyosis may or may not have been diagnosed prenatally in a high-risk family. The history should carefully explore the following questions:

• Is the couple consanguineous?
• Does the couple have another child with ichthyosis?
• Does the family have a history of severe skin disorders?
• Do the parents or family members have a history of intrauterine or neonatal death?
• What was the expected date of delivery?
• Were decreased fetal movements or intrauterine growth retardation noted during the pregnancy?
• Did the mother undergo prenatal ultrasonography?
• Were prenatal procedures (eg, amniocentesis, fetal skin biopsy) performed?

The following findings may be noted at physical examination:

• Skin: Severely thickened skin with large, shiny plates of hyperkeratotic scale is present at birth. Deep, erythematous fissures separate the scales.
• Eyes: Severe ectropion is present. The free edges of the upper and lower eyelids are everted, leaving the conjunctivae at risk for desiccation and trauma.
• Ears: The pinnae may be small and rudimentary or absent.
• Lips: Severe traction on the lips causes eclabium and a fixed, open mouth. This may result in feeding difficulties.
• Nose: Nasal hypoplasia and eroded nasal alae may occur.
• Extremities: The limbs are encased in the thick, hyperkeratotic skin, resulting in flexion contractures of the arms, the legs, and the digits. Limb motility is poor to absent. Circumferential constriction of a limb can occur, leading to distal swelling or even gangrene. Hypoplasia of the fingers, toes, and fingernails is reported. Polydactyly is described.
• Temperature dysregulation: Thickened skin prevents normal sweat gland function and heat loss. The infants are heat intolerant and can become hyperthermic.
• Respiratory status: Restriction of chest-wall expansion can result in respiratory distress, hypoventilation, and respiratory failure.
• Hydration status: Dehydration from excess water loss can cause tachycardia and poor urine output.
• Central nervous system: Metabolic abnormalities can cause seizures. CNS depression can be a sign of sepsis or hypoxia. Hyperkeratosis may restrict spontaneous movements, making neurologic assessment difficult.

Genetic factors

Mutations in a gene known as ABCA12 (adenosine triphosphate [ATP]-binding cassette transporter, subfamily A, member 12), in chromosome region 2q35, underlie this disorder.^{[3, 4]} Patients with harlequin ichthyosis are usually homozygous for this mutation consistent with autosomal recessive inheritance.

The ABC superfamily of genes encodes proteins that transport a number of substrates across cell membranes.^[5]ABCA12 is thought to encode a transmembrane protein that mediates lipid transport.

This ABCA12 -mediated lipid-transfer system is thought to be essential to the transfer of lipids from the cytosol of the corneocyte into lamellar granules. Lamellar granules are intracellular granules that originate from the Golgi apparatus of keratinocytes 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 the cornified layer. The extruded lipids are arranged into lamellae in the intercellular space with the help of concomitantly released hydrolytic enzymes. The lamellae form the skin's hydrophobic sphingolipid seal.

In harlequin ichthyosis, 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 intercellular 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.^[6]

The exact mechanism of this transport abnormality has yet to be elucidated. One hypothesis involves abnormal calcium-mediated signaling 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.^[7]

The pivotal role of ABCA12 in harlequin ichthyosis is supported by in vitro data. Studies have demonstrated normalization of lipid transport when the wild-type ABCA12 gene is transferred to keratinocytes of patients with harlequin ichthyosis.^[8]

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

Other chromosomal abnormalities are described. One patient with a de novo deletion of chromosome arm 18q has been reported.^[9]

Histopathologic, ultrastructural, and biochemical factors

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

The 2 main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. The relationship between mutations in the gene ABCA12 and abnormal lamellar granules is well documented. The pathophysiology of the other abnormalities documented below has yet to be elucidated.

Abnormal lamellar granule structure and function

The pivotal role of lamellar granules in maintaining a normal skin barrier is described in the Genetic factors bullet points at the beginning of this section.

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 polyprotein 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.

Some patients have a persistence of profilaggrin and an absence of filaggrin in the stratum corneum. A defect in protein phosphatase activity and subsequent lack of conversion of profilaggrin to filaggrin is hypothesized.

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.