Harlequin Ichthyosis

Harlequin-type ichthyosis (also harlequin ichthyosis, ichthyosis congenita, ichthyosis fetalis, keratosis diffusa fetalis; Harlequin fetus) is a congenital, autosomal recessive skin disorder classified in the ICD as Q80.4. It is the most severe form of congenital ichthyosis and is characterized primarily by the accumulation of keratinized layers in the skin of the fetus, i.e. a disorder of keratinization. 

Children with this condition have skin composed of hard, thick, yellowish scales. The eyes and ears are often improperly developed. The scaly and fissured skin, forming deep cracks, severely and painfully restricts the child’s movement and, as areas with exposed, bleeding tissue present a markedly increased risk of bacterial infection and contamination, the infant is in constant danger of life-threatening infection. The severity of HTI is divided into three levels, of which the second and third are invariably lethal.

The designation harlequin-type is derived from the characteristic facial expression (eclabium) and the large scales resembling the pattern on the garments of court jesters (Harlequin – Arlecchino). These external features, however, are caused by severe hyperkeratosis. The disease can be diagnosed in utero using a method known as chorionic villus biopsy (with sampling typically performed between the 11th and 14th week of pregnancy), when the physician collects a sample of the placenta, or by morphological analysis of amniotic fluid called amniocentesis. Physicians can also identify early manifestations of the disease using ultrasound and thus assess the condition of the fetus. The ultrasound method has the advantage of being non-invasive.

Diagnosis

In medical genetics, a mutation of the ABCA12 gene, located on chromosome 2, specifically on the long (q) arm, is currently considered the main causative factor in the development of HTI. If this gene is absent from the genotype or present in a markedly reduced amount, it leads to numerous problems in the development of the epidermis in both the prenatal and postnatal periods. 

The function of ABCA12 is primarily to provide instructions for the production of a protein known as ABC (ATP-binding cassette), which is essentially a transporter protein carrying molecular substrates across cellular membranes. If this defect is caused by a mutation in the ABCA12 gene, it results in the development of HTI or other severe skin disorders, such as lamellar ichthyosis type 2, which, although not as dangerous or life-threatening for the newborn as HTI, nevertheless represents a serious congenital developmental disorder.

Treatment

In the past, this condition was almost always fatal due to limited availability of medical care, and it remains incurable to this day. Dehydration, infections, sepsis, and restricted respiration brought about the end of life in these children in a very painful manner; although individuals with harlequin ichthyosis are usually temporarily blind and deaf at birth, their ability to perceive external stimuli, including the sensation of pain, is fully preserved. Newborns affected by this disorder, in the mildest form, did not survive even one week, while in more severe manifestations they survived only a few hours. It also occurs that a woman carrying an affected fetus undergoes spontaneous miscarriage.

However, treatments such as isotretinoin (e.g. the preparation Isotrex) are now available, which can at least partially improve the condition of the skin, although the procedures and handling are time-consuming and the condition requires daily care. Nevertheless, thanks to improvements in the quality of neonatal care and clinical genetics, there are now also known cases in which patients have survived beyond childhood into adolescence or even adulthood.

• craniofacial deformities caused by pressure of thickened skin
• poorly developed to completely rudimentary ears, nose, and eyelids
• the eyelids are affected by ectropion (malposition), the conjunctiva is affected by chemosis, and the globes are not visible; moreover, they are highly susceptible to damage and are often completely nonfunctional
• stretched lips extending over the anterior part of the jaw with dry, inelastic skin, fixed in a wide grimace, so-called eclabium
• the arms, feet, and fingers are often swollen and deformed to the extent that flexion is not possible hypotrophic hair and nails
• possible polydactyly (extra digits)
• respiratory difficulties – restricted breathing due to impaired contraction and expansion of the chest, hypoventilation up to respiratory arrest
• impaired thermoregulation – excessive sensitivity to temperature changes and overheating due to thickened skin
• inability to retain even small amounts of water due to their scales, frequent dehydration