Harlequin Syndrome

Congenital skin disease in which the skin builds up and scales (“fish skin disease”). Associated with a very poor prognosis (usually death if infant is younger than 1 week).

Harlequin Fetus; Harlequin-Type Ichthyosis.

First reported in the diary of the Reverend O. Hart in 1750. Inheritable disorder of keratinization caused by a structural defect of tonofibrils (abnormal alpha-protein structure of keratin). This lesion is distinct from the lamellar exfoliative type of congenital ichthyosis, the prognosis of which is better.

Rare (three cases per year in the United Kingdom). Harlequin syndrome is one of the four reported genetic disorders of keratinization displaying a structural defect of tonofibrils; the other three are bullous (or congenital) ichthyosiform erythroderma, Curth-Macklin form of ichthyosis hystrix, and ichthyosis hystrix gravior.

Autosomal recessive. Chromosome 18 might carry the gene responsible for the disorder (transglutaminase 1 [TGM1]). Prenatal diagnosis is available (skin biopsies of the fetus).

In the harlequin fetus, an abnormal radiographic diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. A suggested cause for this finding is an abnormality of keratinization.

Characteristic clinical picture. Skin biopsy demonstrating severe cornification. Mutations in TGM1 are identified by sequence analysis of complementary DNA isolated from a fresh 2-mm skin punch biopsy.

Many are stillborn. Others are of low birth weight for dates and, as a rule, die in less than 1 week as a consequence of severe restriction of chest movement and abdomen incompatible with respiration and feeding. Thermoregulation disorders. Plaques, measuring up to 4 or 5 cm per side, have a diamond-like configuration resembling the suit of a harlequin clown. One patient survived 6 years with considerable failure to thrive, probably related to the enormous losses of protein in desquamated skin.

In practice, because of the severity of the disease, harlequin syndrome patients are not eligible for surgery and anesthesia. Assess the severity of the disease, particularly in regard to the thoracic and abdominal involvement. Limit skin desiccation by providing continuous warm humidification of the baby. Assess nutritional state. Exclude the presence of hypovolemia caused by poor feeding. Check core temperature since hypothermia is often present. Investigations: hemoglobin, arterial blood gas analysis, serum protein, and albumin levels.

Venous access is often difficult. Strict aseptic measures must be taken for venous cannulation because the impaired skin barrier is predisposed to infection. Secure the venous cannulas with petroleum jelly gauze and tie or suture down. Adhesive tape likely will denude the skin and cause bleeding. ECG monitoring may require needle electrodes or pads without adhesive for the same reason. Semiflexed rigid limbs require careful positioning to prevent pressure sores. Severe ectropion and bulging eyes require ointment and careful taping to prevent ocular injury. Measures to maintain normothermia should be instituted. Involvement of the chest and abdomen that interferes with respiration may necessitate mandatory postoperative ventilatory support.

Dehydration and hypoalbuminemia may affect the kinetics of drug distribution and excretion.

Bullous Ichthyosiform Erythroderma (Epidermolytical Hyperkeratosis): Autosomal dominant disorder present at birth. It is characterized by thick warty scales on most of the body, especially in the creases of skin surfaces involved mostly with flexures. Blisters may occur. It is believed to result from an abnormal arrangement of tonofibrils.

Curth-Macklin Type of Ichthyosis Hystrix: Characterized by ichthyosis ranging from mild to severe. Severe palmoplantar keratoderma may occur with no other symptoms, or the whole body surface may be covered with scales. It is caused by concentric unbroken shells of abnormal tonofilaments around the nucleus.

Ichthyosis Hystrix Gravior (Porcupine Man; Lambert type Ichthyosis): Part of a group of epidermal nevus syndrome characterized by distinctive nevi on the skin apparent at birth that form in a line and usually are excessively pigmented. Often associated with neurologic and skeletal abnormalities (e.g., excessive bone growth, scoliosis, and clubfeet). Mental retardation, brain atrophy, brain cysts, seizures, and eye abnormalities may occur. Transmission is suggested to be an autosomal dominant trait that occurs in approximately two thirds of cases. Singular or multiple forms of the five major types of epidermal nevi have been described: raised wart-like streaks, polyp-like masses forming in lines, dark velvety spots, scaly streaks, or an orange, hairless, velvety patch covering part of the face, nose, eyes and scalp.

Ichthyosis Lamellar: Serious skin disorder characterized by cornification that is the conversion of the upper layer of the skin into scaly or plate-like (squamous) skin. In serious cases, the ectropion of the eyelids and lips may be present. Erythroderma and palmoplantar keratoderma are present in the newborn. Lipid analysis from the stratum corneum of the skin shows increased free sterols and ceramides but normal hydrocarbon (alkane) content. Autosomal recessive and dominant forms have been reported.

Keratosis Ichthyosis Deafness (KID) Syndrome: Present at birth and characterized by corneal keratitis, skin plaques on the extremities and face, palmar-plantar keratosis, and deafness. It is genetically transmitted as autosomal recessive and autosomal dominant forms.

Recessive X-linked Ichthyosis: X-linked ichthyosis occurs only in males and usually is present at birth or during infancy. It is characterized by large, dark, sometimes fine scales that are prominent on the neck and trunk. Skin on the palms and soles is normal. Opacities in the cornea of the eye occur. It is believed to result from an inborn error of metabolism and a steroid sulfatase deficiency.

Netherton Syndrome: Hereditary polymalformative syndrome characterized by abnormal hair, ichthyosis, abnormal fingerand toenails, loss of subcutaneous fat resulting in a prematurely aged-looking face, mild mental retardation, and various neurologic disorders.