July 2000

DIAGNOSIS: Harlequin Ichthyosis

Harlequin ichthyosis (HI) is the most severe manifestation of the congenital ichthyoses, which include X-linked ichthyosis, autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris, ichthyosis bullosa of Siemens, and non-bullous congenital ichthyosiform erythroderma, among others. Characteristic physical exam findings in this disorder of epidermal keratinization include a dense yellow waxy scale with irregular deep fissures covering the body surface, a serniflexed posture, severe ectropion and eclabium secondary to the mechanical pull of the thickened skin surface on the softer conjunctiva and oral mucosa, and hypoplasia of terminal appendages including ears, nose, and digits. The most prominent clinical complications of the harlequin fetus occur secondary to breakdown of the protective epithelial barrier and include sepsis and dehydration with resulting hypernatremia, in addition to impaired nutrition and pneumonia from the restrictive effect of the scale on sucking and respiration. The prognosis for affected fetuses is grim, with most dying within days or weeks of birth.

Unlike many of the other congenital ichthyoses, the gene defect in HI has not been identified. Pedigree analysis suggests autosomal recessive inheritance. Laboratory studies have demonstrated heterogeneity in protein expression and morphology of harlequin keratinocytes, leading to the classification of HI into three histopathologic subtypes despite essentially identical clinical presentations, perhaps reflecting distinct complementation groups for the disorder. The pathophysiologic mechanism of disease in HI is unknown, although dysgenesis of lamellar granules and follicular hyperkeratosis have been described, as well as defects in profilaggrin processing and/or expression in vitro with evidence for a protein phosphatase 2A dependent mechanism.

Initial treatment of the harlequin fetus focuses on supportive care measures including protective topical barriers, antibiotic treatment at the earliest signs of infection, and respiratory and nutritional support as required. Early intervention with topical retinoids has resulted in multiple case reports of long-term survival of harlequin fetuses, usually to the age of one year or less but in one report as long as eight years. In these long-term survivors, the harlequin ichthyosis appears to resolve into a condition resembling non-bullous congenital ichthyosiform erythroderma, a severe persistent dermatosis with few treatment options and significant morbidity. Case reports of successful prenatal diagnosis of HI via ultrasound, fetoscopy, and amniocentesis have provided the option of midpregnancy termination to high risk families, although these are still experimental procedures given the lack of data on the the chronologic maturation of the HI phenotype in utero.

References:

B.A. Dale and E. Kam. (1993) Arch. Derm., 129: 1471-1477.

M. Haftek, F. Cambazard, D. Dhouailly, A. Reano, M. Simon, A. Lachaux, G. Serre, A. Claudy, and D. Schmitt. (1996) Br. J. Derm., 135: 448-453.

E Kam,W Nirunsiksiri, B Hager, P Fleckman, and B Dale. (1997) Br. J. Derm., 137: 874-882.

F. Lawlor and S. Peiris. (1985) Br. J. Derm., 112: 585-590.

W. Watson and L. Mabee, Jr. (1995) J. Ultrasound Med. 14: 241-243.

M. Akiyama, K. Suzumori, and H. Shimizu. (1999) Prenatal Diagnosis, 19: 167-171.

My thanks to Drs. Aimee Payne, John Streidl and Michael Heffernan and for assisting in the presentation of this case.