Harlequin ichthyosis: a review of 50 cases and update of ABCA12 mutation analysis

Abstract

Mutations in the ABCA12 gene underlie the most severe form of recessive congenital ichthyosis, Harlequin ichthyosis (HI). Due to the rarity of cases, there are no large series reporting the outcomes of babies born with HI. To improve the care of HI families, the authors have established a major referral centre for HI genetic screening and conducted an international study of 50 children born with this condition. The aim of this study is to assess the clinical outcomes of patients with HI referred to us for ABCA12 analysis and thereby report neonatal complications and long-term sequelae. Secondly, this study aims to identify novel mutations to facilitate prenatal diagnosis. Referring physicians were asked to review medical notes and retrospectively complete a clinical questionnaire. Adults and children over five were asked to complete a dermatology life quality index (DLQI) questionnaire. Mutation analysis was performed using PCR and sequencing but in one consanguineous case, reverse transcriptase-PCR (RT-PCR) on a parental skin biopsy was performed, followed by copy number analysis. Fifty responses were received. All infants had a typical appearance at birth and thereafter developed a persistent, diffuse scaly erythema with hair thinning and nail deformities. In most cases, acitretin was started shortly after birth. Approximately 54% of neonates survived into childhood and beyond. Mortality was associated with respiratory distress and sepsis. Early childhood skin infections with Staphylococcus, Streptococcus, Pseudomonas and MRSA were reported in one third. Problems maintaining weight necessitating nasogastric feeding in infancy and a high-calorie diet thereafter were seen in 58%. Older children experienced joint pain and there were two cases of inflammatory arthritis. While most children attended a mainstream school, 57% in the UK needed statementing. Despite the severity of the disease, the average children9s DLQI score was only 10/30. Eight novel ABCA12 mutations were identified and another three patients have been shown to harbour the common Pakistani mutation 7322delC. In the consanguineous case, a deletion of exons 12–15 was detected by RT-PCR and subsequently confirmed using copy number analysis. This is the first large-scale study of HI and provides important prognostic information for clinicians and affected families.