Harlequin ichthyosis (HI) is the most severe variant of autosomal recessive congenital ichthyosis (ARCI; see this term). It is characterized at birth by the presence of large, thick, plate-like scales over the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe scaling erythroderma.
The prevalence is estimated to be less than 1/1,000,000.
Affected infants born encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with armorlike plates, distributed throughout the body, which severely restrict movement. Facial features are distorted due to extreme ectropion, conjonctival edema, eclabium and broadened nose. Infants also present with contractures, synechiaes of auricles and/or toes with a possible risk of autoamputation. The risk of death is high during the neonatal period, babies being susceptible to severe temperature dysregulation, feeding difficulties, infections and respiratory problems. When they survive, the collodion membrane sheds after a few weeks and transforms into severe erythroderma with severe scaling and persistent ectropion. Other clinical features are often associated such as palmoplantar keratoderma, failure to thrive, short stature, malformed ears and digits, nail deformities and alopecia.
HI is due to recessive mutations in the ABCA12 gene encoding the ATP-binding cassette (ABC) transporter, involved in lipid transport from lamellar granules to the apical surface of granular layer keratinocytes. Genotype-phenotype correlation have been poorly elucidated but most mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains or transmembrane domains resulting in impaired lipid barrier function.
Diagnosis is based on clinical examination. Biopsy is not useful but reveals massive compact orthohyperkeratosis. Skin ultrastructure shows vesicular lamellar bodies ghosts and a paucity of secreted lamellar granules in the stratum corneum. Molecular analysis, if available, reveals ABCA12 mutations.
HI may be confused with the less severe appearance of collodion baby. Later in life, the differential diagnosis includes congenital ichthyosiform erythroderma (CIE), lethal restrictive dermopathy, infantile systemic hyalinosis, and Neu-Laxova syndrome (see these terms).
Prenatal diagnosis is mandatory and consists in DNA analysis of amniocentesis and chorion villus sampling materials, rather than fetal skin biopsies. Ultrasonography shows diffuse scaling, digital contractures, flattened rudimentary external ear, nasal hypoplasia, everted eyelids, typical fish mouth, open fetal mouth, and macroglossia.
The disease is transmitted as an autosomal recessive trait. Genetic counseling should be offered to the affected families informing them of the 25% risk of recurrence.
In the neonatal period, management requires a multidisciplinary approach (ophthalmologists, surgeons, dieticians, and psychologists for family support). Gastrostomy may be necessary. Emollients and oral retinoids (1mg/kg/d) are recommended. It is important to keep invasive procedures to a minimum in order to avoid skin infections. Management of survivors is similar to management of severe CIE and includes use of emollients, keratolytics, and retinoids.
HI is associated with substantial (<50%) morbidity and mortality soon after birth. Survivors have a normal life expectancy but may develop severe skin disease with eye complications related to persistent ectropion, with delayed developmental milestones, motor and social skills.
Last update: January 2012
- Pr Juliette MAZEREEUW-HAUTIER