Harlequin ichthyosis (ORPHA:457)
A rare autosomal recessive congenital ichthyosis characterized at birth by the presence of large, thick, plate-like shell over the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe scaling erythroderma. Harlequin ichthyosis is the most severe disorder of this group.
Epidemiology
The incidence is estimated to be less than 1/300,000 births.
Clinical description
Affected infants born encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with armorlike white-grayish scales, distributed throughout the body, and divided into irregular and quadrangular plates by deep fissures, with severe restriction of movements. Facial features are distorted due to extreme ectropion, conjunctival edema, eclabium and broadened nose. Infants also present with contractures, synechiae 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.
Etiology
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. Homozygous mutations in this gene cause protein function loss and affect important nucleotide-binding fold domains and transmembrane domains resulting in impaired lipid barrier function.
Diagnostic methods
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 reveals homozygous ABCA12 mutations.
Differential diagnosis
HI may be confused with less severe forms of ichthyosis. Later in life, the differential diagnosis includes other disorders from the autosomal recessive congenital ichthyosis (ARCI) group, restrictive dermopathy, infantile systemic hyalinosis, and Neu-Laxova syndrome.
Antenatal diagnosis
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.
Genetic counseling
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 each pregnancy.
Management and treatment
In the neonatal period, management requires a multidisciplinary approach (dermatologists, neonatologists, ophthalmologists, surgeons, dieticians, and psychologists for family support). Gastrostomy may be necessary. Emollients and oral retinoids (1-2mg/kg/day) are recommended. It is important to keep invasive procedures to a minimum in order to avoid skin infections. Management of survivors is similar for all severe ARCIs and includes the use of emollients, keratolytics, and retinoids.
Prognosis
HI is associated with substantial (50%) morbidity and mortality soon after birth and throughout childhood due to sepsis and/or respiratory failure (75% of cases). Survivors can have a normal life expectancy but may develop severe skin disease with eye complications related to persistent ectropion, delayed developmental and motor milestones, and social difficulties. Current medical treatments achieved a significant improvement in quality and expectancy of life, however the severity of the disease might still affect life duration. The prognosis of the disease with actual treatments is still under evaluation.

                            Last update: 
                            December 2022


                            - Expert reviewer(s): 
                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin*


                                * European Reference Network