Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan

Abstract

Ichthyoses are a group of disorders marked by whitish, brown or dark-brown scales on the skin of almost the whole body. Harlequin ichthyosis (HI) is the most severe form. Neonatal death from HI was once common. Due to intensive neonatal care and, probably, to the early introduction of oral retinoids, HI outcome has improved. For definitive diagnosis and the exclusion of other disorders, such as lamellar ichthyosis, which also shows a collodion baby phenotype, it is helpful to refer to electron microscopy of abnormal or absent lamellar granules and a heavy accumulation of lipid droplets in the keratinocytes. ATP-binding cassette transporter A12 (ABCA12) is known as the causative gene of HI. Severe ABCA12 deficiency results in malformation of intercellular lipid layers in the cornified layers and leads to epidermal lipid barrier disruption. In HI patients, at least one mutation on each allele must be a truncation or deletion mutation to cause serious loss of ABCA12 function. Identification of the gene underlying HI has enabled DNA-based prenatal diagnosis for HI at the earlier stages of pregnancy with low risk. There are no curative treatments for HI. Abca12-deficient mice were created as a model of HI. Treatment of the model mice with retinoid or steroid has not been successful.

Case of harlequin ichthyosis with a favorable outcome: Early treatment and novel, differentially expressed, alternatively spliced transcripts of the ATP‐binding cassette subfamily A member 12 gene

“…They concluded that early retinoid therapy as well as intensive neonatal care improve the prognosis of HI. 3 In our case, we believe that early retinoid therapy and the administration of antibiotics led to a favorable prognosis.…”

“…In Japan, Shibata and Akiyama carried out a nationwide review of HI, and reported that among the 16 HI babies born between 2005 to 2010, 13 survived (81.3%) and three died (18.7%). They concluded that early retinoid therapy as well as intensive neonatal care improve the prognosis of HI . In our case, we believe that early retinoid therapy and the administration of antibiotics led to a favorable prognosis.…”

“…It is a rare disease, with a prevalence of approximately 1/0.3 million births . The mortality rate of HI is high, but recent advances in neonatal care units (NICU) and the early administration of oral retinoids have improved survival rates up to 81.3% in Japanese cases . HI is caused by loss of function in the epidermal lipid transporter, ATP‐binding cassette subfamily A member 12 (ABCA12), although ABCA12 mutations are also responsible for other ARCI, congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI).…”

“…1 The mortality rate of HI is high, 2 but recent advances in neonatal care units (NICU) and the early administration of oral retinoids have improved survival rates up to 81.3% in Japanese cases. 3 HI is caused by loss of function in the epidermal lipid transporter, ATP-binding cassette subfamily A member 12 (ABCA12), 4 although ABCA12 mutations are also responsible for other ARCI, congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). The phenotypic differences in these ARCI are dependent on the ABCA12 mutation, 1,5 but ABCA12 genotypes are not fully understood in the survivors of HI.…”

Compound heterozygous mutations with novel missenseABCA12mutation in harlequin ichthyosis

“…Close monitoring of body temperature is essential as dysregulation of body temperature can occur due to impaired sweating from obstruction of sweat glands by the thickened stratum corneum 2. Ventilatory support may be required if the rigid chest wall restricts breathing and pulmonary function 1.…”