Compound Heterozygous Mutations Including a De Novo Missense Mutation in ABCA12 Led to a Case of Harlequin Ichthyosis with Moderate Clinical Severity

Abstract

Harlequin ichthyosis (HI) is one of the most devastating genodermatoses. Recently, ABCA12 mutations were identified as the cause of HI. A newborn Japanese male demonstrated the typical features of HI. The patient was treated with oral etretinate and his general condition has been good (now aged 1.5 years). This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5' triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein. Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells. Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient. No de novo mutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis. The present case suggested that a de novo ABCA12 mutation might underlie HI.

Harlequin ichthyosis: A rare dermatological disorder

“…Harlequin ichthyosis is extremely rare, and is the most severe form of the keratinizing disorders characterized by profound thickening of stratum corneum [1]. A dense armor like scale covers the body.…”

Clinical Manifestation and Classification of Japanese patients with Inherited Keratinizing Disorders

“…We also experienced one case of harlequin ichthyosis(HI) diagnosed by the extraordinary clinical manifestation at birth. Although compound heterozygous mutations of ABCA12 have recently been reported in a case of HI 15) , we had not determined the genetic mutation of our case at diagnosis. We diagnosed 16 cases of X-linked ichthyosis (XLI) using diagnostic markers such as low activities of leukocyte steroid sulfatase 16) , and detection of the genetic defect using FISH probe and PCR analysis.…”

Compound Heterozygous <i>ABCA12</i> Mutations Including a Novel Nonsense Mutation Underlie Harlequin Ichthyosis

“…More than half of HI newborns including cases with a serious functional loss of ABCA12 can now survive beyond the perinatal period [7, 8, 15]. The exact reasons for the improved prognosis of our HI patient are unknown, whether it was due to the nature of the mutations or to the successful intensive care and retinoid treatment during the perinatal period or some combination of the two.…”

“…Recently, the prognosis of newborns affected with HI has improved, owing to remarkable progress in neonatal intensive care and earlier, targeted oral retinoid treatment [4,5,6,7,8]. More than half of HI newborns including cases with a serious functional loss of ABCA12 can now survive beyond the perinatal period [7, 8, 15].…”

“…Until the 1980s, newborns affected with HI rarely survived beyond the neonatal period. However, recently, HI babies often have a better prognosis [4,5,6,7,8]. In order to obtain clues to determine the definitive features of HI patients with a better prognosis, we report an HI male patient with compound heterozygous ABCA12 mutations including a novel nonsense mutation leading to the typical HI phenotype presentation at birth.…”