Prenatal Diagnosis Of Harlequin Ichthyosis Research Articles

Postnatal diagnosis of harlequin ichthyosis a case report

Objective: Ichthyoses are cornification disorders in which irregular epidermal separation and desquamation result in a faulty epidermal membrane. Harlequin ichthyosis (HI) was a rare and extreme type that led to neonatal death. It was caused by mutations in the ABCA12 gene, and the inheritance pattern is autosomal recessive. Case report: We present a case of HI that was diagnosed postnatally by clinical review. Extreme ectropion, eclabium, flattened nose, and primitive ears were discovered in the fetus. As a result of HI complications, the fetus died. Conclusion: The presence of HI was linked to a poor prognosis and a high mortality rate. Prenatal ultrasound and genetic analysis were critical for prenatal diagnosis of HI, but genetic modalities were not available and were prohibitively costly, despite their utility in providing appropriate prenatal therapy to families with HI babies. This case was recorded because of its rarity, as well as to draw attention to the connection between.

Prenatal Diagnosis of Harlequin Ichthyosis Using 3- and 4-Dimensional Sonography

Received October 5, 2009, from the Department of Obstetrics and Gynecology, Medical University of Silesia, Katowice, Poland (M.J.K.); and Department of Obstetrics and Gynecology, University Hospitals, Catholic University of Leuven, Leuven, Belgium (D.T.). Revision requested October 6, 2009. Revised manuscript accepted for publication October 12, 2009. Address correspondence to Marek J. Kudla, MD, Department of Obstetrics and Gynecology, Medical University of Silesia, Medykow 14, 40-780 Katowice, Poland. E mail: marekkudla@hotmail.com Abbreviations 4D, 4-dimensional; HI, harlequin ichthyosis; NLS, Neu-Laxova syndrome; 3D, 3-dimensional; 2D, 2dimensional he patient, aged 26 years, was admitted for a second-opinion sonographic examination in the 26th week of pregnancy. Her medical history was gravida 3, para 2 with a history of 1 early spontaneous abortion in the sixth week and 1 birth of a healthy infant in the 40th week. All pregnancies were with the same nonconsanguineous partner. Her first detailed examination, performed in the 13th week, displayed no fetal anatomic malformation, with a nuchal translucency thickness (1 mm) within the normal range. A second-opinion evaluation was requested because of abnormalities observed during previous sonographic examinations in the 17th and 23rd weeks. Apart from structural findings, discordance of around 2 weeks between gestational age and fetal growth was noted. The amount of amniotic fluid was increased. Amniocentesis, offered and performed in the 18th week, yielded normal findings and a 46,XY karyotype. Our second-opinion examination confirmed a discrepancy of around 4 weeks between fetal growth and the dates. Pathologic features observed during this 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D) examination included polyhydramnios, fixed flexion of the extremities, short digits, a flat nose, bilateral clubfeet, clenched hands, a short neck, a flat face profile, thick lips, eclabion, open eyes, ectropion, cataracts, a constantly open mouth, micrognathia, hypoplasia of the ears, choroid plexus cysts, and a short umbilical cord (Figures 1–4).

DNA-Based Prenatal Diagnosis of Harlequin Ichthyosis and Characterization of ABCA12 Mutation Consequences

Until the identification of ABCA12 as the causative gene, prenatal diagnosis (PD) for harlequin ichthyosis (HI) had been performed by electron microscopic observation of fetal skin biopsy samples. We report the first case of HI DNA-based PD. Direct sequence analysis of ABCA12 revealed that the deceased proband was a compound heterozygote for two novel mutations. The maternal nonsense mutation p.Ser1249Term likely leads to nonsense-mediated messenger RNA decay. The paternal mutation c.7436G>A affects the last codon of exon 50 and was expected to be a splice site mutation. For their third pregnancy, the parents requested PD. Direct sequence analysis of fetal genomic DNA from amniotic fluid cells at 17 weeks gestation revealed the fetus was a compound heterozygote for both mutations. The parents requested the pregnancy to be terminated. Analysis of ABCA12 transcripts of cultured keratinocytes from the abortus showed the presence of six abnormally spliced products from the allele carrying the splice site mutation. Four of them lead to premature termination codons whereas the two others produced shortened proteins missing 21 and 31 amino acids from the second ATP-binding cassette. This report provides evidence for residual ABCA12 expression in HI, and demonstrates the efficiency of early DNA-based PD of HI.

Prenatal exclusion of harlequin ichthyosis; potential pitfalls in the timing of the fetal skin biopsy

Harlequin ichthyosis (HI) is a severe and usually fatal congenital skin disorder with autosomal recessive inheritance. Several cases of HI prenatal diagnosis have been performed using fetal skin biopsy, mainly at around 23 weeks estimated gestational age (EGA), and reported in the literature. However, prenatal testing must be done earlier than 21 weeks EGA in several countries including Japan where the present HI families live, because termination is legally allowed only until 22 weeks EGA. We report the successful prenatal exclusion of HI in two fetuses from two independent families and discuss the technical difficulties and potential pitfalls in the prenatal exclusion of HI at early gestation stages. Fetal skin biopsy specimens and amniotic fluid samples at 19 and 20 weeks EGA from two fetuses at risk of HI were examined by light and electron microscopy. For the prenatal diagnosis in case 1, the fetal skin biopsy samples were obtained at 20 weeks EGA and showed normal keratinization in the hair canals; no abnormalities were observed in the keratinized cells. In case 2, the interfollicular epidermis and the hair follicles in the samples obtained at 19 weeks EGA had not differentiated enough to show proper keratinization. However, lamellar granules were normally formed in the inner root sheath cells of the late bulbous hair pegs. From these ultrastructural findings, the case 1 fetus was diagnosed as unaffected with HI, and the case 2 fetus was diagnosed as unlikely to be affected. Subsequently, both were born as healthy, unaffected babies. The timing of biopsies at 19 weeks EGA is not ideal for fetal skin biopsy because the samples are not always sufficiently differentiated for the prenatal diagnosis of HI. However, morphological observations of lamellar granules gives us important additional information useful for HI prenatal diagnosis.

Harlequin ichthyosis unmasked: a defect of lipid transport

Harlequin ichthyosis (HI)--the most severe form of keratinizing disorders, often lethal in the neonatal period--is characterized by a profound thickening of the keratin skin layer, a dense "armor"-like scale that covers the body, and contraction abnormalities of the eyes, ears, and mouth. In this issue of the JCI, Akiyama et al. report that mutations in ABCA12 caused defective lipid transport that significantly impacted normal development of the skin barrier. Lipid secretion was recovered after corrective ABCA12 gene transfer into patient keratinocytes. These results should allow for early prenatal diagnosis of HI and lend hope to the possibility of a specific treatment for this devastating disorder.

Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks' estimated gestational age

Harlequin ichthyosis (HI) is an extremely severe and usually fatal congenital keratinization disorder whose responsible genes have not yet been identified. For prenatal diagnosis, the fetal skin biopsy is the only available method and has been usually performed at 21 to 22 weeks' estimated gestational age (wEGA). Hair canal keratinization is thought to occur around 15 wEGA prior to the interfollicular keratinization, and characteristic abnormalities of HI are known to be expressed more strongly in the hair canal. Thus, we expected the fetal skin specimen at 19 wEGA to have sufficient information for prenatal diagnosis. Fetal skin biopsy was undertaken from a fetus at risk at 19 wEGA. Electron microscopy demonstrated abnormal vacuoles in keratinized cells and malformation of lamellar granules in the hair canal. Clumps of aberrantly keratinized cells containing lipid droplets were seen in the amniotic fluid. The fetus was diagnosed as affected. The abortus at 21 wEGA demonstrated HI phenotype clinically. The present results indicate that the prenatal diagnosis of HI is possible at 19 wEGA, an earlier stage of gestation than previously reported, by the ultrastructural observation of the hair canal and the amniotic fluid cells, but not the interfollicular epidermis, of fetuses at risk.

Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks' estimated gestational age

Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks' estimated gestational age

Prenatal diagnosis of harlequin ichthyosis by fetal skin biopsy; Report of two cases

Two cases of harlequin ichthyosis were successfully diagnosed prenatally by fetal skin biopsy. The aborted fetuses were later confirmed to be afflicted with this very unusual skin disease. Both families had a previous history of harlequin ichthyosis. In performing the biopsy, it was found that amniotic fluid cytology can also be very helpful in the diagnosis of this kind of severe ichthyosis. With regard to these families, the disease may have been transmitted in an autosomal dominant fashion, and not in a recessive manner as is commonly believed.