Harlequin ichthyosis with epidermal lipid abnormality

Buxman, M. M.

doi:10.1001/archderm.115.2.189

Cited by 36 publications

(26 citation statements)

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“…Our neonatal HI model mice skin showed no apparent keratohyalin granules within any of their granular layer cells, which was consistent with Buxman's study. 10 Furthermore, our immunoblotting results confirmed defective profilaggrin/filaggrin conversion, which was consistent with the studies by Dale et al 11 and Fleckman et al 12 Our immunostaining and immunoblotting results showed reduced expression of KLK5 in neonatal…”

Section: Discussionsupporting

confidence: 92%

“…Until now, abnormalities in keratinocyte differentiation have been reported in HI patients. Morphologically, Buxman et al 10 have reported that granular layers were absent or poorly formed in HI patient epidermis. Dale et al reported abnormal lamellar granules and defective profilaggrin conversion both in HI patients skin and their cultured keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

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Self-Improvement of Keratinocyte Differentiation Defects During Skin Maturation in ABCA12-Deficient Harlequin Ichthyosis Model Mice

Yanagi

Akiyama

Nishihara

et al. 2010

The American Journal of Pathology

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Harlequin ichthyosis (HI) is caused by loss-of-function mutations in the keratinocyte lipid transporter ABCA12. The patients often die in the first 1 or 2 weeks of life, although HI survivors' phenotypes improve within several weeks after birth. In order to clarify the mechanisms of phenotypic recovery, we studied grafted skin and keratinocytes from Abca12-disrupted (Abca12 ؊/؊ ) mice showing abnormal lipid transport. Abca12 ؊/؊ neonatal epidermis showed significantly reduced total ceramide amounts and aberrant ceramide composition. Immunofluorescence and immunoblotting of Abca12 ؊/؊ neonatal epidermis revealed defective profilaggrin/filaggrin conversion and reduced protein expression of the differentiation-specific molecules, loricrin, kallikrein 5, and transglutaminase 1, although their mRNA expression was up-regulated. In contrast, Abca12 ؊/؊ skin grafts kept in a dry environment exhibited dramatic improvements in all these abnormalities. Increased transepidermal water loss, a parameter representing barrier defect, was remarkably decreased in grafted Abca12 ؊/؊ skin. Ten-passage sub-cultured Abca12 Harlequin ichthyosis (HI) (OMIM 242500) is one of the most severe genetic skin disorders, and its clinical features at birth include severe ectropion, eclabium, flattening of the ears, and large thick plate-like scales over the entire body. 1Infants affected with HI frequently die within the early neonatal period, although an increasing survival rate for HI newborns has recently been highlighted. 2 In 2005, we and another independent research group identified mutations in the ATP-binding cassette transporter A12 (ABCA12) gene as the cause of HI. 3,4 We previously demonstrated that a severe ABCA12 deficiency causes defective lipid transport in lamellar granules in the upper spinous and granular layer keratinocytes, resulting in malformation of intercellular lipid layers at the granular/cornified layer interface and epidermal lipid barrier disruption resulting in HI phenotype. 3 We recently generated Abca12-disrupted (Abca12 Ϫ/Ϫ ) mice by targeting Abca12, which closely reproduced the human HI phenotype and died soon after birth. 5 We tried systemic retinoid administration to the pregnant female mice as a form of fetal therapy, although no therapeutic effect was

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Self-Improvement of Keratinocyte Differentiation Defects During Skin Maturation in ABCA12-Deficient Harlequin Ichthyosis Model Mice

Yanagi

Akiyama

Nishihara

et al. 2010

The American Journal of Pathology

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“…Other ultrastructural features of HI in humans and mice can include focal absence of intercellular lipid lamellae, 5,9,12,13 large mitochondria with vesicular changes, 4,16,17,27 reduced size or distribution of keratohyalin granules, 27 and fewer tonofilaments in the granular layer. 9,11 None of these findings, however, were noted in the kudu cases in this report. Lack of these findings could indicate difficulties with formalin fixation and loss of cell membranes and detail, or could indicate the unique ultrastructural changes of this particular form of harlequin ichthyosis in greater kudu or artiodactylids.…”

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confidence: 71%

“…22 Defects in lipid biosynthesis as well as the conversion of profilaggrin to filaggrin in the epidermis of human HI patients have been identified. 2,9,12,13,18 In vitro studies of keratinocytes from human HI patients show decreased epidermal protein phosphatase 2A (PP) activity, which could affect both lipid and profilaggrin pathways and ultrastructural findings of the disease. 18 In mice models with HI, overexpression of keratin 6 and filaggrin in the epidermis has been linked to a mutant gene locus on mouse chromosome 19.…”

mentioning

confidence: 99%

Harlequin Ichthyosis in Two Greater Kudu (Tragelaphus strepsiceros)

Chittick¹,

Olivry²,

Dalldorf³

et al. 2002

Vet Pathol

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Abstract. Two greater kudu calves (Tragelaphus strepsiceros) born 7 years apart were found with fissures and thickened, scaly, cutaneous plates covering over 80% of their bodies. One was dead at presentation, and the other was euthanized shortly after birth. Both animals shared a common sire. On necropsy, chemosis, ectropion, eclabium, and bilateral valgus deformities of the tarsal joints were observed in one calf, presumed to be secondary to the plates restricting normal fetal development. The principal microscopic lesion was severe lamellar orthokeratosis, with focal mild parakeratosis. Ultrastructural epidermal lesions included the absence of normal lamellar granules, large dilated endoplasmic reticulum, and abnormal retention of organelles and vesicles. Gross, histopathologic, and electron microscopic findings in both kudu calves were consistent with those of harlequin ichthyosis, a rare dermatosis of humans believed to have an autosomal recessive inheritance pattern. The underlying genetic and molecular abnormality and heritability of this condition in this greater kudu herd were not determined.Key words: Greater kudus; harlequin ichthyosis; histopathology; skin; ultrastructure.Two deformed greater kudu calves with the same sire were found on exhibit at the North Carolina Zoological Park over a period of 7 years. Both animals were found within hours after birth and showed similar external abnormalities. The first calf, kudu No. 1, was found dead in October 1993, approximately 24 hours after its dam had displayed signs of premature labor. The calf was small, female, and had a hairless, pigmented integument with numerous fissures and cracks. The texture of the skin was described as that of ''leather.'' The lungs appeared dark pink and did not float in formalin. Tissues were reported to be moderately autolyzed, but other morphologic abnormalities were not noted on gross necropsy.The second kudu calf, kudu No. 2, was found alive within 6 hours of birth with its 11-year-old mother in July 2000 after a normal gestation length. Over 80% of the calf's body was covered with a 0.3-0.5 mm thick dark gray/brown platelike material that was dry, fissured, and incorporated underlying hair (Figs. 1, 2). The limbs were tucked beneath the body in a fetal position and could not be extended. Additionally, both rear limbs had mild valgus rotation at the tarsal joints. Ocular abnormalities included chemosis, erythematous conjunctiva, and diffuse lens opacity bilaterally. Both aural pinnae were dry, thickened, and curled at the tips. The taut platelike tissue everted the lower lip and eyelids. Fifteen hours after birth the calf was unable to stand or nurse, apparently because of restriction of movement by the scaly plates, and was euthanized by intravenous injection of sodium pentobarbital.Postmortem examination revealed a 9.4-kg male neonate that was fully haired underneath the gray/brown plate carapace. On internal examination a hemorrhagic patent urachus was filled with clear yellow urine. Testes were located inguinally. In th...

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“…In Refsum's disease, where the ability to oxidize phytanic acid is impaired, epidermal lipids contain large amounts of phytanic acid in the phospholipid, sterol ester, and triglyceride fractions (33). Moreover, a case of Harlequin fetus, a lethal form of congenital ichthyosis, was reported that demonstrated increased quantities of sterols and triglycerides, as well as retained lipid vacuoles, in the stratum corneum (34).…”

Section: Resultsmentioning

confidence: 99%

Stratum corneum lipids in disorders of cornification: increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis.

Williams¹,

Elias²

1981

J. Clin. Invest.

186

103

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A B S T R A C T Activity of the microsomal enzyme, steroid sulfatase, is absent in keratinocytes, fibroblasts, and leukocytes of patienits with recessive xlinked ichthyosis. This study was uiidertaken to determine if cholesterol sulfate, a substrate of this enzyme, accumulates in the pathological scale of these patients.Scales from 8 patients with recessive x-linked ichthyosis, 10 patienits with other fornms of ichthyosis, and normal human outer stratum corneum were extracted with chloroform/water (1:2:0.8 by vol) and lipids were fractionated by quantitative, sequential thin-layer chromatography. Cholesterol sulfate was identified by cochromatography in several solvent systemns, by its staining characteristics, by biochemical analysis, and by mass spectrometry. The mean cholesterol sulfate content of recessive x-linked ichthyotic scale was 12.5+0.8% of the total lipid, a fivefold increase over normal (P < 0.0025), whereas the cholesterol sulfate content of other ichthyotic scale was normal. This increase in cholesterol sulfate content was accompanied by a decrease in total neutral lipids (P < 0.0025) and free sterols (P < 0.025) but no change in sterol esters or total sterols. These results demonstrate that deficiency of steroid sulfatase in recessive x-linked ichthyosis results in excessive accumulation of a substrate, cholesterol sulfate, in the pathologic scale, which may underly the pathogenesis of the scaling in this disorder. Measurement of cholesterol sulfate content in scale provides an alternative method to enzymatic assay for the diagnosis of this form of ichthyosis.

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Harlequin ichthyosis with epidermal lipid abnormality

Cited by 36 publications

References 0 publications

Self-Improvement of Keratinocyte Differentiation Defects During Skin Maturation in ABCA12-Deficient Harlequin Ichthyosis Model Mice

Self-Improvement of Keratinocyte Differentiation Defects During Skin Maturation in ABCA12-Deficient Harlequin Ichthyosis Model Mice

Harlequin Ichthyosis in Two Greater Kudu (Tragelaphus strepsiceros)

Stratum corneum lipids in disorders of cornification: increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis.

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