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Altered Lamellar Body Secretion and Stratum Corneum

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Altered Lamellar Body Secretion and Stratum Corneum OBSERVATION Altered Lamellar Body Secretion and Stratum Corneum Membrane Structure in Netherton Syndrome Differentiation From Other Infantile Erythrodermas and Pathogenic Implications Manige´ Fartasch, MD; Mary L. Williams, MD; Peter M. Elias, MD Background: The infant with Netherton syndrome (NS) tum corneum layer was largely replaced by parakera- typically displays a generalized erythroderma covered by totic cells. A distinctive feature—premature secretion of fine, translucent scales, which can be difficult to distin- lamellar body contents—occurred only in NS. Further- guish clinically from erythrodermic psoriasis, nonbul- more, lamellar body–derived extracellular lamellae and lous congenital ichthyosiform erythroderma, or other in- stratum corneum lipid membranes were separated ex- fantile erythrodermas. Some infants with NS develop tensively by foci of electron-dense material. Finally, trans- progressive hypernatremic dehydration, failure to thrive, formation of lamellar body–derived lamellae into ma- and enteropathy. Such complications can be fatal. Diag- ture lamellar membrane structures was disturbed in NS. nosis is typically delayed until the appearance of a pa- thognomonic hair shaft anomaly, trichorrhexis invagi- Conclusions: Premature lamellar body secretion and foci nata (bamboo hair). To facilitate the early diagnosis of of electron-dense material in the intercellular spaces of NS, we obtained biopsy specimens from 7 patients with stratum corneum, features not observed in other eryth- erythrodermic NS and compared their morphologic find- rodermic disorders, appear to be frequent and relatively ings to those of 3 patients with erythrodermic psoriasis specific markers for NS. These ultrastructural features and 2 with congenital ichthyosiform erythroderma. Bi- could permit the early diagnosis of NS before the appear- opsy specimens were processed for light and electron mi- ance of the hair shaft abnormality. These abnormalities croscopy using postfixation with osmium tetroxide and could explain the impaired permeability barrier in NS, ruthenium tetroxide. and account for hypernatremia and dehydration in in- fants with NS. Observation: In NS, and often in congenital ichthyo- siform erythroderma and erythrodermic psoriasis, the stra- Arch Dermatol. 1999;135:823-832 ETHERTON syndrome ease.5,6 Although ILC is the predominant (NS) is a rare autosomal cutaneous manifestation in older pa- recessive disorder of tients with NS,5,7-10 erythrodermic infants cornification, character- with NS are often misdiagnosed as hav- ized by the triad of ich- ing the following: (1) another metabolic Nthyosis, hair shaft defects, and atopy. The disease with generalized dermatitis, such nature of the ichthyosiform dermatosis in as immunodeficiency disorder with der- this syndrome has been the subject of con- matitis (so-called Leiner disease) or acro- siderable debate, raising the question of dermatitis enteropathica; (2) a severe form whether NS is a heterogeneous condi- of more common disorders, such as eryth- tion.1 Although some patients with NS re- rodermic psoriasis (PsoE)11; or (3) an- From the Department of veal a distinctive ichthyosiform pheno- other recessive disorder of cornification, Dermatology, University of type of erythematous, polycyclic plaques eg, nonbullous congenital ichthyosiform Erlangen/Nuremberg, Erlangen, with “double-edged” scale (ichthyosis lin- erythroderma (CIE).1,4,12,13 Because ILC and Germany (Dr Fartasch); the earis circumflexa [ILC]), this feature usu- its characteristic hair shaft abnormalities Departments of Dermatology ally appears after infancy,2 as do pili torti, typically do not become evident until after (Drs Williams and Elias) and trichorrhexis nodosa, and the pathogno- the first year of life, a definitive diagnosis Pediatrics (Dr Williams), monic trichorrhexis invaginata. Most in- of NS is usually delayed.6 University of California, San Francisco; and the Dermatology fants with NS display a generalized exfo- A high rate of morbidity and mortal- Service, Veterans liative erythroderma, with or without an ity accompanies the erythroderma in in- 3,4 5,6 Administration Medical Center, atopic diathesis. Recent studies suggest fants with NS. Although some au- San Francisco, Calif that ILC and erythroderma/dermatitis rep- thors5,14 suggest that systemic complications (Drs Williams and Elias). resent different phases of the same dis- of NS could be due to a severe, underlying ARCH DERMATOL / VOL 135, JULY 1999 823 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 METHODS expression.23 Finally, for morphologic control studies, we used freshly excised, surgical margins from 9 subjects with- PATIENTS out skin disease (from extensor surface; upper arms). In 6 of the 7 ultrastructurally studied NS cases, clinical data MORPHOLOGIC STUDIES were available. They showed generalized involvement with a congenital or early-onset ichthyosiform erythroderma After rinsing in buffer, biopsy specimens were fixed in (Table 1 and Figure 1). Table 1 summarizes the sex, age, cacodylate-buffered 2.5% glutaraldehyde and then divided, and clinical features of the patients at the time of investi- with one half postfixed with 0.5% ruthenium tetroxide gations. In all patients except patient 3, diagnosis was ul- and 0.25% aqueous potassium ferrocyanide,20,24 and the timately established by demonstration of the typical hair other in 1% aqueous osmium tetroxide containing potas- shaft defect. All patients showed marked inflammation with sium ferrocyanide in the dark at 4°C. Tissue sections were areas of oozing, and in some, superficial blisters and ero- dehydrated in graded ethanols and embedded in either sions. Elliptical or punch biopsy specimens were taken from ruthenium tetroxide–fixed samples (Spurr resin; Poly- involved, uninfected skin sites. sciences, Warrington, Pa) or osmium tetroxide–fixed Because of the close clinical resemblance of NS to PsoE samples (Epon 812; Polysciences). Thin sections were and CIE, we also analyzed biopsy specimens from in- examined before and after double staining with ethanolic volved skin from 3 patients with PsoE and 2 with CIE. Pa- uranyl acetate plus lead citrate on an electron microscope tients with CIE fulfilled the following published criteria for operated at 100 kV. Serial semithin sections of the osmium autosomal recessive ichthyosis21,22: collodion membrane at tetroxide–fixed samples were stained with 1% methylene birth followed by subsequent erythroderma and fine scales blue. Tissue specimens were also fixed and processed rou- in a generalized distribution and ectropion. Neither tinely for histologic testing, sectioned at 6 µm, and stained patient with CIE demonstrated genetic linkage to the trans- with hematoxylin-eosin, periodic acid-Schiff, and Giemsa glutaminase: 1 (TGase1) gene or abnormal TGase1 staining. Table 1. Clinical Features of Erythrodermic Patients With Netherton Syndrome* Noncutaneous Syndromes Patient No./ Biopsy Bamboo Hypernatremic Failure Sex/Age† Site Outcome Hair Phenotype Dehydration to Thrive Other 1/M/2 mo Buttock Death within 1 y + E + + Aminoaciduria, IgE 15, myocarditis, pneumonia, no diarrhea 2/F/18 mo Unknown Alive with disease + E 0 − Elevated IgE level 137 units (nl,15) at 1 mo with positive radioallergosorbent test result to milk (6825; nl,500); pneumonia in neonatal nursery; group A streptococcus septicemia at age 2 wks 4/M/4 y Buttock Alive with disease + E 0 + Diarrhea severe in infancy with low protein and albumin levels, IgE 4964 (1 y); IgE 500 (nl,25) at 2 y; recurrent pneumonia and skin infections; anaphylactic reactions to cinnamon and eggs 5/F/5 y Buttock Alive with disease + E 0 ++ Severe infantile diarrhea; developed hypoproteinemia and transient low zinc (normalized with replacement, did not recur); anaphylactic reactions to cinnamon, eggs, and brazil nuts; IgE 3250 at3y(nl.5.6) 6/M/1 y Buttock Alive with disease + E 0 + IgE 2000; new brother was also affected, especially on face, scalp, and diaper area 7/F/4 mo Back Alive with disease + E O ++ Severe failure to thrive without diarrhea; hypertonia; septicemia *Plus signs indicate present; minus signs, absent; nl, normal; and double plus signs, severe. †There were no clinical data for patient 3. Patient 5 was the sister of patient 4. immunodeficiency, recent studies6 demonstrate that, apart brane unit structures within the intercellular spaces of from markers of atopy such as increased IgE, significant the stratum corneum (SC). In this study, we attempted immune defects are not present. Others5,15-17 have pro- to delineate a structural basis for the putative permeabil- posed that increased rates of transcutaneous water loss, re- ity barrier abnormality in NS using ruthenium tetroxide sulting in hypernatremic dehydration and hypothermia in postfixation, which permits ultrastructural analysis of SC the neonatal period, are a more likely cause of morbidity membrane structures,18-20 and to compare these find- and mortality in NS. Such a pathogenic scenario implies ings with the ultrastructural characteristics of PsoE and that a severe disturbance in the cutaneous permeability bar- CIE—disorders that clinically resemble the erythroder- rier is an important feature of this subgroup of NS. mic form of NS. Our findings suggest first, that prema- The normal skin barrier is provided by hydropho- ture lamellar body (LB) secretion is a distinctive feature bic lipids organized into repeating arrays of lamellar mem- of erythrodermic NS,
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