The ichthyoses are a heterogeneous group of inherited and acquired disorders of cornification. Despite genetic and molecular advances, diagnosis can be difficult. X-linked recessive ichthyosis (XLRI) is clinically characterized by gray-brown scale on the trunk and extremities. Autosomal recessive congenital ichthyosis (ARCI) is characterized by two polar phenotypes, lamellar ichthyosis (LI) with plate-like brown scale and congenital ichthyosiform erythroderma (CIE) with fine white scale and underlying erythroderma. Eight genes have been identified to cause ARCI, the most common being TGM1 (ARCI-TGM1). Because there are few systematic descriptions of XLRI and ARCI histopathology, we planned to characterize and compare their features.
We systemically evaluated 117 slides from 111 subjects enrolled in the National Registry for Ichthyosis and Related Disorders (Registry) using a standardized scoring sheet for the presence or absence of each feature and a score of severity (1 mild to 3 severe) blinded to clinical information. Subsequently, Registry diagnoses were obtained. Analysis of epidermolytic hyperkeratosis was previously reported.1 Eight XLRI and 8 ARCI subjects with TGM1 mutations,2 of whom one had 2 biopsies, were identified. The 8 XLRI and 9 ARCI-TGM1 slides were compared using Fisher’s exact test for binomial dependent variables (i.e. present/absent) and Wilcoxon-Mann-Whitney test for ordinal dependent variables (i.e. 0–3).
Results are shown in Figure 1 and summarized in Supplemental Table 1. Both XLRI and ARCI-TGM1 biopsies showed hyperkeratosis with focal parakeratosis; however, there were statistically significant differences in the stratum granulosum and stratum spinosum. Unlike early reports of a normal to slightly thickened granular layer,3,4 we found that most XLRI biopsies showed a normal to slightly thinned granular layer. ARCI-TGM1 had 3.0±1.1 cells in the granular layer compared to XLRI with 1.8±0.7 cells, p=0.02. Mild to moderate acanthosis was seen in 67% of ARCI-TGM1 (average severity 1.1±0.7) and seen mildly in 25% of XLRI (average severity 0.2±0.4), p=0.05. Mild to moderate psoriasiform hyperplasia was seen in 44% of ARCI-TGM1 biopsies compared to none in XLRI biopsies (p=0.04).
Figure 1.
A, ARCI biopsy showing focal parakeratosis, thickened granular layer, acanthosis and psoriasiform hyperplasia. Inset of biopsy from another patient with ARCI showing more prominent hypergranulosis. (Hematoxylin and eosin stain, original magnification × 200). B, XLRI biopsy showing slightly atrophic granular layer and no acanthosis. Both biopsies show compact hyperkeratosis and mild dermal infiltrate. (Hematoxylin and eosin stain, original magnification × 200).
Sweat glands were present in 75% of XLRI and 56% of ARCI-TGM1 biopsies (NS), some with mild to moderate plugging or hyperkeratosis. Follicles were seen in 50% of XLRI and 78% of ARCI-TGM1 (p=0.3) with mild plugging, hyperkeratosis, and dilatation in both conditions. ARCI patients are often heat intolerant. The mild-moderate plugging or hyperkeratosis seen in the minority of ARCI-TGM1 biopsies may correlate to abnormal sweat production, but this is difficult to interpret given that the presence and appearance of sweat glands depend on the age of the patient and the site biopsied. Overall, we found no differences in the presence or appearance of adnexal structures between XLRI and ARCI-TGM1.
Lymphohistiocytic perivascular infiltrates were seen in all the biopsies from XLRI and ARCI-TGM1, a finding that has not been highlighted previously in either XLRI or ARCI. Blood vessels were mildly to severely tortuous and dilated in 56% in ARCI-TGM1, as has been previously reported.5 Mitosis was seen in 44% of the ARCI-TGM1 group and none in the XLRI group (p=0.05).
Although considerable overlap remains, our study refines and identifies histopathologic features that may help distinguish XLRI from ARCI.
Supplementary Material
Acknowledgments
We thank Oliver Chang, M.D. Ph.D., for his assistance in procuring the histopathology images and acknowledge Jorge Toro, M.D., and his lab for performing the transglutaminase gene sequencing and sharing their data with this group.
IRB approved by the University of Washington for human subjects research (HSD #27188) and met criteria for Rhode Island Hospital IRB exemption.
This publication was supported by funds from the Foundation for Ichthyosis and Related Skin Types, the National Institutes of Health award N01-AR-1-2252, and the National Center for Advancing Translational Sciences of the National Institutes of Health award UL1TR000423. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
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Conflict of interest: the authors have no conflicts of interest to declare.
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