Association of the Severity of Alopecia With the Severity of Ichthyosis | Congenital Defects | JAMA Dermatology | JAMA Network
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Figure.  Frontal Scalp Alopecia
Frontal Scalp Alopecia

A, Recession of hairline in a female patient with autosomal recessive congenital ichthysosis, TGM1, and a Severity of Alopecia Tool (SALT) score of 34. B, White scale in a female patient with Netherton syndrome, SPINK5, a Visual Index of Ichthyosis Severity score of 22, and SALT score of 13. SPINK5 indicates serine peptidase inhibitor, Kazal type 5, and TGM1, transglutaminase-1.

Table.  Descriptive Summary of Ichthyosis Severity and Alopecia Severity by Genotype
Descriptive Summary of Ichthyosis Severity and Alopecia Severity by Genotype
1.
Richard  G. Autosomal recessive congenital ichthyosis. In Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, Washington: University of Washington, Seattle; 1993-2018.
2.
Farasat  S, Wei  MH, Herman  M,  et al.  Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA.  J Med Genet. 2009;46(2):103-111. doi:10.1136/jmg.2008.060905PubMedGoogle ScholarCrossref
3.
Foundation for Ichthyosis and Related Skin Types, Inc. National Registry for Ichthyosis and Related Disorders. www.firstskinfoundation.org/. Accessed July 2, 2019.
4.
Marukian  NV, Deng  Y, Gan  G,  et al.  Establishing and validating an Ichthyosis Severity Index.  J Invest Dermatol. 2017;137(9):1834-1841. doi:10.1016/j.jid.2017.04.037PubMedGoogle ScholarCrossref
5.
Olsen  EA, Hordinsky  MK, Price  VH,  et al; National Alopecia Areata Foundation.  Alopecia areata investigational assessment guidelines–part II.  J Am Acad Dermatol. 2004;51(3):440-447. doi:10.1016/j.jaad.2003.09.032PubMedGoogle ScholarCrossref
6.
Yoneda  K.  Inherited ichthyosis: syndromic forms.  J Dermatol. 2016;43(3):252-263. doi:10.1111/1346-8138.13284PubMedGoogle ScholarCrossref
Research Letter
July 31, 2019

Association of the Severity of Alopecia With the Severity of Ichthyosis

Author Affiliations
  • 1Section of Dermatology, Division of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 2Drexel University College of Medicine, Philadelphia, Pennsylvania
  • 3Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
  • 4Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
  • 5University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
JAMA Dermatol. 2019;155(9):1077-1078. doi:10.1001/jamadermatol.2019.1520

Congenital ichthyoses are characterized by abnormal epidermal barrier function. Scarring and nonscarring alopecia has been reported, but the pathogenesis is not well understood.1

Clinically, it is difficult to predict which individuals are likely to experience hair loss and at what severity level.1 The question often arises whether alopecia is extensive among patients with more severe skin disease. The primary aim of our study was to investigate the association between severity of ichthyosis and severity of alopecia. The secondary aim of our study was to characterize the severity of alopecia among patients with ichthyosis by genotype.

Hair phenotype could serve as a clue in narrowing the diagnosis of ichthyosis type when access to genetic testing is limited. Patients with autosomal recessive congenital ichthyosis and alopecia are most likely to have transglutaminase-1 (TGM1) mutations; otherwise, research investigating the association between hair phenotype and ichthyosis genotype is limited.2

Methods

For this study, the National Registry for Ichthyosis and Related Skin Types3 was queried for individuals with genotypic data and standardized professional photographs of the scalp and body; 86 individuals met the criteria. Institutional review board approval was obtained by Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, and Yale University, New Haven, Connecticut. All patients from the registry provided written informed consent.

Ichthyosis severity was assessed by 2 experts (L.M. and K.C.) using photographs and Visual Index of Ichthyosis Severity (VIIS),4 a validated instrument to quantify ichthyosis disease severity using a 0 to 32 scoring system (for the combined score, 0 is least severe and 32 is most severe; scoring can be divided into erythema [range, 0-16] and scale [range, 0-16]). Written descriptions of the clinical characteristics for erythema and scale for 4 body sites are defined in this instrument. Investigators (E.P. and L.C.) were blinded to genotype-calculated Severity of Alopecia Tool (SALT) scores based on the Olsen system.5 The SALT scores standardly used for alopecia areata were used because no tool currently exists for ichthyosis alopecia.

Genotypes were revealed to all investigators after VIIS and SALT scores were collected, and correlation statistics were completed. Two-tailed, P < .05 indicated statistical significance. Statistical calculations with 95% CIs were performed using Stata/IC, version 15.1 (StataCorp).

Results

Among 86 individuals (37 [43.0%] males with mean [SD] age of 27.5 [20.5] years), there was a positive correlation between VIIS and SALT scores, but the findings were not statistically significant (Spearman ρ = 0.20; 95% CI, 0.01-0.40; P = .08). Within the TGM1 and ABCA12 genotype subgroups, there were significant positive Spearman correlations between the VIIS and SALT scores (ρ = 0.54 [95% CI, 0.19-0.89; P = .001] vs ρ = 0.78 [95% CI, 0.39-1.16; P = .008]) (Table).

Discussion

We examined the associations among severity of alopecia, severity of ichthyosis, and ichthyosis genotype. In this population, severity of alopecia did not correlate significantly with severity of ichthyosis, suggesting that genotype rather than phenotypic severity of disease may have a stronger association with hair loss.

Among patients with autosomal recessive congenital ichthyosis, those with mutations in ABCA12 or TGM1 had similar severities of alopecia (Table and Figure). These results corroborate earlier work showing associations between alopecia and TGM1 mutations and suggest that ABCA12 mutations may also be associated with alopecia, an established feature of Harlequin ichthyosis phenotype.2 In contrast, patients with autosomal recessive congenital ichthyosis with 12(R)-lipoxygenase (ALOX12B), and ICHTHYIN (NIPA-like domain containing 4 [NIPAL4]) mutations did not have alopecia. Finally, patients with serine protease inhibitor Kazal type 5 (SPINK5) mutations reported alopecia, consistent with phenotypic characterizations of Netherton syndrome (Figure).6

Within the ABCA12 and TGM1 subgroups, severity of alopecia correlated positively with severity of ichthyosis. Thus, while severities did not appear to be associated in patients with ichthyosis overall, they may have been associated in patients with ABCA12 and TGM1 mutations.

Our study was limited by a small sample size and inability to control for age. Some experts report anecdotally that alopecia in this population improves or worsens. The population was composed of 8 genotypes, and larger studies focusing on single genotypes might bear different results. Nevertheless, the findings suggest that in patients with TGM1 and ABCA12 genotypes, alopecia may be more extensive in cases of severe skin disease.

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Article Information

Accepted for Publication: April 20, 2019.

Corresponding Author: Leslie Castelo-Soccio, MD, PhD, Section of Dermatology, Division of Pediatrics, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, The Richard Wood Pediatric Ambulatory Care Center, Room 3335, Philadelphia, PA 19104 (castelosocciol@email.chop.edu).

Published Online: July 31, 2019. doi:10.1001/jamadermatol.2019.1520

Author Contributions: Drs Castelo-Soccio, Choate, and Milstone had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Putterman, Zaki, Castelo-Soccio.

Acquisition, analysis, or interpretation of data: Putterman, Zaki, Milstone, Castelo-Soccio.

Drafting of the manuscript: Putterman, Zaki.

Critical revision of the manuscript for important intellectual content: Putterman, Zaki, Milstone, Castelo-Soccio.

Statistical analysis: Putterman, Castelo-Soccio.

Obtained funding: Castelo-Soccio.

Administrative, technical, or material support: Putterman, Zaki, Castelo-Soccio.

Supervision: Zaki, Castelo-Soccio.

Conflict of Interest Disclosures: Drs Choate and Castelo-Soccio reported receiving a research grant from the Foundation for Ichthyosis and Related Skin Types to support the National Registry for Ichthyosis and Related Skin Types. No other disclosures were reported.

Additional Contributions: We thank the patient for granting permission to publish this information. We thank the Foundation for Ichthyosis and Related Skin Types for supporting families and for its efforts to start the National Registry for Ichthyosis and Related Skin Types.

References
1.
Richard  G. Autosomal recessive congenital ichthyosis. In Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, Washington: University of Washington, Seattle; 1993-2018.
2.
Farasat  S, Wei  MH, Herman  M,  et al.  Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA.  J Med Genet. 2009;46(2):103-111. doi:10.1136/jmg.2008.060905PubMedGoogle ScholarCrossref
3.
Foundation for Ichthyosis and Related Skin Types, Inc. National Registry for Ichthyosis and Related Disorders. www.firstskinfoundation.org/. Accessed July 2, 2019.
4.
Marukian  NV, Deng  Y, Gan  G,  et al.  Establishing and validating an Ichthyosis Severity Index.  J Invest Dermatol. 2017;137(9):1834-1841. doi:10.1016/j.jid.2017.04.037PubMedGoogle ScholarCrossref
5.
Olsen  EA, Hordinsky  MK, Price  VH,  et al; National Alopecia Areata Foundation.  Alopecia areata investigational assessment guidelines–part II.  J Am Acad Dermatol. 2004;51(3):440-447. doi:10.1016/j.jaad.2003.09.032PubMedGoogle ScholarCrossref
6.
Yoneda  K.  Inherited ichthyosis: syndromic forms.  J Dermatol. 2016;43(3):252-263. doi:10.1111/1346-8138.13284PubMedGoogle ScholarCrossref
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