Association of the Severity of Alopecia With the Severity of Ichthyosis

Abstract

This study assesses the association between the severity of alopecia and ichthyosis disease severity and characterizes the severity of alopecia by genotype.

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).

Table. Descriptive Summary of Ichthyosis Severity and Alopecia Severity by Genotype.

Affected Gene	Clinical Ichthyosis Type	Individuals, No.	Males, No.	Age, Mean (SD), y	SALT Score (%)	VIIS Score	Spearman ρ (95% CI)	P Value
ABCA12	ARCI	10	3	23.9 (11.1)	11.5 (22.6)	18. (4.2)	0.78 (0.39 to 1.16)	.008
ALOX12B	ARCI	7	2	48.6 (23.0)	0	16 (5.9)	NA
TGM1	ARCI	24	8	24.8 (19.3)	11.2 (15.9)	16.5 (4.9)	0.54 (0.19 to 0.88)	.01
ICHTHYIN	ARCI	5	4	20.8 (12.2)	0	14.4 (6.5)	NA
KRT1	Epidermolytic	8	2	25.1 (13.2)	0.6 (1.0)	22.5 (2.9)	0.43 (−0.20 to 1.05)	.34
KRT10	Epidermolytic	20	11	26.9 (23.0)	1.8 (3.5)	19.3 (5.7)	0.12 (−0.36 to 0.59)	.63
SPINK5	Netherton	8	5	35 (25.9)	24.0 (38.1)	18.3 (4.5)	−0.15 (−1.07 to 0.77)	.75
STS	X-linked recessive	4	4	16.5 (7.7)	0	11 (1.7)	NA

Abbreviations: ABCA12, ATP binding cassette subfamily A12; ALOX12B, arachidonate 12-lipoxygenase; ARCI, autosomal recessive congenital ichthyosis; ICHTHYIN (NIPAL4), NIPA-like domain containing 4; KRT1, keratin 1; KRT10, keratin 10; SALT, Severity of Alopecia Tool; SPINK5, serine peptidase inhibitor, Kazal type 5; STS, steroid sulfatase; TGM1, transglutaminase-1; VIIS, Visual Index of Ichthyosis Severity.

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

Figure. 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.

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.