Clinico-Epidemiologic Profile of Non-Syndromic Congenital Ichthyosis – A Retrospective Chart Review of 107 Patients

Abstract

Background:

Congenital ichthyoses are a rare Mendelian group of disorders affecting the integument with a heterogeneous clinical presentation amongst which scaling is a constant feature. There is scanty epidemiologic data regarding the clinical profile and histologic patterns of inherited ichthyosis from resource-poor countries.

Aims and Objectives:

The study was aimed at assessing the clinic-epidemiologic characteristics associated with the different forms of non-syndromic congenital ichthyosis.

Materials and Methods:

This was a retrospective chart review of ichthyosis patients that presented between July 2016 and Jun 2020. Details including demographic profile, clinical characteristics along with any relevant investigations done were included.

Results:

During the study period of 4 years, 107 patients with congenital non-syndromic ichthyosis were seen. The most frequent diagnosis was of common ichthyoses, followed by autosomal recessive congenital ichthyosis, epidermolytic ichthyosis and erythrokeratoderma, in decreasing order.

Conclusion:

Important clinical findings like erythema and the type of scales as well as histological differences including an absent or reduced granular layer in ichthyosis vulgaris can help differentiate among the clinical phenotypes of inherited non-syndromic ichthyosis especially in resource-poor settings. Also, there is a high prevalence of vitamin D deficiency and hence a need for screening for the same in all patients of congenital ichthyosis including the milder phenotypes.

Introduction

Inherited ichthyoses are monogenetic disorders occurring due to mutations in one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis.[1] They clinically present as scaling in varying combinations with xerosis, fissuring, erythema, pruritus, and in certain forms, suprabasal epidermolysis.[2] The clinical spectrum varies from common, milder forms including ichthyosis vulgaris (IV) and X-linked recessive ichthyosis (XLRI) to rare, more severe forms like congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI) whose course is complicated by the development of ectropion, eclabium, hypohidrosis, palmoplantar keratoderma and digital fibrous bands leading to autoamputation of fingers. There are only a few studies worldwide reporting the epidemiology of congenital ichthyosis.[3,4,5] The exact prevalence of congenital ichthyosis has not been determined in India but has been estimated at 13.3 per million people in a study in France.[4]

Materials and Methods

This was a retrospective chart review of patients with non-syndromic congenital ichthyosis who attended the Paediatric Clinic at the outpatient department of the Department of Dermatology, Venereology, and Leprosy of a tertiary centre in Chandigarh during the period of July 2016–Jun 2020. Data including demographic profile, clinical features and laboratory investigations including serum vitamin D levels and histology findings on skin biopsy was retrieved from the Paediatric Dermatology Clinic files. The Ichthyosis Area and Severity Index (IASI) was calculated by scoring the erythema and scaling from 0–4 along with the percentage involvement of the involved sites to give a composite score similar to the psoriasis area severity index. The ichthyosis was classified on the basis of the 2009 consensus classification.[2] The statistical analysis was done using the software SPSS 22.0. The Chi-square test was used to test the homogeneity of the data with respect to age, gender, age at onset, duration of illness, body surface area involvement and for determining any significant difference between the demographic variables in various sub-groups. A P value of less than 0.05 was taken as significant.

Results

One hundred and seventeen patients of non-syndromic congenital ichthyoses were identified during the study period of 3 years. The common ichthyoses (52 patients/44.4% including IV 18/15.38% and XLRI 34/29.05%) was the most frequently identified group followed by autosomal recessive congenital ichthyosis (ARCI –46/39.31%; CIE-27/23.07%, LI-17/14.5%, BSI 2/1.7%), Keratinopathic ichthyosis (EI/SEI –11, 9.4%), erythrokeratoderma (7, 5.9%): PSEK –5 (4.2%), 2 (1.7%), and others (1, 1.7%). There was a male preponderance with 75 (64%) patients being males. The maximum number of patients belonged to the age group of 0–10 years [Figure 1].

Figure 1.

Frequency of various types of non-syndromic congenital ichthyosis

Clinical characteristics, vitamin D status and histopathology according to the type of ichthyosis

Ichthyosis vulgaris: Eighteen patients of ichthyosis vulgaris were identified with a mean age of onset of disease being 12.44 ± 7.22 months [Figure 2 and Table 1]. A positive family history could not be elicited in any of the patients. Clinical examination revealed grey-brown scales as the most frequent type of scaling with erythema a rare finding seen only in one patient. The serum vitamin D levels were documented for 14 patients out of which 12 patients had vitamin D deficiency and two patients had vitamin D insufficiency. However, clinical or radiological signs of rickets were not observed in any of the patients. There was no statistically significant correlation between the ichthyosis severity and serum vitamin D levels (r = -0.12, P = 0.67). The most consistent histopathological finding in the skin biopsy of six patients was hyperkeratosis and superficial dermal inflammatory infiltrate which were present in 83.33% of the samples. Hypogranulosis or an absent granular layer was present in all the samples, while acanthosis was present in just 22.22% patients.

Figure 2.

Clinical photographs of patients with X-linked recessive ichthyosis (a) lamellar ichthyosis (b) Epidermolytic ichthyosis (c) frank rickets in patient with lamellar ichthyosis (d)

Table 1.

Clinical features of patients with non-syndromic ichthyosis

Patient profile (n=117)	Ichthyosis vulgaris	X-linked recessive ichthyosis	Autosomal recessive congenital ichthyosis			Keratinopathic	Erythrokeratoderma and other non-syndromic ichthyosis			P
			CIE	LI	BSI		PSEK	EKV	LoK
Mean age at presentation (years)	8.44±4.52	6.09±3.98	9.05±7.93	8.95±7.58	14.00±8.48	1.64±3.74	22.90±19.39	7.00±7.07	7.00	<0.001
Mean age of onset (months)	12.44±7.22	11.03±8.40	0.43±0.88	0.56±0.86	1.00±1.41	7.60±7.68	9.40±5.17	10.00±11.31	8.00	<0.001
Family history (%)	0	23.5	7.4	11.8	0	9.1	40	50	0	0.133
Erythema (%)	5.6	0	96.3	47.1	100	36.4	60	100	0	<0.001
Type of scales (%)										<0.001
Grey–brown	38.9	2.9	3.7	5.9	0	0	0	100	0
Light brown	61	5.9	92.6	11.8	0	18.2	20	0	0
Dark brown	0	91.2	3.7	82.4	100	81.8	80	0	100
Mean ichthyosis score	1.67±1.19	4.14±1.40	21.74±10.85	27.47±13.52	19.50±6.36	17.81±16.22	8.40±5.31	7.00±1.41	7.00	<0.001
Mean serum vitamin D levels (ng/ml)	12.04±6.51	19.13±10.91	23.74±18.9	15.55±13.37	19.57±12.57	8.04±5.68	28.30±5.02	14.85±16.75	-	0.044
Proportion of patients with vitamin D deficiency (%)	85.7	54.2	57.7	81.3	50	100	0	50	-	0.010
X-ray/clinical findings of rickets (%)	0	8.8	14.8	0	0	9.1	0	0	0	0.614
Histology (%)
Hyperkeratosis	83.3	88.9	100	100	-	83.3	100	-	100	0.687
Parakeratosis	33.3	5.6	30.8	12.6	-	33.3	33.4	-	100	0.200
Hypogranulosis	16.7	5.6	0	0	-	16.7	0	-	0	0.770
Granular layer absent	83.3	0	0	0	-	0	0	-	0	<0.001
Hypergranulosis	0	22.2	0	12.5	-	50	33.3	-	0	0.123
Acanthosis	22.2	22.2	38.5	50	-	50	66.7	-	100	0.354
Superficial dermal inflammatory infiltrate	83.3	77.8	92.3	100	-	83.3	100	-	100	0.721

BSI=Bathing suit ichthyosis, CIE=Congenital ichthyosiform erythroderma, EKV=Erythroderma keratovariabilis, LI=Lamellar ichthyosis, LoK=Loricirin keratoderma, PSEK=Progressive symmetric erythrokeratoderma

X-linked recessive ichthyosis: A total of 34 patients of XLRI were seen representing the major phenotype of ichthyosis patients in this study. The mean age of onset was 11.03 ± 8.40 months which was slightly less than that observed in the ichthyosis vulgaris group. A positive family history was present in eight patients (23.5%). Dark brown scales were seen in the majority of patients with none of them having erythema. One patient was found to have undescended testes on clinical examination. Serum vitamin D levels were performed for 24 patients, out of which 13 patients were vitamin D deficient, seven were vitamin D insufficient and only four had vitamin D levels in the normal range. There was no statistically significant correlation between the ichthyosis severity and serum vitamin D levels (r = 0.14, P = 0.51). Hyperkeratosis followed by superficial dermal inflammatory infiltrate were the most consistent findings observed in 18 biopsy samples with a frequency of 88.88% and 77.77%, respectively. Acanthosis and hypergranulosis were the next most frequent findings, each present in 22.22% of the patients.

Autosomal recessive congenital ichthyosis: Forty-six patients of ichthyosis were present in this chart review with the most frequent congenital ichthyosiform erythroderma in 58.6% patients followed by LI in 36.95% and bathing suit ichthyosis in just 4.3%. A history of collodion at birth was present in 18 patients (39.13%) while a positive family history was present in four patients. Clinical examination findings revealed erythema in 36 patients being found more frequently in patients of congenital ichthyosiform erythroderma than LI. Dark brown scales predominated in LI, while light brown scales were seen in most patients with congenital ichthyosiform erythroderma. Complications in the form of ectropion and palmoplantar keratoderma were present in 54.3% and 65.2% of patients, respectively. Serum vitamin D levels were documented for 44 patients, out of which 29 patients were vitamin D deficient, four were vitamin D insufficient and 11 had vitamin D levels in the normal range. Four patients had clinical or X-ray findings of rickets. There was no statistically significant correlation between the ichthyosis severity and serum vitamin D levels (r = 0.07, P = 0.61). As seen in IV and XLRI, hyperkeratosis (100%) and superficial dermal inflammatory infiltrate (95.2%) were the most frequent findings observed in the skin biopsy samples of patients with ARCI. This was followed by acanthosis present in 42.8% of the patients, while hypergranulosis was present in just 4.7% of patients.

Keratinopathic ichthyosis: Eleven patients with a diagnosis of epidermolytic ichthyosis/superficial epidermolytic ichthyosis were present in the study. The median age of onset was at birth with a history of blistering present in all the patients. Dark brown scales predominated in the majority with erythema seen in four patients. Serum vitamin D levels were estimated in 9 patients with all of them being vitamin D deficient, although frank rickets was diagnosed only in one patient. There was no statistically significant correlation between the ichthyosis severity and serum vitamin D levels (r = 0.25, P = 0.50). Out of six patients who were biopsied, 83.33% had the findings of hyperkeratosis and superficial dermal inflammatory infiltrate. Acanthosis and hypergranulosis were each seen in 50% of the patients. A frank subcorneal bulla was present in 16.6% patients, while spongiosis and prominent keratohyaline granules were present in 33.33% patients.

Erythrokeratodermas and other non-syndromic ichthyosis: This group comprised of eight patients with a diagnosis of progressive symmetric Erythrokeratoderma in five, Erythrokeratoderma variablis in two and Loricrin keratoderma in one. The median age of disease onset was 9.5 months with a positive family history present in 27.2% of patients. Serum vitamin D levels of five patients revealed vitamin D deficiency in one and insufficiency in three. There was no statistically significant correlation between the ichthyosis severity and serum vitamin D levels (r = -0.20, P = 0.74). Hyperkeratosis and superficial dermal inflammatory infiltrate were constant findings in the histopathologic examination of four patients who underwent skin biopsy. Acanthosis was present in 75% of the patients.

Discussion

According to the First Ichthyosis Consensus Conference in Soreze, 2009, inherited ichthyosis has been clinically classified into two principal groups: syndromic form, which involves the skin as well as internal organs, and non-syndromic form, which is limited to the skin.[2] IV is considered to be the most common form of ichthyosis with an incidence of up to 1/100.[1] IV patients comprised 15.38% of the study population in our study as compared to reported rates of 75.4% in previous studies.[3] This discrepancy can be explained by the milder disease severity for which the patients might not seek medical attention. Also, the patients who are referred to our hospital from outside tend to have a more severe disease phenotype. Male patients constituted 64% of the study population which is similar to previously reported rate of 65.1%.[3] The fact that XLRI, which was the most common diagnosis in our study, presents mostly in males is reflected in the skewed sex ratio.

The mean age of onset of disease and presentation was significantly lower in the keratinopathic ichthyosis and ARCI as compared to XLRI and IV. This finding corroborated the significant difference in the ichthyosis severity index between the disease phenotypes, reflecting the fact that patients with more severe diseases tend to seek medical attention earlier in the disease course. Although all our patients with ARCI had the disease onset in early life, mutations in LIPN (encoding epidermal lipase N) have been associated with a late-onset form of recessive ichthyosis in which generalized scaling can develop up to 5 years of age without any preceding history of collodion.[6] Hence, a later onset of the disease cannot be used as a reliable indicator to differentiate ARCI from common ichthyoses.

Clinical examination findings of dark brown scales were more suggestive of LI, XLRI or keratinopathic ichthyosis while light brown to grey–brown scales predominated in patients of IV and CIE. Erythema was mostly found in patients with ARCI, especially CIE and BSI and erythrokeratoderma. In the study by Paller et al., erythema in patients with ARCI strongly correlated with interleukin 17-related genes.[7]

The mean serum vitamin D levels were lowest for patients with keratinopathic ichthyosis (8.04 ± 5.68 ng/ml) followed by ichthyosis vulgaris (12.04 ± 6.27) with vitamin D deficiency in 100% and 86% of the patients, respectively. Thick scales acting as a physical sunscreen and hindering the ultraviolet B rays induced vitamin D synthesis in the skin have been hypothesized as a cause of vitamin D deficiency in patients with ichthyosis.[8] However, the finding of a higher incidence of vitamin D deficiency in patients of IV as compared to ARCI contradicts this hypothesis, pointing towards the role of some alternate factors unrelated to skin scaling. Although the mean vitamin D levels were relatively on the higher side for ARCI (20.57 ± 17.02 ng/ml) as compared to other forms of ichthyosis, it had the maximum patients (8.6%) with clinical/radiological evidence of rickets. Although there was a statistically significant difference in the mean vitamin D levels between the ichthyosis phenotypes, there was no correlation between the serum vitamin D levels and ichthyosis severity scores (r = 0.07, P = 0.44). We have recently shown an association of Fok-1 polymorphism along with age and raised serum ALP levels as potential factors for determining CI-related vitamin D deficiency.[9]

Histopathologic examination of the skin biopsies revealed hyperkeratosis and superficial dermal inflammatory infiltrate as the most consistent findings in all forms of ichthyosis. However, there was no statistically significant difference among the different types of ichthyoses for the presence of these findings. Hypogranulosis/absent granular layer was identified in all patients of IV but was lacking in all other types of ichthyoses. IV is caused by mutations in the filaggrin gene and since filaggrin forms the major component of the keratohyaline granules of granular layer its reduced expression is associated with reduced or absent granular layer. Thus, it acts as a definitive marker of IV and helps to differentiate between IV and XLRI in cases of diagnostic dilemma. There are important differences in the granular and spinous layers of patients with ARCI and XLRI as has been demonstrated in the study by Yang et al.[10] Acanthosis was found in 42.8% of patients with ARCI as compared to 22.2% of patients with XLRI. On the other hand, hypergranulosis was more frequent in patients with XLRI (22.2%) as compared to ARCI (4.7%).

The molecular diagnosis of ichthyosis is limited by its high cost, involvement of a vast number of genes, genetic heterogeneity and inability to detect pathogenic mutations in a subset of patients.[11] Thus, establishing clinico-histologic indicators to differentiate between the phenotypes of congenital ichthyoses can be a cost-effective strategy in resource poor settings.

Conclusion

Important clinical findings like erythema and the type of scales as well as histological differences including an absent or reduced granular layer in IV can help differentiate among the clinical phenotypes of inherited non-syndromic ichthyosis especially in resource poor settings where facilities for genetic testing may not be easily available. Also, there is a high prevalence of vitamin D deficiency and hence a need for screening for the same in all patients of congenital ichthyosis including the milder phenotypes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.