Table 1. [Autosomal Recessive Congenital Ichthyosis: Genes and Distinguishing Clinical Features]. - GeneReviews®

Gene ¹	% of All ARCI ²	Distinguishing Clinical Features	Other	Selected OMIM Links / References
ABCA12	3%-12%	Accounts for >93% of HI; biallelic complete loss-of-function variants were assoc w/most severe HI. CIE or LI presented in those w/variants w/partial function; often assoc w/severe erythroderma & PPK. Albeit extremely rare, a mosaic form of CIE due to postzygotic somatic mosaicism has been observed.	~4% of distinct variants are large deletions/duplications. ³ Missense variants in the region coding for the 1st nuclear binding fold were assoc w/LI & predicted to interfere w/specific functions of this protein domain.	OMIM 601277; OMIM 242500; Sakai et al [2009], van Leersum et al [2020]
ALOX12B	9%-21%	>75% of affected persons w/ALOX12B variants were born w/collodion membrane & later had mild-to-moderate CIE w/fine scaling & erythema. Persons w/self-improving collodion ichthyosis	~2% of distinct variants are large deletions/duplications. ³ The variant p.Tyr521Cys accounts for 22% of disease alleles.	OMIM 242100; Hotz et al [2021]
ALOXE3	3%-10%	>33% of affected persons w/ALOXE3 variants were born w/collodion membrane & later had mild-to-moderate CIE w/fine scaling & erythema. Intermediate phenotypes Persons w/self-improving collodion ichthyosis	More common in Austria ~10% of distinct variants are large deletions/duplications. ³ The variant p.Pro630Leu accounts for 40% of disease alleles & p.Arg234Ter accounts for 21%.	OMIM 606545; Harting et al [2008], Hotz et al [2021]
CASP14	Rare	No collodion membrane at birth, generalized fine, whitish scales, & no erythema	1 homozygous frameshift variant was observed in 2 Algerian families. To date, no large deletions/duplications have been reported. ³	OMIM 617320
CERS3	<1%-3%	Collodion membrane at birth, erythema & fine scales on face & trunk, larger, gray-brown scales on lower limbs, & hyperlinear palms/soles A distinct feature is keratotic lichenification w/prematurely aged appearance of skin.	More common in Iran (5.6% of variants) 1 multigene deletion reported incl CERS3 assoc w/syndromic ichthyosis. See also footnote 4.	OMIM 615023
CYP4F22	3%-10%	Typically, erythroderma at birth but w/o collodion membrane & later in life present w/LI w/larger, white-gray scales & hyperlinear palms/soles Persons w/self-improving collodion ichthyosis	~3% of distinct variants are large deletions/duplications. ³ Less common in northern Europeans	OMIM 604777; Scott et al [2013], Bučková et al [2016], Diociaiuti et al [2016], Noguera-Morel et al [2016]
LIPN	<1%	Childhood onset w/generalized fine, white scaling & minimal erythema	5% of variants in Middle Eastern populations To date, no large deletions/duplications have been reported. ³	OMIM 613943
NIPAL4	5%-9%	<30% of persons w/NIPAL4 variants have collodion membrane at birth. Congenital ichthyosis w/coarse, gray-white scales, mild-to-moderate erythroderma, & sparing of face Yellowish PPK & hypohidrosis Specific electron microscopic (EM) abnormalities (classified as ARCI EM type 3) w/abnormal lamellar bodies & elongated perinuclear membranes in granular layer	More common in Scandinavia (12.5%) Higher prevalence in Sweden, Denmark, & Norway, where NIPAL4-related ARCI accounts for ~90% of ARCI w/o collodion membrane presentation in those w/o TGM1 variants. The variant p.Asn176Asp is a mutation hot spot, observed in 87% of disease alleles & 70% of persons tested. To date, no large deletions/duplications have been reported. ³	OMIM 612281; Dahlqvist et al [2007], Scott et al [2013], Bučková et al [2016], Ballin et al [2019]
PNPLA1	≤5%	Typically, collodion membrane at birth & then transition to CIE phenotype w/scalp involvement & hyperlinear palms/soles Mild disease w/generalized fine exfoliation & hyperkeratotic plaques over knees resembling progressive symmetric erythrokeratoderma Ectropion, eclabium, & alopecia are lacking.	More common in Iran (15% of variants) Higher prevalence in northern Africa, Spain, & Iran, likely due to founder variants To date, no large deletions/duplications have been reported. ³	OMIM 615024; Vahidnezhad et al [2017], Zimmer et al [2017]
SDR9C7	1%	CIE & intermediate phenotypes w/PPK & frequent fungal infections of skin & nails.	More common in Austria (6% of variants) To date, no large deletions/duplications have been reported. ³	OMIM 617574
SLC27A4	Rare; 4%-5% in Scandinavia & northern Europe	IPS: polyhydramnios & premature birth Severe perinatal presentation w/respiratory asphyxia & thick, vernix caseosa-like scale or cobblestone-like hyperkeratosis on scalp, forehead, & trunk Skin findings resolve over several weeks, transitioning to mild generalized follicular hyperkeratosis	Mainly in persons from Scandinavia & northern Europe The variant c.504C>A (p.Cys168Ter) is a founder variant in persons of Scandinavian ancestry. A deletion of exon 3 has been reported. ³	OMIM 608649; Sobol et al [2011], Lwin et al [2016]
SULT2B1	<1%	Collodion membrane at birth in most affected persons; later, LI-like phenotype w/milder scaling in large skin folds	Reported in few consanguineous families from North Africa, Middle East, & South Asia	Heinz et al [2017]
TGM1	24%-34%	~70%-90% of persons w/LI phenotype have TGM1 variants. TGM1 variants also reported in many persons w/much milder non-erythrodermic phenotypes. Persons w/"bathing suit ichthyosis" Persons w/self-improving collodion ichthyosis	More common in Scandinavia & Galicia The variant c.877-2A>G is a Norwegian/German founder variant & is common in Norway, Finland, & North America. The variants c.2278C>T (p.Arg760Ter) & c.1223_1227delACACA are founder variants in Galician population of Spain. <1% of variants are large deletions/duplications. ³	OMIM 242300; Shevchenko et al [2000], Raghunath et al [2003], Mazereeuw-Hautier et al [2009], Hackett et al [2010], Rodríguez-Pazos et al [2011], Fachal et al [2014]
Unknown ⁵	7%-17%

Gene ¹

% of All ARCI ²

Distinguishing Clinical Features

Other

Selected OMIM Links / References

ABCA12

3%-12%

Accounts for >93% of HI; biallelic complete loss-of-function variants were assoc w/most severe HI.
CIE or LI presented in those w/variants w/partial function; often assoc w/severe erythroderma & PPK.
Albeit extremely rare, a mosaic form of CIE due to postzygotic somatic mosaicism has been observed.

~4% of distinct variants are large deletions/duplications. ³
Missense variants in the region coding for the 1st nuclear binding fold were assoc w/LI & predicted to interfere w/specific functions of this protein domain.

OMIM 601277;
OMIM 242500;
Sakai et al [2009], van Leersum et al [2020]

ALOX12B

9%-21%

>75% of affected persons w/ALOX12B variants were born w/collodion membrane & later had mild-to-moderate CIE w/fine scaling & erythema.
Persons w/self-improving collodion ichthyosis

~2% of distinct variants are large deletions/duplications. ³
The variant p.Tyr521Cys accounts for 22% of disease alleles.

OMIM 242100;
Hotz et al [2021]

ALOXE3

3%-10%

>33% of affected persons w/ALOXE3 variants were born w/collodion membrane & later had mild-to-moderate CIE w/fine scaling & erythema.
Intermediate phenotypes
Persons w/self-improving collodion ichthyosis

More common in Austria
~10% of distinct variants are large deletions/duplications. ³
The variant p.Pro630Leu accounts for 40% of disease alleles & p.Arg234Ter accounts for 21%.

OMIM 606545;
Harting et al [2008], Hotz et al [2021]

CASP14

Rare

No collodion membrane at birth, generalized fine, whitish scales, & no erythema

1 homozygous frameshift variant was observed in 2 Algerian families.
To date, no large deletions/duplications have been reported. ³

OMIM 617320

CERS3

<1%-3%

Collodion membrane at birth, erythema & fine scales on face & trunk, larger, gray-brown scales on lower limbs, & hyperlinear palms/soles
A distinct feature is keratotic lichenification w/prematurely aged appearance of skin.

More common in Iran (5.6% of variants)
1 multigene deletion reported incl CERS3 assoc w/syndromic ichthyosis.
See also footnote 4.

OMIM 615023

CYP4F22

3%-10%

Typically, erythroderma at birth but w/o collodion membrane & later in life present w/LI w/larger, white-gray scales & hyperlinear palms/soles
Persons w/self-improving collodion ichthyosis

~3% of distinct variants are large deletions/duplications. ³
Less common in northern Europeans

OMIM 604777;
Scott et al [2013], Bučková et al [2016], Diociaiuti et al [2016], Noguera-Morel et al [2016]

LIPN

<1%

Childhood onset w/generalized fine, white scaling & minimal erythema

5% of variants in Middle Eastern populations
To date, no large deletions/duplications have been reported. ³

OMIM 613943

NIPAL4

5%-9%

<30% of persons w/NIPAL4 variants have collodion membrane at birth.
Congenital ichthyosis w/coarse, gray-white scales, mild-to-moderate erythroderma, & sparing of face
Yellowish PPK & hypohidrosis
Specific electron microscopic (EM) abnormalities (classified as ARCI EM type 3) w/abnormal lamellar bodies & elongated perinuclear membranes in granular layer

More common in Scandinavia (12.5%)
Higher prevalence in Sweden, Denmark, & Norway, where NIPAL4-related ARCI accounts for ~90% of ARCI w/o collodion membrane presentation in those w/o TGM1 variants.
The variant p.Asn176Asp is a mutation hot spot, observed in 87% of disease alleles & 70% of persons tested.
To date, no large deletions/duplications have been reported. ³

OMIM 612281;
Dahlqvist et al [2007], Scott et al [2013], Bučková et al [2016], Ballin et al [2019]

PNPLA1

≤5%

Typically, collodion membrane at birth & then transition to CIE phenotype w/scalp involvement & hyperlinear palms/soles
Mild disease w/generalized fine exfoliation & hyperkeratotic plaques over knees resembling progressive symmetric erythrokeratoderma
Ectropion, eclabium, & alopecia are lacking.

More common in Iran (15% of variants)
Higher prevalence in northern Africa, Spain, & Iran, likely due to founder variants
To date, no large deletions/duplications have been reported. ³

OMIM 615024;
Vahidnezhad et al [2017], Zimmer et al [2017]

SDR9C7

CIE & intermediate phenotypes w/PPK & frequent fungal infections of skin & nails.

More common in Austria (6% of variants)
To date, no large deletions/duplications have been reported. ³

OMIM 617574

SLC27A4

Rare; 4%-5% in Scandinavia & northern Europe

IPS: polyhydramnios & premature birth
Severe perinatal presentation w/respiratory asphyxia & thick, vernix caseosa-like scale or cobblestone-like hyperkeratosis on scalp, forehead, & trunk
Skin findings resolve over several weeks, transitioning to mild generalized follicular hyperkeratosis

Mainly in persons from Scandinavia & northern Europe
The variant c.504C>A (p.Cys168Ter) is a founder variant in persons of Scandinavian ancestry.
A deletion of exon 3 has been reported. ³

OMIM 608649;
Sobol et al [2011], Lwin et al [2016]

SULT2B1

<1%

Collodion membrane at birth in most affected persons; later, LI-like phenotype w/milder scaling in large skin folds

Reported in few consanguineous families from North Africa, Middle East, & South Asia

Heinz et al [2017]

TGM1

24%-34%

~70%-90% of persons w/LI phenotype have TGM1 variants.
TGM1 variants also reported in many persons w/much milder non-erythrodermic phenotypes.
Persons w/"bathing suit ichthyosis"
Persons w/self-improving collodion ichthyosis

More common in Scandinavia & Galicia
The variant c.877-2A>G is a Norwegian/German founder variant & is common in Norway, Finland, & North America.
The variants c.2278C>T (p.Arg760Ter) & c.1223_1227delACACA are founder variants in Galician population of Spain.
<1% of variants are large deletions/duplications. ³

OMIM 242300;
Shevchenko et al [2000], Raghunath et al [2003], Mazereeuw-Hautier et al [2009], Hackett et al [2010], Rodríguez-Pazos et al [2011], Fachal et al [2014]

Unknown ⁵

7%-17%

From: Autosomal Recessive Congenital Ichthyosis

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