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Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12 , ALOX12B , ALOXE3 , CERS3 , CYP4F22 , NIPAL4 , PNPLA1 , SDR9C7 , SULT2B1 , and TGM1 . The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12 . Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12 . Our study comprises 34 novel mutations in ABCA12 , expanding the mutational spectrum of ABCA12 -associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene ( ABHD5 , MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous ABHD5 mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a de novo ABHD5 mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1 , ALOX12B , ALOXE3 , NIPAL4 , CYP4F22 , ABCA12 , PNPLA1 , CERS3 , SDR9C7 , and SULT2B1 . The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3 , which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3 . We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.

Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth, a collodion membrane or similar severe hyperkeratosis was reported in almost all patients with HI and LI, and in nearly half of patients with CIE and PI. Persistent ectropion was more common in HI (85%) and LI (57%), than in CIE (35%) and PI (5%). Anhidrosis was a frequent problem in all 4 groups (58-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27A4 (n = 5), CYP4F22 (n = 3), PNPLA1 (n = 1) and ABHD5 (n = 1). In conclusion, by performing a deep phenotyping and gene screening, ARCI can be definitely diagnosed in 85% of cases in Scandinavia, with a prevalence of 1:100,000 and > 8 different aetiologies.