Alternative titles; symbols
SNOMEDCT: 13059002, 718632004; ICD10CM: Q80, Q80.9; ICD9CM: 757.1; ORPHA: 100976, 281122, 281127, 313; DO: 0060656;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q12 | Ichthyosis, congenital, autosomal recessive 1 | 242300 | Autosomal recessive | 3 | TGM1 | 190195 |
A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-1 (ARCI1) is caused by homozygous or compound heterozygous mutation in the gene encoding keratinocyte transglutaminase (TGM1; 190195) on chromosome 14q12.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).
NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006).
In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005).
Genetic Heterogeneity of Autosomal Recessive Congenital Ichthyosis
Autosomal recessive congenital ichthyosis-2 (ARCI2; 242100) is caused by mutation in the ALOX12B gene (603741) on chromosome 17p13. ARCI3 (606545) is caused by mutation in the ALOXE3 gene (607206) on chromosome 17p13. ARCI4A (601277) and ARCI4B (harlequin ichthyosis; 242500) are caused by mutation in the ABCA12 gene (607800) on chromosome 2q35. ARCI5 (604777) is caused by mutation in the CYP4F22 gene (611495) on chromosome 19p13. ARCI6 (612281) is caused by mutation in the NIPAL4 gene (ichthyin; 609383) on chromosome 5q33. ARCI7 (615022) has been mapped to chromosome 12p11. ARCI8 (613943) is caused by mutation in the LIPN gene (613924) on chromosome 10q23. ARCI9 (615023) is caused by mutation in the CERS3 gene (615276) on chromosome 15q26. ARCI10 (615024) is caused by mutation in the PNPLA1 gene (612121) on chromosome 6p21. ARCI11 (602400) is caused by mutation in the ST14 gene (606797) on chromosome 11q24. ARCI12 (617320) is caused by mutation in the CASP14 gene (605848) on chromosome 19p13. ARCI13 (617574) is caused by mutation in the SDR9C7 gene (609769) on chromosome 12q13. ARCI14 (617571) is caused by mutation in the SULT2B1 gene (604125) on chromosome 19q13.
Ichthyosis prematurity syndrome (608649) is a self-improving form of ichthyosis that includes respiratory complications at birth and persistent eosinophilia and is caused by mutation in the FATP4 (SLC27A4; 604194) gene. A rare syndromic form of NCIE, Chanarin-Dorfman syndrome (275630), is caused by mutation in the ABHD5 gene (604780).
The neonate with lamellar ichthyosis presents at birth with a collodion-like membrane encasing the neonate; the skin later develops large, brown, platelike scales covering the entire body (Williams and Elias, 1985). See picture in Sorsby (1953). Russell et al. (1994) reported patients with a severe LI phenotype (nonerythrodermic) from 13 families; 17 patients from 7 U.S. families and 10 patients from 6 Egyptian families. The skin disease was congenital in all patients. Of 22 patients in whom this information was available, 21 had a history of collodion presentation at birth. Nineteen of 27 patients had ectropion, and half had alopecia with scarring of the scalp.
Tok et al. (1999) reported monozygotic African American twin girls who were born with collodion membrane, ectropion, and eclabium. The membranes were shed within 4 to 6 weeks, and the ectropion and eclabium also resolved spontaneously within 3 weeks without sequelae. At 2 months of age, both infants developed large thick brown scales covering nearly the entire integument, sparing only the face and flexural surfaces. The authors also described a male infant of Italian origin, born with collodion membrane, ectropion, and eclabium, who developed large thick scales throughout the entire integument including the face and flexural surfaces. The ectropion and eclabium resolved without sequelae. Both sets of parents were unaffected.
Cruz et al. (2000) reviewed the eyelid abnormalities in 8 patients with lamellar ichthyosis and 2 patients with nonbullous congenital ichthyosiform erythroderma. All 8 patients presented with cicatricial lagophthalmos (inability to appose the eyelids due to cutaneous scarring). Of the 8 patients with classic LI, 5 had ectropion of all 4 eyelids, 1 had only lower ectropion, and 2 had no ectropion. The 2 patients with NCIE had distinct eyelid abnormalities, including madarosis (eyelash loss) and eyelash retraction. Three patients with classic LI had severe visual loss from corneal damage. Of these 3 patients, 2 did not have upper ectropion. The authors concluded that severe corneal damage and visual loss could occur in LI even in the absence of upper or lower ectropion.
Lugassy et al. (2008) studied a female infant with ARCI from a consanguineous Iranian family, in whom they identified homozygosity for a frameshift mutation in the TGM1 gene. The patient was born with collodion membrane and in the second month of life showed erythroderma and widespread scaling. No hair was visible on any part of the body, and she also had severe nail dystrophy and failure to thrive.
Self-Healing Collodion Baby
Collodion babies look very much alike at birth, but later take different clinical courses. Most patients evolve into the different types of congenital ichthyosis, but about 10% heal spontaneously within the first few weeks (Raghunath et al., 2003). This benign and self-limited clinical course, termed 'self-healing collodion baby,' distinguishes this condition from TGM1-deficient lamellar ichthyosis.
Mazereeuw-Hautier et al. (2009) reported a nonconsanguineous French family in which 2 sisters had different ichthyosis phenotypes: the older sister was born as a classic generalized collodion baby, and later developed the lamellar form of ichthyosis, with large dark scales all over her body. The younger sister presented at birth with a collodion baby phenotype in a localized acral distribution, with only the 2 distal phalanges of her fingers and toes embedded in glistening, tight skin leading to constricting bands and cracks. The dorsal surface of the hands appeared slightly edematous, but the rest of the skin was normal apart from mild scaling and erythema that appeared to be related to the newborn status. Her skin abnormalities healed within a few weeks and she had normal skin at 7 years of age. The parents reported no family history of similar skin changes in the newborn period. Histochemical transglutaminase-1 assay in skin biopsies from the 2 sisters showed that the younger sister with acral self-healing collodion baby had slightly reduced enzyme function compared to a control skin biopsy, whereas the older sister with LI had complete absence of enzyme activity.
Vahlquist et al. (2010) studied 11 Swedish and 4 Danish patients with autosomal recessive congenital ichthyosis of the 'self-healing' type, all of whom were born with a variably thick collodion membrane, with ectropion present in 8 cases. The membrane was spontaneously shed after 2 to 4 weeks, exposing almost normal-appearing skin. Examination at 2 years to 37 years of age, however, revealed that all of the patients had varying degrees of mild ichthyosis, consisting of scaling in the armpits, acral hyperkeratosis and keratoderma, coarse scales on the scalp, and fine scaling around the neck, together with xerotic extremities and red cheeks that stung with exposure to salt water. All but 1 of the patients exhibited moderate to severe anhidrosis; the patient with normal sweating was an 18-year-old Swedish girl who was compound heterozygous for mutations in the TGM1 gene and whose residual skin symptoms, consisting of fine scaling and xerosis with palmoplantar fissures, improved in summer. Vahlquist et al. (2010) proposed the term 'self-improving collodion ichthyosis' (SICI) as a better designation for this phenotype.
Bathing Suit Distribution of Ichthyosis
Bathing suit ichthyosis (BSI) is a form of ARCI characterized by collodion membrane at birth, encasing the entire skin, with clinical healing of the ichthyosis on the arms and legs during the first weeks of life (Oji et al., 2006).
Petit et al. (1997) described a 4-year-old girl with an unusual distribution of the lamellar form of ichthyosis, which involved large dark brown scales affecting the trunk, neck, and scalp but sparing the face and limbs.
Yang et al. (2001) reported a Japanese girl and a Korean boy who had similar clinical histories: both were born with collodion membrane and developed ectropion and eclabium at 1 day of age. At 1 month of age, the ectropion and eclabium had improved, and the dry collodion membrane peeled off to reveal large, slightly brownish scales primarily on the trunk, with near-normal appearance of other body sites, although the skin was dry. At 6 months of age, the girl's scales became fine and white, and were successfully controlled with petroleum. By 1 year of age, the brownish scales in the boy were confined to his forehead, buttocks, and flanks.
Akiyama et al. (2001) described a 56-year-old Japanese woman, born of nonconsanguineous parents, who had a mild form of lamellar ichthyosis involving thick dark gray lamellar scales covering her neck, abdomen, center of the back, and bilateral axillae. She was not born with collodion, and thick scales had appeared during infancy. The skin on her face and extremities appeared normal, and she did not display hyperkeratosis of the palms or soles. The severity of scaling was stable without the use of retinoids or topical steroids, although the scaling worsened and affected areas enlarged during the summer. Family history revealed that an older sister with ichthyosis had died at 1 week of age of unknown cause. Light microscopy of lesional skin showed marked hyperkeratosis with only a small number of parakeratotic cells, and electron microscopy demonstrated thickening of the cornified cell envelope during keratinization of the epidermis.
Jacyk (2005) reported 13 South African black patients from 12 families who displayed the lamellar form of autosomal recessive ichthyosis in a distribution involving the trunk, the most proximal parts of the upper limbs including the axillae, scalp, and neck, but sparing the central face and extremities. The scales were dark brown, large, and plate-like. Palms and soles were dry, with diffuse, mild hyperkeratosis; the dorsal surfaces appeared normal and there were no nail changes. Skin lesions were present at birth in all, and in 10 patients the presentation was compatible with collodion baby. Consanguinity was denied but both parents of 10 patients belonged to the same ethnic group and came from the same rural area, often from the same village. Light microscopy of biopsies from the lower back showed marked hyperkeratosis, no parakeratosis, granular layer of 1 to 3 layers of cells, mild to moderate acanthosis, and mild lymphocytic infiltrate in the upper dermis. Electron microscopy did not reveal cholesterol clefts or lipid droplets in the thickened corneal layer. Jacyk (2005) proposed the term 'bathing suit ichthyosis' for this condition.
Oji et al. (2006) described 10 probands from Germany, France, Turkey, the Netherlands, or Morocco who fulfilled the clinical criteria for BSI. All patients were born with collodion membrane, and during the first to second month of life, they developed a lamellar scaling on the trunk, whereas the 4 limbs and face were almost completely spared. The severity of scaling varied widely, with some patients having large, thick, dark scales with involvement of very specific areas on the extremities and the face, others having mild brownish scaling that was most pronounced in the axillae and on the neck, and a few having moderate scaling of affected areas. A 16-year-old proband from Germany and his affected brother had a variable course, presenting with a bathing suit distribution in infancy but developing a tendency towards more generalized and rather mild ichthyosis. Five patients displayed fine linear scaling on the inner forearm and very pronounced scaling in the axillae, on the neck, and on medial parts of the trunk, sparing the suprarenal lumbar areas. Digital thermography in healthy individuals showed a striking correlation between warmer body sites and the 'bathing suit' distribution of scaling, leading Oji et al. (2006) to conclude that temperatures above approximately 33 degrees Celsius predispose to the development of ichthyosis in these patients.
Ultrastructural Features of Autosomal Recessive Congenital Ichthyosis
Patients with autosomal recessive congenital ichthyosis have structural changes affecting terminal differentiation and keratinization within the epidermis, which can be seen using electron microscopy (EM). Dahlqvist et al. (2007) stated that about half of patients with ARCI investigated by EM lack unique characteristics of the epidermis, but the remaining patients show defined ultrastructural markers that can be categorized into 4 main patterns: type I is characterized by broad stratum granulosum and numerous lipid vacuoles in corneocytes; type II shows clefts of former cholesterol crystals in stratum corneum; type III is characterized by abnormal lamellar bodies in stratum granulosum and perinuclear, elongated membranes; and type IV shows lipid membrane aggregations in upper epidermal cells. All individuals but 1 studied by Dahlqvist et al. (2007) in whom NIPAL4 (609383) mutations were found (ARCI6; 612281) fulfilled the EM criteria of ARCI EM type III.
Laiho et al. (1999) restudied 38 Finnish families with autosomal recessive congenital ichthyosis, in 13 (34%) of which TGM1 mutations had been found (Laiho et al., 1997), and compared the molecular genetic alterations with clinical and electron microscopic findings of these patients. On the basis of electron microscopy in ichthyosis congenita, the families were classified as types I, II, III, IV, and an undefined group. TGM1 gene mutations were found in all of the autosomal recessive congenital ichthyosis cases of type II and in one-third of type I families. The typical clinical phenotype of the TGM1 mutation carrier included large, thick, brownish scales, but ichthyosis of some of the patients tended to be milder. Type II is the most clearly defined of the congenital ichthyosis groups. Patients have a clear clinical picture of classic lamellar ichthyosis with large brown scales. Crystalloid structures (cholesterol clefts) in the thickened corneal layer are used as an electron-microscopic marker for ichthyosis congenita type II and were found in every patient. The ultrastructural markers in type III patients were elongated membrane structures, abnormal keratinosomes, and vesicular complexes in upper epidermal and horny cells. The clinical picture differed from that in other types: the onset of ichthyosis was variable, ichthyosis as well as erythema could be patchy or generalized, and flexures were typically involved.
In the stratum corneum of patients with lamellar ichthyosis, the amount of free fatty acids is decreased, the ceramide profile is altered, and there are elevated levels of transepidermal water loss indicative of an impaired barrier function. As ceramides and free fatty acids are essential for a proper barrier function, Pilgram et al. (2001) hypothesized that changes in the composition of these lipids would be reflected in the lipid organization in stratum corneum of patients with lamellar ichthyosis. They investigated lateral lipid packing using electron diffraction and lamellar organization using freeze-fracture electron microscopy. In LI stratum corneum, hexagonal packing was predominant, whereas orthorhombic packing was observed only occasionally. The finding that the lateral lipid organization in LI skin is predominantly hexagonal was in good agreement with stratum corneum lipid model studies showing that long-chain free fatty acids are required to form an orthorhombic lattice. The results in this study also confirmed the hypothesis that an orthorhombic packing is required for proper stratum corneum barrier function.
Aufenvenne et al. (2009) studied 8 of the TGM1 mutations that were identified by Oji et al. (2006) in patients who had ichthyosis in a bathing suit distribution (BSI; see, e.g., 190195.0029-190195.0032) as well as 3 mutations associated with classic LI (see, e.g., 190195.0007). Using fluorescence spectrometry to analyze enzyme activity, Aufenvenne et al. (2009) demonstrated that both the BSI- and LI-associated mutations had decreased enzyme activity compared to wildtype, but the BSI mutations exhibited a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius, with residual activity ranging between 13% and 16.5% at the lower temperature, whereas activity at 37 degrees Celsius was less than 7.5%. Deficient activity of the BSI mutations could be reconstituted by decreasing the temperature to below 33 degrees Celsius. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in BSI is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
Aufenvenne et al. (2013) developed liposomal preparations with encapsulated recombinant human TGM1 and tested them in a skin-humanized mouse model. In situ monitoring revealed a restoration of TGM1 activity, and cholesterol clefts vanished ultrastructurally. Immunohistochemical staining of TGM1 substrates showed a normalization of the distribution patterns. Measurement of transepidermal water loss showed that normal epidermal barrier function was restored. Aufenvenne et al. (2013) concluded that this topical approach might be a promising strategy towards a causal cure for individuals with chronic and disfiguring TGM1 deficiency, who often must spend 2 to 3 hours a day in treatment for their skin.
Wile (1924) reported 3 affected males, the offspring of matings in which 2 brothers married 2 sisters, who were their first cousins. Arce and Berchmans (1969) described ichthyosiform dermatosis in 13 members of an inbred Brazilian kindred.
Nix et al. (1963) described 9 cases among 22 offspring of 3 couples of German extraction. All 6 parents had a common ancestral couple.
Rossmann-Ringdahl et al. (1986) described NCIE in a woman and both of her children. Although her husband was not known to be related, this was thought to be pseudodominant inheritance. Williams and Elias (1986), however, thought that this might represent a true dominant form of 'lamellar' ichthyosis (146750). They pointed to the kindred reported by Traupe et al. (1984) with affected persons in 3 generations and mentioned a similar family of their own.
Russell et al. (1994) cited a prevalence of lamellar ichthyosis of approximately 1 in 200,000 persons.
Lefevre et al. (2006) stated that the estimated incidence of ARCI is between 1 in 300,000 and 1 in 500,000.
Studying families with LI in the United States and in Egypt, Russell et al. (1994) tested for linkage with markers in the region of genes that are candidates for the site of the mutation by reason of being involved in formation of the stratum corneum. Analysis in both inbred and outbred families showed that severe LI was linked to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. The transglutaminase-1 gene maps to the same region and encodes one of the enzymes responsible for crosslinking epidermal proteins during formation of the stratum corneum. Russell et al. (1994) showed that TGM1 and LI were linked with no recombinants; maximum lod = 9.11.
Arita et al. (2007) performed SNP genotyping on DNA samples from 8 South African black patients with autosomal recessive congenital ichthyosis in a bathing suit distribution, 5 of whom had been previously reported by Jacyk (2005). From the SNP assay analysis, 7 regions of the genome were found to have large blocks of homozygosity for all affected individuals, including a 1.2-Mb interval on chromosome 14q11 that contains the TGM1 gene.
Huber et al. (1995) observed that affected individuals in 3 families with autosomal recessive lamellar ichthyosis exhibited drastically reduced transglutaminase activity; in 2 of the families, expression of TGM1 transcripts was diminished or abnormal and no TGM1 protein was detected. Analysis of the TGM1 gene revealed homozygous or compound heterozygous mutations of the TGM1 gene in all 3 families (see 190195.0001-190195.0005). The results suggested that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.
In 2 multiplex families with severe autosomal recessive lamellar ichthyosis that had been linked to 14q11 and TGM1 by Russell et al. (1994), Russell et al. (1995) identified compound heterozygosity for missense mutations in the TGM1 gene (190195.0006 and 190195.0007).
Laiho et al. (1997) analyzed the TGM1 gene in 49 patients from 38 Finnish families with autosomal recessive congenital ichthyosis and identified homozygosity or compound heterozygosity for 5 different mutations in affected individuals from 13 families (see 190195.0004, 190195.0006, 190195.0008, 190195.0009, and 190195.0023). In 2 patients the second mutation was unknown. Some patients had the lamellar form of ichthyosis whereas others exhibited nonbullous congenital ichthyosiform erythroderma. Haplotype analysis revealed that the most common mutation, R142C (190195.0004), had been introduced twice into the Finnish population.
In a 4-year-old girl with an unusual distribution of the lamellar form of ichthyosis, which involved large dark brown scales affecting the trunk, neck, and scalp but sparing the face and limbs, Petit et al. (1997) identified homozygosity for a missense mutation in the TGM1 gene (V382M; 190195.0010). Functional analysis of cultured keratinocytes demonstrated a profound reduction of membrane-bound as well as cytosolic transglutaminase (TG) activity in both affected and unaffected skin from the patient compared to controls. Immunoblot analysis of cytoplasmic and membrane keratinocyte extracts revealed no detectable TGK protein in affected or unaffected skin from the patient, although Northern blot analysis showed TGM1 mRNA of normal size and comparable amounts with an age-matched control. Petit et al. (1997) proposed that other mechanisms may compensate for TGK deficiency in unaffected skin, and suggested that the regulation of the formation of the cornified envelope might differ between these different areas of skin.
Pigg et al. (1998) studied 36 Norwegian families with lamellar ichthyosis and 7 with nonbullous congenital ichthyosiform erythroderma using microsatellite markers linked to the TGM1 gene, and found a common haplotype for 2 markers on 74% of disease-associated chromosomes. In 3 individuals homozygous for the common haplotype, 2 with lamellar ichthyosis and 1 with congenital ichthyosiform erythroderma, homozygosity for a splice site mutation in the TGM1 gene was identified (IVS5-2A-G; 190195.0002). Screening of probands from the remaining 40 families revealed the splice site mutation on 61 of 72 alleles associated with lamellar ichthyosis and on 9 of 15 alleles associated with congenital ichthyosiform erythroderma. These findings suggested a single founder mutation for most patients with ARCI in Norway.
In African American twin girls with lamellar ichthyosis that spared the face and flexural surfaces, Tok et al. (1999) identified homozygosity for a missense mutation in the TGM1 gene (R315L; 109195.0033). In a male infant of Italian extraction who had lamellar ichthyosis over his entire integument, they identified compound heterozygosity for mutations in TGM1.
Shevchenko et al. (2000) studied 5 American families with the IVS5-2A-G mutation in the TGM1 gene, noting that all had the lamellar form of ichthyosis and that patients who were homozygous for the splice site mutation were less severely affected than many of the compound heterozygotes. None were of Norwegian ancestry, and genealogic information provided evidence that the founder chromosome may have arisen in the Westphalia region of Germany, with introduction into the Norwegian population around 1000 to 1100 A.D.
In a Japanese boy with ARCI who displayed nonbullous congenital ichthyosiform erythroderma consisting of fine gray or light brown scales on an erythematous skin, Akiyama et al. (2001) identified compound heterozygosity for a missense mutation and a 1-bp deletion in the TGM1 gene (190195.0011 and 190195.0012, respectively).
Cserhalmi-Friedman et al. (2001) analyzed the TGM1 gene in 10 ARCI patients with the lamellar form of ichthyosis and identified compound heterozygosity for 14 different mutations in 7 patients (see, e.g., 190195.0014-190195.0020 and 190195.0024-190195.0026). Erythema in the 10 patients varied from mild to moderate, and 2 of them had small scales. Cserhalmi-Friedman et al. (2001) stated that the clinical presentation of patients with and without mutations was virtually indistinguishable.
In a Japanese girl and a Korean boy with similar clinical histories, who both had ichthyosis in a distribution affecting primarily the trunk, Yang et al. (2001) identified compound heterozygosity for missense mutations in the TGM1 gene, N228T (190195.0021), R306W (190195.0022), and D101V (190195.0027).
In a 56-year-old Japanese woman with a mild form of lamellar ichthyosis limited to the neck, abdomen, center of the back, and bilateral axillae, Akiyama et al. (2001) identified compound heterozygosity for 2 missense mutations in the TGM1 gene, R306W and L204Q (190195.0028).
Raghunath et al. (2003) described 2 sibs with ARCI who presented the self-healing collodion baby phenotype; they had markedly diminished TGM1 epidermal activity and were found to be compound heterozygous for missense mutations in the TGM1 gene (190195.0013 and 190195.0014). Molecular modeling and biochemical assays of mutant proteins under elevated hydrostatic pressure suggested significantly reduced activity in G278R and a chelation of water molecules in D490G that locked the mutated enzyme in an inactive trans conformation in utero. After birth, these water molecules were removed and the enzyme was predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition.
Oji et al. (2006) sequenced the TGM1 gene in 10 ARCI probands from Germany, France, Turkey, the Netherlands, or Morocco, who fulfilled the clinical criteria for 'bathing suit' ichthyosis (BSI), and identified homozygosity or compound heterozygosity for TGM1 mutations in all patients (see, e.g., 190195.0002, 190195.0007, 190195.0029-190195.0032). Digital thermography in healthy individuals showed a striking correlation between warmer body sites and the 'bathing suit' distribution of scaling, and in situ TGase testing in the skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees Celsius. Oji et al. (2006) concluded that the bathing suit form of ichthyosis is caused by TGM1 deficiency and that it is a temperature-sensitive phenotype.
In 8 South African black patients with autosomal recessive congenital ichthyosis in a bathing suit distribution mapping to chromosome 14q11, 5 of whom had previously been reported by Jacyk (2005), Arita et al. (2007) sequenced the candidate gene TGM1 and identified homozygosity for a missense mutation (R315L; 190195.0033). Arita et al. (2007) noted that the R315L mutation had previously been identified by Tok et al. (1999) in African American twins who had a more classic presentation of lamellar ichthyosis in which skin scaling was extensive, sparing only the face and the flexures.
In a French family in which 1 sister had a lamellar ichthyosis phenotype and another sister presented a self-healing collodion baby phenotype limited to an acral distribution, Mazereeuw-Hautier et al. (2009) identified 3 mutations in the TGM1 gene: the sister with the self-healing collodion baby phenotype was compound heterozygous for 2 missense mutations in TGM1, V359M (190195.0034) and R396H (190195.0035), whereas the sister with classic LI was compound heterozygous for R396H and a 7-bp deletion (190195.0036). Their unaffected mother was heterozygous for the R396H mutation, and their apparently unaffected father was a compound heterozygote for V359M and the 7-bp deletion; none of the mutations were found in 100 unrelated Caucasian controls. Mazereeuw-Hautier et al. (2009) noted that a transient and mild anomaly of the skin at birth could not be ruled out in the father.
In a female infant with ARCI from a consanguineous Iranian family, Lugassy et al. (2008) identified homozygosity for a 1-bp deletion in the TGM1 gene that segregated with disease in the family and was not found in 50 controls. The patient was born with collodion membrane and in the second month of life showed erythroderma and widespread scaling. No hair was visible on any part of the body, and she also had severe nail dystrophy.
In 16 Spanish ARCI families from Galicia, Rodriguez-Pazos et al. (2011) analyzed 5 ARCI-associated genes and identified TGM1 mutations in 11 probands, who all exhibited the lamellar form of ichthyosis. Three mutations accounted for 41%, 23%, and 14% of the TGM1 mutant alleles, respectively (see, e.g., 190195.0038 and 190195.0039). In 4 probands, no causative variants were identified; and 1 proband, who a congenital ichthyosiform erythroderma phenotype, was compound heterozygous for missense mutations in the ALOXE3 gene. Rodriguez-Pazos et al. (2011) concluded that the high percentage of patients with the same TGM1 mutation, together with the high number of homozygous probands (64%), indicated the existence of a strong founder effect in this population, with an estimated prevalence of 1:122,000 for Galicia.
Genetic Heterogeneity
Huber et al. (1995) demonstrated apparent genetic heterogeneity of lamellar ichthyosis; they described 2 sporadic cases with normal transglutaminase activity and by Western and Northern blot analyses normal size and quantities of keratinocyte transglutaminase protein and mRNA. Sequencing of the 15 exons and their flanking regions demonstrated no deviation from the published sequence. Consanguinity was suspected in one case but not in the second.
By linkage analysis, haplotype analysis, and direct sequencing, respectively, Petit et al. (1997) excluded the TGM1 gene as the cause of ARCI in 4 patients from 3 families. Two of the patients were sisters who exhibited a classic lamellar form of ichthyosis, whereas the other 2 patients had moderate lamellar ichthyosis with finer scaling and variable erythema.
Eckl et al. (2009) studied 250 unrelated patients representing the entire phenotypic spectrum of ARCI, including 15 patients from families previously studied by Eckl et al. (2005), and found that mutations in TGM1 accounted for 38% of the cases, whereas mutations in the ALOX12B (603741) and ALOXE3 (607206) genes each represented 6.8% of the cases.
Fischer (2009) stated that in a cohort of 520 independent ARCI families, mutations were identified in 78% of patients by direct sequencing of 6 genes associated with ARCI: 32% of patients were found to have mutations in TGM1, 12% in ALOX12B, and 5% in ALOXE3, accounting for 49% of the total; 29% of the mutations were found in the remaining 3 genes: 16% in ichthyin (NIPAL4; 609383), 8% in CYP4F22 (611495), and 5% in ABCA12 (607800).
In 15 Scandinavian patients with ARCI of the self-healing collodion baby type, Vahlquist et al. (2010) analyzed 7 ARCI-related genes and identified homozygosity or compound heterozygosity for mutations in the ALOX12B gene in 8 patients (see, e.g., 603741.0012 and 603741.0013), in the ALOXE3 gene in 3 patients (see, e.g., 607206.0008), and in the TGM1 gene in 1 patient. No mutations were identified in the 3 remaining patients, suggesting that mutations in additional, as yet unidentified genes may also lead to a self-improving collodion ichthyosis phenotype.
Associations Pending Confirmation
For discussion of a possible association between a lethal form of ichthyosis and variation in the UGCG gene, see 602874.0001.
Hennies et al. (1998) investigated the genotype/phenotype correlation in 14 families with lamellar ichthyosis. Linkage analyses using microsatellites in the region of the TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1 gene, the second region identified on chromosome 2 and a further candidate region on chromosome 20 were excluded, confirming as well the existence of at least 3 loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in families compatible with linkage of lamellar ichthyosis to that locus revealed 7 different missense mutations, 5 of which had not previously been reported, and 1 splice mutation. No genotype/phenotype correlation for the mutations in the TGM1 gene could be found in this group of patients, which included 2 unrelated patients homozygous for the same mutation. Similarly, no clear difference in the same clinical picture was seen between patients with the TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications of patients with lamellar ichthyosis showed no consistency and thus indicated that clinical criteria used at that time could not discriminate between the molecularly different forms of the disease.
Farasat et al. (2009) identified TGM1 mutations in 57 (55%) of 104 patients with autosomal recessive congenital ichthyosis, including 22 novel mutations. The presence of a TGM1 mutation was significantly associated with collodion membrane at birth, ectropion, plate-like scales, and alopecia. Patients with at least 1 truncating mutation were more likely to have severe hypohidrosis and overheating at onset of symptoms compared to those with missense mutations. There was a high frequency of mutated arginine codons, most likely due to the deamination of CpG dinucleotides. The most common mutation was an A-to-G transition in intron 5 (190195.0002), which accounted for 28% of the mutated alleles.
Hackett et al. (2010) reported TGM1 mutations in 5 patients with ARCI who were born with collodion membrane, 3 of whom went on to develop the characteristic bathing suit distribution of ichthyosis (BSI; see, e.g., 190195.0033) and 2 of whom developed a self-healing collodion baby phenotype. The authors also reviewed the phenotypes associated with the more than 40 reported mutations in TGM1 and noted that BSI and SHCB mutations appeared to cluster in exons 5, 6, and 7 of the TGM1 gene.
Vahlquist (2010) proposed a subclassification of ARCI for the self-improving forms of ichthyosis, including self-healing collodion baby and ichthyosis prematurity syndrome (IPS), to be designated 'pleomorphic ichthyosis' (PI). Traupe (2010) argued that 'pleomorphic' was not an ideal term since in most cases the ichthyosis simply improves, and suggested 'congenital ichthyosis with mild scaling' (CIMS). In addition, Traupe (2010) noted that the concept of an umbrella term to describe mild ARCI cases was not universally accepted at the Soreze consensus conference on ichthyosis (Oji et al., 2010) and did not enter the new classification scheme. Taieb and Morice-Picard (2010) stated that the IPS subtype would be better termed 'self-healing congenital verruciform hyperkeratosis.'
MacKee and Rosen (1917) reviewed the subject of congenital ichthyosiform erythroderma.
Rand and Baden (1983) considered recessive lamellar ichthyosis to be synonymous with congenital nonbullous ichthyosiform erythroderma, whereas Wells and Kerr (1965) considered them separate entities. Williams (1983) noted that there may be biochemical differences. The experience of Holbrook et al. (1988) suggested that diagnosis on the basis of the morphology of fetal skin biopsies is fraught with uncertainty.
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