Congenital ichthyosis is a clinically and genetically heterogeneous group of disorders of keratinization characterized by a significant and incapacitating scaling of the skin. Most forms are congenital and display different modes of inheritance. Among them, autosomal recessive lamellar ichthyosis is a severe condition with an estimated prevalence of 1 per 200,000 newborns, presenting a 'collodion-baby' syndrome at birth: the newborn is embedded in a hyperkeratotic skin. Spontaneous shedding of the membrane leaves residual ichthyosis and may lead to grave sequela, such as joint contractures, ectropion and secondary corneal involvement. Sometimes during adulthood, scarring alopecia, palmoplantar keratoderma and associated erythroderma are observed, and are therefore features of phenotypic variability.
By homozygosity mapping, the localization of the gene causing lamellar ichthyosis 1 could be identified to a locus on chromosome 14q. Several transcribed genes have been mapped to the chromosome 14 region containing the lamellar ichthyosis gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus is completely linked to lamellar ichthyosis, suggesting that TGM1 is a good candidate for further investigation of this disorder.
In six inbred Egyptian families with 10 affected patients, Russell et al. (1994) mapped the disease locus for severe autosomal recessive lamellar ichthyosis (LI) to chromosome 14q11 and showed complete linkage with transglutaminase-1 gene (TGM1), suggesting that TGM1 is a good candidate for further investigation of this disorder. The patients selected for this study all had a severe form of LI with brown, plate-like scale covering the entire body surface. All patients had congenital onset of their skin disease. At least some patients had a history of collodion presentation at birth, ectropion, and/or alopecia with scarring of the scalp. Later, Russell et al. (1995) identified compound heterozygosity for missense mutations (R141H, R142H) in the TGM1 gene in two of these multiplex LI Egyptian families used in the linkage study.
Shawky et al. (2004) investigated forty-three autosomal recessive congenital ichthyosis (ARCI) Egyptian individuals in 16 families with severe lamellar ichthyosis (LI) and 10 families with congenital ichthyosiformis erythroderma (CIE). Shawky et al. (2004) demonstrated that the ARCI Egyptian families in Upper Egypt was ethnically pure and had a tendency not to be a hybrid with other populations in Lower Egypt, Delta zone and Cairo city.
Sawardekar (2005) conducted a study to establish the prevalence of major congenital malformations in children born during a 10-year period in Nizwa Hospital. Of the 21,988 total births in the hospital, four children were born with congenital icthyosis. Sawardekar (2005) hinted for a possible genetic contribution in these children.
Al-Zayir amd Al-Amro Al-Akloby (2004) conducted a retrospective study of 10,455 new dermatology patients seen at the Dermatology Clinic of King Fahad Hospital (Al-Khobar, Eastern Province) between January 1990 and December 1995, including 71 patients (0.67 per 1000 new patients) each with a histopathologically confirmed diagnosis of one specific type of primary hereditary ichthyosis (PHI). The 71 patients consisted of 44 males and 27 females (ratio, 1.63:1), 61 of which were Saudi nationals. The clinical pattern of PHI was as follows: 31 patients (45%) with ichthyosis vulgaris (IV), 21 (30%) with nonbullous ichthyosiform erythroderma (NBIE), 12 (17%) with X-linked recessive ichthyosis (XLRI), four (6%) with lamellar ichthyosis (LI), and three (4%) with bullous ichthyosiform erythroderma (BIE). Parental consanguinity was high (approximately 85%, mostly first cousins), and the family history was positive in 53 of the 71 cases (75%). Al-Zayir and Alakloby (2004) also observed a high percentage of patients with a positive family history, and many siblings affected by the severest forms of PHI, namely NBIE, BIE, and LI, which accounted for 39% of all cases of PHI. In an independent study, Al-Amro Al-Akloby and Al-Zayir (2004) conducted a study over a 6-year period between 1990 and 1995 to document the epidemiological and clinical features of patients with congenital nonbullous ichthyosiform erythroderma (CNBIE). Of the 10,455 patients presented to the clinic, 21 had CNBIE. Of these patients, five were males and 16 females with a male to female ratio of 1:3.2. Nineteen of the 21 patients were Saudis. All affected patients presented at birth, and 19 patients were born with collodion membranes. The parents of 20 CNBIE patients were either first-degree or second-degree relatives. The high rate of parental consanguinity among the parents of CNBIE patients may be the cause of the high incidence rate of this genodermatosis in eastern Saudi Arabia.
Al Aboud et al. (2007) described an inbred Saudi tribe in which 20 patients, aged between 4 and 16-years, presented with lamellar ichthyosis. All affected individuals came from five sibships and were born with a thick membrane around them, which shed off later, and was followed by development of generalized scaling. At the time of the study, all of them had generalized thick dark scales. There was no associated pruritis or erythroderma. However, some of the children showed ectropion and alopecia. Interestingly, none of the parents were found to be affected. The patients were managed with topical emollients.
Wakil et al., (2016) described three unrelated Saudi patients born to consanguineous parents. All patients had thick adherent polygonal large scales all over the body, ectropion and. All three patients were born at full term with a collodion membrane. Sequencing of TGM1 gene identified two novel mutations (p.Tyr136Ter) and (p.Ser326Cysfs*8) in the three families. A combined approach of homozygosity mapping and direct sequencing analysis was helpful in confirming the diagnosis of these patients.
Al Talabani et al. (1998) studied the pattern of major congenital malformations in 24,233 consecutive live and stillbirth at Corniche hospital, which is the only maternity hospital in Abu Dhabi, between January 1992 and January 1995. A total of 401 babies (16.6/1,000), including 289 Arabs, were seen with major malformation. Single gene disorders accounted for 24% of the cases, 76% were due to autosomal recessive disorders. In their study, Al Talabani et al. (1998) observed one case of autosomal recessive lamellar ichthyosis in a consanguineous family from the United Arab Emirates. Recurrence was reported in the family. Al Talabani et al. (1998) concluded that their study was very close to representing the true incidence of congenital abnormalities in the whole United Arab Emirates, as they investigated over 98% of deliveries in Abu Dhabi, the capital of United Arab Emirates.
Bastaki et al. (2017) identified the underlying mutations affecting 5 Emirati congenital ichthyosis patients. Patient 1 was a female child born as a collodion baby to a consanguineous family. She exhibited sparse scalp hair, bilateral ectropion, generalized large thick skin plates with cracks and thin membranes in-between, peeling of skin and eclabium. She was diagnosed with Lamellar Ichthyosis. DNA analysis helped uncover a novel homozygous variant c.1085T>G (p.Leu362Arg) in exon 7 of the patient’s TGM1 gene. The mutation was predicted to affect a highly conserved catalytic core domain of the TGM1 protein. Both parents were found to be heterozygous for the variant.
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