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Novel Compound Heterozygous TGM1 Mutations in Lamellar Ichthyosis in Taiwan
Hsiu-Mien Chang , Cheng-Hui Lin , Sheau-Chiou Chao , Shao-Ping Chang
Dermatol Sinica 25: 279-281, 2007

A full-term female newborn was born encased in a yellow, tight, shiny collodion membrane with mild ectropion (Fig. 1). Her hair, teeth and nails appeared normal. She had no other congenital anomalies except the bilateral pre-auricular pits. Her parents are not consanguineous and no other family members had similar symptoms before. Since birth, she was placed in an incubator and bathed with warm normal saline. Vital signs and electrolytes were closely monitored to present from excessive transepidermal water loss and hypothermia. The collodion membrane gradually desquamated in 7-14 days of life. The mild ectropion resolved and all her fingers and toes were freely movable. Thus, incubator was discontinued on day 10 and she was discharged on day 21.
While she was 3-month-old, large, dark, plate-like scales gradually formed on the trunk, especially the ventral side with small scales on the back and flexural surface of her extremities (Fig. 2). Based on the clinical presentations, the diagnosis of lamellar ichthyosis was made. There were no plate-like scales on the face, palms and soles so far.
Autosomal recessive lamellar ichthyoses (ARLI) represent a heterogeneous group of diseases with variable severity. To date, four genes have been localized: LI1 (MIM 242300) on chromosome 14q11; LI2 (MIM 601277) on chromosome 2q33-35; LI3 (MIM 604777) on chromosome 19p12-q12; and LI5 (MIM 606545), also known as NCIE1 (MIM 242100), on chromosome 17p13.1-3
Direct sequencing of the proband’s and her mother’s PCR products showed an A-to-G transition in exon 2 of TGM1, resulting in the change of a codon for isoleucine (ATA) to methionine (ATG) at codon 140 (I140M). Direct sequencing of the proband’s and her father’s PCR products showed a T-to-A transition at position in exon 6, resulting in the change of a codon for tyrosine (TAT) to asparagines (AAT) at codon 374 (Y374N) (Fig. 3).
The ichthyoses are a heterogeneous group of disorders, with both inherited and acquired forms. The inherited form can present at birth or develop later in life. Due to the great clinical heterogeneity, a specific diagnosis can be challenging. Genetic approaches to understanding the inherited disorders of cornification will help us to classify the dermatoses.4-5
The collodion presentation may, over time, evolve into a group of diseases that fall in a spectrum of different clinical severity including LI, congenital ichthyosiform erythroderma (CIE), or minimal involvement (self-healing collodion baby). Thus, when a newborn with collodion without past family history was consulted, it’s impossible to classify the dermatoses and predict the further development by the clinical presentation alone.6 Genetic linkage studies were performed by Russell, et al. on a group of families affected with the severe phenotype of classic LI in 1994.7They found classic LI is linked to markers on chromosome 14 in the region of the transglutaminase 1 gene locus.
TGMase 1 is one of the key enzymes which catalyze the cross-linkage of precursor proteins such as involucrin, loricrin and small proline-rich proteins for deposition on the inner side of the plasma membrane.1,7,8
There are more than 55 different mutations reported in TGM1 gene. Different mutation may alter the activity of TGMase 1 which depends on the residual function of the product of TGase1.9-10 The fact that the phenotype of our case improved gradually with supportive care may indicate that the residual function of the TGM1 is not totally absent. Both immunofluorescent labeling and in vitro enzyme activity assay have been tried to classify the disease.11
In conclusion, PCR and direct sequencing-based mutation screening can be quickly performed using only a little blood sample, provide a definite result, and therefore can be recommended as the least invasive and most informative first step of the evaluation protocol of a baby with colloidion membrane. However, even we found a mutation, the corresponding enzyme function and the future clinical manifestations are still unpredictable. Thus we need to pay more effort in the survey of genes and enzymes to better understand the diseases.

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