Hypohidrotic ectodermal dysplasia – EDA, EDAR, EDARADD and WNT10A genes
Hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, is one of about 100 types of ectodermal dysplasia. This syndrome is characterized by alterations of the glands of the skin, hair, nails, teeth, and sweat glands, which occur before birth, during their development. Signs and symptoms associated with HED include hypohidrosis (reduced sweating), hypotrichosis (reduced pilosity) and hypodontia (decreased number of teeth). The inability to sweat can cause hyperthermia, especially in hot weather, and in some cases it can lead to life-threatening medical problems. The characteristic facial features of this disease include a prominent forehead, thick lips and a flattened nose bridge. Other additional features include thin and wrinkled skin, dark skin around the eyes, eczema and ocena (foul-smelling nasal discharge).
This syndrome is due to mutations in the EDA (ectodysplasin A), EDAR (ectodysplasin A receptor), EDARADD (EDAR associated death domain), and WNT10A (Wnt family member 10A) genes. Mutations in the EDA gene are the most frequent cause of the disease and represent more than half of all cases. The mutations of the EDAR, EDARADD and WNT10A genes represent a smaller percentage of cases. In approximately 10 percent of people with HED, the genetic cause is unknown.
The EDA, EDAR and EDARADD genes encode the proteins ectodysplasin A, ectodysplasin receptor and cell death domain associated with WWTP, respectively. These proteins act together during embryonic development, forming part of a critical signaling pathway for the interaction between two layers of cells, ectoderm and mesoderm. In the embryo, these layers of cells form the basis of many of the organs and tissues of the organism. Ectoderm-mesoderm interactions are essential for the formation of various structures that arise from the ectoderm, including the glands of the skin, hair, nails, teeth, and sweat glands.
More than 300 mutations in the EDA gene have been identified in people with hypohydrotic ectodermal dysplasia (HED). The EDA gene is located on the long arm of the X chromosome (Xq13.1). Mutations in the EDA gene cause the X-linked form of the disease, which accounts for more than half of all cases of HED. Some mutations in the EDA gene change base pairs, while other mutations insert or remove genetic material in the gene. These changes result in the synthesis of a non-functional version of the ectodysplasin protein. This abnormal protein cannot trigger the chemical signals necessary for normal interactions between ectoderm and mesoderm. Without these signals, hair follicles, teeth, sweat glands and other ectodermal structures do not form properly, giving rise to the characteristic features of this disease.
In the EDAR gene, located on the long arm of chromosome 2 (2q13), about 50 mutations have been identified in people with HED, and represent approximately 10 percent of all cases. In most of the mutations in the EDAR gene, the nucleotides that encode the amino acids in the EDAR protein receptor change, although deletions of genetic material from the EDAR gene also occur. These genetic changes alter the signaling pathway necessary for the formation of ectodermal structures such as hair follicles and sweat glands. When this type of mutation is present in a copy of the EDAR gene in each cell, it causes the autosomal dominant form of HED. Other mutations in the EDAR gene result in the synthesis of an abnormal version of the ectodysplasin receptor protein, and as a consequence, the receptor is not available to trigger the chemical signals necessary for ectoderm-mesoderm interactions and normal ectodermal structure development. When these types of mutations are present in two copies of the EDAR gene in each cell, cause an autosomal recessive form of HED.
In the EDARADD gene, located on the long arm of chromosome 1 (1q42.3-q43), at least 10 mutations have been described in individuals with HED, most of which consist of amino acid changes in the receptor protein, which prevent effective interaction between EDARADD protein and the ectodysplasin receptor. As a consequence, the receptor probably cannot trigger the signals necessary for ectoderm-mesoderm interactions and normal development of hair follicles, sweat glands, and other ectodermal structures. This disruption in ectodermal development gives rise to the characteristic features of HED.
The WNT10A gene, located on the long arm of chromosome 2 (2q35), encodes a protein that is part of the Wnt signaling pathway, which controls the activity of certain genes and regulates interactions between cells during embryonic development. The signaling that involves the WNT10A protein is critical for the development of ectodermal structures, particularly the teeth. It is estimated that mutations in the WNT10A gene represent approximately 5 percent of all cases of HED. WNT10A gene mutations affect the function of the protein, which alters the development of teeth and other structures that arise from the ectodermal cell layer. When HED is due to mutations in the WNT10A gene, its characteristics are more variable than when it is due to mutations in the EDA, EDAR or EDARADD gene.
Hypohidrotic ectodermal dysplasia (HED) has different inheritance patterns. Most cases are due to mutations in the EDA gene, which is inherited with a recessive pattern linked to the X chromosome. In males, an altered copy of the gene in each cell is sufficient to give rise to the disease, while in women a mutation must be present in both copies of the gene to express the alteration. Males are affected by X-linked recessive alterations more frequently than females. A characteristic of the X-linked inheritance is that parents cannot transmit X-linked traits to their children. Less frequently, HED has an autosomal dominant or autosomal recessive pattern of inheritance. Mutations in the EDAR, EDARADD or WNT10A gene can cause autosomal dominant or recessive HED. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to express the disease. Some affected individuals inherit the mutation of an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of the disease in their family. Autosomal recessive inheritance means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with dementia with Lewy bodies, by means of the complete PCR amplification of the exons of the EDA, EDAR, EDARADD and WNT10A genes, respectively, and their subsequent sequencing.
Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).