1. Introduction
Ectodermal dysplasia is a hereditary disorder ( X-Linked ) that occurs as a consequence of disturbances in the ectoderm of the developing embryo.
Hypohidrotic ectodermal dysplasia (HED, Wikipedia) represents a large and complex group of diseases comprising more than 170 different clinical conditions. The incidence of this condition is 1:100,000, with a mortality rate of 28% in males up to 3 years of age.
As it’s an X-linked disease, we’ll have a different rate of distribution between genders, with prevalence in males. Treating this argument, we’ll focus on the development of salivary glands and how these are affected by HED.
For further information concerning death ratios linked to HED and diagnosis, visit:
Mortality in X-linked Hypohidrotic Ectodermal Dysplasia, 2005
Prenatal diagnosis of X-linked anhidrotic ectodermal dysplasia with X-chromosome inversion, July 2005
2. Diseases characteristic
HED is characterized by:
1) Hypotrichosis (sparseness of scalp and body hair, Wikipedia )
2) Hypohidrosis (reduced ability to sweat and produce saliva, Wikipedia )
3) Hypodontia (congenital absence of teeth, Wikipedia ).
The cardinal features of HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow-growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia. Only a few abnormally formed teeth erupt, and at a later than average age. Physical growth and psychomotor development are otherwise within normal limits.
Clinical Cases
3. Genetic causes
The gene (Genetics Home Reference, November 2013) involved in this disease is called “ectodysplasin A” or EDA, which provides instructions for making a namesake protein called ectodysplasin A (UniprotKD, November 2013 ). This protein is part of a signaling pathway that plays an important role in development before birth and, most specifically, it is critical for interactions between ectoderm and the mesoderm. Ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, such as the ones involved in HED.
The EDA gene provides instructions for producing many versions of ectodysplasin A, stimulating activities such as division, growth, and maturation.
THE GENE
Over 80 different mutations in the EDA gene have been identified in people with HED. These mutations cause the X-linked form of the disorder (95% of all cases related to HED) and consist in insertions or deletion of genetic material. These changes lead to the production of a nonfunctional version of the ectodysplasin A protein: it cannot trigger chemical signals and without these signals, hair follicles, teeth, sweat glands, and other ectodermal structures do not form properly (Blocking proteolytic release of ectodysplasin-A cause X-linked hypohidrotic ectodermal dysplasia, June 2001 ). The EDA gene is located in the cytogenetic Location: Xq12-q13.1 (long arm (q) of the X chromosome) and is long around 420.000 bases.
For further informations concerning diagnostic tests on DNA visit NCBI: HED gene review, June 2013
4. How does the EDA protein work?
Using Workbench we searched for the percentage in amminoacidic composition in the EDA protein. In this file everyone can consult the results that underline a prevalence of gln and leu regions in the protein.
A recent model see Eda and BMP family members as potential activators and inhibitors, respectively. Essential features are: the ability of soluble Eda to activate expression of itself, BMPs, and transcriptional effectors of placode fate (image a ); more extensive diffusion of BMPs than of soluble Eda; and the ability of BMPs to inhibit production of soluble Eda (image b ). The BMPs could inhibit Eda production indirectly. For example, BMPs could inhibit expression of a paracrine molecule required for cleavage of Eda from the cell surface. The model also postulates that Eda activates expression of the EdaR. Together with the other features, this could explain why RNA of the putative EdaR is concentrated in placodes but that of Eda is uniformly expressed. By the way this model hasn't been confirmed yet since is really hard to monitor these proteins levels during the embryonic development. (Of ancient tales and hairless tails, April 2013 )
Another hypotesis suggests that Gln acts as an antiapoptotic factor, inhibiting caspases in their activation. At the beginning of the development of the glands, the environment is rich in gln, which sends the cells the input to proliferate (rather than go towards apoptosis). While the quantity of gln lowers (because it's used in EDA synthesis), the cells migrate in order to find places with higher quantity of Glutamine. During the migration, due to a lack of gln, inner cells' apoptosis gets over cell proliferation creating the tubular lumen, which is typical of glands. At a certain point, the expression of differentiation factors reduce significantly the production of EDA (the gln is now used in other cellular processes such as the synthesis of the secretum ) creating a stable situation.
Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming, August 2012
Ectodysplasin (Eda) and its receptor (Edar) are members of the TNF superfamily shown to play critical roles during the development of ectodermal derivatives. Eda-A1, the biologically active isoform, binds specifically to Edar activate NF-κB (NF-κB on wikipedia) translocation into the nucleus to regulate the transcription of NF-κB responsive genes, including genes associated with DNA repair, cell cycle progression, cell survival, and apoptosis.
IAPs (Inhibitors of Apoptosis, Wikipedia) play an important role in cell migration during embryogenesis.
For more details IAPs on the move: role of inhibitors of apoptosis proteins in cell migration
A more detailed view of the previous scheme
EDA/EDAR system is important for balancing mitogenesis and apoptosis during embryonic development especially for what concerns the proliferation and survival of epithelial cells. Laboratory tests shown that when EDA is missing, but EDAR is present, the effect in mice is the hypoplasia of the glands. On the other hand, when EDA is present but EDAR is completely absent, the mice show a total dysplasia of the glands. This suggests that the function of EDAR cannot be substituted by any other receptor, while the lack in EDA can be compensated by the presence of other ligands. (Ectodysplasin receptor-mediated signaling is essential for embryonic submandibular salivary gland development, March 2003 )
5. Effects on glands and odontogenesis
For the activation of it’s own receptor, EDAR, membrane-bound EDA must be released as a soluble protein after a proteolitic cut. At the site of EDAR activation, a NF-kB-dependent pathway induces neutralization of placode inhibitors, thus opening the way to the development of skin-derived structures such as hair, teeth or sweat glands (hair and teeth that form despite the absence of EDA are often morphologically abnormal).
The following images show what happens at a microscopical level for the development of glands. In particular, the second image shows two histological sections of submandibular glands in mice. (Salivary gland development by A.S. Tucker, April 2007 )
Here is a tab containing genes expressed during tooth development in mouse. There is evidence in EDA/EDAR presence during most phases.
Here is an example of what happens in dentation for the previously described reasons.
6. Therapy and conclusions.
Unfortunately there isn’t a known cure for this disease. ED patients undergo severe social problems and suffer from poor psychological and physiological development as a result of unacceptable esthetics and abnormal function of orofacial structures. Oral rehabilitation thus becomes mandatory, although it is often difficult; particularly in pediatric patients. A multidisciplinary team comprising of dermatologist, psychiatrist, stomatologist, orthodontist, prosthodontist and pedodontist have responsibility to rehabilitate these patients.
Other references:
The cutting-edge of mammalian development; how the embryo makes teeth, July 2004
Hyohidrotic Ectodermal Dysplasia, April 2003
Embryonic Salivary Gland Branching Morphogenesis, 2006
Ectodermal Dysplasia with Anodontia: A Report of Two Cases, 2011
Christ Siemens Touraine syndrome: a case report, 2009
For a more biological/biomolecular view visit:
The EDA gene Undergoes Alternative Splicing and Encodes Ectodysplasin-A with Deletion Mutations in Collagenous Repeats, 1998
Mutations leading to X-linked HED affect three major functional domains in the TNF family member ectodysplasin-A, March 2001
Andrea Baldi/Edoardo Alberto Vergano
Odontoiatria e Protesi Dentaria
