| Hypohidrotic ectodermal dysplasia | |
|---|---|
| Other names | Anhidrotic ectodermal dysplasia, Christ-Siemens-Touraine syndrome [1] : 570 |
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| This condition is inherited in an X-linked recessive manner. | |
| Specialty | Medical genetics  |
Hypohidrotic ectodermal dysplasia is one of about 150 types of ectodermal dysplasia in humans. Before birth, these disorders result in the abnormal development of structures including the skin, hair, nails, teeth, and sweat glands. [2]
Most people with hypohidrotic ectodermal dysplasia have a reduced ability to sweat (hypohidrosis) because they have fewer sweat glands than normal or their sweat glands do not function properly. Sweating is a major way that the body controls its temperature; as sweat evaporates from the skin, it cools the body. An inability to sweat can lead to a dangerously high body temperature (hyperthermia) particularly in hot weather. In some cases, hyperthermia can cause life-threatening medical problems.[ citation needed ]
Affected individuals tend to have sparse scalp and body hair (hypotrichosis). The hair is often light-coloured, brittle, and slow-growing. This condition is also characterized by absent teeth (hypodontia) or teeth that are malformed. The teeth that are present are frequently small and pointed.[ citation needed ]
Hypohidrotic ectodermal dysplasia is associated with distinctive facial features including a prominent forehead, thin lips, and a flattened bridge of the nose. Additional features of this condition include thin, wrinkled, and dark-colored skin around the eyes; chronic skin problems such as eczema; and a foul-smelling discharge from the nose (ozena). Hypohidrotic ectodermal dysplasia is the most common form of ectodermal dysplasia in humans. It is estimated to affect at least 1 in 17,000 people worldwide.[ citation needed ]
Mutations in the EDA , EDAR , and EDARADD genes cause hypohidrotic ectodermal dysplasia. The EDA, EDAR, and EDARADD genes provide instructions for making proteins that work together during embryonic development. These proteins form part of a signaling pathway that is critical for the interaction between two cell layers, the ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the body's organs and tissues. Ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands.[ citation needed ]
Hypohidrotic ectodermal dysplasia has several different inheritance patterns.
Most cases are caused by mutations in the EDA gene, which are inherited in an X-linked recessive pattern, called x-linked hypohidrotic ectodermal dysplasia (XLHED). A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.[ citation needed ]
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. Since females operate on only one of their two X chromosomes (X inactivation) a female carrier may or may not manifest symptoms of the disease. If a female carrier is operating on her normal X she will not show symptoms. If a female is operating on her carrier X she will show symptoms. In about 70 percent of cases, carriers of hypohidrotic ectodermal dysplasia experience some features of the condition. These signs and symptoms are usually mild and include a few missing or abnormal teeth, sparse hair, and some problems with sweat gland function. Some carriers, however, have more severe features of this disorder.
In January 2013, Edimer Pharmaceuticals, a biotechnology company based in Cambridge, MA, USA, initiated a Phase I, open-label, safety and pharmacokinetic clinical study of EDI200, a drug aimed at the treatment of XLHED. During development in mice and dogs EDI200 has been shown to substitute for the altered or missing protein resulting from the EDA mutation which causes XLHED. A second trial in newborn infants with XLHED tested the synthetic protein in 10 subjects between 2013 and 2016 at 6 sites in the US and Europe. [3] As the treated group "didn’t see significant changes in sweat gland function and other early markers of biologic activity", [4] prenatal administration of the drug was considered.
Following the Edimer trials, Dr. Holm Schneider, the principal investigator of these trials which indicated sufficient safety of the replacement protein, [5] injected EDI200 via amniocentesis with better development of tooth buds and sweat glands than in the postnatal trial and persistent sweating ability in all three treated boys. [6] [7]
Less commonly, hypohidrotic ectodermal dysplasia results from mutations in the EDAR or EDARADD gene. Both EDAR and EDARADD mutations can have an autosomal dominant or autosomal recessive pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal recessive inheritance means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.[ citation needed ]
The eponym Christ-Siemens-Touraine syndrome was named after its discoverers: Josef Christ (1871–1948), a German dentist and physician from Wiesbaden, who was the first physician to identify the condition, Hermann Werner Siemens (1891–1969), a pioneering German dermatologist from Charlottenburg, who clearly identified its pathological characteristics in the early 1930s, and Albert Touraine (1883–1961), a French dermatologist who likewise noted and identified additional characteristics of the disease in the late 1930s.[ citation needed ]
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm and endoderm. It emerges and originates from the outer layer of germ cells. The word ectoderm comes from the Greek ektos meaning "outside", and derma meaning "skin".
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.
Ectodermal dysplasia (ED) is a group of genetic syndromes all deriving from abnormalities of the ectodermal structures. More than 150 different syndromes have been identified.
Meleda disease (MDM) or "mal de Meleda", also called Mljet disease, keratosis palmoplantaris and transgradiens of Siemens, is an extremely rare autosomal recessive congenital skin disorder in which dry, thick patches of skin develop on the soles of the hands and feet, a condition known as palmoplantar hyperkeratosis. Meleda Disease is a skin condition which usually can be identified not long after birth. This is a genetic condition but it is very rare. The hands and feet usually are the first to show signs of the disease but the disease can advance to other parts of the body. Signs of the disease include thickening of the skin, on hands and soles of feet, which can turn red in color. There currently is no cure and treatment is limited, but Acitretin can be used in severe cases.
Anodontia is a rare genetic disorder characterized by the congenital absence of all primary or permanent teeth. It is divided into two subsections, complete absence of teeth or only some absence of teeth. It is associated with the group of skin and nerve syndromes called the ectodermal dysplasias. Anodontia is usually part of a syndrome and seldom occurs as an isolated entity. There is usually no exact cause for anodontia. The defect results in the dental lamina obstruction during embryogenesis due to local, systemic and genetic factors.
Ectrodactyly–ectodermal dysplasia–cleft syndrome, or EEC, and also referred to as EEC syndrome and split hand–split foot–ectodermal dysplasia–cleft syndrome is a rare form of ectodermal dysplasia, an autosomal dominant disorder inherited as a genetic trait. EEC is characterized by the triad of ectrodactyly, ectodermal dysplasia, and facial clefts. Other features noted in association with EEC include vesicoureteral reflux, recurrent urinary tract infections, obstruction of the nasolacrimal duct, decreased pigmentation of the hair and skin, missing or abnormal teeth, enamel hypoplasia, absent punctae in the lower eyelids, photophobia, occasional cognitive impairment and kidney anomalies, and conductive hearing loss.
Amastia refers to a rare clinical anomaly in which both internal breast tissue and the visible nipple are absent on one or both sides. It affects both men and women. Amastia can be either isolated or comorbid with other syndromes, such as ectodermal dysplasia, Syndactyly and lipoatrophic diabetes. This abnormality can be classified into various types, and each could result from different pathologies. Amastia differs from amazia and athelia. Amazia is the absence of one or both mammary glands but the nipples remain present, and athelia is the absence of one or both nipples, but the mammary gland remains.
Naegeli–Franceschetti–Jadassohn syndrome (NFJS), also known as chromatophore nevus of Naegeli and Naegeli syndrome, is a rare autosomal dominant form of ectodermal dysplasia, characterized by reticular skin pigmentation, diminished function of the sweat glands, the absence of teeth and hyperkeratosis of the palms and soles. One of the most striking features is the absence of fingerprint lines on the fingers.
Hay–Wells syndrome is one of at least 150 known types of ectodermal dysplasia. These disorders affect tissues that arise from the ectodermal germ layer, such as skin, hair, and nails.
Rosselli–Gulienetti syndrome, also known as Zlotogora–Ogur syndrome and Bowen–Armstrong syndrome, is a type of congenital ectodermal dysplasia syndrome. The syndrome is relatively rare and has only been described in a few cases.
Uncombable hair syndrome (UHS) is a rare structural anomaly of the hair with a variable degree of effect. It is characterized by hair that is silvery, dry, frizzy, wiry, and impossible to comb. It was first reported in the early 20th century. It typically becomes apparent between the ages of 3 months and 12 years. UHS has several names, including "pili trianguli et canaliculi," "cheveux incoiffables," and "spun-glass hair." This disorder is believed to be autosomal recessive in most instances, but there are a few documented cases where multiple family members display the trait in an autosomal dominant fashion. Based on the current scientific studies related to the disorder, the three genes that have been causally linked to UHS are PADI3, TGM3, and TCHH. These genes encode proteins important for hair shaft formation. Clinical symptoms of the disorder arise between 3 months and 12 years of age. The quantity of hair on the head does not change, but hair starts to grow more slowly and becomes increasingly "uncombable." To be clinically apparent, 50% of all scalp hair shafts must be affected by UHS. This syndrome only affects the hair shaft of the scalp and does not influence hair growth in terms of quantity, textural feel, or appearance on the rest of the body.
Ectodysplasin A (EDA) is a protein that in humans is encoded by the EDA gene.
Ectodysplasin A receptor (EDAR) is a protein that in humans is encoded by the EDAR gene. EDAR is a cell surface receptor for ectodysplasin A which plays an important role in the development of ectodermal tissues such as the skin. It is structurally related to members of the TNF receptor superfamily.
Ectodysplasin-A receptor-associated adapter protein is a protein that in humans is encoded by the EDARADD gene.
EEM syndrome is an autosomal recessive congenital malformation disorder affecting tissues associated with the ectoderm, and also the hands, feet and eyes.
ANOTHER syndrome consists of alopecia, nail dystrophy, ophthalmic complications, thyroid dysfunction, hypohidrosis, ephelides and enteropathy, and respiratory tract infections. This is an Autosomal recessive variant of ectodermal dysplasia.
Kohlschütter-Tönz syndrome (KTS), also called amelo-cerebro-hypohidrotic syndrome, is a rare inherited syndrome characterized by epilepsy, psychomotor delay or regression, intellectual disability, and yellow teeth caused by amelogenesis imperfecta. It is a type A ectodermal dysplasia.
Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract. It is a monogenetic disease caused by mutation in the IKBKG gene. NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus.
Odontoonychodermal dysplasia is a rare genetic disorder which is characterized by systemic abnormalities of the teeth, the nails of the fingers and toes, the skin, the hair cells, and the sweat glands. It is a type of syndromic ectodermal dysplasia.
Hypohidrotic/anhidrotic ectodermal dysplasia with immune deficiency is a rare genetic condition characterized by a combination of the features of ectodermal dysplasia alongside immunodeficiency.