| Hypohidrotic ectodermal dysplasia with immune deficiency | |
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| This condition is usually inherited in an X-linked recessive manner | |
| Specialty | Medical genetics |
Hypohidrotic/anhidrotic ectodermal dysplasia with immune deficiency is a rare genetic condition characterized by a combination of the features of ectodermal dysplasia alongside immunodeficiency.
Individuals with this condition typically exhibit a milder version of the symptoms that patients with another type of ectodermal dysplasia would display, these include: [1] [2]
These symptoms are accompanied by an immunodeficiency that affects the entire body and impairs the body's antibody response (especially that to polysaccharides). It causes various complications in and on itself, alongside a failure to thrive. [2]
Most complications exhibited by people with the condition are associated with the immunodeficiency that is characteristic of it. These complications include:
Early death (usually in infancy) can occur as a complication in some cases. [5]
This condition has two known genetic causes, and both genetic causes have different inheritance patterns: [6] [7]
The first cause (and most common out of the 2) is a genetic mutation in the IKBKG gene, located in the X chromosome at the q28 locus. [1]
The protein that is encoded by this gene serves as the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, it helps activate NF-κB, which in turn activates multiple genes that play an important role in inflammation, immunity, cell survival, and other pathways. [8] [9] [10]
The mutation involved in this disorder significantly alters the function of the NF-kappa-B essential modulator protein, this impairs the protein's ability of regulating itself. It's this impairment that causes the interruption of various signaling pathways within the cells that form ectodermal tissue and the immune cells, this disruption causes the abnormal/poor development of ectodermal tissues and the immunodeficiency characteristic of this condition. Whether or not the condition is severe is determined by the amount of appropriate function the protein can perform on itself, [11] loss-of-function mutations of the gene can cause antenatal male lethality. [12]
This mutation is inherited following an X-linked recessive pattern, which means that for a person to exhibit the symptoms of the condition, they must have inherited a copy of the malfunctioning gene in all of their copies of the X chromosome. For this reason, the condition affects males more than it affects females, this is due to the fact that females carry two copies of the X chromosome, one of which may carry a healthy copy of the gene, while men on the other hand carry only one copy of the X chromosome, the other copy being the Y chromosome they inherited from their fathers; if they inherit the malfunctioning copy of the gene in their only X chromosome, they will automatically be homozygous for the disease and thus they will have the symptoms of the syndrome. Since males inherit one copy of the X chromosome from their mother and one copy of the Y chromosome from their father, the condition can only be inherited maternally. Females who do end up inheriting a malfunctioning copy of the gene will be heterozygous, which in turn will leave them as unaffected carriers. [13]
The second cause (and least common out of the 2) is a genetic mutation in the NFKBIA gene, located in chromosome 14 at the q13.2 locus. [14]
The protein that is encoded by this gene inhibits the NF-κB transcription factor through the masking of nuclear localization signals from NF-κB transcription factor proteins, this process keeps them in an inactive state in the cytoplasm. It also helps blocking the NF-κB transcription factors protein's ability of binding itself to DNA. The latter process is essential for the protein's appropriate functioning. [15]
The way this mutation works is almost exactly the same as the way of the previously mentioned mutation works, however, a key difference between this mutation and the aforementioned one is that it is inherited following an autosomal dominant manner. [16]
Autosomal dominant inheritance means that for a condition to exhibit itself on a person, said person needs to have at least one copy of the mutated version of the gene, this copy had to either appear spontaneously (a phenomenon known as de novo mutation) or it had to be inherited from one of the person's parents. [17]
This condition can be diagnosed through methods such as genetic testing (encompassing terms such as whole exome sequencing, Sanger sequencing, etc.), routine laboratory tests, and physical examination. [2] [8] [18] [19]
Bone marrow transplants have been reported as being both successful and unsuccessful at managing the symptoms caused by the disorder. [20] The latter (unsuccessful transplants) are usually not efficient at treating symptoms due to the transplants themselves causing post-surgical complications and, in some cases, death.
The X-linked recessive form of HHED-I has an estimated incidence of about 1 out of every 250,000 live births. [2]
The autosomal dominant form of HHED-I only has 13 to 27 cases reported in medical literature as of September 2022 (source: OMIM). [21] [1] [2]
This condition was first discovered in 2000, by Zonana et al, when they described various male individuals belonging to 4 unrelated families. Said individuals showed signs of ectodermal dysplasia (with symptoms such as teeth dysplasia, poor ability of sweating, and, in some cases, sparse hair) and had presented to various doctor visits since the early years of their life due to recurrent bacterial infections and their complications. Laboratory studies showed increased levels of IgM, low levels of IgA, equally low levels of IgG, and dysgammaglobulinemia. Tests done on their immunological responses showed an absent antibody response to pneumonoccal infections, while their body's response to tetanus was normal. Genetic tests done on the males revealed a loss-of-function mutation in exon 10 of their IKBKG gene, the mutation was present in a hemizygous state. The most severely affected patients were 2 brothers from the fourth family in the study, who had died at the age of 3 years old after a strong viral infection which their body got overwhelmed with. [22]
The autosomal dominant variant of this condition was discovered in 2003 by Courtois et al, their patient was a 7-year-old male child born to healthy, unrelated non-consanguineous parents. He had infancy-onset chronic diarrhea, hepatosplenomegaly, failure to thrive, recurrent bronchopnemonitis, presence of moderately sparse hair of the scalp, conical teeth, and rough dry skin. After having genetic testing done on him, it was found that he carried a missense gain-of-function mutation in serine 32 of his NFKBIA gene, the mutation was present in a heterozygous state. He had a successful bone marrow transplant, with the bone marrow having been donated by his (unaffected) sister, and as total donor chimerism set in his blood cells, his body's immune responses improved in quality. [23]
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.
Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disorder that affects the skin, hair, teeth, nails and central nervous system. It is named from its appearance under a microscope.
X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.
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.
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.
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.
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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.
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An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:
Ectodysplasin A (EDA) is a protein that in humans is encoded by the EDA gene.
Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome. It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherited in autosomal recessive fashion due to a defect in the AIRE gene , which is located on chromosome 21 and normally confers immune tolerance.
BENTA disease is a rare genetic disorder of the immune system. BENTA stands for "B cell expansion with NF-κB and T cell anergy" and is caused by germline heterozygous gain-of-function mutations in the gene CARD11. This disorder is characterized by polyclonal B cell lymphocytosis with onset in infancy, splenomegaly, lymphadenopathy, mild immunodeficiency, and increased risk of lymphoma. Investigators Andrew L. Snow and Michael J. Lenardo at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health first characterized BENTA disease in 2012. Dr. Snow's current laboratory at the Uniformed Services University of the Health Sciences is now actively studying this disorder.
Caspase-8 deficiency (CEDS) is a very rare genetic disorder of the immune system. It is caused by mutations in the CASP8 gene that encodes the protein caspase-8. The disorder is characterized by splenomegaly and lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus or other viral infections, and hypogammaglobulinemia. Investigators in the laboratory of Dr. Michael Lenardo at the National Institutes of Health described this condition in two siblings from a consanguineous family in 2002, and several more affected family members have since been identified.
DOCK8 deficiency, also called DOCK8 immunodeficiency syndrome, is the autosomal recessive form of hyperimmunoglobulin E syndrome, a genetic disorder characterized by elevated immunoglobulin E levels, eosinophilia, and recurrent infections with staphylococcus and viruses. It is caused by a mutation in the DOCK8 gene.
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.
ROSAH syndrome is a genetic disease of innate immune activation. ROSAH stands for Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and Headache and the name emphasizes some, but not all, of the features that can be associated with the syndrome. The disease is inherited in an autosomal dominant manner and caused by heterozygous missense mutations in the ALPK1 gene, an innate immune sensor for bacterial sugars.
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.
Spondyloenchondrodysplasia is the medical term for a rare spectrum of symptoms that are inherited following an autosomal recessive inheritance pattern. Skeletal anomalies are the usual symptoms of the disorder, although its phenotypical nature is highly variable among patients with the condition, including symptoms such as muscle spasticity or thrombocytopenia purpura. It is a type of immunoosseous dysplasia.
