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| ICF syndrome | |
|---|---|
| Other names | Immunodeficiency-centromeric instability-facial anomalies syndrome |
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ICF syndrome (or Immunodeficiency, Centromere instability and Facial anomalies syndrome) [1] is a very rare autosomal recessive [2] immune disorder.
It is characterized by variable reductions in serum immunoglobulin (IgG, IgM and/or IgA) levels which cause most ICF patients to succumb to infectious diseases before adulthood. ICF syndrome patients exhibit facial anomalies which include hypertelorism, low-set ears, epicanthal folds and macroglossia. [3] Other frequent symptoms observed in individuals with ICF syndrome include intellectual disability, recurrent and prolonged respiratory infections, and integumentary and digestive system infections. [4]
Mutations in four genes can cause this syndrome: [5] Cell division cycle associated protein 7 (CDCA7), DNA-methyltransferase 3b (DNMT3B), Lymphoid specific helicase (HELLS) and Zinc finger- and BTB domain containing protein 24 (ZBTB24).[ citation needed ]
The CDCA7 gene is located on chromosome 2 (2q31.1).[ citation needed ]
The DNMT3B gene is located on chromosome 20 (20q11.2)). [6] [7]
The HELLS gene is located on chromosome 10 (10q23.33)[ citation needed ]
The ZBTB24 gene is located on chromosome 6 (6q21)[ citation needed ]
This disease is inherited in an autosomal recessive manner. [2]
Diagnosis can occur using a karyotype or linkage analysis or DNA sequence analysis. This can occur prior to birth in families with a known history of the condition. [3]
For ICF patients the most diffused therapy consists of repeated intravenous infusions of immunoglobulins for the patients entire lifespan. In 2007, Gennery et al. cured the humoral and cellular immunological defect in three ICF1 patients by hematopoietic stem cell transplantation (HSCT). The only side effect was related to the development of autoimmune phenomena in two of them. [8] This is the only documented case of restoring the immune conditions and growth improvement in these patients. [9]
Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.
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.
Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections. It causes severe pyogenic infections. It can be caused by autosomal dominant inheritance of the ELANE gene, autosomal recessive inheritance of the HAX1 gene. There is an increased risk of leukemia and myelodysplastic cancers.
Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.
Hypergammaglobulinemia is a medical condition with elevated levels of gamma globulin. It is a type of immunoproliferative disorder.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.
X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.
Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.
Hyper IgM syndrome type 2 is a rare disease. Unlike other hyper-IgM syndromes, type 2 patients identified thus far did not present with a history of opportunistic infections. One would expect opportunistic infections in any immunodeficiency syndrome. The responsible genetic lesion is in the AICDA gene found at 12p13.
The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.
Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.
DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome.
Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition.
Hyper-IgM syndrome type 3 is a form of hyper IgM syndrome characterized by mutations of the CD40 gene. In this type, Immature B cells cannot receive signal 2 from helper T cells which is necessary to mature into mature B cells.
Hyper-IgM syndrome type 4 is a form of Hyper IgM syndrome which is a defect in class switch recombination downstream of the AICDA gene that does not impair somatic hypermutation.
LIG4 syndrome is an extremely rare condition caused by mutations in the DNA Ligase IV (LIG4) gene. Some mutations in this gene are associated with a resistance against multiple myeloma and Severe Combined Immunodeficiency. Severity of symptoms depends on the degree of reduced enzymatic activity of Ligase IV or gene expression. Ligase IV is a critical component of the non-homologous end joining (NHEJ) mechanism that repairs DNA double-strand breaks. It is employed in repairing DNA double-strand breaks caused by reactive oxygen species produced by normal metabolism, or by DNA damaging agents such as ionizing radiation. NHEJ is also used to repair the DNA double-strand break intermediates that occur in the production of T and B lymphocyte receptors.
Nasodigitoacoustic syndrome, also called Keipert syndrome, is a rare congenital syndrome first described by J.A. Keipert and colleagues in 1973. The syndrome is characterized by a misshaped nose, broad thumbs and halluces, brachydactyly, sensorineural hearing loss, facial features such as hypertelorism, and developmental delay.
Cernunnos deficiency is a form of combined immunodeficiency characterized by microcephaly, due to mutations in the NHEJ1 gene, it is inherited via autosomal recessive manner Management for this condition is antiviral prophylaxis and antibiotic treatment.
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.
Acromesomelic dysplasia is a rare skeletal disorder that causes abnormal bone and cartilage development, leading to shortening of the forearms, lower legs, hands, feet, fingers, and toes. Five different genetic mutations have been implicated in the disorder. Treatment is individualized but is generally aimed at palliating symptoms, for example, treatment of kyphosis and lumbar hyperlordosis.