Diagnosis
 | This section is empty. You can help by adding to it. (December 2017) |
| monoMAC syndrome | |
|---|---|
| Other names | MonoMAC/DCML, monocytopenia and mycobacterium avium complex/dendritic cell, monocyte, B and NK lymphocyte deficiency |
| Specialty | Medical genetics |
MonoMAC syndrome is a rare autosomal dominant syndrome associated with: monocytopenia, B and NK cell lymphopenia; mycobacterial, viral, fungal, and bacterial opportunistic infections; and virus infection-induced cancers. The disorder often progresses to the development of myelodysplasia, myeloid leukemias, and other types of cancer. MonoMAC is a life-threatening and precancerous disorder. [1] [2]
Inactivating mutations in one of the two parental GATA2 genes is responsible for the many diverse presentations of a genetic disorder that groups these presentations together into a single disease termed GATA2 deficiency. These autosomal dominant mutations are known or presumed to cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, and/or other disorders that may begin as apparently benign abnormalities but commonly progress to severe organ (e.g. lung) failure, enhanced susceptibility to opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or various types of leukemia. MonoMAC is a presentation of GATA2 deficiency that involves primarily signs and symptoms of immune deficiency that cause an extremely high susceptibility to infections and infection-induced benign and malignant tumors. In addition to this, however, MonoMAC-afflicted individuals often show one or more signs and symptoms of other GATA2 presentations. [3] [4]
MonoMAC was first described by Vihn and colleagues in 2010 as an autosomal dominant familial disease. [5] One year later, Dickinson and colleagues discovered that the MonoMAC disorder in four individuals was associated with any one of four different mutations in the GATA2 gene. [6] Subsequent studies identified numerous other GATA2 gene mutations that are associated with the development of MonoMAC, showed that these mutations inactivated or were considered likely to inactivate one of two parental GATA2 genes, and found that essentially all individuals with MonoMAC had one of the mutations known or considered to inactivate GATA2. [3]
This syndrome is characterized by an increased susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. There is profound monocytopenia, B lymphocytopenia and NK lymphocytopenia. Patients have an increased chance of developing malignancies, including: myelodysplasia/leukemia vulvar carcinoma, metastatic melanoma, cervical carcinoma, Bowen disease of the vulva, and multiple Epstein–Barr virus(+) leiomyosarcoma. Patients may also develop pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Last, patients may develop autoimmune phenomena, including lupus like syndromes, primary biliary cirrhosis or aggressive multiple sclerosis.[ citation needed ]
Of the 26, now 28, patients probably afflicted by this syndrome, 48% died of causes ranging from cancer to myelodysplasia with a mean age at death of 34.7 years and median age of 36.5 years.
| Clinical feature | Overall (%) | Autosomal dominant patients (%) | Sporadic patients (%) |
|---|---|---|---|
| Infection | |||
| Mycobacteria | 78 | 86 | 73 |
| HPV | 78 | 86 | 73 |
| Fungi | 28 | 43 | 18 |
| Complication | |||
| PAP | 33 | 29 | 36 |
| Panniculitis/erythema nodosum | 33 | 29 | 36 |
| Myelodiysplasia/acute myeloid leukemia | 50 | 71 | 36 |
| Death | 28 | 43 | 18 |
12 distinct mutations in the GATA2 gene have been identified. They include missense mutations affecting the zinc finger-2 domain and insertion/deletion mutations leading to frameshifts and premature termination.[ citation needed ]
| | This section is empty. You can help by adding to it. (December 2017) |
Bone marrow transplants are currently the only treatment.[ citation needed ]
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.
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.
Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.
GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.
Autoimmune lymphoproliferative syndrome (ALPS) is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis.
Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis. The name derives from the initial observation of gray appearance of platelets with a paucity of granules on blood films from a patient with a lifelong bleeding disorder.
Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.
The interferon-gamma receptor (IFNGR) protein complex is the heterodimer of two chains: IFNGR1 and IFNGR2. It binds interferon-γ, the sole member of interferon type II.
WHIM syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
Pelger–Huët anomaly is a blood laminopathy associated with the lamin B receptor, wherein several types of white blood cells have nuclei with unusual shape and unusual structure.
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.
PASLI disease is a rare genetic disorder of the immune system. PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood. These include bacterial infections of the respiratory system and chronic viremia due to Epstein–Barr virus (EBV) and/or cytomegalovirus (CMV). Individuals with PASLI disease also have an increased risk of EBV-associated lymphoma. Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition which they called Activated PI3K Delta Syndrome (APDS).
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.
Neutrophil-specific granule deficiency is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils.
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.
The Emberger syndrome is a rare, autosomal dominant, genetic disorder caused by familial or sporadic inactivating mutations in one of the two parental GATA2 genes. The mutation results in a haploinsufficiency in the levels of the gene's product, the GATA2 transcription factor. This transcription factor is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissues. The syndrome includes as its primary symptoms: serious abnormalities of the blood such as the myelodysplastic syndrome and acute myeloid leukemia; lymphedema of the lower limbs, and sensorineural hearing loss. However, the anomalies caused by GATA2 mutations are highly variable with some individuals showing little or no such symptoms even in old age while others exhibit non-malignant types of hematological anomalies; lymphedema in areas besides the lower limbs, little or no hearing loss; or anomalies in other tissues. The syndrome may present with relatively benign signs and/or symptoms and then progress rapidly or slowly to the myelodysplastic syndrome and/or acute myeloid leukemia. Alternatively, it may present with one of the latter two life-threatening disorders.
GATA2 deficiency is a grouping of several disorders caused by common defect, viz., familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.
Hypohidrotic/anhidrotic ectodermal dysplasia with immune deficiency is a rare genetic condition characterized by a combination of the features of ectodermal dysplasia alongside immunodeficiency.