Emberger syndrome

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Emberger syndrome
Autosomal dominant - en.svg
This syndrome is autosomal dominant

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 (i.e. reduction) 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 (i.e. fluid retention and tissue swelling caused by a compromised lymphatic system) 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 (i.e. over years or decades) to the myelodysplastic syndrome and/or acute myeloid leukemia. Alternatively, it may present with one of the latter two life-threatening disorders. [1] [2]

Contents

The Emberger syndrome is only one of the manifestations of inactivating GATA2 mutations. Other manifestations include: 1 Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell, Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC or MonoMAC/DCML); 2) familial myelodysplastic syndrome/acute myeloid leukemia (i.e. familial MDS/AML); 3) chronic myelomonocytic leukemia; 4) pediatric myelodysplastic syndrome; and 5) various other hematological abnormalities such as aplastic anemia, anemia, chronic neutropenia; and/or various immunological defects. Individuals with the Emberger syndrome may exhibit signs or symptoms that are more characteristic of the latter manifestations. Since most individuals with inactivating GATA2 mutations progress to a leukemic disorder, the Emberger syndrome is a Precancerous condition. [1] [3]

The age of onset and types of symptoms that occur in individuals afflicted with the Emberger syndrome are highly variable even in family members presumed to have identical GATA2 gene mutations. This variability as well as the variability in the different manifestations of GATA2-inactivating mutations are not fully understood. They likely relate, at least in part, to: individual differences in the: 1) levels of the GATA2 transcription factor which are expressed; 2) genetic backgrounds; 3) occurrence of illnesses or other events that stress the bone marrow; and, possibly, 4) development of other "secondary" genetic abnormalities that often develop during the course of these disorders. [1] [3] [4] Because of these many complexities, recent reports have grouped together all of the different manifestations of GATA2 inactivating mutations into a single pleotropic genetic disorder termed GATA2 deficiency, GATA2 haploinsufficiency, or the GATA2 deficiency syndrome. Even currently, however, the Emberger syndrome (e.g. its MIM entry is #614038) and MonoMac/DCML (e.g. its MIM entry is #614172) are often classified as distinct clinical disorders. [1] [2] [5] [6] The Emberger syndrome is here considered as a distinct disorder.

Signs and symptoms

The age of onset of the Emberger syndrome is variable with rare individuals showing first symptoms such as lymphedema occurring in early infancy while others are symptomless or develop first symptoms in their middle and latter years. [5] [7] This variability can occur between members of the same family who are documented to have the same GATA2 mutation. [8] The syndrome's most common times of onset are infancy and early childhood. [7] The syndrome may present with unexplained lymphedema, hearing loss, and/or hematological defects like neutropenia, anemia, thrombocytopenia, and/or the circulation of abnormal blood cells. Other defects less commonly associated with and the syndrome include hypotelorism, epicanthic folds, hydrocele, webbed neck, and warts caused be human papillomavirus infection. [1] [5] [7] In these case of relatively benign symptoms and signs, the syndrome commonly progresses rapidly or slowly to myelodysplastic syndrome followed by acute myeloid leukemia. Less commonly, Emberger syndrome presents with the myelodysplastic syndrome and/or acute myeloid leukemia. [7] [9]

Genetics

GATA2 gene

GATA2 is a member of the evolutionarily conserved GATA transcription factor family of genes:: all tested vertebrates express six GATA genes. [10] The human GATA2 gene is located on the long arm (or "q" arm) of chromosome 3 at position 21.3 (i.e. located at 3q21.3). [11] [4] In humans, it is expressed in hematologic cells at the stem cell and later progenitor cell stages of their development. Increases and/or decreases in the gene's expression regulate the progression of these immature cells toward their final forms as blood cells such as erythrocytess, certain types of lymphocytes, monocytes, and platelets) as well as certain types of tissue cells such as macrophages and mast cells. [4] The GATA2 gene is also expressed in human endothelium, certain types of non-hematological stem cells, and, to lesser extents, prostate, endometrium, and some cancerous tissues. [1] [4] [10]

Monosomy of chromosome 7 (i.e. lose of one of the two chromosomes 7) or deletion of the "q" (i.e. short) in one of these two chromosomes often occurs in the various GATA2 deficiency manifestations including the Emberger syndrome. These genetic abnormalities are known causes of acute myeloid leukemia and, while not essential for, may contribute to the development of acute myeloid leukemia in the syndrome by, for example, lowering the age and/or increasing the chances of the disorder evolving into acute myeloid leukemia. [4]

GATA2 transcription factor

The GATA2 transcription factor contains two zinc finger (i.e. ZnF) structural motifs. C-ZnF is located toward the protein's C-terminus and is responsible for binding to specific DNA sites. N-ZnF is located toward the proteins N-terminus and is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two transactivation domains and one negative regulatory domain which interact with nuclear proteins to up-regulate and down-regulate, respectively, its activity. [4]

GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G) on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses these genes' expression. However, there are thousands of sites in human DNA with this nucleotide sequence but, for unknown reasons, GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may interfere with GATA2 binding or even displace GATA2 already bound to these sites. For example, the displacement of GATA2 bond to this sequence by GATA1 appears important for the normal development of certain hematological stem cells. This phenomenon is termed the "GATA switch". Given these many variables, the GATA2 transcription factor's actions in promoting or inhibiting its target genes is exceedingly complex and not completely understood. [1] [4] [6] [7]

Pathophysiology

The GATA2 transcription factor is critical for the emergence of hematologic stem cells from the hemogenic endothelium during embryogenesis. Deletion of both Gata2 genes in mice is lethal by about day 10 of embryogenesis due to collapse in the formation of mature blood cells. Inactivation of one mouse Gata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency except that these animals have ~50% reduction in their hematologic stem cells. The latter findings as well as clinical studies in vitro experiments on human tissues support the notion that both parental GATA2 genes are needed to produce levels of the GATA2 transcription factor sufficient for developing and maintaining normal levels of hematological stem and progenitor cells in humans. [4] The transcription factor's role in performing this function involves complex and incompletely understood interactions with a network of hematopoietic transcription factors including RUNX1, TAL1, MYB, GFI1, FLI1, LYL1, and PU.1. It is not exactly clear how reduced levels of GATA2 cause any of Emberger syndrome's hematological disorders. [6]

The role of GATA2 in promoting the normal development of the lymphatic stem cells may be responsible for the other two key features of the Emberger syndrome. That is, failure to develop competent valves and/or vessels in the lymphatic system, it is proposed, is responsible for the lymphedema of Emberger syndrome while failure to generate the perilymphatic space around the inner ear's semicircular canals, it is proposed, is responsible for the syndrome's sensorineural hearing loss. [3]

Diagnosis

Examination of circulating blood cells, bone marrow cells, and the GATA2 nucleotide sequence of individuals with Emberger syndrome typically evidences abnormalities which are not distinctively different from those of individuals with other manifestations of GATA2 deficiency. The specific diagnosis of Emberger syndrome depends on detecting mutations of the GATA2 gene in a setting of clinical findings of hematological disorders, lymphedema, and neurosensory hearing loss. It may be especially difficult to diagnose the syndrome in the absence of at least one of the latter two clinical signs or in individuals who exhibit anomalies strongly associated with one of the other manifestations of GATA2 deficiency. DNA sequencing of the full GATA2 gene coding region including the intron4 enhancer by Sanger sequencing or high-throughput methods along with DNA copy number analysis should establish the presence of GATA2 gene mutations; comparison of detected gene mutations to the list of inactivating GATA2 gene mutations plus the clinical presentation and family history are essentials in making the diagnosis of the syndrome and its type of presentation. [2] [5] [9]

Treatment

Standard measures are use for the treatment of lymphedema, sensorineural hearing loss, and the other non-malignant anomalies associated with the Emberger syndrome. However, treatment of the disorder's myelodysplastic syndrome and acute myeloid leukemia differs somewhat from standard measures. Like other GATA2 insufficiencies, Emberger syndrome is associated with a deficiency of hematological stem and early progenitor cells that is often due to a hereditary loss of one GATA2 gene. [4] Consequently, the use of radical myeloablative conditioning regimens to remove native bone marrow stem/progenitor cells in preparation for hematopoietic stem cell transplantation may entail excessive morbidity and mortality. While no controlled studies on the treatment of the hematological disorders of the syndrome have been reported, current recommendations by multiple authorities suggest the use of hematopoietic stem cell transplantation using non-myeloablative conditioning methods be used when indicated. The use of this procedure should be anticipatory and occur before the development of an excess of progenitor cells populate the bone marrow in cases of myelodyspasia as well as before the development of acute myeloid leukemia. Accordingly, individuals should be routinely monitored by bone marrow examinations and complete blood counts. Furthermore, the relatives of patients afflicted with the syndrome or any of other manifestations of GATA2 deficiency should be tested for GATA2 mutations. Individuals with such mutations are not candidates for donating their stem cells of Emberger syndrome patients. [1] [2] [3] [4] [9] [12] Reversion of the bone marrow to full immune restitution with improved expression of GATA2 can take up to several years after transplantation. [1]

Prognosis

Prognosis of the Emberger syndrome depends heavily on the speed of its progression to bone marrow failure, myelodysplasia with excessive blast cells, or acute myeloid leukemia. Intervention with non-myeloablative hematopoietic stem cell transplantation before development of the latter two disorders is thought to improve survival indefinitely in most cases. [1] [2] [3] [4] [9] [12] While not yet tested, this transplantation intervention would seem to offer a similar benefit in cases of severe, potentially lethal bone marrow failure.[ citation needed ]

History

The Emberger syndrome was first described by J.M. Emberger in 1979 as an unusual and not previously described constellation of symptoms (sensorineural hearing loss, lower limb lymphedema, and hematological disorders) in 4 individuals from two generations of a single family. [13] A subsequent study published in 2011 and conducted on three different families found that 8 members of these families with clinically diagnosed Emberger syndrome [14] as well as six sporadic cases of individuals with this clinical diagnosis exhibited one of eight different mutations in one of their two parental GATA2 genes. Each mutation was predicted to reduce the levels of functional GATA2. Thus, reduced levels of functionally competent GATA2 transcription factor resulting from a mutation in one of its genes is responsible for the Emberger syndrome. [5]

Related Research Articles

Leukemia Group of blood cancers that usually begin in the bone marrow

Leukemia, also known as leukaemia, is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

Myelodysplastic syndrome Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, so do not become 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.

Eosinophilia Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 x 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

Fanconi anemia Medical condition

Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), and 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity.

Tumors of the hematopoietic and lymphoid tissues Medical condition

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid malignancies are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making myeloproliferation and lymphoproliferation closely related and often overlapping problems.

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.

Acute myeloid leukemia Cancer of the myeloid line of blood cells

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.

GATA1

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.

Chronic myelomonocytic leukemia Medical condition

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.

Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia that affects children mostly aged 4 and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of myelodysplastic and myeloproliferative disorders.

ETV6

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

PDGFRB Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene.

GATA2

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.

Acute megakaryoblastic leukemia Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Acute panmyelosis with myelofibrosis (APMF) it is a poorly defined disorder that arises as either a clonal disorder, or following toxic exposure to the bone marrow.

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.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

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. These autosomal dominant mutations 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, 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.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

References

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  2. 1 2 3 4 5 Rastogi N, Abraham RS, Chadha R, Thakkar D, Kohli S, Nivargi S, Prakash Yadav S (November 2017). "Successful Nonmyeloablative Allogeneic Stem Cell Transplant in a Child With Emberger Syndrome and GATA2 Mutation". Journal of Pediatric Hematology/Oncology. 40 (6): e383–e388. doi:10.1097/MPH.0000000000000995. PMID   29189513. S2CID   19080505.
  3. 1 2 3 4 5 Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM (August 2017). "Heterogeneity of GATA2-related myeloid neoplasms". International Journal of Hematology. 106 (2): 175–182. doi: 10.1007/s12185-017-2285-2 . PMID   28643018.
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  5. 1 2 3 4 5 Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S (September 2011). "Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)" (PDF). Nature Genetics. 43 (10): 929–31. doi:10.1038/ng.923. PMID   21892158. S2CID   23449974.
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  7. 1 2 3 4 5 Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S, Lunt P, Jeffery S, Dokal I, Vulliamy T, Gibson B, Hodgson S, Cottrell S, Kiely L, Tinworth L, Kalidas K, Mufti G, Cornish J, Keenan R, Mortimer P, Murday V (September 2010). "Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases". American Journal of Medical Genetics. Part A. 152A (9): 2287–96. doi:10.1002/ajmg.a.33445. PMID   20803646. S2CID   205312771.
  8. ↑ Brambila-Tapia AJ, García-Ortiz JE, Brouillard P, Nguyen HL, Vikkula M, Ríos-González BE, Sandoval-Muñiz RJ, Sandoval-Talamantes AK, Bobadilla-Morales L, Corona-Rivera JR, Arnaud-Lopez L (September 2017). "GATA2 null mutation associated with incomplete penetrance in a family with Emberger syndrome". Hematology (Amsterdam, Netherlands). 22 (8): 467–471. doi: 10.1080/10245332.2017.1294551 . PMID   28271814.
  9. 1 2 3 4 Babushok DV, Bessler M (March 2015). "Genetic predisposition syndromes: when should they be considered in the work-up of MDS?". Best Practice & Research. Clinical Haematology. 28 (1): 55–68. doi:10.1016/j.beha.2014.11.004. PMC   4323616 . PMID   25659730.
  10. 1 2 Chlon TM, Crispino JD (November 2012). "Combinatorial regulation of tissue specification by GATA and FOG factors". Development. 139 (21): 3905–16. doi:10.1242/dev.080440. PMC   3472596 . PMID   23048181.
  11. ↑ "GATA2 GATA binding protein 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  12. 1 2 Hsu AP, McReynolds LJ, Holland SM (February 2015). "GATA2 deficiency". Current Opinion in Allergy and Clinical Immunology. 15 (1): 104–9. doi:10.1097/ACI.0000000000000126. PMC   4342850 . PMID   25397911.
  13. ↑ Emberger JM, Navarro M, Dejean M, Izarn P (October 1979). "[Deaf-mutism, lymphedema of the lower limbs and hematological abnormalities (acute leukemia, cytopenia) with autosomal dominant transmission]". Journal de Génétique Humaine (in French). 27 (3): 237–45. PMID   295075.
  14. ↑ Ostergaard, P; Simpson, MA; Connell, FC; Steward, CG; Brice, G; Woollard, WJ; Dafou, D; Kilo, T; Smithson, S; Lunt, P; Murday, VA; Hodgson, S; Keenan, R; Pilz, DT; Martinez-Corral, I; Makinen, T; Mortimer, PS; Jeffery, S; Trembath, RC; Mansour, S (4 September 2011). "Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)" (PDF). Nature Genetics. 43 (10): 929–31. doi:10.1038/ng.923. PMID   21892158. S2CID   23449974.
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