Emberger syndrome

Emberger syndrome
This syndrome is autosomal dominant

The Emberger syndrome is a rare,

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.

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

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]

References