Article Category: Technical Report
Published Online: Sep 19, 2018
Page range: 19 - 21
DOI: https://doi.org/10.2478/ebtj-2018-0028
Keywords
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Stefano Paolacci, Alice Bruson, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Primary lymphedema with myelodysplasia)
Emberger syndrome (ES) is a very rare genetic disorder with primary lymphedema and myelodysplasia progressing to acute myeloid leukaemia (AML). ES may present as: primary lymphedema mostly of the lower extremities (unilateral or bilateral); genital lymphatic abnormalities (lymphedema, lymphangiectasis, hydrocele); myelodysplasia/AML (low CD4/CD8); acute lymphangitis, multiple warts and deafness may develop due to immune dysfunction (1, 2). Other features that may be present are the following: hypotelorism, epicanthic folds, webbed neck, long and tapering fingers, and recurrent cellulitis (1).
The prevalence is not available, but is estimated to be very rare, less than 1 case per 1,000,000 of population. The age of onset is, usually, during late childhood or puberty.
Clinical diagnosis should look for the above phenotypic manifestations through medical history, clinical assessments, lymphoscintigraphy, color Doppler echography, magnetic resonance, lymphangiography and testing for mutations in the coding region of the
ES (OMIM disease 614038) allelic disorders include immunodeficiency 21 (IMD21, OMIM disease 614172), acute myeloid leukemia (AML, OMIM disease 601626) and myelodysplastic syndrome (MDS, OMIM 614286) (3).
ES is caused by mutations in the
The syndrome has autosomal dominant inheritance with incomplete penetrance, and sporadic cases due to
Pathogenic variants may include missense, nonsense, splicing, small insertions and deletions.
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
The test is listed in the Orphanet database and is offered by 9 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 5 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
Sanger sequencing is used for the detection of nucleotide variations in coding exons and flanking introns in the
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated. Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of pathogenic variants in the
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
alterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically based diseases.
In autosomal dominant transmission, the probability that an affected carrier transmit the variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the gene and disease.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: the complete sequencing of the
Clinical specificity is estimated at approximately 99.99% (Author’s laboratory data) (8).
The genetic test is appropriate when:
the patient meets the diagnostic criteria for ES;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
| Clinical management | Utility |
|---|---|
| Confirmation of clinical diagnosis | Yes |
| Differential diagnosis | Yes |
| Couple risk assessment | Yes |
| Availability of clinical trials can be checked on-line at | |