Article Category: Technical Report
Publicado en línea: 19 sept 2018
Páginas: 13 - 15
DOI: https://doi.org/10.2478/ebtj-2018-0026
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© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Stefano Paolacci, Carla Marinelli, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Distichiasis-lymphedema syndrome; lymphedema with distichiasis)
Lymphedema-distichiasis (LD, OMIM disease 153400) syndrome is a rare genetic disorder that affects the lymphatic system. It combines lymphedema of the lower extremities and double rows of eyelashes (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair) (1). Affected individuals may also have renal abnormalities (nephritis, duplex kidney, recurrent infections, chronic sclerosing glomerulopathy), diabetes mellitus (2), varicose veins, cleft palate, extradural cysts, congenital heart defects (tetralogy of Fallot, ventricular septal defects), ocular findings, such as photophobia, exotropia, droopy eyelids (ptosis), ectropion and cataracts (3, 4).
The estimated prevalence of LD is currently unknown.
The clinical diagnosis of LD is based on: primary lymphedema (chronic swelling of the extremities caused by intrinsic dysfunction of the lymphatic vessels); distichiasis (aberrant and/or extra row of eyelashes originating from the tarsal gland) (1).
Approximately 80% of individuals with lymphedema-distichiasis syndrome have lymphedema by early adulthood (age 30 years), although a few individuals may develop lymphedema later. Approximately 94% of affected individuals also have distichiasis (5).
Differential diagnosis is necessary with respect to other diseases that manifest lymphedema or distichiasis, including Milroy disease, Meige disease microcephaly with/without chorioretinopathy, lymphedema, or mental retardation, Emberger syndrome, hypotrichosis lymphedema telangiectasia syndrome, yellow nail syndrome, blepharocheilodontic syndrome, isolated distichiasis, and trichiasis (1).
LD is inherited in an autosomal dominant manner, although approximately one quarter of cases are the result of
Pathogenic variants in FOXC2 are identified in 95% of cases with LD (1). Since 5% of patients with LD does not carry pathogenic variants in FOXC2, genetic heterogeneity can be hypothesized.
Pathogenic variants are either gain-of-function or loss-of-function and may include missense, nonsense, small insertions and deletions, small indels and gross deletions or duplications.
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 47 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 14 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
Since it is single gene disorder, we advise Sanger sequencing for the detection of nucleotide variations in coding exons and flanking introns in the
Multiplex Ligation Probe Amplification (MLPA) is used to detect duplications and deletions in
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%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: Variations in
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 LD;
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 | |