Article Category: Technical Report
Publicado en línea: 19 sept 2018
Páginas: 26 - 31
DOI: https://doi.org/10.2478/ebtj-2018-0030
Palabras clave
© 2018 Stefano Paolacci, Yeltay Rakhmanov, Paolo Enrico Maltese, Francesca Fanelli, Raul Ettore Mattassi, Bruno Amato, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Vascular anomalies are a group of diseases; see phenotypic variants)
Vascular anomalies (VAs) combine an extremely heterogeneous group of congenital abnormalities of the vascular system. VAs include vascular tumours, such as hemangioma, and malformations of veins, arteries, capillaries and the lymphatic system. Anomalies may occur during embryogenesis. They may be morphological, structural and/or functional defects affecting different types and calibers of vessels in any anatomical area (1). When more than one type of vessel is affected, the term
Prevalence is unknown.
Diagnostic work-up may include clinical history, clinical examination, vascular echo-Doppler and vascular magnetic resonance imaging.
Vascular anomalies can be classified on the basis of the vessels affected:
Capillary infantile hemangioma (OMIM disease 602089) can be sporadic or have autosomal dominant inheritance. It can be caused either by somatic mutations in
Verrucous venous malformation (OMIM disease not available) is sporadic and is caused by somatic mutations in
Pyogenic granuloma (OMIM disease not available) is sporadic and is caused by somatic mutations in
Multiple cutaneous and mucosal venous malformations (VMCM, OMIM disease 600195) can be caused either by mutations in
Glomuvenous malformations (GVM, OMIM disease 138000) can have dominant or paradominant inheritance and are caused by mutations in
Cerebral cavernous malformations type 1 (CCM1, OMIM disease 116860), type 2 (CCM2, OMIM disease 603284) and type 3 (CCM3, OMIM disease 603285) have dominant or paradominant inheritance and are caused by mutations in
Blue rubber bleb nevus syndrome (OMIM disease 12200) is sporadic and is caused by somatic mutations in
Congenital capillary malformations (CMC, OMIM disease 163000) are sporadic and are caused by somatic mutations in
Parkes Weber syndrome (PKWS, OMIM disease 608355) has dominant or paradominant inheritance and is caused by mutations in
Sturge-Weber syndrome (SWS, OMIM 185300) is sporadic and is caused by somatic mutations in
Capillary malformations-arteriovenous malformations (CMAVM, OMIM 608354) can be sporadic or have dominant inheritance and are caused either by somatic mutations in
Hereditary hemorrhagic telangiectasia type 1 (HHT1, OMIM disease 187300) and type 2 (HHT2, OMIM disease 600376) have dominant or paradominant inheritance and are caused by mutations in
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JPHT, OMIM disease 175050) has autosomal dominant inheritance. It is caused by mutations in
Klippel-Trénauny-Weber syndrome (OMIM disease 149000) and congenital lipomatous overgrowth, vascular malformations and epidermal nevi syndrome (CLOVES, OMIM disease 612918) are sporadic and are caused by somatic mutations in
Multiple enchondromatosis, Maffucci type (OMIM disease 614569) is sporadic and is caused by somatic mutations in
Proteus syndrome (OMIM disease 176920) is sporadic and is caused by somatic mutations in
Loeys-Dietz syndrome type 1 (OMIM disease 609192), type 2 (OMIM disease 600168), type 3 (OMIM disease 613795) and type 4 (OMIM disease 614816) have autosomal dominant inheritance. They are caused by mutations in
Ehlers-Danlos syndrome, vascular type (EDSVASC, OMIM disease 130050) has autosomal dominant inheritance. It is caused by mutations in
Arterial tortuosity syndrome (ATS, OMIM disease 208050) has autosomal recessive inheritance. It is caused by mutations in
Cowden syndrome type 1 (CWS1, OMIM disease 158350), type 5 (CWS5, OMIM disease 615108) and type 6 (CWS6, OMIM disease 615109) have autosomal dominant inheritance. They are caused by mutations in
Marfan syndrome (MFS, OMIM disease 154700) has autosomal dominant inheritance. It is caused by mutations in
Pseudoxanthoma elasticum (PXE, OMIM disease 264800) has autosomal recessive inheritance. It is caused by mutations in
Microcephaly-capillary malformation syndrome; (MIC-CAP, OMIM disease 614261) has autosomal recessive inheritance. It is caused by mutations in
Recently, somatic mutations in
Pathogenic variants may include missense, nonsense, splicing, small insertions and deletions, small indels, gross insertions, duplications and complex rearrangements.
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 27 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 4 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in disease-specific chapters of Genetics Home Reference (ghr.nlm.
Clinically distinguishable syndromes can be analyzed by sequencing only those genes known to be associated with that specific disease using Sanger or Next Generation Sequencing (NGS); if the results are negative, or more generally if clinical signs are ambiguous for diagnosis, a multi-gene NGS panel is used to detect nucleotide variations in coding exons and flanking introns of the above genes.
The efficiency of targeted NGS is precious for VAs because of their complex inheritance pattern and genetic and phenotypic heterogeneity. DNA extracted from blood (or saliva) should always be analyzed in tandem with DNA extracted from affected tissues (
Figure 1
Flow chart of genetic testing for vascular anomalies.
Multiplex Ligation Probe Amplification (MLPA) is used to detect duplications and deletions in
Sporadic cases with negative test outcome or positive results in genes with paradominant inheritance (
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.
A frozen intra-lesional biopsy specimen, in addition to blood or saliva, is necessary to test for somatic variations.
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 above genes confirms the clinical diagnosis and is an indication for family studies.
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 protein 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 following possibilities
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 genomic regions not investigated by the 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.
If the identified pathogenic variant has autosomal dominant transmission, the probability that an affected carrier transmit the disease variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
In autosomal recessive mutations, both parents are usually healthy carriers. In this case, the probability of transmitting the disorder to the offspring is 25% in any pregnancy of the couple, irrespective of the sex of the child. An affected individual generates healthy carrier sons and daughters in all cases, except in pregnancies with a healthy carrier partner. In these cases, the risk of an affected son or daughter is 50%.
In paradominant inheritance, only the germline genetic variant is transmitted in an autosomal dominant fashion and the probability that carriers transmit the germline pathogenic variant to their children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the genes and diseases.
Currently, there is no evidence of a genotype-phenotype correlation between mosaicism level and the severity of clinical manifestation.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MINISEQUENCING Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
The variations in the aforementioned genes depend closely on the specific disorder. Clinical sensitivity and specificity, based on current genetic knowledge and internal case studies, can be estimated at 20-30% and 99.78%, respectively (42).
No epidemiological data is available for private variants (specific to one or very few families). In such cases, clinical sensitivity is estimated on the basis of internal case studies (42).
The genetic test is appropriate when:
the patient meets the diagnostic criteria for Vas (43);
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 | |