Article Category: Technical Report
Published Online: Sep 19, 2018
Page range: 22 - 25
DOI: https://doi.org/10.2478/ebtj-2018-0029
Keywords
© 2018 Paolo Enrico Maltese, Yeltay Rakhmanov, Alessandra Zulian, Angelantonio Notarangelo, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Cystic hygroma of the neck)
Cystic hygroma (CH) or hygroma colli is characterized by abnormal accumulation of fluid in the region of the fetal neck and is one of the major anomalies associated with aneuploidy (1, 2). In contrast with simple increased nuchal translucency, CH is considered a possible cause of perinatal disability (3).
CH presents as a single or multiloculated fluid-filled cavity, usually in the neck. Morphologically characterized by failure of the lymphatic system to communicate with the venous system in the neck, it often leads to hydrops and fetal death (4).
Clinical manifestation depends on cyst size and location. CH usually causes functional impairment of nearby structures and organs, as well as disfigurement of affected areas (5, 6). When identified postnatally, it usually appears as a soft bulge under the skin (7). The size of the cavities may increase due to infection or bleeding within the cyst. The cyst may exert pressure on other structures, causing swallowing difficulties, obstructive sleep apnea, airway obstruction, hemorrhage, infection and deformation of surrounding bony structures and teeth (if left untreated) (8).
Prenatal diagnosis of CH via ultrasound is based on demonstration of a bilateral, largely symmetrical, septate or non septate cystic structure in the occipitocervical region (9).
Ultrasonographic diagnosis of septate CH is relatively easy, and chromosome analysis by chorion villus sampling or amniocentesis is generally accepted as a sequential step in its management (3).
The incidence of CH is estimated at one case per 6000-16,000 live births (10). CH can be part of a chromosome disorder or a monogenic syndrome or can manifest as an isolated trait (11). Mendelian CH has autosomal dominant (12, 13) or autosomal recessive inheritance (14, 15).
Differential diagnosis should consider Meige disease, yellow nail syndrome and capillary, arteriovenous malformations, especially RASopathies.
Achondrogenesis type II (ACG2, OMIM disease 200610) -
Cornelia de Lange syndrome-1 (CDLS1, OMIM disease 122470) –
Lymphedema-distichiasis syndrome (OMIM disease 153400) -
Noonan syndrome-1 (NS1, OMIM disease 163950) -
Noonan syndrome-3 (NS3, OMIM disease 609942) -
Noonan syndrome-5 (NS5, OMIM disease 611553) -
Carpenter syndrome-1 (CRPT1, OMIM disease 201000) -
Congenital erythropoietic porphyria (CEP, OMIM disease 263700) –
Multiple pterygium syndrome, lethal type (LMPS, OMIM disease 253290) -
Since a link may exist between CH and genes involved in angiogenesis and lymphangiogenesis, these genes can be also evaluated (13, 23).
Pathogenic variants may include missense, nonsense, splicing, small insertions, small 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 GTR database, offered by 1 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
A multi-gene next generation sequencing panel is used for the detection of nucleotide variations in coding exons and flanking introns of the above genes.
Potentially causative variants and regions with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
Multiplex Ligation Probe Amplification (MLPA) may be used for detection of 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 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 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.
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%.
The test is limited by current scientific knowledge regarding the genes and diseases.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: data not available.
Clinical specificity: data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for CH;
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 | |