Article Category: Technical Report
Data publikacji: 19 wrz 2018
Zakres stron: 16 - 18
DOI: https://doi.org/10.2478/ebtj-2018-0027
Słowa kluczowe
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Alice Bruson, Tommaso Beccari, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Hennekam lymphangiectasia-lymphedema syndrome; generalized lymphatic dysplasia)
Hennekam Syndrome (HS) combines symptoms such as congenital lymphedema and intestinal lymphangiectasia. Symptoms such as facial anomalies, variable intellectual disabilities and occasionally other malformations can also manifest (1).
Lymphedema is evident at birth and often affects the face and lower extremities asymmetrically. Intestinal lymphangiectasia causes visceral lymphatic vessel rupture and accumulation of lymph in the abdomen. Lymphangiectasia may also involve the kidneys, thyroid gland, pleura, pericardium and the skin. Patients with HS may have microcephaly, craniosynostosis, syndactyly, camptodactyly, chylothorax and the following facial features: flattish median line of face and nose bridge, puffy eyelids, hypertelorism, small low-set ears and small mouth with gingival hypertrophy (2). Prognosis reflects the wide variability of symptoms. Thus, the life expectancy of HS patients varies from death in childhood to survival into adulthood. However, early death caused by severe manifestations has been reported in very few cases (3). The syndrome has autosomal recessive inheritance. The prevalence rate is not available but is estimated to be very rare: since its discovery only about 50 cases have been described (4).
Diagnostic measures include: clinical anamnesis, clinical examinations, lymphoscintigraphy, duodenal biopsy.
Differential diagnosis necessary to distinguish from Noonan and Aagenaes syndromes.
Hennekam syndrome is caused by homozygous or compound heterozygous mutation of the
The condition has autosomal recessive inheritance.
Hennekam lymphangiectasia-lymphedema syndrome 1 (HKLLS1, OMIM disease 235510) -
Hennekam lymphangiectasia-lymphedema syndrome 2 (HKLLS2, OMIM disease 616006) -
Hennekam lymphangiectasia-lymphedema syndrome 3 (HKLLS3 OMIM disease not available) -
Pathogenic variants may include missense, 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 6 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 3 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.
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.
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 gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity is approximately 40-45%, but in many cases these are individual variations (identified in one or few families) (5, 6).
Clinical sensitivity: data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for HS;
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 | |