Hennekam syndrome
| Classification according to ICD-10 | |
|---|---|
| Q87.8 | Other specified congenital malformation syndromes, not elsewhere classified |
| ICD-10 online (WHO version 2019) | |
The Hennekam syndrome (abbreviated HS) is a very rare congenital disease with the main characteristics lymphedema , lymphangiectasia in the intestine , mental retardation of variable severity and facial abnormalities.
Synonyms are: HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 1 ; HKLLS1 ; LYMPHATIC DYSPLASIA, GENERALIZED
The name refers to the first author of the first description from 1989 by RCM Hennekam and colleagues.
distribution
The frequency is given as less than 1 in 1,000,000, and about 50 patients have been reported to date. Inheritance is autosomal - recessive .
Cause and classification
There is presumably an abnormal development of the lymph vessels.
Depending on the underlying genetic defect, a distinction is made between three forms:
- I: mutations in the CCBE1 gene at location 18q21.32
- II: Mutations in the FAT4 gene at location 4q28.1
- III: Mutations of the ADAMTS3 gene at location 4q13.3
For HS types I and III, the molecular causes of lymphedema have been relatively well researched. In type I, the CCBE1 protein does not function adequately due to the genetic defect. This protein acts as a helper protein in the activation of the growth factor VEGF-C , which is necessary for the development and maintenance of the lymphatic system. In type III, the ADAMTS3 enzyme, which activates the growth factor VEGF-C, is affected by the genetic defect. The molecular function of FAT4 is unknown.
Clinical manifestations
Clinical criteria are:
- Rapidly growing lymphedema, which occurs at birth or shortly thereafter, mainly in the face, legs and pelvis
- Intestinal involvement with protein losses , growth retardation , edema and ascites
- Facial abnormalities such as flat face, broad flat nose , hypertelorism , epicanthus , ears set deep in the ear with a narrow ear canal
diagnosis
The diagnosis comes from the clinic.
In laboratory tests , hypogammaglobulinaemia , hypoalbuminemia , lymphopenia, and increased excretion of alpha-1-antitrypsin may indicate involvement of the bowel.
Differential diagnosis
The differential diagnosis are the cholestasis-lymphedema syndrome and Noonan syndrome delineate.
therapy
Parenteral nutrition is available for treatment of intestinal involvement . The lymphedema can make surgery necessary. Apart from symptomatic treatment (including lymph massage, compression stockings), there are still no causal treatment options for lymphedema. At the moment only one drug against lymphedema is being clinically tested ( Lymfactin ). However, these studies do not target hereditary lymphedema, but acquired lymphedema, which occurs as a side effect of breast cancer surgery. The clinical studies on the effectiveness of the active substances Ubenimex / Ketoprofen have been discontinued because the results were disappointing. Lymphedema symptoms in children with HS type III largely disappear during febrile illness (which contradicts the previous view that lymphedema symptoms worsen with increased temperature), but whether this observation can be translated into a therapeutic concept is unclear.
literature
- IDC Van Balkom, M. Alders, J. Allanson, C. Bellini, U. Frank, G. De Jong, I. Kolbe, D. Lacombe, S. Rockson, P. Rowe, F. Wijburg, RCM Hennekam: Lymphedema– lymphangiectasia – mental retardation (Hennekam) syndrome: A review. In: American Journal of Medical Genetics. Vol. 112, No. 4, 2002, pp. 412-421, doi: 10.1002 / ajmg.10707 , PMID 12376947 .
- M. Heruth, P. Müller, L. Liebscher, G. Kurz, T. Richter: Exudative enteropathy in congenital lymphangiectasia-lymphedema syndrome. In: Clinical Pediatrics. Vol. 218, No. 1, 2006 Jan-Feb, pp. 27-30, doi: 10.1055 / s-2004-832486 , PMID 16432772 .
- P. Frosk, B. Chodirker, L. Simard, W. El-Matary, A. Hanlon-Dearman, J. Schwartzentruber, J. Majewski,., C. Rockman-Green: A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature. In: BMC Medical Genetics. Vol. 16, 2015, p. 28, doi: 10.1186 / s12881-015-0175-0 , PMID 25925991 .
Individual evidence
- ↑ a b c d e Hennekam syndrome. In: Orphanet (Rare Disease Database).
- ↑ RC Hennekam, RA Geerdink, BC Hamel, FA Hennekam, P. Kraus, JA Rammeloo, AA Tillemans: Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. In: American journal of medical genetics. Vol. 34, No. 4, December 1989, pp. 593-600, doi: 10.1002 / ajmg.1320340429 , PMID 2624276 .
- ↑ Hennekam lymphangiectasia-lymphedema syndrome 1. In: Online Mendelian Inheritance in Man . (English)
- ↑ Hennekam lymphangiectasia-lymphedema syndrome 2. In: Online Mendelian Inheritance in Man . (English)
- ↑ Hennekam lymphangiectasia-lymphedema syndrome 3. In: Online Mendelian Inheritance in Man . (English)
- ↑ M. Jeltsch, SK Jha, D. Tvorogov, A. Anisimov, V.-M. Leppänen, T. Holopainen, R. Kivelä, S. Ortega, T. Kärpanen, K. Alitalo: CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3 – Mediated Vascular Endothelial Growth Factor-C Activation. In: Circulation. Vol. 129, No. 19, May 2014, pp. 1962–1971, doi: 10.1161 / CIRCULATIONAHA.113.002779 , PMID 24552833 .
- ^ A b P. Brouillard, L. Dupont, R. Helaers, R. Coulie, GE Tiller, J. Peeden, A. Colige, M. Vikkula: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. In: Human Molecular Genetics. Vol. 26, No. 21, November 2017, pp. 4095-4104, doi: 10.1093 / hmg / ddx297 , PMID 28985353 .
- ↑ US National Library of Medicine: Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE). Retrieved April 3, 2019 .
- ↑ Eiger Biopharmaceuticals: Eiger BioPharmaceuticals Announces Phase 2 ULTRA Results of Ubenimex in Lower Leg Lymphedema: Study Did Not Meet Primary or Secondary Endpoint. Retrieved April 3, 2019 .
