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Description
Hennekam syndrome is an inherited disorder that is characterized by abnormalities of the lymphatic system, which is part of both the circulatory system and the immune system. The lymphatic system is a network of vessels that transport white blood cells (lymphocytes), nutrients, and proteins in a fluid called lymph. In people with Hennekam syndrome, the lymphatic vessels are often dilated (lymphangiectasia), which can slow down the flow of lymph and cause the vessels to leak. As a result, people with this condition experience puffiness or swelling that is caused by a buildup of fluid within certain tissues (lymphedema
). The affected vessels may also break open (rupture).
The lymphedema in people with Hennekam syndrome is typically present at birth and often affects the legs and genitalia. Severely affected infants may have extensive swelling caused by fluid buildup before birth (hydrops fetalis).
People with Hennekam syndrome may have lymphangiectasia in the kidneys, lungs, and the membrane covering the heart (pericardium
). Many affected infants have intestinal lymphangiectasia, which affects the vessels that transport lymph to and from the intestines. This can cause lymph to leak into the intestines, which can interfere with the absorption of proteins and other nutrients. Affected individuals may also have a buildup of lymph in the abdomen, which can cause swelling (chylous ascites). The lymphedema that is seen in individuals with Hennekam syndrome may affect one side of the body more severely than the other.
Distinctive facial features are common among people with Hennekam syndrome. Affected individuals often have a flattened appearance to the middle of the face and the bridge of the nose, puffy eyelids, widely spaced eyes (hypertelorism
), low-set ears, and a small mouth with overgrowth of the gums (gingival hypertrophy
). Some individuals with Hennekam syndrome have intellectual disabilities, and these can range from mild to severe. Seizures and growth delays may also occur.
The skeletal abnormalities that can be seen in people with Hennekam syndrome include a premature fusion of the skull bones (craniosynostosis), permanently bent fingers and toes (camptodactyly
), and a fusion of the skin between the fingers and toes (cutaneous syndactyly
). Affected individuals may also have inward- and upward-turning feet (clubfeet
), a narrow upper chest that may have a sunken appearance (pectus excavatum), and an abnormal side-to-side curvature of the spine (scoliosis
).
Additional features can include structural abnormalities of the heart, kidneys, or genitals; a soft out-pouching around the belly-button (umbilical hernia); hearing loss; and excessive body hair (hirsutism).
The signs and symptoms of Hennekam syndrome vary widely, even among members of the same family. Because of the potentially serious complications, the life expectancy of individuals with Hennekam syndrome also varies.
Frequency
Hennekam syndrome is rare, although the exact prevalence is not known. At least 100 cases of Hennekam syndrome have been reported worldwide.
Causes
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the CCBE1, ADAMTS3, or FAT4 gene cause Hennekam syndrome.
The CCBE1 and ADAMTS3 genes provide instructions for making proteins that are found in the extracellular matrix, which is the intricate lattice of proteins and other molecules that forms in the spaces between cells. The CCBE1 and ADAMTS3 proteins work together to help regulate the activity of another protein called vascular endothelial growth factor receptor 3 (VEGFR3). This protein plays an important role in the development and maintenance of the lymphatic system.
The CCBE1 and ADAMTS3 gene variants that cause Hennekam syndrome reduce the amount of functional protein that is available to help regulate the activity of VEGFR3. A disruption in VEGFR3 activity impairs the development of the lymphatic system and contributes to the lymphangiectasia and lymphedema seen in people with Hennekam syndrome. Since the lymphatic system extends throughout the body, a disruption in its early development may change the balance of fluids and impair the normal development of other structures.
Research suggests that the protein produced from the FAT4 gene is involved in determining the position of cells and their components within various tissues. Proper cell positioning within a tissue allows cells to coordinate their activity and plays an important role in tissue structure and function. The FAT4 gene variants that cause Hennekam syndrome interfere with the proper positioning of cells within the developing lymphatic vessels, which contributes to the lymphangiectasia and lymphedema seen in affected individuals.
Inheritance
Hennekam syndrome is inherited in an autosomal recessive pattern
, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.
Other Names for This Condition
- Hennekam lymphangiectasia-lymphedema syndrome
- HKLLS
- Lymphedema-lymphangiectasia-intellectual disability syndrome
Additional Information & Resources
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R. Further delineation of Hennekam syndrome. Clin Dysmorphol. 2003 Oct;12(4):227-32. doi: 10.1097/00019605-200310000-00003. Citation on PubMed
- Alders M, Al-Gazali L, Cordeiro I, Dallapiccola B, Garavelli L, Tuysuz B, Salehi F, Haagmans MA, Mook OR, Majoie CB, Mannens MM, Hennekam RC. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet. 2014 Sep;133(9):1161-7. doi: 10.1007/s00439-014-1456-y. Epub 2014 Jun 7. Citation on PubMed
- Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB, Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, Hennekam RC. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009 Dec;41(12):1272-4. doi: 10.1038/ng.484. Citation on PubMed
- Alders M, Mendola A, Ades L, Al Gazali L, Bellini C, Dallapiccola B, Edery P, Frank U, Hornshuh F, Huisman SA, Jagadeesh S, Kayserili H, Keng WT, Lev D, Prada CE, Sampson JR, Schmidtke J, Shashi V, van Bever Y, Van der Aa N, Verhagen JM, Verheij JB, Vikkula M, Hennekam RC. Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations. Mol Syndromol. 2013 Mar;4(3):107-13. doi: 10.1159/000342486. Epub 2012 Oct 2. Citation on PubMed or Free article on PubMed Central
- Brouillard P, Dupont L, Helaers R, Coulie R, Tiller GE, Peeden J, Colige A, Vikkula M. Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum Mol Genet. 2017 Nov 1;26(21):4095-4104. doi: 10.1093/hmg/ddx297. Citation on PubMed
- Elmansour I, Chiheb S, Benchikhi H. Hennekam syndrome: a rare cause of primary lymphedema. Dermatol Online J. 2014 Aug 17;20(8):13030/qt4xk755pd. Citation on PubMed
- Kapoor S. Hennekam syndrome: a rare and often ignored cause of intestinal lymphangiectasia. Endoscopy. 2014 Jun;46(6):542. doi: 10.1055/s-0034-1365291. Epub 2014 May 28. No abstract available. Citation on PubMed
- Ozyurt A, Sevinc E, Baykan A, Arslan D, Argun M, Pamukcu O, Uzum K. Variable clinical presentation in primary lymphoedema: report of two cases. Clin Dysmorphol. 2014 Jul;23(3):83-87. doi: 10.1097/MCD.0000000000000036. Citation on PubMed
- Scheuerle AE, Sweed NT, Timmons CF, Smith ED, Alcaraz WA, Shinde DN. An additional case of Hennekam lymphangiectasia-lymphedema syndrome caused by loss-of-function mutation in ADAMTS3. Am J Med Genet A. 2018 Dec;176(12):2858-2861. doi: 10.1002/ajmg.a.40633. Epub 2018 Nov 18. Citation on PubMed
- Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, Kolbe I, Lacombe D, Rockson S, Rowe P, Wijburg F, Hennekam RC. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002 Nov 1;112(4):412-21. doi: 10.1002/ajmg.10707. Citation on PubMed
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