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Hennekam syndrome

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Description

Hennekam syndrome is an inherited disorder resulting from malformation of the lymphatic system, which is part of both the circulatory system and immune system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body.

The characteristic signs and symptoms of Hennekam syndrome are lymphatic vessels that are abnormally expanded (lymphangiectasia), particularly the vessels that transport lymph fluid to and from the intestines; puffiness or swelling caused by a buildup of fluid (lymphedema); and unusual facial features.

Lymphangiectasia often impedes the flow of lymph fluid and can cause the affected vessels to break open (rupture). In the intestines, ruptured vessels can lead to accumulation of lymph fluid, which interferes with the absorption of nutrients, fats, and proteins. Accumulation of lymph fluid in the abdomen can cause swelling (chylous ascites). Lymphangiectasia can also affect the kidneys, thyroid gland, the outer covering of the lungs (the pleura), the membrane covering the heart (pericardium), or the skin.

The lymphedema in Hennekam syndrome is often noticeable at birth and usually affects the face and limbs. Severely affected infants may have extensive swelling caused by fluid accumulation before birth (hydrops fetalis). The lymphedema usually affects one side of the body more severely than the other (asymmetric) and slowly worsens over time.

Facial features of people with Hennekam syndrome may include a flattened appearance to the middle of the face and the bridge of the nose, puffy eyelids, widely spaced eyes (hypertelorism), small ears, and a small mouth with overgrowth of the gums (gingival hypertrophy). Affected individuals may also have an unusually small head (microcephaly) and premature fusion of the skull bones (craniosynostosis).

Individuals with Hennekam syndrome often have intellectual disability that ranges from mild to severe, although most are on the mild end of the range and some have normal intellect. Many individuals with Hennekam syndrome have growth delay, respiratory problems, permanently bent fingers and toes (camptodactyly), or fusion of the skin between the fingers and toes (cutaneous syndactyly).

Abnormalities found in a few individuals with Hennekam syndrome include a moderate to severe shortage of red blood cells (anemia) resulting from an inadequate amount (deficiency) of iron in the bloodstream, multiple spleens (polysplenia), misplaced kidneys, genital anomalies, a soft out-pouching around the belly-button (umbilical hernia), heart abnormalities, hearing loss, excessive body hair growth (hirsutism), a narrow upper chest that may have a sunken appearance (pectus excavatum), an abnormal side-to-side curvature of the spine (scoliosis), and inward- and upward-turning feet (clubfeet).

The signs and symptoms of Hennekam syndrome vary widely among affected individuals, even those within the same family. Life expectancy depends on the severity of the condition and can vary from death in childhood to survival into adulthood.

Frequency

At least 50 cases of Hennekam syndrome have been reported worldwide.

Causes

Mutations in the CCBE1 or FAT4 gene can cause Hennekam syndrome.

The CCBE1 gene provides instructions for making a protein that is found in the lattice of proteins and other molecules outside the cell (extracellular matrix). The CCBE1 protein is involved in the maturation (differentiation) and movement (migration) of immature cells called lymphangioblasts that will eventually form the lining (epithelium) of lymphatic vessels.

The function of the protein produced from the FAT4 gene is largely unknown. Research shows that the FAT4 protein may be involved in determining the position of various components within cells (cell polarity).

CCBE1 gene mutations that cause Hennekam syndrome change the three-dimensional shape of the protein and severely decrease its function. The abnormal protein cannot play its role in the formation of the lymphatic vessel epithelium. The resulting malformation of lymphatic vessels leads to lymphangiectasia, lymphedema, and other features of Hennekam syndrome. Since the lymphatic system extends throughout the body, a disruption to the vessels can affect almost any organ. Altered lymphatic development before birth may change the balance of fluids and impair normal development, contributing to many of the other signs of Hennekam syndrome such as unusual facial features.

FAT4 gene mutations that cause Hennekam syndrome result in a FAT4 protein with decreased function. Reduced FAT4 protein activity seems to impair normal development of the lymphatic system, but the mechanism is unknown.

Together, mutations in the CCBE1 and FAT4 genes are responsible for approximately half of all Hennekam syndrome cases. The cause of the remaining cases is unknown.

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • generalized lymphatic dysplasia
  • Hennekam lymphangiectasia-lymphedema syndrome
  • intestinal lymphagiectasia-lymphedema-mental retardation syndrome
  • lymphedema-lymphangiectasia-intellectual disability syndrome

Additional Information & Resources

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Research Studies from ClinicalTrials.gov

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. Review. 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, Adès 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
  • 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. 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):83-7. doi: 10.1097/MCD.0000000000000036. 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. Review. Citation on PubMed
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