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Hennekam lymphangiectasia-lymphedema syndrome 2(HKLLS2)

MedGen UID:
863376
Concept ID:
C4014939
Disease or Syndrome
Synonym: HKLLS2
 
Gene (location): FAT4 (4q28.1)
 
Monarch Initiative: MONDO:0014454
OMIM®: 616006

Definition

Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014). For a discussion of genetic heterogeneity of Hennekam lymphangiectasia-lymphedema syndrome, see HKLLS1 (235510). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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).

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).

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).

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.

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 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.

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.  https://medlineplus.gov/genetics/condition/hennekam-syndrome

Clinical features

From HPO
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Intestinal lymphangiectasia
MedGen UID:
9828
Concept ID:
C0024215
Disease or Syndrome
Angiectasia of lymph vessels (i.e., dilatation of lymphatic vessels) in the intestines.
Pulmonary lymphangiectasia
MedGen UID:
340882
Concept ID:
C1855480
Finding
Abnormal dilatation of the pulmonary lymphatic vessels. Lymphatic fluid in the lung is derived from normal leakage of fluid out of the blood capillaries in the lung. In pulmonary lymphangiectasia, the pulmonary lymphatics are not properly connected and become dilated with fluid.
Pericardial lymphangiectasia
MedGen UID:
341077
Concept ID:
C1856140
Finding
An abnormal dilatation of lymph vessels in the pericardium.
Lymphedema
MedGen UID:
6155
Concept ID:
C0024236
Disease or Syndrome
Localized fluid retention and tissue swelling caused by a compromised lymphatic system.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Congenital Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Absence of concavity or convexity of the face when viewed in profile.
Irregular dentition
MedGen UID:
347297
Concept ID:
C1856765
Finding
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Professional guidelines

PubMed

Shinwari K, Wu Y, Rehman HM, Xiao N, Bolkov M, Tuzankina I, Chereshnev V
BMC Bioinformatics 2023 Jun 15;24(1):251. doi: 10.1186/s12859-023-05361-6. PMID: 37322437Free PMC Article

Recent clinical studies

Etiology

Shinwari K, Wu Y, Rehman HM, Xiao N, Bolkov M, Tuzankina I, Chereshnev V
BMC Bioinformatics 2023 Jun 15;24(1):251. doi: 10.1186/s12859-023-05361-6. PMID: 37322437Free PMC Article
Mihara M, Hara H, Shibasaki J, Seki Y, Hayashi A, Iida T, Adachi S, Uchida Y, Kaneko H, Haragi M, Murakami A
Ann Vasc Surg 2015 Aug;29(6):1111-22. Epub 2015 May 27 doi: 10.1016/j.avsg.2015.02.013. PMID: 26025477

Diagnosis

Shinwari K, Wu Y, Rehman HM, Xiao N, Bolkov M, Tuzankina I, Chereshnev V
BMC Bioinformatics 2023 Jun 15;24(1):251. doi: 10.1186/s12859-023-05361-6. PMID: 37322437Free PMC Article
Aukema SM, Ten Brinke GA, Timens W, Vos YJ, Accord RE, Kraft KE, Santing MJ, Morssink LP, Streefland E, van Diemen CC, Vrijlandt EJ, Hulzebos CV, Kerstjens-Frederikse WS
Am J Med Genet A 2020 Sep;182(9):2152-2160. Epub 2020 Jul 2 doi: 10.1002/ajmg.a.61743. PMID: 32618121
Mihara M, Hara H, Shibasaki J, Seki Y, Hayashi A, Iida T, Adachi S, Uchida Y, Kaneko H, Haragi M, Murakami A
Ann Vasc Surg 2015 Aug;29(6):1111-22. Epub 2015 May 27 doi: 10.1016/j.avsg.2015.02.013. PMID: 26025477

Prognosis

Shinwari K, Wu Y, Rehman HM, Xiao N, Bolkov M, Tuzankina I, Chereshnev V
BMC Bioinformatics 2023 Jun 15;24(1):251. doi: 10.1186/s12859-023-05361-6. PMID: 37322437Free PMC Article
Mihara M, Hara H, Shibasaki J, Seki Y, Hayashi A, Iida T, Adachi S, Uchida Y, Kaneko H, Haragi M, Murakami A
Ann Vasc Surg 2015 Aug;29(6):1111-22. Epub 2015 May 27 doi: 10.1016/j.avsg.2015.02.013. PMID: 26025477
Shah S, Conlin LK, Gomez L, Aagenaes Ø, Eiklid K, Knisely AS, Mennuti MT, Matthews RP, Spinner NB, Bull LN
PLoS One 2013;8(9):e75770. Epub 2013 Sep 26 doi: 10.1371/journal.pone.0075770. PMID: 24086631Free PMC Article

Clinical prediction guides

Shinwari K, Wu Y, Rehman HM, Xiao N, Bolkov M, Tuzankina I, Chereshnev V
BMC Bioinformatics 2023 Jun 15;24(1):251. doi: 10.1186/s12859-023-05361-6. PMID: 37322437Free PMC Article
Mihara M, Hara H, Shibasaki J, Seki Y, Hayashi A, Iida T, Adachi S, Uchida Y, Kaneko H, Haragi M, Murakami A
Ann Vasc Surg 2015 Aug;29(6):1111-22. Epub 2015 May 27 doi: 10.1016/j.avsg.2015.02.013. PMID: 26025477
Shah S, Conlin LK, Gomez L, Aagenaes Ø, Eiklid K, Knisely AS, Mennuti MT, Matthews RP, Spinner NB, Bull LN
PLoS One 2013;8(9):e75770. Epub 2013 Sep 26 doi: 10.1371/journal.pone.0075770. PMID: 24086631Free PMC Article

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