Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)

What is Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)?

Hennekam syndrome is a rare disease which affects the lymphatic system. The lymphatic system also involves the circulatory and immune systems. It is what transports immune and lymph cells around the body.

Symptoms and life expectancy with the syndrome can vary widely between patients, including those within the same family. Some patients survive into adulthood. There are currently 50 cases of the syndrome reported worldwide. The syndrome is usually recognized at birth.

This syndrome is also known as:
Hennekam Lymphangiectasia-lymphedema Syndrome Hennekam syndrome Lymphatic Dysplasia, Generalized

What gene changes cause Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)?

It is caused by mutations in the CCBE1, FAST4 or ADAMTS3 genes. Hennekam syndrome is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)?

Lymphangiectasia, or lymph vessels that are swollen, is the most common symptom of Hennekam syndrome. This tends to affect most severely the vessels that carry lymph cells to and from the intestines. This can also affect the skin, kidneys and heart of an affected individual or patient.

Another main symptom is Lymphedema, which is a build up of fluid in the body that causes puffiness and swelling.

Unique facial features include a flattened middle part of the face, puffy eyelids, widely-spaced eyes, small ears and mouth. A small head and premature fusing of the skull bones are also recognized features of Hennekam syndrome.

Other features include mild to severe intellectual disability, anemia (a shortage of red blood cells), multiple spleens, misplaced kidneys, genital abnormalities and umbilical hernia. Excessive body hair, scoliosis and clubfoot are also recognized as symptoms of the disease.

Possible clinical traits/features:
Coronal craniosynostosis, Cryptorchidism, Cutaneous finger syndactyly, Conical incisor, Epicanthus, Erysipelas, Ectopic kidney, Conductive hearing impairment, Malar flattening, Delayed eruption of teeth, Delayed skeletal maturation, Smooth philtrum, Autosomal recessive inheritance, Sensorineural hearing impairment, Oligodontia, Seizure, Pachygyria, Periorbital edema, Pericardial effusion, Pericardial lymphangiectasia, Vesicoureteral reflux, Retrognathia, Pleural effusion, Pleural lymphangiectasia, Broad forehead, Hirsutism, Horseshoe kidney, Hyperactivity, Hydronephrosis, Mild postnatal growth retardation, Hypertelorism, Hypoalbuminemia, Hypoplastic iliac wing, Short foot, Glaucoma, Gingival overgrowth, Depressed nasal bridge, Narrow mouth, Narrow palate, Pectus excavatum, Joint contracture of the hand, Intellectual disability, Intestinal lymphangiectasia, Low-set ears, Lymphedema, Atrial septal defect, Bilateral single transverse palmar creases, Wide nasal bridge, Protein-losing enteropathy

How does someone get tested for Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)?

The initial testing for Hennekam Lymphangiectasia-Lymphedema syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Hennekam Lymphangiectasia-Lymphedema syndrome 1 (HKLLS1)

Hennekam et al., (1989) described a brother and two sisters, and a cousin from an inbred pedigree, with a syndrome combining intestinal lymphangiectasia, lymphoedema of the limbs and face, and unusual facies. Onset of the lymphoedema was between 1 and 12 years. Affected individuals suffered from recurrent bouts of erysipelas. In other cases oedema has been present at birth, is progressive, and can be asymmetrical. The facies were flat with malar hypoplasia and marked hypertelorism, a flat nasal bridge, a small mouth, delayed eruption of the teeth, which were irregularly spaced, and small ears with narrow external meati and a thick helix. There are prominent lateral palatine ridges. Mild short stature, mental retardation and seizures were also part of the condition. Gabrielli et al., (1991) reported a further affected male who also had gum hypertrophy, supernumerary oral frenula and skin syndactyly of the fingers. There was pachygyria in the parietal region.
Mikelsaar and Lurie (1992) reported a boy with features of Aarskog syndrome and lymphoedema of the legs. There were similarities to Hennekam (1989), but intelligence was normal. Yasunaga et al., (1993) reported a mildly affected boy with the characteristic facial features but with little oedema and again with normal intelligence.
Cormier-Daire et al., (1995) reported a case with craniosynostosis of the coronal sutures and an ectopic kidney. Angle and Hersh (1997) reported an affected girl with the condition. She was also noted to have atretic ear canals, vesicoureteral reflux, rectal prolapse, and syndactyly of 4th and 5th toes. She also had a ventricular septal defect. Erkan et al., (1998) reported a 17 month old Turkish girl with features of the condition. The parents were consanguineous. It is difficult to evaluate the facial features from the clinical photographs however. Huppke et al., (2000) reported two brothers with features of the condition. MRI scans revealed small subcortical hyperintensities in both patients and a large cystic lesion in the younger patient, probably representing an old infarction.
Scarcella et al., (2000) reported two sisters with features of the condition. Unfortunately photographs were not published. Additional complications were hypothyroidism and hypertrophic pyloric stenosis. Both sisters died early within the first year of life. Glaucoma is present in about 10% of cases.
Forzano et al., (2002) reported a possible severely affected case. Four further cases were reported by Al-Gazali et al., (2003).
Bellini et al., (2003) reported a case with nonimmune hydrops fetalis, a congenital chylothorax and pulmonary lymphangiectasia.
Van Balkom et al., (2002) provide an excellent review. The patient reported by Musumeci et al., (2006), had massive genital involvement, including groups of red-violet pseudo-vesicular lesions.
The condition has now been mapped to 18q21 and mutations found in CCBE1 (Alders et al., 2009). Alders et al., (2013) looked at patients with CCB1 mutations and those without - they found no significant clinical differences between the 2 groups. The degree of lymphatic dysplasia was more severe in the mutation positive group.
Alders et al., (2014) looked at patients who were CCB1 negative and using exome sequencing found homozygous mutations in FAT4, the gene responsible for Van Maldergem syndrome. The families testing positive were those of Al-Gazali et al., (2003), Hennekam et al., (1989) and Erkan et al., (1998). DEspite a good deal of overlap, lymphedema is not a feature of Van Maldergem syndrome. Facial pictures shown by these authors of both conditions are convincingly similar.
Note the relatively mild case reported by Frosk et al., (2015). Polydactyly was present (in the case report post-axial, in the discussion pre-axial).

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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