Hennekam lyphagectasia lyphedema syndrome
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Here is a comprehensive overview of Hennekam Lymphangiectasia-Lymphedema Syndrome (HKLLS).
Hennekam Lymphangiectasia-Lymphedema Syndrome (HKLLS)
OMIM: #235510 (HKLLS1), #616006 (HKLLS2), #618154 (HKLLS3)
Overview
First described by Dutch physician R.C.M. Hennekam in 1989, HKLLS is a rare autosomal recessive disorder of generalized lymphatic dysplasia. Fewer than 50 cases were in the literature by early reports, though whole-exome sequencing is identifying more. It is classified among the primary (genetic) lymphedemas.
Genetics
Three causative genes have been identified, all disrupting the VEGFR3/VEGF-C signaling axis critical for lymphangiogenesis:
| Subtype | Gene | Chromosome | Mechanism |
|---|---|---|---|
| HKLLS1 | CCBE1 (collagen and calcium-binding EGF domains 1) | 18q21 | Reduces activation of VEGF-C → impairs VEGFR3 signaling |
| HKLLS2 | FAT4 (FAT atypical cadherin 4) | 4q28 | Planar cell polarity; overlaps with Van Maldergem syndrome-2 |
| HKLLS3 | ADAMTS3 (a disintegrin and metalloproteinase with thrombospondin motifs 3) | 4q13 | Processes pro-VEGF-C → reduces VEGFR3 activity |
A 2023 report identified FBXL7 as a potential novel fourth gene in HKLLS-like phenotypes. All known mutations impair lymphatic vessel formation before birth; since the lymphatic system is widespread, disruption affects multiple organs.
Clinical Features
1. Lymphatic Abnormalities (Core Features)
- Intestinal lymphangiectasia — dilated lymphatic vessels of the gut → protein-losing enteropathy: low albumin, hypoproteinemia, immune deficiency (loss of lymphocytes and immunoglobulins)
- Lymphedema — typically congenital or infantile onset; affects:
- Lower extremities (most common)
- Genitalia
- Face (can be asymmetric — one side more severely affected)
- Pericardial lymphangiectasia / pericardial effusion — recurrent, refractory (a 2025 case report highlights this as a diagnostic challenge even in middle-aged adults)
- Pleural and pulmonary lymphangiectasia
- Renal lymphangiectasia
- Chylous ascites — accumulation of lymph fluid in the abdomen
2. Facial Dysmorphism (Characteristic)
- Flat midface with depressed/broad nasal bridge
- Hypertelorism (wide-set eyes)
- Epicanthal folds, puffy/blepharoptotic eyelids (blepharophimosis)
- Small mouth with gingival hypertrophy (gum overgrowth)
- Low-set, small ears with narrow ear canals
- Irregular dentition
3. Neurodevelopmental
- Intellectual disability — variable, ranging from mild to severe (inconsistent; not always present)
- Seizures
- Growth delay / poor overall growth
4. Skeletal & Other
- Craniosynostosis (premature skull fusion)
- Camptodactyly (permanently bent fingers/toes)
- Cutaneous syndactyly
- Clubfeet
- Pectus excavatum
- Scoliosis
- Hearing loss
- Umbilical hernia
- Structural anomalies of heart, kidneys, or genitals
- Hirsutism
Differential Diagnosis
Key differentials in the setting of lymphedema + intellectual disability:
| Condition | Gene | Distinguishing Feature |
|---|---|---|
| Milroy disease | VEGFR3, VEGF-C | Congenital lower-limb lymphedema only; no intestinal involvement |
| Lymphedema-distichiasis | FOXC2 | Extra eyelash row; no intellectual disability |
| MCLMR syndrome | KIF11 | Microcephaly + chorioretinopathy |
| Hypotrichosis-lymphedema-telangiectasia | SOX18 | Hair loss + telangiectasia |
| Emberger syndrome | GATA2 | Lymphedema + predisposition to AML |
| Van Maldergem syndrome | FAT4 | Overlapping with HKLLS2 |
Diagnosis
Clinical diagnosis is based on the triad:
- Lymphangiectasia (especially intestinal)
- Lymphedema
- Facial dysmorphism ± intellectual disability
Laboratory:
- ↓ Serum albumin, ↓ total protein (protein-losing enteropathy)
- ↓ Lymphocytes, ↓ immunoglobulins
- ↑ Stool α1-antitrypsin (marker of protein loss into gut)
Imaging:
- MRI/CT lymphangiography: demonstrates dilated lymphatic channels
- Endoscopy: white-tipped villi (intestinal lymphangiectasia) — note: biopsy may be normal even in proven cases
- Echocardiography: pericardial effusion if suspected
Genetic confirmation:
- Sequencing of CCBE1, FAT4, ADAMTS3 (also FOXC2, GJC2, KIF11 if negative)
- Whole-exome sequencing is recommended if targeted panel is non-diagnostic (identifies novel variants)
Management
There is no curative therapy. Management is symptomatic and multidisciplinary:
| Problem | Intervention |
|---|---|
| Intestinal lymphangiectasia / protein loss | Low-fat diet with medium-chain triglycerides (MCTs bypass lymphatics); high-protein supplementation |
| Lymphedema | Complete decongestive therapy (CDT): manual lymphatic drainage, compression garments, skin care |
| Pericardial effusion | Drainage if symptomatic; treat underlying lymphatic cause |
| Pleural effusion | Drainage; octreotide may reduce lymph flow |
| Seizures | Standard anticonvulsants |
| Intellectual disability | Early developmental intervention, special education |
| Immune deficiency | IVIG replacement if severely low immunoglobulins; infection prophylaxis |
Prognosis
Prognosis depends on severity of protein-losing enteropathy and degree of lymphedema. Intestinal lymphangiectasia leading to severe hypoproteinemia and immunodeficiency is the major source of morbidity. Recurrent pericardial or pleural effusions can be life-threatening if unrecognized.
Key References
- Fitzpatrick's Dermatology, 9th ed. — lymphatic malformation genetics table; HKLLS gene classification
- Harrison's Principles of Internal Medicine, 22e (2025) — listed among genetic primary lymphedemas (CCBE1 gene)
- Zhang R et al. (2025). Recurrent pericardial effusion due to Hennekam lymphangiectasia-lymphedema syndrome. BMC Cardiovasc Disord [PMID: 40394495] — highlights whole-exome sequencing for refractory pericardial effusion
- MedlinePlus Genetics – Hennekam syndrome — comprehensive gene/mechanism summary
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