Table 1.
Genes implicated in isolated and syndromic lymphedema forms
| Syndrome | OMIM number | Associated clinical signs (non-exhaustive list) | Gene(s) implicated | Inheritance | Estimated prevalence (Orphanet 2018) |
|---|---|---|---|---|---|
| Milroy syndrome | #153100 | – | FLT4/VEGFR3 | AD | 1/2500 to 1/10,000 |
| Milroy-like syndrome | #615907 | – | VEGFC | AD | < 1/100,000 |
| Meige syndrome | #613480 | – | GJC2 | AD | < 1/100,000 |
| Turner syndrome (X-monosomy) |
Short stature Ovarian insufficiency Bone anomalies Deafness Cardiovascular malformations Digestive malformations Cardiac malformations |
– | de novo | 1/2500 to 1/10,000 | |
| Down syndrome (trisomy 21) | #190685 |
Facial dysmorphy Digestive malformations Skeletal malformations Cardiac malformations Extremities anomalies Hypotony |
– | AD | 1/2500 to 1/10,000 |
| Noonan syndrome types 1 and 4 |
#163950 #610733 |
Arterial pulmonary stenosis Facial dysmorphy Pterygium colli (webbed neck) Learning difficulties |
PTPN11 SOS1 |
AD | 1/2500 to 1/10,000 |
| CM-AVM syndrome | #608354 |
Capillary malformations Arteriovenous malformations |
RASA1 | AD/mosaic | 1/10,000 to 1/100,000 |
| Lymphedema–distichiasis |
#153400 #153300 |
Distichiasis Ungual dystrophy |
FOXC2 | AD | 1/10,000 to 1/100,000 |
| Emberger’s syndrome | #614038 |
Facial dysmorphy Deafness Pancytopenia Myelodysplasia |
MET HGF GATA2 |
AD | 1/100,000 to 1/1,000,000 |
| Aagenaes syndrome | #214900 |
Neonatal cholestatic liver disease Hepatomegaly Jaundice Cirrhosis Splenomegaly Infantile malabsorption |
15q | AR | < 1/1,000,000 |
| Microcephaly syndrome | 152950 |
Facial dysmorphia Microcephaly Learning difficulties Retinopathy |
KIF11 | AD (de novo) | 1/100,000 to 1/1,000,000 |
| Hennekam syndrome | #235510 |
Intestinal lymphangiectasia Exudative enteropathy Learning difficulties Deafness Cardiac, renal, extremity malformations |
CCBE1 | AR | < 1/1000,000 |
| Van Maldergem’s syndrome (type 2) | # 615546 |
Facial dysmorphia Learning difficulties Deafness Genitourinary malformations |
FAT4 | AR | < 1/1000,000 |
| Hereditary lymphedema type III | #616843 |
Facial dysmorphia Deafness Learning difficulties Lymphangiectasia |
PIEZO1 | AR | < 1/1,000,000 |
| Oculodentodigital dysplasia | #16420 |
Facial dysmorphy Microcephaly Psychomotor retardation Neurological involvement Deafness Ophthalmological abnormalities (microphthalmia, cataract…) Dental anomalies Cardiac malformations Extremity anomalies |
GJA1 | AD (de novo) | < 1/1,000,000 |
| Lymphedema-choanal atresia | #613611 | Choanal atresia | PTPN14 | AR | < 1/1,000 000 |
| OLEDAID syndrome | #300301 |
Ectodermic dysplasia Osteopetrosis Immunodeficiency |
IKBKG/NEMO | XLR | < 1/1,000,000 |
| Hypotrichosis–lymphedema–telangiectasia syndrome |
#607823 #137940 |
Facial dysmorphia Hypotrichosis of the scalp and face Telangiectasia Glomerulosclerosis |
SOX18 | AR/AD | < 1/1,000,000 |
AD autosomal dominant, AR autosomal recessive, OLEDAID osteopetrosis–lymphedema–ectodermal dysplasia anhidrotic with immunodeficiency, XLR X-linked recessive