Table 6.

Inherited/germline conditions involving lymphatic malformations.

Associated malformation or syndrome	Inheritance	Clinical phenotype	Candidate gene	Protein function or suspected role (if known)	Clinical evaluation	References
Primary lymphedema (Nonne-Milroy disease)	AD	• Lower-limb lymphedema, present as pedal edema at birth or soon after • Usually bilateral • Hydrocele (males) • Prominent veins • Upslanting toenails • Papillomatosis • Urethral anomalies in males	FLT4 VEGFR3	• Endothelial cell tyrosine kinase receptor, important for lymphangiogenesis (VEGF-C receptor) • Transcription factor, regulates PDGFβ	• MR lymphangiography or NM lymphoscintigraphy (lack of uptake radioactive colloid in ilioinguinal lymph nodes) • PT/OT evaluation • Compression fitting • Good skin hygiene • Genetic testing and counseling	(3, 10, 11, 15)
Late-onset lymphedema (Meige Disease)	Probable AD	• Most common subtype of primary lymphedema (~80% all cases) • Present at birth but onset of symptoms at puberty • Edema begins in feet and ankles and progresses to legs and knees	FOXC2 GJC2	• Transcription factor, regulates PDGFβ• Gap junction protein	• Evaluation as per primary lymphedema plus • Evaluation to rule out secondary lymphedema (malignancy, thrombosis, etc.)	(3)
Microcephaly-lymphedema-chorioretinal dysplasia	AD, or sporadic	• Patients have persistence of fetal lymphedema • Hypotonia, • Microcephaly • Intellectual disability • Chorioretinopathy	KIF11	• Spindle motor protein, may affect microtubule function	• Evaluation as per primary lymphedema plus • Ophthalmology exam • Echocardiogram • Consider brain MRI (lissencephaly reported)	(3, 15)
Hypotrichosis-lymphedema-telangiectasia syndrome	AR	• Absent eyebrows and eyelashes • Eyelid edema from birth • Lymphedema in the first of second decade of life • Telangiectasias (palms, soles, scalp, scrotum, legs)	SOX18	• Spindle motor protein, may affect microtubule function	• Evaluation as per primary lymphedema plus • Serial echocardiogram (dilation of the ascending aorta reported) • Skin and nail exam	(3, 15)
Lymphedema with distichiasis	AD	• Late onset lymphedema with distichiasis (fine hairs from Meibomian glands on inner eyelid) • Variable cardiac/renal/palate defects, varicose veins • Neck webbing	FOXC2	• Transcription factor, regulates PDGFβ	• Evaluation as per primary lymphedema plus • Ophthalmology exam (corneal irritation, recurrent conjunctivitis, and photophobia, ptosis) • Echocardiogram to rule out congenital heart disease • Spine MRI to rule out extradural arachnoid cysts	(3, 49)
Lymphedema with choanal atresia	AR	• Exceedingly rare, 1 family with lymphedema and choanal atresia	PTPN14	• Loss of function mutation in protein tyrosine phosphatase	• Evaluation as per primary lymphedema	(3)
Cholestasis-lymphedema (Aagenaes Syndrome)	AR	• Jaundice at birth and recurrent through life • Can progress to cirrhosis • Late-onset lower extremity lymphedema • Identified in several Norwegian families	Unknown gene on 15q	• Unknown	• Evaluation as per primary lymphedema plus • Hepatic/GI evaluation including CMP, serum bile acids (elevated), and lipid panel (hyperlipidemia)	(3)
Lymphedema-intestinal LM-mental retardation (Hennekam Syndrome)	AR	• Severe progressive lymphedema including genitalia and face • Mild to severe intellectual disability • Hypoproteinemia • Hearing loss • Renal anomalies • Scoliosis and club feet • Microcephaly ad craniosynostosis	CCBE1 FAT4 ADAMTS3	• Function in migration of lymphatic endothelial cells	• Evaluation as per primary lymphedema plus • Neurologic evaluation • Hearing screen • Abdominal US • Nutritional assessment • Thyroid studies • Screening for anemia • Spine X-rays	(3, 50–52)
Lymphedema-myelodysplasia (Emberger syndrome)	AD	• Lymphedema of limbs and genitalia in early childhood • Myelodysplasia with development of AML • Craniofacial anomalies • Congenital deafness	GATA2	• Transcription factor involved in gene regulation during vascular development and hematopoietic differentiation	• Evaluation per primary lymphedema plus • Hematologic evaluation including bone marrow biopsy • Neurologic and hearing assessments	(3, 53)