Table 2.

Genes of Interest in the Differential Diagnosis of Milroy Disease

Gene(s)DiffDx DisorderMOILymphedema Phenotype of DiffDx DisorderOther Clinical Features
ADAMTS3 Hennekam lymphangiectasia-lymphedema syndrome 3 (OMIM 618154)ARCongenital generalized edemaAssoc features incl facial dysmorphism & protein-losing enteropathy of variable severity
BRAF
KRAS
LZTR1
MAP2K1
NRAS
PTPN11
RAF1
RIT1
SOS1 		Noonan syndrome (NS)AD
(AR 1)		May present w/congenital edema of lower limbs which may or may not resolve. Persons w/NS may present again in childhood or adulthood w/edema of lower limbs & genitalia. There may also be a central conducting lymphatic anomaly presenting w/chylous reflux, chylothoraces, & chylopericardium which may be progressive.Characteristic facies, short stature, CHD, & DD of variable degree. Other findings incl broad or webbed neck, unusual chest shape w/superior pectus carinatum & inferior pectus excavatum, cryptorchidism, varied coagulation defects, & ocular abnormalities.
CCBE1 Hennekam syndrome 1 (OMIM 235510)ARCongenital or childhood-onset generalized edema; systemic involvement: e.g., intestinal lymphangiectasia (cardinal feature) & pleural or pericardial effusionsID 2
FAT4 Hennekam lymphangiectasia-lymphedema syndrome 2 (OMIM 616006)ARChildhood- or adult-onset generalized edemaDysmorphic facial features, microtia, ID
KIF11 Microcephaly-lymphoedema-chorioretinopathy (OMIM 152950)ADEdema indistinguishable from that of Milroy disease; identical lymphoscintigraphy pattern. 3 Intestinal lymphangiectasia may be a complication.Microcephaly, chorioretinopathy, & (in most persons) learning difficulties
PIEZO1 PIEZO1-related generalized lymphatic dysplasia w/systemic involvement (OMIM 616843)ARCongenital or childhood-onset generalized edemaFetal hydrops, atrial septal defects; pleural or pericardial effusions
SOX18 Hypotrichosis-lymphedema-telangiectasia syndrome (OMIM 607823)AR
AD		Childhood-onset lower limb lymphedemaLoss of hair & telangiectasia (particularly on the palms); renal defect
VEGFC VEGFC lymphoedema (OMIM 615907)ADClinically indistinguishable from that of Milroy disease; but lymphoscintigraphy pattern is different. 4Varicose veins

AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance

1.

Noonan syndrome is most often inherited in an autosomal dominant manner; Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

2.

The cognitive impairment with dysmorphic features was originally emphasized as a cardinal clinical sign of CCBE1-associated Hennekam syndrome, but less so in more recent publications [Connell et al 2010, Alders et al 2013, Crawford et al 2016, Jackson et al 2016].

3.
4.

Two families with a phenotype resembling Milroy disease have been shown to have pathogenic variants in VEGFC. Clinically, it is not possible to distinguish these individuals from those with FLT4 pathogenic variants and testing of VEGFC should be considered if FLT4 testing is negative [Gordon et al 2013a, Balboa-Beltran et al 2014, Fastré et al 2018, Nadarajah et al 2018, Gordon et al 2020].

From: Milroy Disease

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