Hydrops fetalis: an unusual prenatal presentation of hereditary congenital lymphedema

Daniel-Spiegel, Etty; Ghalamkarpour, Arash; Spiegel, Ronen; Weiner, Ehud; Vikkula, Miikka; Shalev, Eliezer; Shalev, Stavit

doi:10.1002/pd.1237

Cited by 45 publications

(45 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is usually present at birth, is bilateral, and affects the feet up to the knees (4,5). Patients sometimes present with prenatal pleural effusion or in utero hydrops (6,7). Nonne-Milroy lymphedema is usually an autosomal dominant disorder, yet de novo mutations are not infrequent (7)(8)(9)(10).…”

Section: Vegf-c/vegfr-3 Signaling Axismentioning

confidence: 99%

Genetics of lymphatic anomalies

Brouillard¹,

Boon²,

Vikkula³

2014

J. Clin. Invest.

Self Cite

283

269

View full text Add to dashboard Cite

Lymphatic anomalies include a variety of developmental and/or functional defects affecting the lymphatic vessels: sporadic and familial forms of primary lymphedema, secondary lymphedema, chylothorax and chylous ascites, lymphatic malformations, and overgrowth syndromes with a lymphatic component. Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors. These mutations exert their effects via the RAS/MAPK and the PI3K/AKT pathways and explain more than a quarter of the incidence of primary lymphedema, mostly of inherited forms. More common forms may also result from multigenic effects or post-zygotic mutations. Most of the corresponding murine knockouts are homozygous lethal, while heterozygotes are healthy, which suggests differences in human and murine physiology and the influence of other factors. IntroductionThe lymphatic system plays a crucial role in tissue homeostasis. Blunt-ended lymphatic capillaries collect extravasated fluid, transport it via collecting lymphatic vessels and the thoracic duct, and return it to the blood circulation at the level of the left subclavian vein. The lymph travels through lymph nodes for immune surveillance. Larger lymphatic vessels contain valves to orient the passive flow, driven by neighboring arterial pulsations and muscular contractions. Lymphatic anomalies result from defects in the development, maturation, or function of this system. These include lymphatic malformations (LMs), lymphedema, chylothorax and chylous ascites, and overgrowth syndromes with a lymphatic component, including the Klippel-Trenaunay-Weber, proteus, PTEN hamartoma tumor syndrome, and CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities) syndromes (1). Genetic studies and the generation of genetically modified mice have started to shed light on the etiopathogenic mechanisms underlying these diseases.

show abstract

Section: Vegf-c/vegfr-3 Signaling Axismentioning

confidence: 99%

Genetics of lymphatic anomalies

Brouillard¹,

Boon²,

Vikkula³

2014

J. Clin. Invest.

Self Cite

283

269

View full text Add to dashboard Cite

show abstract

“…De novo mutations are possible too. Gene defects within one of three commonly described lymphangiogenic genes can lead to some degree of hydrops fetalis, such as in Milroy disease (MIM 153100, congenital lymphedema, VEGFR3 mutation), hypotrichosis-lymphedema-telangiectasia syndrome (childhood onset lymphedema, SOX18 mutation), and lymphedema-distichiasis (puberty onset lymphedema, FOXC2 mutation) [3,6]. The current case carries a truncating mutation in the forkhead-related transcription factor FOXC2 (MIM 153400) and stresses the fact that a wide intrafamilial variation in the clinical expression of this mutation is possible.…”

Section: Discussionmentioning

confidence: 99%

Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression

Bruyn¹,

Casaer

Devolder³

et al. 2011

Eur J Pediatr

View full text Add to dashboard Cite

Patients with a mutation in the FOXC2 transcription factor usually show lower limb lymphedema with onset at or after puberty, together with distichiasis. However, the eye manifestations can be very mild and easily overlooked. The association between FOXC2 mutation and neonatal hydrops resulting in terminal respiratory failure is not reported so far. Therefore, in sporadic patients diagnosed with non-immune hydrops fetalis, lymphangiogenic genes should be systematically screened for mutations. In addition, all cases of fetal edema must prompt a thorough analysis of the familial pedigree, in order to detect familial patterns and to facilitate adequate antenatal counseling.

show abstract

“…Prenatal findings suggestive of PCL warrant a targeted ultrasound, fetal karyotyping, and serial limited ultrasounds to look for progression of lymphatic dysfunction as evidenced by worsening lymphedema. Spontaneous resolution of PCL associated lymphedema during fetal life has also been reported to occur [21]. Prenatal genetic testing for PCL is not widely available; however, Sanger sequencing as well as deletion/duplication testing for the VEGFR3/FLT4 gene is available.…”

Section: Discussionmentioning

confidence: 99%

Primary Congenital Lymphedema Complicated by Hydrops Fetalis: A Case Report and Review of the Literature

Singh

Connell

2013

Case Reports in Obstetrics and Gynecology

View full text Add to dashboard Cite

Introduction. Primary congenital lymphedema is a rare disorder associated with insufficient development of lymphatic vessels. Usually most patients present with lower extremity edema seen sonographically. Rarely primary congenital lymphedema may be associated with severe lymphatic dysfunction resulting in hydrops fetalis. Case. A 27-year-old primigravida with a family history of leg swelling throughout multiple generations was diagnosed early in the third trimester with hydrops fetalis. Delivery was undertaken at 32 weeks for nonreassuring fetal status and the infant expired at approximately 45 minutes of life. Primary congenital lymphedema was confirmed via molecular testing of the vascular endothelial growth factor receptor-3 gene. Discussion. The diagnosis of PCL is suspected prenatally when ultrasound findings coincide with a positive family history of chronic lower limb lymphedema. Isolated PCL is rarely associated with significant complications. Rarely, however, widespread lymphatic dysplasia may occur, possibly resulting in nonimmune hydrops fetalis.

show abstract

Hydrops fetalis: an unusual prenatal presentation of hereditary congenital lymphedema

Abstract: PCL should be considered in the differential diagnosis of hydrops fetalis. Knowledge of the favorable course, variable clinical presentation, therapy options and genetic basis should contribute to better pregnancy counseling and management.

Cited by 45 publications

References 18 publications

Genetics of lymphatic anomalies

Genetics of lymphatic anomalies

Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression

Primary Congenital Lymphedema Complicated by Hydrops Fetalis: A Case Report and Review of the Literature

Contact Info

Product

Resources

About