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2002-10-23-09 Primary congenital lymphedema © Gourand

Primary congenital lymphedema (Milroy"s)

Véronique Mirlesse MD*, Ronaldo Levy MD*, Geneviève Brodaty MD*, Pascale Sonigo MD**, Dominique Teillac MD***, Luc Gourand, MD*, Fernand Daffos MD* Fernando Heredia MD"

*  Service de médecine foetale, Institut de Puériculture et Périnatalogie, Paris.
** Service de radio-pédiatrie, Hopital Necker Enfants Malades, Paris
*** Service de dermatologie, Hopital Necker Enfants Malades, Paris
" Women"s Health Alliance, Nashville, Tennessee.

Synonyms: Hereditary lymphedema type I, Nonne-Milroy Lymphedema, early-onset lymphedema, primary congenital lymphedema.

Incidence: 1:33,000 newborn. Male to female ratio 1:2,3[1],[2]

Etiology: Autosomal dominant with incomplete penetrance. The gene mutation has been found near the most telomeric region of  5q35.32,[8] There is also some evidence of 2 different sub-mutations or variants depending on the nucleotide substituted[9],[10],[11],[12],[13].

Pathogenesis:All the anomalies found are due to dysgenesis of lymphatic microvessels. These dysgenesis ranges from mild to severe and even to aplasia of both, the lymphatic capillaries and collectors[14],[15],[16].

Main features: Present in one or both legs at birth. Lymphedema of PCL persists throughout life but does not appear to affect longevity. As the patient matures, the overlying skin displays a slightly rosy hue, and the size of the edematous parts remains proportional to the remainder of the body. It can rarely present with genital edema, resembling sexual ambiguity[3].

Ultrasound appearance:This condition is suggested by the finding of an isolated edema of the dorsum of feet in the fetus, a normal karyotype and absence of other significant malformations.

Case report:

These are images obtained during a 28-week routine ultrasound examination. Fetal weight was over the 97th centile.

Fetal lower limbs: Edema of the lower limbs, specially the distal portions. Compare the width of legs and thighs.

Longitudinal view , cross section and fetal leg MRI also show edema.

The rest of the fetal anatomical survey was unremarkable. The fetal karyotype was normal (46, XY).

The baby boy was delivered uneventfuly and the following images show foot and toe edema.

Differential diagnosis:

  • Non-lymphatic edema.
  • Turner syndrome
  • Noonan syndrome
  • Lymphedema-distichiasis syndrome (double row of eyelashes)[4],[5]
  • Lymphedema and ptosis syndrome.
  • Meige lymphedema (Hereditary lymphedema type II, late-onset congenital lymphedema, lymphedema praecox)[6].
  • Congenital recessive type lymphedema[7].

 Possible complications:

Reported complications, although rare, have been reported:

  • Intestinal lymphangiectasia[17].
  • Bacterial infections of dorsal aspects of feet and toes[18].
  • Recurrent septic arthritis[19].
  • Angiosarcoma[20].
  • Lymphangiosarcoma[21].

Management: If other fetal anomalies are ruled out, and fetal karyotype is normal, parental counseling concerning etiology, management, and possible complications is advisable.


[1] Makhoul IR, Sujov P, Ghanem N, Bronshtein M. Prenatal diagnosis of Milroy"s primary congenital lymphedema. Prenat Diagn  2002 Sep;22(9):823-6

[2] Ferrell RE, Levinson KL, Esman JH, Kimak MA, Lawrence EC, Barmada MM, Finegold DN. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet  1998 Dec;7(13):2073-8

[3] Sarda P, Jalaguier J, Montoya F, Bonnet H. Hereditary congenital lymphedema with pseudosexual ambiguity.J Genet Hum  1988 Aug;36(4):353-60

[4] Dale RF.Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography. J Med Genet  1987 Mar;24(3):170-1

[5] Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome.Am J Hum Genet  2000 Dec;67(6):1382-8

[6] Herbert FA, Bowen PA. Hereditary late-onset lymphedema with pleural effusion and laryngeal edema. Arch Intern Med  1983 May;143(5):913-5

[7] Mucke J, Hoepffner W, Scheerschmidt G, Gornig H, Beyreiss K. Early onset lymphoedema, recessive form--a new form of genetic lymphoedema syndrome. Eur J Pediatr  1986 Aug;145(3):195-8

[8] Evans AL, Brice G, Sotirova V, Mortimer P, Beninson J, Burnand K, Rosbotham J, Child A, Sarfarazi M. Mapping of primary congenital lymphedema to the 5q35.3 region. Am J Hum Genet  1999 Feb;64(2):547-55

[9] Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet  2000 Aug;67(2):295-301

[10] Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA,Alitalo K, Finegold DN. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.Nat Genet  2000 Jun;25(2):153-9

[11] Finegold DN, Kimak MA, Lawrence EC, Levinson KL, Cherniske EM, Pober BR, Dunlap JW, Ferrell RE. Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet  2001 May 15;10(11):1185-9

[12] Holberg CJ, Erickson RP, Bernas MJ, Witte MH, Fultz KE, Andrade M, Witte CL. Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenitalprimary lymphedema families. Am J Med Genet  2001 Feb 1;98(4):303-12

[13] Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science  1997 May 30;276(5317):1423-5

[14] Partsch H, Urbanek A, Wenzel-Hora B. The dermal lymphatics in lymphoedema visualized by indirect lymphography. Br J Dermatol  1984 Apr;110(4):431-8

[15] Bollinger A, Isenring G, Franzeck UK, Brunner U. Aplasia of superficial lymphatic capillaries in hereditary and connatal lymphedema (Milroy"s disease). Lymphology  1983 Mar;16(1):27-30

[16] Pfister G, Saesseli B, Hoffmann U, Geiger M, Bollinger A. Diameters of lymphatic capillaries in patients with different forms of primary lymphedema. Lymphology  1990 Sep;23(3):140-4

[17] Wheeler ES, Chan V, Wassman R, Rimoin DL, Lesavoy MA. Familial lymphedema praecox: Meige"s disease. Plast Reconstr Surg  1981 Mar;67(3):362-4

[18] Mehta SD, Robinson RJ, Bern SA. Pedal manifestations of Milroy"s disease. J Am Podiatr Med Assoc  1996 Aug;86(8):400-2

[19] Albornoz MA, Myers AR. Recurrent septic arthritis and Milroy"s disease. J Rheumatol  1988 Nov;15(11):1726-8

[20] Offori TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphoedema (Milroy"s disease)--diagnostic beacons and a review of the literature. Clin Exp Dermatol  1993 Mar;18(2):174-7

[21] Brostrom LA, Nilsonne U, Kronberg M, Soderberg G. Lymphangiosarcoma in chronic hereditary oedema (Milroy"s disease). Ann Chir Gynaecol  1989;78(4):320-3

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