2006-01-05-14 Hereditary lymphedema I © Martinez www.thefetus.net/
Hereditary lymphedema I
Updated 01/05/2006 by Juliana Leite, MD
Original text 02/07/2002 Raul Martinez, MD
Synonyms: Nonne-Milroy lymphedema, Lymphedema, early-onset. Primary congenital lymphedema.
Definition: Hereditary lymphedema is a rare disease characterized by a firm edema of the lower extremities that can be generalized to the whole leg or limited to feet or toes. It was first described by Milroy in 1828. In general, it is considered as a benign disorder with mainly cosmetic importance.
True congenital lymphedema, or hereditary lymphedema type I (OMIM 153100), usually presents either at, or soon after, birth and may be associated with other congenital malformations.
Onset of clinical symptoms in hereditary lymphedema type II (OMIM 153200) usually occurs during or near either puberty or the menopause.
In 1962 was reported a congenital chylous ascites in an affected infant, whose father had recurrent swelling of the scrotum beginning at the age of 20 years. In 1964 pleural effusion was observed. In 1965, Esterly described one child with congenital type, which implies an intrinsic abnormality of the lymph-conducting pathways or, secondary in type, which implies that external factors such as radiotherapy, severe infection, or surgical excision have damaged lymph drainage routes. Most forms of primary lymphedema are thought to be caused by a congenital abnormality of the lymphatic system.
Case report 1
Raul Martinez, MD
A 22-year-old woman with no family history of malformations or genetic disorders attended the ultrasound unit at 22 weeks and had a routine examination. The scan showed a normally developed female fetus with edema of the right foot and leg, distal to the knee (Figure 1).
The rest of the examination was normal. Second scan was performed at the 27th gestational week, both lower extremities had subcutaneous edema, and there was also a little amount of ascites (Figure 2) and an unilateral pleural effusion demonstrated with M mode (Figure 3).
Fetal echocardiography was normal. The third and last scan was performed at the 31st gestational week, the ascites and pleural effusion had disappeared, but the lower extremities edema persisted, and this time subcutaneous edema could also be seen at the upper extremities distal to the elbows (Figure 4).
Color Doppler did not show vascular dilatation of the extremities. Findings on Doppler velocimetry were normal. Amniocentesis was not performed.
Diagnosis could be reached writing the words ¨pleural effusion¨ on the search bar of the OMIM page over the Internet (Figure 5). 12 entries were found; the first two were about hereditary lymphedema.
Cesarean section was performed at 39 weeks of gestation. The birth weight was 3480 g, birth length 51 cm. The clinical examination showed firm distal edema of the extremities (Figure 6).
The remaining clinical examination was normal. A sonographic scan of the feet and hands performed at 3 months of life, showed a diffuse subcutaneous thickening (Figure 7).
Plain X ray films were taken of the legs and thorax (Figure 8). Abdominal ultrasound was normal, with no evidence of ascites.
Case report 2
Montse Alegre, MD
This is the first pregnancy of a 30 year-old woman. The scan at 20 weeks revealed a lymphedema of the legs and feet. No other anomalies. After two days, the patient came back and she said that an uncle of her husband (a brother of her father in law, who is now 60 years) was born with an anomaly on legs and feet and he still has an edema on feet.
Incidence: It is estimated to occur with an incidence of approximately 1 in 6.000 newborn. The male to female ratio is 1:2,3.
Etiology: The disease has autossomic dominant inheritance with incomplete penetrance (80-84%), variable expressivity and variable age of onset . These features tend to appear at birth or in infancy.
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. This condition results from impaired lymph drainage in the presence of normal capillary filtration. It may be either primary in type, which implies an intrinsic abnormality of the lymph-conducting pathways or, secondary in type, which implies that external factors such as radiotherapy, severe infection, or surgical excision have damaged lymph drainage routes. Most forms of primary lymphedema are thought to be caused by a congenital abnormality of the lymphatic system
Genetic implications: The exact location of the genetic alteration causing the hereditary lymphedema has not been described. However, it has recently been demonstrated that the gene is located to the region 5q34-q35. There is also evidence that the disorder might be associated with mutations in the FLT4 that encodes the vascular endothelial growth factor receptor-3 (VEGFR-3).
Sonographic findings: 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. The disease has variable expressivity and must be suspected in those fetuses with distal subcutaneous edema of the extremities, most frequently of the lower limbs, but the hands can also be involved. Findings can be present in one extremity or in all of them, and there is no concordance in the time of appearance and degree of involvement of each extremity. Occasionally, persistent or transient pleural effusion and ascites can be found. The rest of the examination is normal. The prenatal diagnosis have been suggested in fetus from 15 weeks of gestation. Chylothorax, ascites and pericardia effusion have been described in association with the lymphedema.
Clinical characteristics: Lymphedema is present in one or both legs at birth and it is painless, non-pitting, with no tendency ulceration and no associated varicosities. In the majority of the cases, the lymphedema persists throughout life.
Differential diagnosis: The following dysmorphic syndromes must be considered:
• Turner syndrome
• Noonan syndrome
• Lymphedema-distichiasis syndrome (double row of eyelashes)
• Lymphedema and ptosis syndrome.
• Meige lymphedema (Hereditary lymphedema type II)
• Congenital recessive type lymphedema
Complications: The morbidity is due to infections. There are few significant complications associated with this disorder. There are cases reports of intestinal lymphangiectasia, recurrent septic arthritis, angiosarcoma, lymphangiosarcoma
Associated anomalies: There are reports of associations with distichiasis, hydroceles, atrial septal defect, and characteristic facial changes.
Prognosis: Edema, particularly severe below the waist, sometimes complicated with papillomatosis and nail changes. Present in one or both legs, the lymphedema persists throughout life but does not seem to affect longevity. As the patient grows up, the overlying skin displays a slightly rosy hue, while the size of the edematous parts remains proportional to the remainder of the body
Management: If other fetal anomalies are ruled out, and fetal karyotype is normal, parental counseling concerning etiology, management, and possible complications is advisable. Several individuals ware compression stockings, which are effective in containing the edema, whereas those who are more severely affected attend hospital for compression pumping to reduce limb size.
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
22. Lev-Sagie A, Hamani Y, Raas-Rothschild A, Yagel S, Anteby EY. Prenatal ultrasonographic diagnosis of atypical Nonne- Milyroy lymphedema. Ult Obst Gynecol 2003;21:72-74