HEREDITARY LYMPHEDEMA (1-12)

- NOONE-MILROY LYMPHEDEMA

- LYMPHEDEMA, EARLY-ONSET

- PRIMARY CONGENITAL LYMPHEDEMA

Lymphedema is chronic tissue swelling, that is most commonly manifested in a limb, and results from impaired lymph drainage in the presence of normal capillary

filtration.

Primary hereditary lymphedema:

· intrinsic abnormality of the lymph-conducting pathways (most forms are thought to be congenital in origin).

· hereditary lymphedema type I usually presents either at, or soon after, birth and may be associated with other congenital malformations (3-6).

· hereditary lymphedema type II usually occurs during or near either puberty or the menopause

Secondary hereditary lymphedema - 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.

Prevalence: Nonne-Milroy lymphedema or hereditary lymphedema I is a relatively rare condition (1-2:10,000).

Genetics: Autosomal dominant pattern of inheritance with reduced penetrance (80-84%), variable expressivity and variable age of onset from prenatal to 55 years. The disease has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. In some families the disorder is completely penetrant while in others penetrance is incomplete (80-84%) (13). Male: female ratio = 1:2.3 (13).

Pathogenesis: It has recently been demonstrated that this region (5q34-q35) contains the FLT4 locus encoding the vascular endothelial growth factor receptor-3 (VEGFR-3), whose mutations interfere with normal vascular lymphatic function (11,12). The pathophysiology involves insufficient development of lymphatic vessels.

ULTRASOUND

- 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.

- 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.

- Chylothorax, chylous ascites and chylopericardium may rarely be present.

DIFFERENTIAL DIAGNOSIS

• Non-lymphatic edema.
• Turner syndrome
• Noonan syndrome
• Lymphedema-distichiasis syndrome (double row of eyelashes).
• Lymphedema and ptosis syndrome.
• Meige lymphedema (Hereditary lymphedema type II, late-onset congenital lymphedema, lymphedema praecox).
• Congenital recessive type lymphedema.
• Microcephaly-lymphedema-chorioretinopathy syndrome.
• Diastichiasis lymphedema (can be excluded by examing the father and excluding double rows of lashes, and by early onset lymphedema in his family).

ASSOCIATED ANOMALIES

There are reports of associations with distichiasis (4), hydroceles, atrial septal defect, and characteristic facial changes^.

PROGNOSIS

Edema, particularly severe below the waist, sometimes complicated with papillomatosis and nail changes.

REFERENCES

1. Nonne M.Vier falle von elephantiasis congenita hereditaria. Arch Pathol Anat 1891; 125: 189

2. Milroy WF.Chronic hereditary edema: Milroy´s disease. JAMA 1928; 91: 1172-5

3. Dale RF. Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography. J Med Genet 24:170-171

4. Kolin T, Johns KJ, Wadlington WB, Butler MG, Sunalp MA, Wright KW (1991) Hereditary lymphedema and distichiasis. Arch Ophthalmol 109:980-981

5. Corbett CRR, Dale RF, Coltart DJ, Kinmonth JB (1982) Congenital heart disease in patients with primary lymphoedemas. Lymphology 15:85-90

6. Irons MB, Bianchi DW, Geggel RL, Marx GR, Bhan I (1996) Possible new autosomal recessive syndrome of lymphedema, hydroceles, atrial septal defect, and characteristic facial changes. Am J Med Genet 66:69-71

7. Rosen, F. S.; Smith, D. H.; Earle, R., Jr.; Janeway, C. A.; Gitlin, D. : The etiology of hypoproteinemia in a patient with congenital chylous ascites. Pediatrics

30: 696-706, 1962.

8. Hurwitz, P. A.; Pinals, D. J. : Pleural effusion in chronic hereditary lymphedema (Nonne, Milroy, Meige's disease): report of two cases. Radiology 82: 246-

248, 1964.

9. Esterly, J. R. : Congenital hereditary lymphoedema. J. Med. Genet. 2: 93-98, 1965.

10. P. Franceschini, D. Licata, G. Rapello, A. Guala, G. Di Cara and D. Franceschini Prenatal diagnosis of Nonne-Milroy limphedema

Ultrasound in Obstetrics & Gynecology Volume 18 Issue 2 Page 182 - August 2001

11 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

12. 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; 25: 153-9

13. Ferrell RE, Levinson KL, Esman JH et.al. Hereditary lymphedema: evidence for linkage and genetic heterogenicity. Hum Mol Genet 1998;7:2073-2078.