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

Mexico

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 27^th 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 31^st 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

Spain

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.

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