Lymphedema, Primary, With Myelodysplasia

A number sign (#) is used with this entry because of evidence that primary lymphedema with myelodysplasia is caused by heterozygous mutation in the GATA2 gene (137295) on chromosome 3q21.

Immunodeficiency-21 (IMD21; 614172) is an allelic disorder with overlapping clinical features.

Clinical Features

Emberger et al. (1979) reported a family in which 3 individuals over 2 generations, who had severe congenital deafness, also developed lower limb lymphedema in childhood and hematologic abnormalities, including pancytopenia in 2 of them and acute myeloblastic leukemia in 1 individual. The male proband was born deaf and developed bilateral lymphedema of the lower extremities at 4 years of age. At age 12 years, he was found to have acute myeloblastic leukemia, and died 1 year later. His older sister, who also had profound congenital deafness, developed lymphedema of her right leg at age 13 years and was found to have anemia with leukopenia at age 21 years. Hematologic evaluation at age 26 years for anemia showed increased hemolysis, with a red cell half-life of 17.5 days; bone marrow function was normal with only slightly reduced daily hemoglobin synthesis. A younger brother had only congenital deafness, without edema or hematologic abnormalities. The older sister had a son who was born with profound bilateral deafness and at the age of 3 years developed edema of the left leg; transient granulocytopenia was noted at that time. A distant relative developed lymphedema of the left lower extremity at age 26 years, but did not have hearing loss or hematologic abnormalities. At 48 years of age, during a hospitalization for macronodular cirrhosis, mitral sclerosis, and cerebellar atrophy, 'elephantiasis-like' edema of the left leg was also noted. She died of hematuria at 51 years of age. The proband's parents were clinically unaffected and had no hematologic abnormalities.

Drony et al. (1983) reported a 23-year-old woman who underwent surgery at 19 years of age for lymphedema of both lower extremities; she also had bilateral syndactyly of the second and third toes. During a febrile episode she was noted to be pancytopenic and was diagnosed with acute myeloblastic leukemia. She achieved complete remission with chemotherapy, but relapsed 3 months later and died within 1 year. Drony et al. (1983) also reported a 20-year-old man who underwent surgery for lymphedema of the right lower extremity at 12 years of age. He was later noted to have granulocytopenia; 2 years later he was anemic and bone marrow examination showed 60% undifferentiated cells of erythroblastic lineage, suggestive of acute myeloblastic leukemia. Chemotherapy was complicated by infections and hemorrhage, and he died suddenly 5 months after diagnosis of apparent cardiac complications.

Attal et al. (1985) reported a male patient who at 18 years of age developed bilateral lymphedema that was complicated by streptococcal erysipelas and other infections over the next 3 years. At 21 years of age, he was noted to have pancytopenia with a cellular marrow, which was attributed to early myelodysplasia with refractory cytopenia; bone marrow karyotype showed 47 chromosomes (monosomy unspecified). A year later, he developed acute myeloblastic leukemia and died 18 months later without ever achieving remission. A sister had died at 13 years of age from acute myeloblastic leukemia, and a brother had cytopenic myelodysplasia with a cellular marrow; neither had lymphedema, and none of the 3 sibs had hearing loss. Attal et al. (1985) reviewed 4 previously reported cases, noting that all were young patients and that in 3 of the 4 cases, there was a preceding prolonged cytopenia suggestive of early acquired myelodysplasia.

Mansour et al. (2010) described 7 unrelated patients with primary lymphedema associated with myelodysplasia, 1 of whom had a significant family history. The authors noted that the lymphedema typically presented in 1 or both lower limbs, before the hematologic abnormalities, with onset between infancy and puberty and frequently involved the genitalia. Acute myeloid leukemia was often preceded by pancytopenia or myelodysplasia with a high incidence of monosomy 7 in the bone marrow (5 probands and 2 relatives). Associated anomalies included hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing (4 patients), recurrent cellulitis in the affected limb (4 patients), generalized warts (2 patients), and congenital high-frequency sensorineural deafness (1 patient). Mansour et al. (2010) concluded that children with lower limb and genital lymphedema should be screened for hematologic abnormalities and immunodeficiency.

Molecular Genetics

Ostergaard et al. (2011) performed whole-exome sequencing in 3 unrelated individuals with primary lymphedema and myelodysplasia, 2 with familial disease who were previously studied by Mansour et al. (2010) and 1 with sporadic disease, and identified a different heterozygous truncating mutation in the GATA2 gene (137295.0009-137295.0011) in each proband. The 2 variants identified in the familial cases were shown to be transmitted across generations between affected individuals within the kindred. Sanger sequencing of GATA2 in 5 additional probands, 3 of whom had previously been studied by Mansour et al. (2010), revealed heterozygous mutations in each (see, e.g., 137295.0012 and 137295.0013). None of the 8 GATA2 variants was found in 300 unrelated control chromosomes.

Exclusion Studies

Mansour et al. (2010) analyzed various candidate genes in 5 unrelated patients with primary lymphedema and myelodysplasia from whom DNA was available, but did not identify any pathogenic mutations.