Revealing new mutations in pediatric myelodysplastic syndromes

May 03, 2013


In February of 2010, Inga Hofmann, MD, PhD—then a junior faculty member in hematology at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and a hematopathologist at Boston Children’s Hospital—led the charge to launch the Pediatric MDS/BMF Registry, the first case registry for pediatric myelodysplastic syndromes and bone marrow failure disorders (e.g., refractory anemia, refractory cytopenia, aplastic anemia and Diamond Blackfan anemia ).

The registry's main goal, "to collaborate with national and international centers to advance scientific knowledge in the field and work toward the discovery of new targets for therapy" fuels a larger mission: to support research that will advance both understanding and treatment of this group of rare conditions.

"MDS is the most common hematologic malignancy among the elderly, but pediatric MDS is very rare," says Hofmann. "The incidence is only about four out of every million children.

"One of the biggest challenges for those of us caring for these patients is that the underlying etiology and biology of MDS is still poorly understood," she continues. "I think we have barely started to scratch the surface."

Change may be on the horizon, however, because the efforts of Hofmann and her collaborators—including Dana-Farber/Boston Children's chief, David Williams, MD, and Boston Children's Hospital pathologist-in-chief, Mark Fleming, MD, DPhil —to build the registry have started to bear fruit. They have found that mutations in a gene called GATA2 may play a larger-than-realized role in a spectrum of hematologic conditions represented in the registry.

"In reviewing case histories, family pedigrees and mutation status, we have noted a spectrum of GATA2 mutation phenotypes that reveal themselves in features of patients' hematology, immunology and infection susceptibilities," Hofmann says. 

After initially discovering GATA2 mutations in two MDS patients with family histories of hematologic disorders and lymphedema or warts, Hofmann and her colleagues sequenced GATA2 in blood and bone marrow samples of 94 registered patients diagnosed with bone marrow failure or primary MDS ranging from . They identified 12 individuals with a GATA2 mutation: six patients, two first-degree relatives and four sporadic cases.

"This is a much higher mutation prevalence than we would have expected to see," Hofmann notes.

The cases and families studied from the registry displayed a range of GATA2 mutations, including nonsense, frameshift and missense mutations. All of the patients in this group had MDS ranging from low grade to very advanced forms that had transformed to acute myeloid leukemia.Those mutations were also linked to a similarly wide a range of clinical phenotypes, including lymphatic disorders, susceptibility to typical infections, gastrointestinal bleeding, and warts.

Based on the genetic and pedigree data, a profile of GATA2-related MDS has started to emerge:

  • A diagnosis of RAEB/AML or RCC
  • A median age of 15
  • Primarily in males
  • Association with monosomy 7
  • Distinct megakaryocytic dysplasia

Hofmann notes that several novel genetic mutations have been identified in adult MDS (e.g., ASXL1, TET2, EZH2, TP53, SF3B1, UMODL1). Might they play a role in pediatric disease? She and her colleagues are now conducting whole and targeted exome sequencing on more than 100 additional patients to find out.

Hofmann's take-home message: "There is a wide phenotypic spectrum in pediatric MDS and BMF disorders, requiring a multidisciplinary approach to care. They are challenging diseases to study, but next-generation sequencing technologies and familial analyses are providing valuable new insights, and we can learn from every single patient."

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