TMD Screening

TMD is estimated to occur in approximately 10% of newborns with Down syndrome and the mortality rate may be as high as 15 - 20%. In addition, 20-30% of individuals with TMD will go on to develop leukemia (AML) within the first four years of life. Early detection and treatment of this disease is important to promote a positive outcome.

Most people reading this blog know that we are the parents of a son with Down syndrome. Malcolm was diagnosed with TMD within hours of birth. Several weeks later he developed life-threatening complications from the TMD that, through timely and appropriate treatment, were successfully overcome. When he was 20 months old it was established that the disease was progressing to leukemia. He completed treatment for AML and continues to be disease-free. The physician attending his birth ordered a CBC because he had an unusual rash at birth. She mentioned that, were the rash absent, she likely would not have ordered the bloodwork. We subsequently found that whether or not a CBC is ordered for newborns with Down syndrome varies widely among primary health care providers, and that the majority of infants with TMD are asymptomatic at birth. We are concerned because we feel that his positive outcomes were due to early diagnosis of the disease, which ensured close monitoring by hematology/oncology specialists.

We are seeking to raise awareness of the importance of screening for TMD to promote positive outcomes in all children with Down syndrome who may have the disease. Below is text from a letter we have written to various Canadian organizations in hopes that they will assist in educating doctors about the disease in the importance of screening:

We are writing to urge you to consider an addition to the Health Care Guidelines for Individuals with eHealth Care Guidelines for Individuals withHDown Syndrome [1] in common use by physicians and pediatricians in Canada. We believe that the guidelines should clearly indicate that all newborns with a preliminary diagnosis of Down syndrome should be screened for evidence of Transient Myeloproliferative Disorder (TMD). It is important that physicians understand the importance of a complete blood count to screen for TMD.

TMD has, historically, been considered by the broader medical community to be a relatively benign disorder that usually resolves spontaneously. Although the Down Syndrome Medical Interest Group in 1999 recommended a hematocrit or complete blood count for all newborns with Down syndrome as a screening measure, it appears that this recommendation has not been well communicated to primary care physicians and the blood count does not appear to be routinely ordered in Canada. This is in spite of several recent peer reviewed articles and reviews in prominent medical journals that present strong evidence that TMD is not a benign disorder and that there would be benefit (and minimal cost) were all newborn children with Down syndrome screened.

It is estimated that TMD occurs in as many as 10% of newborns with Down syndrome [2]. There have been large studies in the United States, Japan and Europe that recently report that early death resulted in 15 to 20% of infants with TMD (not including stillbirths; [2,3]). Deaths are typically the result of cardiopulmonary, liver and/or hematological complications resulting from the TMD. The majority of newborns are asymptomatic [4] while others are symptomatic. Infants that develop severe symptoms may require an exchange transfusion or similar procedure, chemotherapy and/or supportive nursing care.

In addition to the risk of death due to TMD, it is estimated that 20-25% of infants with TMD will go on to develop acute megakaryoblastic leukemia (AMKL), a type of AML, within the first four years of life ([2,5,6]; 13-33% in ref. [4]). While therapies continue to improve, it is generally estimated that up to 20% of these children will not survive [3]. A positive prognostic factor is a young age (under two years old for AMKL specifically in [7]; under four for AML in general in [8]) at time of diagnosis.

There are, then, two strong reasons for screening for TMD. The first reason is to ensure that the TMD itself is carefully monitored, particularly given the lack of symptoms in most newborns, to watch for the development of severe symptoms that could lead to death in the first few months of life. The second reason is to monitor all children with TMD for progression to AMKL to ensure the onset of this disease is diagnosed as early as possible in order to promote the best possible outcome.

Both of these reasons are, to us, compelling and we are concerned that the medical community has not taken the appropriate steps to ensure that robust screening practices are in place. There has been much research into TMD, AMKL and the connection between these disorders over the past decade resulting in a greatly increased understanding among hematologists of both diseases. However, this understanding has not yet translated into changes in clinical practice to better identify those most at risk.

It is our sincere hope that you will champion and promote screening of infants with Down syndrome in Canada to your members and the broader medical community. We are confident that you will find that the recent medical science in relation to TMD supports screening more strongly than ever. Determining which infants have TMD is necessary to ensure the wellbeing of a vulnerable group of children.

References

[1] Cohen WI. Health Care Guidelines for individuals with Down Syndrome – 1999 revision. Down Syndrome Quarterly. 1999; 4:1-16.

[2] Hitzler JK. Acute Megakaryoblastic Leukemia in Down Syndrome. Pediatric Blood & Cancer. 2007; 49:1066-1069.

[3] Malinge S, Izraeli S and Crispino JD. Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood. 2009; 113:2619-2628.

[4] Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood. 2008; 111:2991-2998.

[5] Hitzler JK and Zipursky A. Origins of Leukemia in Children with Down Syndrome. Nature Reviews – Cancer. 2005; 5:11-20.

[6] Xavier AC, Ge Y and Taub J. Unique clinical and biological features of leukemia in Down syndrome children. Expert Reviews. 2010; 3(2):175-186.

[7] Gamis AS. Acute myeloid leukemia and down syndrome evolution of modern therapy – state of the art review. Pediatric Blood & Cancer. 2005. 44: 13-20.

[8] Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J and Zimmermann M. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia. 2005; 19: 1355-1360.

Additional references:

Dixon N, Kishnani PS and Zimmerman S. Clinical Manifestations of Hematologic and Oncologic Disorders in Patients with Down Syndrome. American Journal of Medical Genetics Part C Seminars in Medical Genetics. 2006; 142C: 149-157.

Massey GV. Transient Leukemia in Newborns with Down Syndrome. Pediatric Blood & Cancer. 2005; 44:29-32.

Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. Blood. 2006; 107:4606-4613.

Roy A, Roberts I, Norton A and Vyas P. Acute megakaryoblastic leukemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. British Journal of Haematology. 2009; 147:3-12.