We report the prevalence of ID and IDA in a convenience sample of children and adolescents with DS recruited from a DS Clinic. The prevalence of ID (10.5%) and IDA (2.6%) in our sample is comparable with that found in the general pediatric population reported in the NHANES III study from 1988 to 1994 (26
). We did not find any statistically significant difference in the distribution of ID among children with DS with respect to sex or ethnicity compared with the unaffected/iron replete children
Only 2 of the 114 subjects had a MCV result that was below the normal range for age, and both of those patients had clear IDA. Aside from those two subjects, the distribution of MCV values overlapped between the normal, ID and IDA groups. In our cohort a low MCV and low MCH individually had poor sensitivity for screening of ID/IDA consistent with our hypothesis. Even when examined in combination with other RBC indices (MCV, MCH, MCHC, and RDW), the sensitivity was unacceptably low at 61%. Therefore, our data indicates that the macrocytosis of DS can mask the diagnosis of ID/IDA, confirming the suggestion by Starc (5
The NPV is the probability that the disease is not present when the test is negative and the area under the ROC curve determines the ability of a test to discriminate between subjects with the disease from those without the disease (tests with areas > 0.9 generally considered excellent and those with areas between 0.8 and 0.9 considered good). In our study, the ROC of low TS was 0.91; the combination of abnormal RBC indices (MCV, MCH, MCHC and RDW) along with low TS was 100% sensitive and had a NPV of 100% for identifying patients with ID/ IDA. Adding serum ferritin concentration, FEP and ZCP had little utility in increasing the sensitivity or NPV of the screening panel. We found that low TS was the best individual screening predictor of whether or not a patient had ID/IDA.
We still recommend obtaining a CBC and reticulocyte count at diagnosis and subsequent follow up after iron replacement has been initiated not only to determine response to therapy but also to establish the true baseline of these RBC indices for the individual patient. Serum ferritin concentration as a sole indicator of iron depletion was not sensitive enough for screening of ID/IDA in our sample. However a low serum ferritin is an important diagnostic clinical tool confirming iron depletion when used in combination with other measurements of iron status. Iron supplementation should be administered until there is no evidence of iron depletion, which usually requires at least 4–6 months of therapy or the individual will eventually progress again into a state of ID/IDA.
Patients who are followed by the DUMC Comprehensive DS Clinic are routinely screened for thyroid disorders and treated accordingly. Patients with a history of thyroid dysfunction were on proper treatment at the time of phlebotomy. None of the peripheral blood smears had findings suggestive of folic acid or vitamin B12 deficiency. We conclude that hypothyroidism or megaloblastic anemia were not a likely explanation for the increased RBC indices including the MCV among our study sample. These findings are consistent with the findings in patients with DS from prior published studies (3
Clear morphological changes in the RBC were only seen in the 3 patients who were diagnosed with IDA, therefore review of the peripheral blood smear was of low utility for screening for ID in this sample. Based on this finding and given that this diagnostic tool requires special expertise and is not usually available in the primary care setting we do not recommend its routine use for screening of ID. However evaluation of the peripheral blood smear continues to be essential for the assessment of anemia not explained by ID or for other worrisome findings in the CBC, especially given the increased risk to develop myelodysplastic syndrome and leukemia among individuals with DS.
Our findings confirm that the underlying macrocytosis of DS can mask a diagnosis of ID and a more thorough laboratory evaluation should be done for screening of ID among these patients. Thirteen out of 15 subjects with ID/IDA would have been missed if we had solely used the standard hemoglobin or MCV that is currently recommended for typically developing children. With this study we suggest that when children with DS are screened for ID/IDA, an expanded laboratory panel should be used, including a CBC, reticulocyte count, serum iron, TIBC, and serum ferritin concentration.
Sufficient iron stores are of great importance to maximize learning and psychomotor development, particularly in children with baseline cognitive delay as in DS. We recommend that baseline screening tests be done between 9 to 12 months of age and annually when children with DS are thought to be at risk for ID/IDA. Other associated conditions that might make children with DS prone for ID/IDA are: surgical interventions in the 1st year of life; feeding problems (hypersensitivity and/or food selectivity); history of menorrhagia; gastro esophageal reflux disease and history of Celiac disease. Macrocytosis among patients with DS has been found with variable frequency (45–66%). In our study, 22% of the total subjects had macrocytosis; this difference in frequency compared with other published data can be due to the number of subjects studied as our cohort is larger than of the previously reported. In our sample macrocytosis was found more frequently among the young children (33% of subjects one to less than six years of age); this finding also supports our recommendation to screen children with DS with an extended panel of laboratory tests early in life when macrocytosis can mask more individuals with ID/IDA, especially given that younger children could be more susceptible to non reversible neuro-cognitive effects related to prolonged IDA when compared with older peers.
A limitation to our study is that we did not use a "gold standard" to diagnosis ID. Gold standard for the diagnosis of ID includes a bone marrow biopsy stained by Prussian Blue for iron stores. Given the invasiveness of obtaining a bone marrow specimen, evaluation of the improvement in the hemoglobin concentration, RBC indices, reticulocyte count and biochemical measures of ID is typically used to assess the response to iron treatment. We encountered difficulties when bringing the subjects back to the DS Comprehensive Clinic or the PCP office for repeated laboratory evaluation after iron therapy, only few of them accomplished this goal, not enough for meaningful comparisons.
ID is an unrecognized problem among children with DS and the effects of ID on this population remain to be studied. A larger, community-based study of ID/IDA in individuals with DS should be done before further screening recommendations are made.