Case

Case Report

Case 1

A 5½-year-old Yemeni girl was initially seen in a primary care clinic at the age of two years because of unsatisfactory growth and pallor. Hematological tests at the time revealed that she was anemic and an iron therapeutic trial was exhibited but without benefit. During a follow-up visit at three years of age, her random blood glucose level was noted to be high at 14.8 mmol/L and she was then admitted for further work-up. During admission, insulin therapy was started after studies showed an elevated fasting blood glucose concentration (8.8 mmol/L) and an abnormal oral glucose tolerance test result. She was maintained on two daily doses of insulin, five units of NPH insulin plus two units of regular insulin in the morning and two units of NPH insulin in the evening. At five years of age, she developed bilateral sensorineural deafness confirmed by auditory evoked responses and audiometry. Her physical examination revealed a pale and deaf girl who was not in distress. Her weight was 15 kg (5th percentile) and her height 101 cm (< 5th percentile). There were several hyperpigmented cafe-au-lait-like spots on her trunk and extremities measuring 0.5 to 1 cm in diameter. Ophthalmic tests including electroretinography (ERG) and flash visual evoked potential (FVEP) revealed optic subatrophy mainly involving the right eye. The remainder of her physical examination was unremarkable.

Investigation of her anemia revealed a hemoglobin of 7.5 g/dl, hematocrit 21.8%, MCV 90.4 fl, MCH 31.2 pg, MCHC 34.5 g/dl, platelets 194 × 10⁹/L and leukocyte count 6.6 × 10⁹/L. The leukocyte differential was: neutrophils 23%, eosinophils 4%, monocytes 3%, and lymphocytes 70%. The peripheral blood smear showed severe anisopoikilocytosis with prominent macrocytosis. The neutrophils showed no hypersegmentation. The bone marrow was very cellular with an abundant megakaryocytosis but the erythropoietic cells showed megaloblastoid features and dyserythropoietic changes, increased stainable iron, and numerous ringed sideroblasts. The myeloid series showed normal maturation and differentiation. Serum iron was 9 mmol/L, iron binding capacity 32 mmol/L, ferritin 213 μg/L, vitamin B₁₂ 423 pg/ml and serum and red cell folate were 4.3 and 3094 ng/ml, respectively.

The hemoglobin electrophoresis, G6PD level, liver function tests and serum electrolytes, urea and creatinine were normal. The direct and indirect Coomb's and Ham's test with sucrose were all negative. Because of the siderblastic changes in her bone marrow, she received a trial of pyridoxine for three months but without any benefit.

At the age of 4½ years, the patient was started on regular blood transfusions every four to six weeks because of inadequate growth and persistently low hemoglobin level in the range of 5 to 7 g/dl. She had received ten blood transfusions before a correct diagnosis could be made.

Case 2

The brother of Case 1, age 20–months, was seen with his sister when he was 4–months old. He subsequently developed left eye esotropia and deafness at the age of 6 and 13 months, respectively. Diabetes mellitus was discovered at 19 months of age when he was admitted for investigation of fever and a routine urinalysis showed glycosuria. At that time, his random blood sugar revealed a level of 14.3 mmol/L with no evidence of ketoacidosis. Subsequently, he had an oral glucose tolerance test which was normal. He was managed initially with regular insulin according to blood sugar level and eventually maintained on two units of NPH insulin once daily. His most recent physical examination revealed a pale looking child with left convergent squint and profound deafness. His weight was 9.8 kg (5th percentile) and his height 81 cm (25th percentile). There was no organomegaly, abnormal skin lesions or other remarkable findings.

Laboratory investigation revealed a hemoglobin of 5.9 g/dl, hematocrit of 16.7%, RBC 1.99 × 10¹²/L, MCV 84.1 ft, MCH 29.6 pg, MCHC 35.3 g/dl, and platelets 279 × 10⁹/L with a differential count of 37% neutrophils, 54% lymphocytes, 8% monocytes, and 1% eosinophil. The reticulocyte counts was 0.6%. The serum iron, iron binding capacity, ferritin, folate and vitamin B₁₂ were within normal limits. Haptoglobin, total bilirubin and hemoglobin electrophoresis were also within normal limits. The peripheral blood smear and bone marrow findings were similar to those of his sister, but with a decreased number of ringed sideroblasts and slight increase in stainable iron in the bone marrow. The audiologic and ophthalmic tests revealed severe bilateral sensorineural deafness and infantile esotropia involving the left eye. His HbAIC was 10.8%.

In both siblings, electrocardiogram, electroencephalogram and intravenous pyelography were normal. Also, investigations for organic aciduria and diabetes insipidus were negative. The two siblings are the only children of a first cousin couple with no family history of anemia, deafness, or diabetes.

The blood transketolase activities and thiamine levels were determined by Bioscientia in Germany in the two siblings and their parents using the HPLC method described by Wielders and Mink [13] (Table 1).

Administration of thiamine, 100 mg, daily administered orally resulted in prompt increase in the hemoglobin levels of both children within two weeks. In Case 1, the Hb was 6.1 g/dl pretreatment, and increased to 10.1 g/dl at the end of the second week, while in Case 2, the Hb was 5.9 g/dl pretreatment and 11.3 g/dl at the end of the second week of treatment. Reticulocytes revealed peaks of 80,000 and 90,000/mm² respectively in the two children at the end of the first week, but the mean corpuscular volume was unchanged in both cases.

The insulin requirements decreased in both siblings to approximately one-half of their initial doses. The plasma C-peptide level increased during therapy in both children especially in the girl (Table 1).

Discussion

The DIDMOAD syndrome in its original form, as reported by Wolfram [2] described the association of diabetes mellitus and optic atrophy but with no mention of diabetes insipidus and deafness. It is now known that sensorineural deafness or abnormal audiometry occurs in at least 39% of cases, central diabetes insipidus in 32% and dilatation of the lower urinary tract in 19%, with many other additional abnormalities occurring in smaller portions of patients [2]. A less frequently encountered triad of thiamine-responsive sideroblastic anemia, diabetes mellitus and sensorineural deafness was first recognized by Roger et al [3] in 1969, but Borgna-Pignatti et al [12] has recently suggested that the triad could be part of the wider spectrum of DIDMOAD syndrome, with both conditions resulting from a defect of thiamine metabolism.

Table 1. Blood thiamine, transketolase and C-peptide level in the two patients and their parents.

 * With concomitant fasting blood glucose level in parenthesis mmol/L.

In our patients, the peripheral blood and bone marrow findings strikingly corresponded to thiamine-responsive anemia described in association with diabetes mellitus and sensorineural deafness [3–12]. A good response to therapy with thiamine, and in particular, the significant increase of hemoglobin level with brisk reticulocytosis confirms this diagnosis. Also, the increase in plasma C-peptide concentration which paralleled the reduction in insulin requirement suggests an increase in endogenous insulin production. This fact together with absence of an HLA-DR₃ or DR₄ haplotype in most of the reported cases suggests that the cause of diabetes in this syndrome may differ from the more common type of insulin-dependent diabetes mellitus and is most probably linked with thiamine metabolism [1,12].

To date, blood thiamine levels and the activities of thiamine-dependent enzymes have been studied in only seven of the fourteen patients affected by this syndrome. However, the results of the studies have not been conclusive and there are some conflicting results. Our patients, as well as their parents, had normal thiamine levels and blood transketolase activities which are in agreement with the findings in the original patient described by Rogers et al [3] who had a normal thiamine level as well as normal pyruvate dehy-drogenase, ketoglutarate dehydrogenase and transketolase activities. These enzymes use thiamine as a cofactor in carbohydrate metabolism. Blood transketolase activity was normal in the patients reported by Mandel et al [6] and by Rosskamp [11]. In contrast however, Borgna-Pignatti et al [12] and Poggi et al [9] found a reduced level of thiamine as well as of thiamine pyrophosphokinase, an enzyme that phosphorylates thiamine to its metabolically active form, thiamine pyrophosphate. Also, Abboud et al [8] found the activity of alpha ketoglutarate dehy-drogenase to be very low in leukocytes, but not in fibroblasts. The exact thiamine-related biochemical abnormalities in thiamine-dependent anemia therefore remains to be more definitely delineated, but a thiamine dependency state is not in doubt, at least as far as the anemia is concerned. In this regard, the disorder is similar to other recognized vitamin dependencies or vitamin responsive inborn errors of metabolism [14–16]. Whether a thiamine dependency state underlines the various clinical manifestations present in the DIDMOAD syndrome remains speculative at the present time [12], and further studies to define the exact metabolic relationships are needed.

Acknowledgments

The authors thank Professor J. B. Familusi for reviewing the manuscript and Ms. Vangie Simbulan-Carrillo for secretarial help.

References