Graves’ disease (GD) and autoimmune type 1 diabetes mellitus (T1DM) are endocrine organ specific autoimmune endocrine disease [1]. Graves’ disease is the commonest cause of thyrotoxicosis in childhood and adults [2]. It is caused by thyroid-stimulating antibodies (TSAb) which mimic thyroid-stimulating hormone (TSH) and result in the overproduction and activity of thyroid hormones [2]. Type 1 diabetes mellitus is caused by destruction of the pancreatic β cells resulting in a deficiency of insulin [3]. Both endocrinopathies share a common genetic background and the occurrence of both in the same individual falls into the arena of autoimmune polyendocrine syndromes [4].

T1DM has been reported to have developed in adult patients with GD of long duration; typically manifesting first in adolescence or early adulthood [5].There are however, few reports of both conditions occurring simultaneously [5] and even one report where both were diagnosed after the administration of SARS-CoV-2 vaccine [6]. Some reports have indicated that diabetes precedes GD [7]. In this report, we discuss the case of a 9-year-old girl with Graves’ disease who developed type 1 diabetes mellitus shortly afterwards. A written informed consent was gotten from the parents.

AK, a 9-year-old girl first presented in the pediatric endocrine clinic of Lagos State University Teaching Hospital in November 2018. Presenting complaints were: bilateral bulging eyes, weight loss, anterior neck swelling and heat intolerance all of five months duration. Weight and height were 23kg (WHO > 97^th percentile) and 129cm (WHO < 85^th percentile) respectively. Physical findings were bilateral exophthalmos, diffuse thyroid gland enlargement measuring 6cm x 3cm in widest diameter without palpable nodules, resting tachycardia (heart rate of 120bpm), and blood pressure (130/90 mmHg: > 99^th centile). Apex beat was displaced to the 6^th left intercostal space midclavicular  line. The  liver  and  spleen  were not enlarged. Initial thyroid stimulating hormone (TSH) < 0.01µIU/ml (0.27 - 4.70µIU/ml), FT₃= 47.3pmol/l (4 – 10 pmol/l), FT₄ =100.0pmol/l (8 – 25 pmol/l), thyroid stimulating hormone antibodies (TSAb) = 63.46 IU/L (<2.0 IU/L). Ultrasound of the neck showed diffuse enlargement of both lobes of the thyroid and the isthmus.

Parenchyma echotexture was heterogeneous and no abnormal calcification was seen. Measurement was 5.15 x 2.08 x 1.77cm, 4.61 x 1.89 x 2.51cm (L x A.P x T) on the right and left respectively. The isthmus measured 8.14mm in height. The surrounding neck vessels were laterally displaced but otherwise normal. A diagnosis of Graves’ disease was made based on the hallmark features of thyrotoxicosis and raised TSAb and she was commenced on propranolol at 1mg/kg/day in two divided doses and carbimazole at 1mg/kg/day in two divided doses. Clinical symptoms subsided and she defaulted from follow-up care after six months. 

Two years and six months later, she presented with new symptoms of polyuria and polydipsia of five months duration. Patient admitted to poor drug compliance in the preceding one year and worsening eye signs of six months duration. There was no known family history of diabetes. Exophthalmos and neck swelling measured 3 x 2cm in its widest diameter were notable findings on examination. Laboratory findings were random blood glucose 456mg/dl (70 – 120mg/dl), glycated haemoglobin16% (4.1 % - 5.7%), and glycosuria (3+). Antibodies to glutamic carboxylase (Anti GAD) and C-peptide were 81.5IU/L (< 10) and 91pmol/L (260 – 1728 pmol/L), respectively. A second diagnosis of T1DM was made on account of the new symptoms, high blood glucose and high titres of anti- GAD.  She was commenced on subcutaneous basal-bolus insulin at a starting dose of 0.5U/kg/day.

GD frequently presents in paediatric endocrine practice with the clinical hallmark feature of thyrotoxicosis [8] and laboratory diagnostic hallmark of TSAb [9]. Methods of treatment of GD include anti-thyroid drugs (ATD), thyroidectomy and ablative radio-iodine therapy. Anti-thyroid drugs, often considered as the first line of treatment is associated with drug reactions and a high risk of recurrence. Thyroidectomy and radio-iodine treatment on the other hand, are associated with complications of surgery and hypothyroidism which require life-long replacement with L-thyroxine [2].

T1DM presents with a history of weight loss, polyuria, polydipsia, and polyphagia; often in the clinical setting of diabetic ketoacidosis (DKA). Laboratory findings include absent or low C-peptide and high HBA1C. High titres of Islet cell cytoplasm (ICA), insulin auto antibody (IAA), antibody to Glutamic Acid decarboxylase (GAD) and ICA512 indicate autoimmunity to islet cells [10]. Treatment is life-long replacement with insulin. 

Antibodies to islet antigens are most often present before the onset of T1DM. However, not all children with positive antibodies to islet cell antigens end up developing T1DM. Studies have shown that antibody to glutamic acid decarboxylase (GAD) among patients with GD is more sensitive and specific in determining those who would develop T1DM in later years [1]. Our patient, who had clinical and laboratory features of GD and T1DM may have developed T1DM because of the presence of ophthalmopathy (which worsened with poor drug compliance), a condition which according to Ferrari et al., was found to have predisposed patients with GD to the development of other autoimmune conditions. 

It is not uncommon to have GD and T1DM in the same patient. Literature has severally reported the diagnosis of T1DM in children, [1] followed by the onset of GD many years later. What stands out in our patient is the diagnosis of GD before that of T1DM and also the relatively short interval between diagnoses of the two conditions in a child. While it may be the practice in some protocols to screen intermittently for other auto-immune conditions in a patient with at least one, it is expected that such development will be over a long-term duration. 

The possibility of a second autoimmune disease occurring after the diagnosis of GD must always be a consideration to clinicians. The presence of ophthalmopathy may play a role in the development of T1DM in GD. Clinicians should also be aware that T1DM may present shortly after the diagnosis of GD in children. To this end, we recommend early screening for T1DM in all paediatric patients with GD.

Acknowledgment

The authors are thankful to the health care workers who participated in the management of this case. 

1. Taniyama, M. et al. “Occurrence of type 1 diabetes in graves’ disease patients who are positive for antiglutamic acid decarboxylase antibodies: An 8-Year Follow-Up Study.” Journal of Thyroid Research, 2011, Article ID 306487. https://doi.org/10.4061/2011/306487.

2. Rivkees, S.A. et al. “The management of graves’ disease in children, with special emphasis on radioiodine treatment.” The Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 11, 1998, pp. 3767–76.

3. Notkins, A.L. and Å. Lernmark. “Autoimmune type 1 diabetes: resolved and unresolved issues.” The Journal of Clinical Investigation, vol. 108, no. 9, 2001, pp. 1247–52.

4. V.E. GS, and P.A. Gottlieb. “Autoimmune polyendocrine syndromes.” The New England Journal of Medicine, vol. 350, 2004, pp. 2068–79.

5. Ahmad, F.A. and B. Mukhopadhyay. “Simultaneous presentation of type 1 diabetes and graves’ disease.” Scottish Medical Journal, vol. 56, no. 1, 2011, pp. 1–2.
   Accessed 5 Jan. 2022. https://journals.sagepub.com/doi/abs/10.1258/smj.2010.010024.

6. Patrizio, A. et al. “A case of graves’ disease and type 1 diabetes mellitus following sars-cov-2 vaccination.” Journal of Autoimmunity, vol. 125, 2021, 102738.

7. Lombardo, F. et al. “Prevalence, presentation and clinical evolution of graves’ disease in children and adolescents with type 1 diabetes mellitus.” Hormone Research in Paediatrics, vol. 76, no. 4, 2011, pp. 221–25.

8. Ferrari, S.M. et al. “The association of other autoimmune diseases in patients with graves’ disease (with or without ophthalmopathy): Review of the literature and report of a large series.” Autoimmunity Reviews, vol. 18, no. 3, 2019, pp. 287–92.

9. Tozzoli, R. et al. “TSH receptor autoantibody immunoassay in patients with graves’ disease: Improvement of diagnostic accuracy over different generations of methods. systematic review and meta-analysis.” Autoimmunity Reviews, vol. 12, no. 2, 2012, pp. 107–13.

10. Chiang, J.L. et al. “Type 1 diabetes in children and adolescents: a position statement by the american diabetes association.” Diabetes Care, vol. 41, no. 9, 2018, pp. 2026–44.