Gastroesophageal Reflux Disease and Progressive Nephropathy After Improving Glycemic Control in an Adolescent With Diabetic Dwarfism

Since the description of Mauriac’s syndrome, or diabetic dwarfism, in 1930s, this syndrome, consisting of growth retardation, delayed puberty, and hepatomegaly, has rarely been encountered in type 1 diabetic children, especially since the advent of better diabetic management by insulin administration. The cause of growth failure has remained obscure, although it is presumably related to poor metabolic control of diabetes and depressed IGF-1 values (1). Improving diabetic control can result in the resolution of Mauriac’s syndrome. However, the clinical response may not be complete and may even result in progressive deterioration of microvascular complications, such as retinopathy or nephropathy (2,3).

We report here a 19-year-old adolescent with 10 years’ duration of type 1 diabetes and typical features of Mauriac’s syndrome who developed gastroesophageal reflux disease (GERD) and progressive nephropathy after improving glycemic control. Since the onset of his overt disease, he received suboptimal insulin therapy (4–10 units/day). He was referred 3 years ago with the problems of short stature and delayed puberty. Hormonal evaluation showed normal thyroid function and increased growth hormone (GH) value (24.3 ng/ml), but his glycemic control was very poor, as shown by an HbA_1c value of 13.2%. Also, there was no evidence of nephropathy (serum creatinine 0.6 mg/dl) or microalbuminuria. Because better diabetic control may normalize growth and delay or prevent microvascular complications, the insulin dose was increased step by step. Unfortunately, GERD occurred 3 months later, and symptomatic treatment was prescribed. During the following 2 years, he achieved a growth rate of 3–4 cm/year after improved diabetic control (HbA_1c values from 13.2 to 9.0 to 5.74%), but progressive nephropathy (serum creatinine 2.0 mg/dl, proteinuria, and hypertension) and deteriorated GERD (from grade 2 to grade 4) was encountered. Delayed puberty (Tanner stage III) and short stature (145 cm, 42 kg) with attenuated bone age (14.5 years old) were still noted. Endocrinological studies were performed again and showed normal values of thyroid hormones, GH, cortisol, leutinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (4.50 ng/ml, lower limit of normal range 3–10 ng/ml). However, an LH-releasing hormone stimulation test revealed blunted FSH response (3.25, 4.14, 4.1, and 4.68 μIU/ml at 0, 15, 30, and 60 min, respectively) but normal LH response (4.26, 13.18, 16.25, and 16.91 μIU/ml at 0, 15, 30, and 60 min, respectively). Because there was no strong evidence of endocrinopathy for his short stature, he received intensive glycemic control, keeping HbA_1c values around 7%, in addition to hypertensive management during the following year. However, GERD and progressive deteriorated renal function persisted and finally resulted in end-stage organ failure and hemodialysis.

Adequate insulin administration and a high degree of metabolic control are needed to support the growth and maturation of children with type 1 diabetes. Increased GH production with decreased IGF-1 concentration is found in prepubertal and pubertal diabetic patients (4). The enhanced GH response in diabetic children is not related to glycemic control, but is probably caused by a lack of IGF-1 negative feedback (1,5). However, insulin also plays an important role in the GH:IGF-1 axis because it can influence GH action at the receptor level, IGF-1 production by the liver, and IGF-1 bioactivity via its regulation of the IGF-1 binding protein IGFBP-1 (1,6). Thus, underinsulinization in type 1 diabetic children can result in growth delay and growth attenuation; when severe, this can result in Mauriac’s syndrome, or diabetic dwarfism. If the underinsulinziation was not of prolonged duration, improved insulin delivery will help in restoring normal growth and maturation in diabetic dwarfism. However, rapid deterioration of retinopathy and nephropathy have been reported when insulin treatment is undertaken too aggressively, and the pathophysiology is still obscure (2,3).

Our patient has diabetes of long-term duration with underinsulinization, which could result in his short stature, delayed puberty, and attenuated bone age, as seen in Mauriac’s syndrome, although we did not check his IGF-1 values. The appearance and progressive deterioration of GERD has not been reported in diabetic dwarfism after improving diabetic control. Also, the absent or blunted FSH response to the LHRH stimulation test may have some impact on the incomplete resolution of maturation after improving glycemic control in Mauriac’s syndrome, because FSH plays an important role in steroidogenesis by inducing maturation of Leydig cells (7) and androgens work in part by enhancing GH secretion and also stimulating IGF-1 production (the testosterone level of our patient is in the lower limit of the normal range). In summary, GERD is a rare, potentially serious complication during efforts to improve glycemic control in Mauriac’s syndrome, and the effect of rapidly improving glycemic control on esophageal motility has not been formally evaluated in diabetic patients (8). This issue should be elucidated in the future.