- Email: [email protected]
Mauriac syndrome still exists
Diabetes Research and Clinical Practice 54 (2001) 219– 221 www.elsevier.com/locate/diabres
Letter to the editor
Mauriac syndrome still exists Sir Mauriac syndrome may occur in children with poor controlled Type 1 diabetes mellitus and is characterized by growth failure delayed puberty, hepatomegaly and Cushingoid features [1 – 3]. With modern insulin therapy Mauriac syndrome has become a rarity. Previous reports of patients with Mauriac syndrome were published before the introduction of glycated haemoglobin (HbA1c) and poor control was only documented by measurement of blood glucose. Consequently, it is unknown to what extent improved control of diabetes is able to reverse the negative effects on growth, pubertal development and liver function in this condition. We report on case of Mauriac syndrome where growth velocity and liver function were strictly dependent on the variations of HbA1c. A 14-year old girl was diagnosed with Type 1 diabetes mellitus at the Department of Paediatrics, Naples when she was 3 years old. Height was at 95th percentile, weight was at 50th percentile (according to the NCHS growth charts), bone age was 3.5 years (Greulich and Pyle method). Socioeconomic level was low and the highest level of education completed by her parents was 8 years. Compliance with diabetes management has been always very poor. Except for the honeymoon
* Corresponding author. Tel.: + 39-081-746-3388; fax: + 39-081-545-1278.
period which lasted 1 year, the girl had persistently poor blood glucose control (mean HbA1c 9.5%, range 8.0 –14.0%; normalB6.0%), and a second admission for ketoacidosis was required at the age of 5 years. Liver function tests assessed yearly were always normal. The girl was lost to our follow-up from age 6.4 to 11.9 years, when she was admitted for growth failure and poor blood glucose control. Her medical records showed that at 10.2 years old she had very high levels of transaminases (AST 213 IU/l and ALT 311 IU/l; normalB40 IU/l) and gamma-glutamyltransferase (gGT) (68 IU/l, normal B 16 IU/l). On examination height was 5th – 10th percentile, weight was 10th –25th percentile, with a relative body weight of 109%; she had Cushingoid features, hepatomegaly and no signs of puberty. Bone age was 10 years. Insulin therapy was 0.9 U/kg in three daily doses. Laboratory data showed HbA1c 11.9%, AST 481 IU/l, ALT 376 IU/l, gGT 79 IU/l, tryglicerides 249 g/l, but bilirubin, prothrombin time, albumin, cholesterol and thyroid hormone levels were normal. Ultrasound scanning showed liver enlargement (right lobe diameter: 19 cm, normal range: 9.3 –13.7 cm) and moderate steatosis [4]. Viral, degenerative, autoimmune and metabolic liver diseases, biliary tract diseases, cystic fibrosis, coeliac disease, inflammatory bowel or neoplastic diseases, drug hepatotoxicity and Addison disease were excluded. No diabetic complications were found. Mauriac syndrome was suspected. Intensified treatment with 1.6 U/kg of insulin in four daily doses, frequent assessment of blood
0168-8227/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 1 ) 0 0 2 9 8 - 4
220
Letter to the Editor
Table 1 Clinical and laboratory data of a diabetic girl from 3–14 year Age (years)
Duration of diabetes (years)
Insulin dose (U/kg/day)
HbA (%)
AST/ALT (IU/l)
gGT (IU/l)
Height velocity (cm/year)
3 4 6.4 10.2 11.9 12 12.6 13.9
Onset 1 3.4 7.2 8.9 9 9.6 10.9
– 0.7 0.8 Unknown 0.9 1.6 1.7 1.7
11.1 7.3 10.9 Unknown 11.9 10 10.6 13.4
26/22 18/15 18/16 213/311 481/376 21/17 14/17 46/105
10 12 10 68 79 12 12 50
Unknown 5 5.6 Unknown 2.4 – 7 3.3
glucose and a strict diet regimen were started. Compliance has been always poor, but through strict medical surveillance with frequent telephonic supports, HbA1c decreased to 10.0% after 3 months, and transaminases, gGT and triglycerides normalized. Since the age of 12 years, catchup growth (7 cm/year) and initial signs of pubertal development were observed (B2 P2 according to Tanner). Liver size at ultrasound scanning was normal (right lobe diameter 13 cm), although mild steatosis persisted. HbA1c was 10.6% with an insulin dosage of 1.7 U/kg/day. At 14 years metabolic control dramatically worsened again with poor compliance (HbA1c 13.4%) and a recurrence of liver disease occurred. The girl redeveloped hypertransaminasaemia, although to lesser extent than before (GOT 46; GPT 105 IU/l), hepatomegaly (right lobe 18.8 mm) and moderate steatosis on ultrasound scanning. Growth velocity decreased to 3.3 cm/year and no further progression of pubertal development was observed; her relative body weight was 112%. The main clinical and laboratory data of the patient are shown in the Table 1, while her growth chart is shown in the Fig. 1; the mid-parental height is 165 cm. Significant deviation from normal somatic development is a peculiar feature of Mauriac syndrome. Several mechanisms may be involved in growth retardation in diabetic children. Insufficient tissue glucose availability, low circulating IGF-1 levels and reduced IGF-1 bioactivity have been reported [5,6]. Similarly, Mauriac syndromerelated liver disease may be dependent on liver
under-insulinization and increased cortisolaemia. Liver enlargement is due to increased glycogen and fat storage [3,7,8]. In the present case height, which was inappropriately high for genetic target at the onset of diabetes, underwent a progressive decline throughout the years (from 95th to 5th centile). A progressive decrease in height gain has
Fig. 1. Growth chart of a diabetic girl. The closed triangle () denotes mid-parental height.
Letter to the Editor
been also observed in a sample of 30 diabetic girls attending our Department until the attainment of final height, in accordance with other reports, indicating that linear growth may be impaired in diabetic children [9]. However, at the end of the growth their final height was still higher than the genetic target height and no delay in pubertal development was observed. In the present case height, which at the onset of diabetes was inappropriately high for genetic target, as has been described in newly diagnosed diabetic children [10], underwent a progressive decline throughout the years. At variance with other diabetic children, at the age of 12 years growth failure was so severe that the patient’s height reached a percentile significantly below to her target height (Fig. 1). With regard to liver disease, the patient presented very high levels of transaminases, which are unusual in Mauriac syndrome [1,2] and resembled those found in acute liver disease. Both growth and liver disease were positively affected by intensified management and improved metabolic control, confirming the diagnosis of Mauriac syndrome. Interestingly, a slight decrease of HbA1c was sufficient to cause catch-up growth and liver test normalization, but this effect vanished with subsequent worsening of HbA1c. The higher degree of hypertransaminasaemia found at 11.7 years may be explained by the longer duration of poor metabolic control compared to that at age 14 years. In conclusion, even though Mauriac syndrome has become rare, it should be still considered in Type 1 diabetic children with impaired growth and liver disease. A slight but prolonged improvement of HbA1c can reverse the negative effects on longitudinal growth and normalize liver function, although the effects of a blunted growth on final height cannot be excluded.
References [1] P. Mauriac, He´ patomegalie, nanisme, obe´ site´ dans le
221
diabe`te infantile, Presse. Med. 54 (1946) 826 – 827. [2] F. Mandell, W. Berenberg, The Mauriac syndrome, Am. J. Dis. Child 127 (1974) 900 – 902. [3] H.S. Traisman, E.S. Traisman, Mauriac syndrome revisited, Eur. J. Pediatr. 142 (1984) 296 – 297. [4] O.L. Konus, A. Ozdemir, A. Akkaya, G. Erbas, H. Celik, S. Isik, Normal liver, spleen, and kidney dimensions in neonates, infants, and children: evaluation with sonography, Am. J. Roentgenol. 171 (1998) 1693 – 1698. [5] N. Mauras, T. Merimee, A.D. Rogol, Function of the growth hormone-insulin-like growth factor I axis in the profoundly growth-retarded diabetic child: evidence for defective target organ responsiveness in the Mauriac syndrome, Metabolism 40 (1991) 1106 – 1111. [6] D.B. Dunger, Insulin and insulin-like growth factors in diabetes mellitus, Arch. Dis. Child 72 (1995) 469 – 477. [7] R.M. Lehman, Poorly controlled diabetes?, Adolesc. Med. 7 (1996) 405 – 408. [8] R. Olsson, C. Wesslau, T.W. Olsson, L. Zettergren, Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia, J. Clin. Gastroenterol. 11 (1989) 541 – 545. [9] M.C. Salerno, A. Argenziano, S. Di Maio, N. Gasparini, S. Formicola, G. De Filippo, A. Tenore, Pubertal growth, sexual maturation, and final height in children with IDDM, Diab. Care 20 (1997) 721 – 724. [10] T. Danne, O. Kordonouri, I. Enders, B. Weber, Factors influencing height and weight development in children with diabetes, Diab. Care 20 (1997) 281 – 285.
A. Franzese*, R. Iorio, P. Buono, M. Mascolo, E. Mozzillo Department of Pediatrics, Uni6ersity of Naples ‘Federico II’ Via S. Pansini, 5 80131, Naples, Italy G. Valerio Department of Pediatrics (DPMSC), Uni6ersity of Udine, Udine, Italy E-mail: [email protected] 13 July 2001
Letter to the editor
Mauriac syndrome still exists Sir Mauriac syndrome may occur in children with poor controlled Type 1 diabetes mellitus and is characterized by growth failure delayed puberty, hepatomegaly and Cushingoid features [1 – 3]. With modern insulin therapy Mauriac syndrome has become a rarity. Previous reports of patients with Mauriac syndrome were published before the introduction of glycated haemoglobin (HbA1c) and poor control was only documented by measurement of blood glucose. Consequently, it is unknown to what extent improved control of diabetes is able to reverse the negative effects on growth, pubertal development and liver function in this condition. We report on case of Mauriac syndrome where growth velocity and liver function were strictly dependent on the variations of HbA1c. A 14-year old girl was diagnosed with Type 1 diabetes mellitus at the Department of Paediatrics, Naples when she was 3 years old. Height was at 95th percentile, weight was at 50th percentile (according to the NCHS growth charts), bone age was 3.5 years (Greulich and Pyle method). Socioeconomic level was low and the highest level of education completed by her parents was 8 years. Compliance with diabetes management has been always very poor. Except for the honeymoon
* Corresponding author. Tel.: + 39-081-746-3388; fax: + 39-081-545-1278.
period which lasted 1 year, the girl had persistently poor blood glucose control (mean HbA1c 9.5%, range 8.0 –14.0%; normalB6.0%), and a second admission for ketoacidosis was required at the age of 5 years. Liver function tests assessed yearly were always normal. The girl was lost to our follow-up from age 6.4 to 11.9 years, when she was admitted for growth failure and poor blood glucose control. Her medical records showed that at 10.2 years old she had very high levels of transaminases (AST 213 IU/l and ALT 311 IU/l; normalB40 IU/l) and gamma-glutamyltransferase (gGT) (68 IU/l, normal B 16 IU/l). On examination height was 5th – 10th percentile, weight was 10th –25th percentile, with a relative body weight of 109%; she had Cushingoid features, hepatomegaly and no signs of puberty. Bone age was 10 years. Insulin therapy was 0.9 U/kg in three daily doses. Laboratory data showed HbA1c 11.9%, AST 481 IU/l, ALT 376 IU/l, gGT 79 IU/l, tryglicerides 249 g/l, but bilirubin, prothrombin time, albumin, cholesterol and thyroid hormone levels were normal. Ultrasound scanning showed liver enlargement (right lobe diameter: 19 cm, normal range: 9.3 –13.7 cm) and moderate steatosis [4]. Viral, degenerative, autoimmune and metabolic liver diseases, biliary tract diseases, cystic fibrosis, coeliac disease, inflammatory bowel or neoplastic diseases, drug hepatotoxicity and Addison disease were excluded. No diabetic complications were found. Mauriac syndrome was suspected. Intensified treatment with 1.6 U/kg of insulin in four daily doses, frequent assessment of blood
0168-8227/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 1 ) 0 0 2 9 8 - 4
220
Letter to the Editor
Table 1 Clinical and laboratory data of a diabetic girl from 3–14 year Age (years)
Duration of diabetes (years)
Insulin dose (U/kg/day)
HbA (%)
AST/ALT (IU/l)
gGT (IU/l)
Height velocity (cm/year)
3 4 6.4 10.2 11.9 12 12.6 13.9
Onset 1 3.4 7.2 8.9 9 9.6 10.9
– 0.7 0.8 Unknown 0.9 1.6 1.7 1.7
11.1 7.3 10.9 Unknown 11.9 10 10.6 13.4
26/22 18/15 18/16 213/311 481/376 21/17 14/17 46/105
10 12 10 68 79 12 12 50
Unknown 5 5.6 Unknown 2.4 – 7 3.3
glucose and a strict diet regimen were started. Compliance has been always poor, but through strict medical surveillance with frequent telephonic supports, HbA1c decreased to 10.0% after 3 months, and transaminases, gGT and triglycerides normalized. Since the age of 12 years, catchup growth (7 cm/year) and initial signs of pubertal development were observed (B2 P2 according to Tanner). Liver size at ultrasound scanning was normal (right lobe diameter 13 cm), although mild steatosis persisted. HbA1c was 10.6% with an insulin dosage of 1.7 U/kg/day. At 14 years metabolic control dramatically worsened again with poor compliance (HbA1c 13.4%) and a recurrence of liver disease occurred. The girl redeveloped hypertransaminasaemia, although to lesser extent than before (GOT 46; GPT 105 IU/l), hepatomegaly (right lobe 18.8 mm) and moderate steatosis on ultrasound scanning. Growth velocity decreased to 3.3 cm/year and no further progression of pubertal development was observed; her relative body weight was 112%. The main clinical and laboratory data of the patient are shown in the Table 1, while her growth chart is shown in the Fig. 1; the mid-parental height is 165 cm. Significant deviation from normal somatic development is a peculiar feature of Mauriac syndrome. Several mechanisms may be involved in growth retardation in diabetic children. Insufficient tissue glucose availability, low circulating IGF-1 levels and reduced IGF-1 bioactivity have been reported [5,6]. Similarly, Mauriac syndromerelated liver disease may be dependent on liver
under-insulinization and increased cortisolaemia. Liver enlargement is due to increased glycogen and fat storage [3,7,8]. In the present case height, which was inappropriately high for genetic target at the onset of diabetes, underwent a progressive decline throughout the years (from 95th to 5th centile). A progressive decrease in height gain has
Fig. 1. Growth chart of a diabetic girl. The closed triangle () denotes mid-parental height.
Letter to the Editor
been also observed in a sample of 30 diabetic girls attending our Department until the attainment of final height, in accordance with other reports, indicating that linear growth may be impaired in diabetic children [9]. However, at the end of the growth their final height was still higher than the genetic target height and no delay in pubertal development was observed. In the present case height, which at the onset of diabetes was inappropriately high for genetic target, as has been described in newly diagnosed diabetic children [10], underwent a progressive decline throughout the years. At variance with other diabetic children, at the age of 12 years growth failure was so severe that the patient’s height reached a percentile significantly below to her target height (Fig. 1). With regard to liver disease, the patient presented very high levels of transaminases, which are unusual in Mauriac syndrome [1,2] and resembled those found in acute liver disease. Both growth and liver disease were positively affected by intensified management and improved metabolic control, confirming the diagnosis of Mauriac syndrome. Interestingly, a slight decrease of HbA1c was sufficient to cause catch-up growth and liver test normalization, but this effect vanished with subsequent worsening of HbA1c. The higher degree of hypertransaminasaemia found at 11.7 years may be explained by the longer duration of poor metabolic control compared to that at age 14 years. In conclusion, even though Mauriac syndrome has become rare, it should be still considered in Type 1 diabetic children with impaired growth and liver disease. A slight but prolonged improvement of HbA1c can reverse the negative effects on longitudinal growth and normalize liver function, although the effects of a blunted growth on final height cannot be excluded.
References [1] P. Mauriac, He´ patomegalie, nanisme, obe´ site´ dans le
221
diabe`te infantile, Presse. Med. 54 (1946) 826 – 827. [2] F. Mandell, W. Berenberg, The Mauriac syndrome, Am. J. Dis. Child 127 (1974) 900 – 902. [3] H.S. Traisman, E.S. Traisman, Mauriac syndrome revisited, Eur. J. Pediatr. 142 (1984) 296 – 297. [4] O.L. Konus, A. Ozdemir, A. Akkaya, G. Erbas, H. Celik, S. Isik, Normal liver, spleen, and kidney dimensions in neonates, infants, and children: evaluation with sonography, Am. J. Roentgenol. 171 (1998) 1693 – 1698. [5] N. Mauras, T. Merimee, A.D. Rogol, Function of the growth hormone-insulin-like growth factor I axis in the profoundly growth-retarded diabetic child: evidence for defective target organ responsiveness in the Mauriac syndrome, Metabolism 40 (1991) 1106 – 1111. [6] D.B. Dunger, Insulin and insulin-like growth factors in diabetes mellitus, Arch. Dis. Child 72 (1995) 469 – 477. [7] R.M. Lehman, Poorly controlled diabetes?, Adolesc. Med. 7 (1996) 405 – 408. [8] R. Olsson, C. Wesslau, T.W. Olsson, L. Zettergren, Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia, J. Clin. Gastroenterol. 11 (1989) 541 – 545. [9] M.C. Salerno, A. Argenziano, S. Di Maio, N. Gasparini, S. Formicola, G. De Filippo, A. Tenore, Pubertal growth, sexual maturation, and final height in children with IDDM, Diab. Care 20 (1997) 721 – 724. [10] T. Danne, O. Kordonouri, I. Enders, B. Weber, Factors influencing height and weight development in children with diabetes, Diab. Care 20 (1997) 281 – 285.
A. Franzese*, R. Iorio, P. Buono, M. Mascolo, E. Mozzillo Department of Pediatrics, Uni6ersity of Naples ‘Federico II’ Via S. Pansini, 5 80131, Naples, Italy G. Valerio Department of Pediatrics (DPMSC), Uni6ersity of Udine, Udine, Italy E-mail: [email protected] 13 July 2001