Neonatal diabetes mellitus with recurrent hepatitis
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《美国医学杂志》
Kanchi Kamakoti Childs Trust Hospital, 12-A, Nageswara Road, Nungambakkam, Chennai-600 034. Tamil Nadu, India
A 10-month-old female infant, diagnosed earlier as permanent neonatal diabetes mellitus, on regular insulin, presented with 2 episodes of jaundice over a period of 6 months. The present episode of jaundice was for 3 days and associated with passage of high colored urine and normal colored stools. There was no history of pedal edema, bleeds, ascites, altered sensorium or abdominal distension. Her appetite had decreased and she was lethargic. She was not given any form of indigenous medications. On examination she was afebrile, icteric, weighed 8 kg and length was 72 cm (both appropriate for age). Examination of abdomen revealed an enlarged, smooth, firm liver 6 cm below the right costal margin and spleen 3 cm below left costal margin. Examination of other systems was normal. Investigations showed Hb of 12.1 g/dl, leucocyte count of 8600-cells/cu. mm with lymphocyte predominance (65%). Her total serum bilirubin was 7.2 mg/dl with indirect 2.6 mg/dl and direct 4.6 mg/dl, SGOT 1500 IU/L, SGPT 1366 IU/L and SAP 627 IU/L. Random blood sugar was 187mg/dl. Blood urea and serum creatinine were normal. Ultrasound abdomen was reported as hepatosplenomegaly with homogenous echo texture. There was no ascites. Chest X ray was normal. Liver biopsy showed macrosteatosis with nuclear glycogenosis and inflammatory cells in the portal triad and lobule. There was no evidence of chronic hepatitis or cirrhosis. She was managed with insulin and supportive treatment. Within three weeks the hepatosplenomegaly regressed and serum aminotransferases decreased to 48 IU/L (SGPT) and 60 IU/L (SGOT). The first episode of jaundice at 4 months of age was similar with jaundice and elevated transaminases, which resolved with supportive management. TORCH screening and viral markers for Hepatitis A, B and E done twice were negative. She was admitted at 2 months of age and diagnosed as neonatal diabetes when she presented with tachypnoea, vomiting and drowsiness. Investigations during that period revealed hyperglycemia (blood sugar: 697 mg/dl), metabolic acidosis (serum bicarbonate 7 mmol/l), ketonuria (3+) and prerenal azotemia (Blood urea 68 mg/dl and serum Creatinine 1 mEq/l). Liver function tests, thyroid profile, ultrasound abdomen, serum amylase, lipase and fecal chymotrypsin and skeletal survey done during the first admission were normal. Her C-peptide was < 0.5 ng/ml and islet cell antibodies were negative. HLA typing was not done due to financial constraints. She was on regular follow up for control of blood sugars and her developmental milestones were appropriate for age.
Neonatal diabetes mellitus (NDM) is defined as an insulin requiring hyperglycemia occurring within the first 3 months of life. It is a rare entity with an estimated incidence of 1 in 4,00,000 live births.[1],[2] About half of them have transient neonatal diabetes (TDNM) that remits within a median of 3 months but often recurs in adolescence.[2] The remainder has permanent diabetes mellitus of newborn (PNDM) that occurs without any period of remission. Massa et al[3] suggested the term permanent diabetes mellitus of infancy (PDMI) instead of PNDM and included infants up to 6 months of age. PDMI may be due to pancreatic dysgenesis or early onset type I diabetes mellitus.[4] Pancreatic dysgenesis is usually associated with exocrine pancreatic insufficiency, elevated serum amylase, lipase and fecal chymotrypsin levels but these features were not present in this child. The unique feature in this child was the recurrent hepatitis apart from the early onset type 1 diabetes mellitus.
Wolcott - Rallison syndrome is a rare autosomal recessive syndrome first reported in 1972 by Wolcott and Rallison who described three siblings with permanent diabetes mellitus of infancy and multiple epiphyseal dysplasia.[5] Idiopathic recurrent self limiting hepatitis, prerenal azotemia, developmental delay, central hypothyroidism, osteoporosis, fractures, short limb dwarfism spondylo-epiphyseal dysplasia, grey blue sclera, high arched palate, tooth discoloration and dry skin constitute the spectrum of manifestations associated with this syndrome.[6] A novel mutation in EIF2AK3 gene on 2p 12 locus which codes translation initiation factor 2 alpha kinase has been identified with this syndrome. This genetic mutation is of help in prenatal diagnosis.[7] In this child with PDMI and recurrent self-limiting hepatitis, a possibility of Wolcott Rallison Syndrome was considered even though epiphyseal dysplasia was not present as this can develop later as reported by Iyer et al.[8]
Wolcott Rallison Syndrome, though very rare, should be suspected in infants with permanent neonatal diabetes mellitus, idiopathic recurrent self-limiting hepatitis, prerenal azotemia and skeletal dysplasia. Though there is no specific treatment apart from good control of diabetes mellitus, prenatal diagnosis is possible and genetic counselling can be offered to the family.
References
1. Bappal B, Raghupathy P, de silva V, Khushiby SM. Permanent neonatal diabetes mellitus. Clinical presentation and epidemiology in Oman. Arch Dis Child Fetal Neonatal Ed 1999; 80: 209-212.
2. Porter JR, Shaw NJ, Barrett TG. Permanent neonatal diabetes in an asian infant. Journal of Pediatr 2005; 146 : 47-49.
3. Massa O, Iafusco D, D'Amato E. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005; 25 : 22-27.
4. Menon PSN, Khatwa UA. Diabetes mellitus in newborns and infants. Indian J Pediatr 2000; 67 : 443-448.
5. Wolcott CD, Rallison ML. Infancy - onset diabetes mellitus and multiple epiphyseal dysplasia J. Pediatr 1972; 80 : 292-297.
6. Abbas BB, Shabib S. Wolcott Rallison syndrome: Clinical, radiological and histological findings in a Saudi child. Annals of Saudi Medicine 2001; 21: 1-2.
7. Brickwood S, Bonthron DT, Gazali-LIAI et al. Wolcott-Rallison syndrome: pathogenic insights in to neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 2003; 40: 685-689.
8. Iyer S, Korada M, Rainbow L et al. Wolcott - Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paeditr 2004; 93: 1195-1201.(Suresh N, Ganesh R, Eswar)
A 10-month-old female infant, diagnosed earlier as permanent neonatal diabetes mellitus, on regular insulin, presented with 2 episodes of jaundice over a period of 6 months. The present episode of jaundice was for 3 days and associated with passage of high colored urine and normal colored stools. There was no history of pedal edema, bleeds, ascites, altered sensorium or abdominal distension. Her appetite had decreased and she was lethargic. She was not given any form of indigenous medications. On examination she was afebrile, icteric, weighed 8 kg and length was 72 cm (both appropriate for age). Examination of abdomen revealed an enlarged, smooth, firm liver 6 cm below the right costal margin and spleen 3 cm below left costal margin. Examination of other systems was normal. Investigations showed Hb of 12.1 g/dl, leucocyte count of 8600-cells/cu. mm with lymphocyte predominance (65%). Her total serum bilirubin was 7.2 mg/dl with indirect 2.6 mg/dl and direct 4.6 mg/dl, SGOT 1500 IU/L, SGPT 1366 IU/L and SAP 627 IU/L. Random blood sugar was 187mg/dl. Blood urea and serum creatinine were normal. Ultrasound abdomen was reported as hepatosplenomegaly with homogenous echo texture. There was no ascites. Chest X ray was normal. Liver biopsy showed macrosteatosis with nuclear glycogenosis and inflammatory cells in the portal triad and lobule. There was no evidence of chronic hepatitis or cirrhosis. She was managed with insulin and supportive treatment. Within three weeks the hepatosplenomegaly regressed and serum aminotransferases decreased to 48 IU/L (SGPT) and 60 IU/L (SGOT). The first episode of jaundice at 4 months of age was similar with jaundice and elevated transaminases, which resolved with supportive management. TORCH screening and viral markers for Hepatitis A, B and E done twice were negative. She was admitted at 2 months of age and diagnosed as neonatal diabetes when she presented with tachypnoea, vomiting and drowsiness. Investigations during that period revealed hyperglycemia (blood sugar: 697 mg/dl), metabolic acidosis (serum bicarbonate 7 mmol/l), ketonuria (3+) and prerenal azotemia (Blood urea 68 mg/dl and serum Creatinine 1 mEq/l). Liver function tests, thyroid profile, ultrasound abdomen, serum amylase, lipase and fecal chymotrypsin and skeletal survey done during the first admission were normal. Her C-peptide was < 0.5 ng/ml and islet cell antibodies were negative. HLA typing was not done due to financial constraints. She was on regular follow up for control of blood sugars and her developmental milestones were appropriate for age.
Neonatal diabetes mellitus (NDM) is defined as an insulin requiring hyperglycemia occurring within the first 3 months of life. It is a rare entity with an estimated incidence of 1 in 4,00,000 live births.[1],[2] About half of them have transient neonatal diabetes (TDNM) that remits within a median of 3 months but often recurs in adolescence.[2] The remainder has permanent diabetes mellitus of newborn (PNDM) that occurs without any period of remission. Massa et al[3] suggested the term permanent diabetes mellitus of infancy (PDMI) instead of PNDM and included infants up to 6 months of age. PDMI may be due to pancreatic dysgenesis or early onset type I diabetes mellitus.[4] Pancreatic dysgenesis is usually associated with exocrine pancreatic insufficiency, elevated serum amylase, lipase and fecal chymotrypsin levels but these features were not present in this child. The unique feature in this child was the recurrent hepatitis apart from the early onset type 1 diabetes mellitus.
Wolcott - Rallison syndrome is a rare autosomal recessive syndrome first reported in 1972 by Wolcott and Rallison who described three siblings with permanent diabetes mellitus of infancy and multiple epiphyseal dysplasia.[5] Idiopathic recurrent self limiting hepatitis, prerenal azotemia, developmental delay, central hypothyroidism, osteoporosis, fractures, short limb dwarfism spondylo-epiphyseal dysplasia, grey blue sclera, high arched palate, tooth discoloration and dry skin constitute the spectrum of manifestations associated with this syndrome.[6] A novel mutation in EIF2AK3 gene on 2p 12 locus which codes translation initiation factor 2 alpha kinase has been identified with this syndrome. This genetic mutation is of help in prenatal diagnosis.[7] In this child with PDMI and recurrent self-limiting hepatitis, a possibility of Wolcott Rallison Syndrome was considered even though epiphyseal dysplasia was not present as this can develop later as reported by Iyer et al.[8]
Wolcott Rallison Syndrome, though very rare, should be suspected in infants with permanent neonatal diabetes mellitus, idiopathic recurrent self-limiting hepatitis, prerenal azotemia and skeletal dysplasia. Though there is no specific treatment apart from good control of diabetes mellitus, prenatal diagnosis is possible and genetic counselling can be offered to the family.
References
1. Bappal B, Raghupathy P, de silva V, Khushiby SM. Permanent neonatal diabetes mellitus. Clinical presentation and epidemiology in Oman. Arch Dis Child Fetal Neonatal Ed 1999; 80: 209-212.
2. Porter JR, Shaw NJ, Barrett TG. Permanent neonatal diabetes in an asian infant. Journal of Pediatr 2005; 146 : 47-49.
3. Massa O, Iafusco D, D'Amato E. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005; 25 : 22-27.
4. Menon PSN, Khatwa UA. Diabetes mellitus in newborns and infants. Indian J Pediatr 2000; 67 : 443-448.
5. Wolcott CD, Rallison ML. Infancy - onset diabetes mellitus and multiple epiphyseal dysplasia J. Pediatr 1972; 80 : 292-297.
6. Abbas BB, Shabib S. Wolcott Rallison syndrome: Clinical, radiological and histological findings in a Saudi child. Annals of Saudi Medicine 2001; 21: 1-2.
7. Brickwood S, Bonthron DT, Gazali-LIAI et al. Wolcott-Rallison syndrome: pathogenic insights in to neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 2003; 40: 685-689.
8. Iyer S, Korada M, Rainbow L et al. Wolcott - Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paeditr 2004; 93: 1195-1201.(Suresh N, Ganesh R, Eswar)