- Email: [email protected]
Early onset of severe diabetes mellitus-related microvascular complications
EARLY ONSET OF SEVERE DIABETES MELLITUS-RELATED MICROVASCULAR COMPLICATIONS JILL HAMILTON, MD, FRCPC, MIJIN BROWN, MD, FRCPC, ROBERT SILVER, MD, FRCPC, AND DENIS DANEMAN, MB BCH, FRCPC
A 16-year-old girl with type 1 diabetes developed painful peripheral neuropathy within 1 month and proliferative retinopathy within 1 year despite excellent glycemic control. We speculate on potential mechanisms that may have contributed to the rapid development of diabetes mellitus-related complications. (J Pediatr 2004;144:281-3)
he morbidity and mortality of type 1 diabetes mellitus (T1DM) are closely associated with the development of long-term microvascular and macrovascular complications.1 Factors known to be associated with complication onset, progression, or both include disease duration, poor glycemic control, hypertension, and smoking.2 There are very few reports of young children or teenagers with T1DM of short duration with accelerated development of microvascular complications.3,4 We report an adolescent who developed symptoms of painful neuropathy immediately before and proliferative retinopathy soon after the diagnosis of diabetes, despite excellent glycemic control.
T
CASE REPORT A 16-year-old girl presented with a 2-week history of fatigue and a 3-year history of intermittent nocturia, polyuria, and polydipsia, but no weight loss. A maternal great uncle had died at 21 years of age with diabetes-related complications. At presentation, her weight was 48 kg (10th centile), and her height was 163 cm (50th centile). Indirect ophthalmoscopy by a pediatric endocrinologist revealed normal fundi. Neurological examination was normal. She was in midpuberty. She had glycosuria, ketonuria, a blood glucose concentration of 33.3 mmol/L, and hemoglobin A1c (HbA1c) of 14.1% (nondiabetic range, 4.0%-6.0%). She started on a twice-daily insulin regimen of split/mixed human neutral protamine Hagedorn and regular insulin before breakfast and supper. One month later, she was readmitted after a history of unrelenting, severe bilateral leg pain. On questioning, a mild burning pain in the feet had been present intermittently for 2 months before diagnosis; however, the symptoms had increased significantly since diagnosis of diabetes and were worse at night with extension from feet to knees. Examination revealed tenderness and increased sensitivity to touch in the anteromedial aspect of her legs. The knee reflexes were sluggish and ankle reflexes absent. Sensory examination revealed bilateral stocking hypesthesia to pinprick and temperature extending to midthigh. Vibration sense was moderately impaired below the knee, and position sense was normal. Gait, motor power, tone, and coordination were normal. There was no From the Division of Endocrinology, Departments of Pediatrics and Mediswelling or erythema. Her blood glucose control was excellent, and her HbA1c had cine, the Hospital for Sick Children and decreased to 7.0%. University Health Network, University of Toronto, Toronto, Ontario, Nerve conduction and electromyography studies were consistent with significant Canada. peripheral sensorimotor neuropathy. Although other causes of peripheral neuropathy Submitted for publication Apr 11, (heavy metal poisoning, sarcoidosis, leprosy, periarteritis nodosa, lupus, and so forth) were 2003; revision received Sept 11, 2003; accepted Oct 28, 2003. not excluded, the resolution of many of the symptoms in response to amitriptyline Reprint requests: Dr Jill Hamilton, suggested that hyperglycemia was the offending agent. She continued to have sluggish Division of Endocrinology, Hospital reflexes and mild sensory loss with persistent abnormal nerve conduction studies. for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. One year after diagnosis, she complained of blurred vision. Dilated funduscopic E-mail: [email protected]. examination by an ophthalmologist revealed proliferative diabetic retinopathy of the right
0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved.
HbA1c
Hemoglobin A1c
T1DM
Type 1 diabetes mellitus
10.1016/j.jpeds.2003.10.060
281
eye with flame and blot hemorrhages, and neovascularization of the disc. Her left eye showed preproliferative retinopathy. She underwent panretinal photocoagulation of her right eye. Six months later, her left eye progressed to proliferative retinopathy with neovascularization, for which she received photocoagulation. She was treated with twice-daily insulin injections and maintained near normoglycemia (HbA1c 4.9%-5.9%) in the 18 months after diagnosis. Other investigations revealed positive islet cell antibodies and negative HLA DR3 and DR4. Albumin excretion rate was normal during the first 2 years after diagnosis. Thyroid hormone, cholesterol, and triglyceride levels have been normal throughout her course. She is currently 25 years old and has been followed by an adult endocrinologist for the past 7 years. Glycemic control remains good (HbA1c 6.1%-8.5%) on twice-daily insulin injections. The retinopathy in both eyes has remained stable. Screening for nephropathy demonstrates intermittent microalbuminuria. She has had no further symptoms of peripheral neuropathy. She remains normotensive.
DISCUSSION Severe diabetes-related complications have been reported very rarely in children in the first few years after diagnosis.3,4 Symptomatic peripheral neuropathy is exceptionally rare in children and teens with T1DM.5 Subclinical neuropathy has been described by using neurophysiological criteria and is associated with longer duration of disease and poor diabetes control.5,6 Less commonly, transient painful neuropathy has occurred after a large (14.1% to 7%) reduction of the HbA1c, as in our subject. There are reports of a 32-yearold man with newly diagnosed T1DM and an 18-year-old woman with poorly controlled T1DM of 8-year duration, both of whom had severe peripheral neuropathy after rapid improvement of hyperglycemia with insulin therapy.7,8 In both, as in our patient, the neuropathy lasted several months, with resolution of symptoms despite persistently abnormal nerve conduction studies. Diabetic papillopathy is a benign transient optic disc edema with massively dilated optic vessels and small hemorrhages that spontaneously resolve.9 This condition may present with complaints of blurred vision soon after diagnosis and may mimic diabetic retinopathy; however, the pathology in our patient continued to progress until panretinal photocoagulation was required. Deterioration of retinopathy has also been described with rapid tightening of blood glucose concentrations after long-standing poor control, but this is the first report in which the retinopathy has progressed to require panretinal photocoagulation.10-12 Hyperglycemia has been implicated in the pathogenesis of microvascular complications, but the mechanisms are complex and likely multifactorial. Contributing factors may include advanced glycosylation end product formation, oxidative stress, and increased sorbitol, diacylglycerol, and protein kinase C levels, which in turn influence levels of various growth factors.13 Not all patients with poorly controlled dia282
Hamilton et al
betes of long duration develop diabetes-related complications, nor does meticulous control prevent the occurrence of complications in everyone. Long duration of exposure to hyperglycemia before the actual diagnosis of T1DM may be a potential contributing factor. This has been reported in T1DM and in subjects with very poorly controlled T1DM of long duration who undergo rapid achievement of normoglycemia.5,10,11,14 Alterations in regional blood flow to neurons and retinal tissue in response to a rapid decline in glucose may also precipitate local tissue hypoxia with resultant damage and earlier complications.15 This may explain our patient’s rapid development of neuropathy and retinopathy. Finally, an undefined genetic predisposition may lead to increased individual risk of early onset of complications. The family history of an uncle with very early mortality from complications of diabetes suggests that this may be important in our patient. Current screening practices reflect the known associations of diabetes-related complications with increasing age and duration of disease. Guidelines recommend screening for retinopathy after age 15 years and 5-year diabetes duration and for nephropathy after puberty and 3-year to 5-year duration, and do not recommend screening for neuropathy during childhood.2 Although our case is clearly exceptional, it does highlight the need for clinical vigilance even early in the course of T1DM and particularly in those with a long prodrome of hyperglycemic symptoms or complaints of visual disturbances.
REFERENCES 1. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86. 2. Sochett E, Daneman D. Early diabetes-related complications in children and adolescents with type 1 diabetes: implications for screening and intervention. Endocrinol Metab Clin North Am 1999;28:865-82. 3. Carroll PB, Herskowitz RD, Goodman AD, Busch RS, Beaser RS. Rapid onset of severe retinopathy, cataracts and neuropathy in young patients with diabetes mellitus. Acta Paediatr 1992;81:355-8. 4. Francis J, Rose SJ, Raafat F, Milford DV. Early onset of diabetic nephropathy. Arch Dis Child 1997;77:524-5. 5. Gamstorp I SS, Engleson G, Redondo D, Traisman HS. Peripheral neuropathy in juvenile diabetes. Diabetes 1966;15:411-8. 6. Kaar ML, Saukkonen AL, Pitkanen M, Akerblom HK. Peripheral neuropathy in diabetic children and adolescents: a cross-sectional study. Acta Paediatr Scand 1983;72:373-8. 7. Dandona P FV, Thomas PK, Llewellyn G, Bolger JP. Painful diabetic neuropathy. Lancet 1985;1:697. 8. Yuen KC, Day JL, Flannagan DW, Rayman G. Diabetic neuropathic cachexia and acute bilateral cataract formation following rapid glycaemic control in a newly diagnosed type 1 diabetic patient. Diabet Med 2001; 18:854-7. 9. Regillo CD, Brown GC, Savino PJ, Byrnes GA, Benson WE, Tasman WS, et al. Diabetic papillopathy: patient characteristics and fundus findings. Arch Ophthalmol 1995;113:889-95. 10. Daneman D, Drash AL, Lobes LA, Becker DJ, Baker LM, Travis LB. Progressive retinopathy with improved control in diabetic dwarfism (Mauriac’s syndrome). Diabetes Care 1981;4:360-5.
The Journal of Pediatrics February 2004
11. Agardh CD, Eckert B, Agardh E. Irreversible progression of severe retinopathy in young type I insulin-dependent diabetes mellitus patients after improved metabolic control. J Diabetes Complications 1992;6:96-100. 12. DCCT Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116:874-86. 13. Clark CM Jr, Lee DA. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 1995;332:1210-7.
14. Lehtinen JM, Uusitupa M, Siitonen O, Pyorala K. Prevalence of neuropathy in newly diagnosed NIDDM and nondiabetic control subjects. Diabetes 1989;38:1307-13. 15. Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, et al. Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia 1996;39:329-35.
50 Years Ago in The Journal of Pediatrics MEDICAL GENETICS IN PEDIATRICS Fraser FC. J Pediatr 1954;44:85-99 ‘‘The great contributions that genetics is making toward our understanding of biological processes in the lower organisms have not been matched by contributions in the medical field. . .Perhaps the most valuable contribution of genetics to medicine is the clarification of the human blood group systems with its applications to the problems of forensic medicine, transfusion and hemolytic disease of the newborn. . .But medical genetics is still in such an early stage of its development that its most important contribution to clinical medicine for some years to come will be the definition of specific disease entities and the provision of reliable data as to their familial distributions.’’ So begins the prophetic paragraph written by a person who in the subsequent 50 years has himself had a tremendous influence on the practice of medical genetics today. In just 15 pages, Dr Fraser reviewed the basic patterns of Mendelian inheritance, emphasized the documentation a formal family history, and encouraged pediatricians to ask about diseases in the family that were relevant to the child’s complaints. He reminded readers about how parental consanguinity leads to autosomal recessive disorders. He next discussed the principles and issues addressed in genetic counseling with a couple that had a child affected with a genetic disorder. ‘‘What is the statistical risk of a subsequent child being affected?. . .How serious is the defect?. . .What will be the effects on future generation?. . .What is the attitude of the parents toward their heredity?’’ He concluded with an extensive glossary of genetic terms and conditions some of which such as ‘‘drepanocythemia’’ ‘‘osteopsathyrosis’’ we know today, respectively, as sickle cell disease and osteogenesis imperfecta. Would it be possible in 2004 to write a 15-page article that summarized the influence that medical genetics now has on the practice of pediatrics? How many pages would be needed to describe the molecular, cytogenetic, and biochemical techniques that are widely available to diagnose, predict, and treat genetic disorders? How much print would be necessary to summarize how understanding of the human genome has led to uncovering the basic pathophysiology of so many disorders, and the ethical and legal implications of this knowledge? Which of the nearly 15,000 disorders that are cataloged in the Online Mendelian Inheritance in Man (OMIM) would be included in this review? How much space would be needed to discuss the failures and successes of gene and enzyme replacement therapy? Finally, could any single author accomplish this in 15 pages? Probably not. Paul M. Fernhoff, MD, FAAP, FACMG Division of Medical Genetics-Department of Human Genetics Emory University School of Medicine Atlanta, GA 30322 YMPD583 10.1016/j.jpeds.2003.10.029
Early Onset of Severe Diabetes Mellitus-Related Microvascular Complications
283
A 16-year-old girl with type 1 diabetes developed painful peripheral neuropathy within 1 month and proliferative retinopathy within 1 year despite excellent glycemic control. We speculate on potential mechanisms that may have contributed to the rapid development of diabetes mellitus-related complications. (J Pediatr 2004;144:281-3)
he morbidity and mortality of type 1 diabetes mellitus (T1DM) are closely associated with the development of long-term microvascular and macrovascular complications.1 Factors known to be associated with complication onset, progression, or both include disease duration, poor glycemic control, hypertension, and smoking.2 There are very few reports of young children or teenagers with T1DM of short duration with accelerated development of microvascular complications.3,4 We report an adolescent who developed symptoms of painful neuropathy immediately before and proliferative retinopathy soon after the diagnosis of diabetes, despite excellent glycemic control.
T
CASE REPORT A 16-year-old girl presented with a 2-week history of fatigue and a 3-year history of intermittent nocturia, polyuria, and polydipsia, but no weight loss. A maternal great uncle had died at 21 years of age with diabetes-related complications. At presentation, her weight was 48 kg (10th centile), and her height was 163 cm (50th centile). Indirect ophthalmoscopy by a pediatric endocrinologist revealed normal fundi. Neurological examination was normal. She was in midpuberty. She had glycosuria, ketonuria, a blood glucose concentration of 33.3 mmol/L, and hemoglobin A1c (HbA1c) of 14.1% (nondiabetic range, 4.0%-6.0%). She started on a twice-daily insulin regimen of split/mixed human neutral protamine Hagedorn and regular insulin before breakfast and supper. One month later, she was readmitted after a history of unrelenting, severe bilateral leg pain. On questioning, a mild burning pain in the feet had been present intermittently for 2 months before diagnosis; however, the symptoms had increased significantly since diagnosis of diabetes and were worse at night with extension from feet to knees. Examination revealed tenderness and increased sensitivity to touch in the anteromedial aspect of her legs. The knee reflexes were sluggish and ankle reflexes absent. Sensory examination revealed bilateral stocking hypesthesia to pinprick and temperature extending to midthigh. Vibration sense was moderately impaired below the knee, and position sense was normal. Gait, motor power, tone, and coordination were normal. There was no From the Division of Endocrinology, Departments of Pediatrics and Mediswelling or erythema. Her blood glucose control was excellent, and her HbA1c had cine, the Hospital for Sick Children and decreased to 7.0%. University Health Network, University of Toronto, Toronto, Ontario, Nerve conduction and electromyography studies were consistent with significant Canada. peripheral sensorimotor neuropathy. Although other causes of peripheral neuropathy Submitted for publication Apr 11, (heavy metal poisoning, sarcoidosis, leprosy, periarteritis nodosa, lupus, and so forth) were 2003; revision received Sept 11, 2003; accepted Oct 28, 2003. not excluded, the resolution of many of the symptoms in response to amitriptyline Reprint requests: Dr Jill Hamilton, suggested that hyperglycemia was the offending agent. She continued to have sluggish Division of Endocrinology, Hospital reflexes and mild sensory loss with persistent abnormal nerve conduction studies. for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. One year after diagnosis, she complained of blurred vision. Dilated funduscopic E-mail: [email protected]. examination by an ophthalmologist revealed proliferative diabetic retinopathy of the right
0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved.
HbA1c
Hemoglobin A1c
T1DM
Type 1 diabetes mellitus
10.1016/j.jpeds.2003.10.060
281
eye with flame and blot hemorrhages, and neovascularization of the disc. Her left eye showed preproliferative retinopathy. She underwent panretinal photocoagulation of her right eye. Six months later, her left eye progressed to proliferative retinopathy with neovascularization, for which she received photocoagulation. She was treated with twice-daily insulin injections and maintained near normoglycemia (HbA1c 4.9%-5.9%) in the 18 months after diagnosis. Other investigations revealed positive islet cell antibodies and negative HLA DR3 and DR4. Albumin excretion rate was normal during the first 2 years after diagnosis. Thyroid hormone, cholesterol, and triglyceride levels have been normal throughout her course. She is currently 25 years old and has been followed by an adult endocrinologist for the past 7 years. Glycemic control remains good (HbA1c 6.1%-8.5%) on twice-daily insulin injections. The retinopathy in both eyes has remained stable. Screening for nephropathy demonstrates intermittent microalbuminuria. She has had no further symptoms of peripheral neuropathy. She remains normotensive.
DISCUSSION Severe diabetes-related complications have been reported very rarely in children in the first few years after diagnosis.3,4 Symptomatic peripheral neuropathy is exceptionally rare in children and teens with T1DM.5 Subclinical neuropathy has been described by using neurophysiological criteria and is associated with longer duration of disease and poor diabetes control.5,6 Less commonly, transient painful neuropathy has occurred after a large (14.1% to 7%) reduction of the HbA1c, as in our subject. There are reports of a 32-yearold man with newly diagnosed T1DM and an 18-year-old woman with poorly controlled T1DM of 8-year duration, both of whom had severe peripheral neuropathy after rapid improvement of hyperglycemia with insulin therapy.7,8 In both, as in our patient, the neuropathy lasted several months, with resolution of symptoms despite persistently abnormal nerve conduction studies. Diabetic papillopathy is a benign transient optic disc edema with massively dilated optic vessels and small hemorrhages that spontaneously resolve.9 This condition may present with complaints of blurred vision soon after diagnosis and may mimic diabetic retinopathy; however, the pathology in our patient continued to progress until panretinal photocoagulation was required. Deterioration of retinopathy has also been described with rapid tightening of blood glucose concentrations after long-standing poor control, but this is the first report in which the retinopathy has progressed to require panretinal photocoagulation.10-12 Hyperglycemia has been implicated in the pathogenesis of microvascular complications, but the mechanisms are complex and likely multifactorial. Contributing factors may include advanced glycosylation end product formation, oxidative stress, and increased sorbitol, diacylglycerol, and protein kinase C levels, which in turn influence levels of various growth factors.13 Not all patients with poorly controlled dia282
Hamilton et al
betes of long duration develop diabetes-related complications, nor does meticulous control prevent the occurrence of complications in everyone. Long duration of exposure to hyperglycemia before the actual diagnosis of T1DM may be a potential contributing factor. This has been reported in T1DM and in subjects with very poorly controlled T1DM of long duration who undergo rapid achievement of normoglycemia.5,10,11,14 Alterations in regional blood flow to neurons and retinal tissue in response to a rapid decline in glucose may also precipitate local tissue hypoxia with resultant damage and earlier complications.15 This may explain our patient’s rapid development of neuropathy and retinopathy. Finally, an undefined genetic predisposition may lead to increased individual risk of early onset of complications. The family history of an uncle with very early mortality from complications of diabetes suggests that this may be important in our patient. Current screening practices reflect the known associations of diabetes-related complications with increasing age and duration of disease. Guidelines recommend screening for retinopathy after age 15 years and 5-year diabetes duration and for nephropathy after puberty and 3-year to 5-year duration, and do not recommend screening for neuropathy during childhood.2 Although our case is clearly exceptional, it does highlight the need for clinical vigilance even early in the course of T1DM and particularly in those with a long prodrome of hyperglycemic symptoms or complaints of visual disturbances.
REFERENCES 1. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86. 2. Sochett E, Daneman D. Early diabetes-related complications in children and adolescents with type 1 diabetes: implications for screening and intervention. Endocrinol Metab Clin North Am 1999;28:865-82. 3. Carroll PB, Herskowitz RD, Goodman AD, Busch RS, Beaser RS. Rapid onset of severe retinopathy, cataracts and neuropathy in young patients with diabetes mellitus. Acta Paediatr 1992;81:355-8. 4. Francis J, Rose SJ, Raafat F, Milford DV. Early onset of diabetic nephropathy. Arch Dis Child 1997;77:524-5. 5. Gamstorp I SS, Engleson G, Redondo D, Traisman HS. Peripheral neuropathy in juvenile diabetes. Diabetes 1966;15:411-8. 6. Kaar ML, Saukkonen AL, Pitkanen M, Akerblom HK. Peripheral neuropathy in diabetic children and adolescents: a cross-sectional study. Acta Paediatr Scand 1983;72:373-8. 7. Dandona P FV, Thomas PK, Llewellyn G, Bolger JP. Painful diabetic neuropathy. Lancet 1985;1:697. 8. Yuen KC, Day JL, Flannagan DW, Rayman G. Diabetic neuropathic cachexia and acute bilateral cataract formation following rapid glycaemic control in a newly diagnosed type 1 diabetic patient. Diabet Med 2001; 18:854-7. 9. Regillo CD, Brown GC, Savino PJ, Byrnes GA, Benson WE, Tasman WS, et al. Diabetic papillopathy: patient characteristics and fundus findings. Arch Ophthalmol 1995;113:889-95. 10. Daneman D, Drash AL, Lobes LA, Becker DJ, Baker LM, Travis LB. Progressive retinopathy with improved control in diabetic dwarfism (Mauriac’s syndrome). Diabetes Care 1981;4:360-5.
The Journal of Pediatrics February 2004
11. Agardh CD, Eckert B, Agardh E. Irreversible progression of severe retinopathy in young type I insulin-dependent diabetes mellitus patients after improved metabolic control. J Diabetes Complications 1992;6:96-100. 12. DCCT Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116:874-86. 13. Clark CM Jr, Lee DA. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 1995;332:1210-7.
14. Lehtinen JM, Uusitupa M, Siitonen O, Pyorala K. Prevalence of neuropathy in newly diagnosed NIDDM and nondiabetic control subjects. Diabetes 1989;38:1307-13. 15. Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, et al. Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia 1996;39:329-35.
50 Years Ago in The Journal of Pediatrics MEDICAL GENETICS IN PEDIATRICS Fraser FC. J Pediatr 1954;44:85-99 ‘‘The great contributions that genetics is making toward our understanding of biological processes in the lower organisms have not been matched by contributions in the medical field. . .Perhaps the most valuable contribution of genetics to medicine is the clarification of the human blood group systems with its applications to the problems of forensic medicine, transfusion and hemolytic disease of the newborn. . .But medical genetics is still in such an early stage of its development that its most important contribution to clinical medicine for some years to come will be the definition of specific disease entities and the provision of reliable data as to their familial distributions.’’ So begins the prophetic paragraph written by a person who in the subsequent 50 years has himself had a tremendous influence on the practice of medical genetics today. In just 15 pages, Dr Fraser reviewed the basic patterns of Mendelian inheritance, emphasized the documentation a formal family history, and encouraged pediatricians to ask about diseases in the family that were relevant to the child’s complaints. He reminded readers about how parental consanguinity leads to autosomal recessive disorders. He next discussed the principles and issues addressed in genetic counseling with a couple that had a child affected with a genetic disorder. ‘‘What is the statistical risk of a subsequent child being affected?. . .How serious is the defect?. . .What will be the effects on future generation?. . .What is the attitude of the parents toward their heredity?’’ He concluded with an extensive glossary of genetic terms and conditions some of which such as ‘‘drepanocythemia’’ ‘‘osteopsathyrosis’’ we know today, respectively, as sickle cell disease and osteogenesis imperfecta. Would it be possible in 2004 to write a 15-page article that summarized the influence that medical genetics now has on the practice of pediatrics? How many pages would be needed to describe the molecular, cytogenetic, and biochemical techniques that are widely available to diagnose, predict, and treat genetic disorders? How much print would be necessary to summarize how understanding of the human genome has led to uncovering the basic pathophysiology of so many disorders, and the ethical and legal implications of this knowledge? Which of the nearly 15,000 disorders that are cataloged in the Online Mendelian Inheritance in Man (OMIM) would be included in this review? How much space would be needed to discuss the failures and successes of gene and enzyme replacement therapy? Finally, could any single author accomplish this in 15 pages? Probably not. Paul M. Fernhoff, MD, FAAP, FACMG Division of Medical Genetics-Department of Human Genetics Emory University School of Medicine Atlanta, GA 30322 YMPD583 10.1016/j.jpeds.2003.10.029
Early Onset of Severe Diabetes Mellitus-Related Microvascular Complications
283