We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset d... more We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset diabetic patients that delivers insulin via the subcutaneous route with a portable pump at constant basal rates with pulse dose increments before meals. Studies in the hospital in 15 diabetic patients for 2–14 days indicated rapid restoration of normal glucose homeostasis. Mean plasma glucose levels on pump therapy averaged 85–90 mg/dl, maximal fluctuations in plasma glucose fell by 50–75%, and glycosuria was eliminated. Minimal plasma glucose values varied between 45 and 67 mg/dl. Cholesterol, triglycerides, and free fatty acids as well as fasting and postprandial branched chain amino acid levels were elevated on conventional treatment but fell to normal after 7 days of pump therapy. Pump treatment also restored to normal increased basal growth hormone levels and excessive exercise-induced rises in growth hormone and catecholamines. Normalization of body fuel metabolism occurred, althoug...
Objective: To describe a case of subcutaneous fat necrosis (SCFN) treated with a single dose of b... more Objective: To describe a case of subcutaneous fat necrosis (SCFN) treated with a single dose of bisphosphonate. Methods: We present the clinical, laboratory, and radiologic findings in an infant with severe hypercalcemia secondary to SCFN and the unique treatment course, as well as a review of relevant literature. Results: A term neonate with history of hypoxic ischemic encephalopathy status post therapeutic cooling was referred for severe hypercalcemia. At 2 weeks of life, he developed pink, indurated confluent plaques on his back and posterior upper arms, consistent with SCFN. Laboratory data showed a calcium level of 17.6 mg/dL and ionized calcium of 8.98 mg/dL. Parathyroid hormone was adequately suppressed at <3 pg/mL. Serum 1,25-dihydroxyvitamin D was elevated at 106 pg/mL and 25-hydroxyvitamin D appropriate at 31 ng/mL. Hypercalcemia persisted at 14.5 mg/dL despite aggressive hydration and furosemide, and the infant developed tachypnea. Pamidronate 0.5 mg/kg was given once and calcium declined to 12.8 mg/dL 12 hours later. The infant was kept on a low calcium diet for a few months with no subsequent hypercalcemia. Conclusion: SCFN is a potentially life-threatening complication due to development of unrecognized hypercalcemia. A single dose of bisphosphonate can be optimal for treatment of hypercalcemia. (AACE Clinical Case Rep. 2017;3:e246-e250) Abbreviations: 1,25-(OH)2D = 1,25-dihydroxyvitamin D; 25-OHD = 25-hydroxyvitamin D; HIE = hypoxic ischemic encephalopathy; PTH = parathyroid hormone; SCFN = subcutaneous fat necrosis
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Dis... more Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Genel and Simpson report serving as expert consultants to the Medical and Scientific Commission of the International Olympic Committee. No other disclosures were reported. Disclaimer: The contents of this article are solely the responsibility of the authors and do not reflect the priorities and policies of the International Olympic Committee or the views of its Medical and Scientific Commission.
mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of ... more mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-_4C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-14C]lysine and [2-14C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation ofthese three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the
Eleven children with documented growth hormone deficiency were studied to assess their cognitive ... more Eleven children with documented growth hormone deficiency were studied to assess their cognitive and emotional functioning and their academic achievement before and after 1 year of human growth hormone replacement therapy. Standardized personality and intelligence measures were used, and records of school achievement, as well as developmental and family history from parents, were obtained. Although some subjects in this group were coping with problems other than their short stature (e.g., other medical and psychosocial problems), their intelligence and academic achievement were found to be positively correlated with socioeconomic status and independent of the condition of hypopituitarism. This study supports others that have found these children vulnerable to problems of emotional adjustment in middle and late childhood. Because of the heterogeneity of the group, findings must be interpreted cautiously. However, the consistent finding of disturbance in visual-motor integration is thought to be significant and demonstrates the need for further research that will examine possible neurological sequelae of long-term growth hormone deficiency.
Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed i... more Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed in poorly controlled, insulin-dependent diabetes. Since the alpha adrenergic system plays an important role in hypothalamic regulation of G H secretion, we tested the hypothesis that altered central adrenergic activity contributes to the increased G H concentrations in diabetes. Clonidine, an a-adrenergic agonist, was administered to nine poorly controlled, young diabetic patients (age 12-19 yr) before and after 1 wk of continuous subcutaneous insulin infusion pump therapy. As expected, continuous subcutaneous insulin infusion lowered mean 24-h plasma glucose (from 203 f 21 to 112 f 7 mg/dl, p < 0.01) and G H (from 17.7 f 2.1 to 9.2 f 1.2 ng/ml, p < 0.01) to values observed in
Recessive and domiAant inheritance of IGHD are associated wit stinct phenotypes. Type I is more c... more Recessive and domiAant inheritance of IGHD are associated wit stinct phenotypes. Type I is more common, autosomal recessive owth hormone (GH) responsive, and insulin sensitive with pica1 facies. Type I1 is autosomal dominant and insulin and resistant. Dominant father-child inheritance of a type I enotype has, however, been suggested in three families, all th very short fathers. Two pairs of brothers, first cousins, presented with IGHD in rly childhood. The mother of one pair (KG height 147 cm) and r brother (RT height 176 em), the father of the others, showed sent or grossly subnormal GH responses to L-Dopa and insulin poglycemia. Pituitary function was otherwise normal. Neither rriage was consanguinous and the spouses of KG and RT were related. All 4 cousins respbnded remarkably well to GH This pedigree is most consistent with dominant inheritance of GHD type I in which variable expressivity is manifest by the ormal stature of RT. The existence of autosomal dominant ransmission of IGHD through individuals of normal stature may ave implications for genetic counselling in familial short
Two teenaged children born of normal parents in a consanguineous family had evidence of abnormal ... more Two teenaged children born of normal parents in a consanguineous family had evidence of abnormal neurological, endocrine, and ectodermal development. They had mental retardation, hearing loss, ocular dysmetria, hyperreflexia, and ataxia consistent with olivopontocerebellar degeneration. They had hypogonadotrophic hypogonadism and extremely short stature despite normal serum growth hormone and somatomedin-C. There was also hypodontia with peg shaped teeth and mid-face hypoplasia. This syndrome of hypoplasia of mid-line structures appeared to be inherited as an autosomal recessive trait. Ectodermal dysplasia is a general term for hereditary disorders which are characterised by abnormal skin, hair, nails, or teeth. A recent review has delineated approximately 55 different syndromes with anomalous development of ectodermal elements.' Olivopontocerebellar degeneration is one of the hereditary spinocerebellar degeneration syndromes with ataxia and tremor, as well as various other motor and sensory deficits.2 3 We have had the opportunity to investigate two children from a consanguineous family who have a unique syndrome characterised by abnormal ectodermal and neurological development as well as short stature and absence of sexual maturation. Case reports The index case was the 3488 g product of an uncomplicated term pregnancy and was delivered by caesarean section for cephalopelvic disproportion. Developmental milestones appeared normal to the parents, but he was referred to a children's hospital at the age of 3 years for failure to thrive. Physical examination revealed a proportionately small child. Laboratory evaluation showed normal serum calcium, phosphate, and protein bound iodine, and *Patients were studied in the Children'
ABSTRA CT Previous studies based on work in the rat and preliminary experiments with human intest... more ABSTRA CT Previous studies based on work in the rat and preliminary experiments with human intestine have suggested that two 8l-galactosidases are present in small intestine, and it is believed that only one of these enzymes is a lactase important for the digestion of dietary lactose. The high prevalence of intestinal lactase deficiency in man prompted more complete study of these enzymes. A portion of this study was presented at the Western Section of the American Federation for Clinical Research, 1 February 1968 and was published as an abstract (Clin. Res. 16: 117).
testicular defect in testosterone secretion has been documented in a pubertal male with a congeni... more testicular defect in testosterone secretion has been documented in a pubertal male with a congenital adrenal hyperplasia due to hereditary deficiency of the A5-isomerase-3fi-hydroxysteroid dehydrogenase enzyme complex (AY-3j-HSD). Diagnosis of the enzymatic defect is based on the clinical picture of ambiguous genitalia and salt-losing crisis in infancy, together with high urinary A5-pregnenetriol and plasma dehydroepiandrosterone when the patient was taken off replacement corticoid treatment. No hormonal response to ACTH or salt deprivation was demonstrable. In addition, in vivo studies revealed a partial enzymatic defect in the testis. Although plasma testosterone was low-normal (250 ng/100 ml), plasma A5-androstenediol was markedly elevated and rose to a greater extent than testosterone after human chorionic gonadotropin administration. In vitro testicular incubation studies suggested a testicular A5-3%-HSD enzyme defect with less A4 products formed from A5 precursors than in a control testis. Histochemical studies of the testis were also consistent with this defect. Testicular biopsy revealed spermato
A 54-year-old woman was referred to hospital because of poor metabolic control. Clinical examinat... more A 54-year-old woman was referred to hospital because of poor metabolic control. Clinical examination revealed marked acanthosis nigricans, and a striking lack of adipose tissue on the limbs, and excess fat deposits on the neck and face. She had been treated for diabetes since 2001 with high doses of insulin along with metformin. Clinical tests showed hypertriglyceridaemia with low high density lipoprotein (HDL) cholesterol, and cholestasis with mild cytolysis. Dunnigan syndrome (familial partial lipodystrophy type 2) was suspected and confirmed by molecular genetics. Pioglitazone was added to her treatment, and follow-up showed improvement of metabolic control 7 months after introducing pioglitazone, and improvement of insulin sensitivity 2 years later. Diabetes related to mutations of the lamin A/C gene is difficult to treat because of severe insulin resistance. Nevertheless, therapy with pioglitazone resulted in marked and sustained improvements in metabolic control and insulin sensitivity.
We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset d... more We have evaluated the efficacy of an insulin infusion system in the treatment of juvenile-onset diabetic patients that delivers insulin via the subcutaneous route with a portable pump at constant basal rates with pulse dose increments before meals. Studies in the hospital in 15 diabetic patients for 2–14 days indicated rapid restoration of normal glucose homeostasis. Mean plasma glucose levels on pump therapy averaged 85–90 mg/dl, maximal fluctuations in plasma glucose fell by 50–75%, and glycosuria was eliminated. Minimal plasma glucose values varied between 45 and 67 mg/dl. Cholesterol, triglycerides, and free fatty acids as well as fasting and postprandial branched chain amino acid levels were elevated on conventional treatment but fell to normal after 7 days of pump therapy. Pump treatment also restored to normal increased basal growth hormone levels and excessive exercise-induced rises in growth hormone and catecholamines. Normalization of body fuel metabolism occurred, althoug...
Objective: To describe a case of subcutaneous fat necrosis (SCFN) treated with a single dose of b... more Objective: To describe a case of subcutaneous fat necrosis (SCFN) treated with a single dose of bisphosphonate. Methods: We present the clinical, laboratory, and radiologic findings in an infant with severe hypercalcemia secondary to SCFN and the unique treatment course, as well as a review of relevant literature. Results: A term neonate with history of hypoxic ischemic encephalopathy status post therapeutic cooling was referred for severe hypercalcemia. At 2 weeks of life, he developed pink, indurated confluent plaques on his back and posterior upper arms, consistent with SCFN. Laboratory data showed a calcium level of 17.6 mg/dL and ionized calcium of 8.98 mg/dL. Parathyroid hormone was adequately suppressed at <3 pg/mL. Serum 1,25-dihydroxyvitamin D was elevated at 106 pg/mL and 25-hydroxyvitamin D appropriate at 31 ng/mL. Hypercalcemia persisted at 14.5 mg/dL despite aggressive hydration and furosemide, and the infant developed tachypnea. Pamidronate 0.5 mg/kg was given once and calcium declined to 12.8 mg/dL 12 hours later. The infant was kept on a low calcium diet for a few months with no subsequent hypercalcemia. Conclusion: SCFN is a potentially life-threatening complication due to development of unrecognized hypercalcemia. A single dose of bisphosphonate can be optimal for treatment of hypercalcemia. (AACE Clinical Case Rep. 2017;3:e246-e250) Abbreviations: 1,25-(OH)2D = 1,25-dihydroxyvitamin D; 25-OHD = 25-hydroxyvitamin D; HIE = hypoxic ischemic encephalopathy; PTH = parathyroid hormone; SCFN = subcutaneous fat necrosis
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Dis... more Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Genel and Simpson report serving as expert consultants to the Medical and Scientific Commission of the International Olympic Committee. No other disclosures were reported. Disclaimer: The contents of this article are solely the responsibility of the authors and do not reflect the priorities and policies of the International Olympic Committee or the views of its Medical and Scientific Commission.
mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of ... more mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-_4C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-14C]lysine and [2-14C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation ofthese three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the
Eleven children with documented growth hormone deficiency were studied to assess their cognitive ... more Eleven children with documented growth hormone deficiency were studied to assess their cognitive and emotional functioning and their academic achievement before and after 1 year of human growth hormone replacement therapy. Standardized personality and intelligence measures were used, and records of school achievement, as well as developmental and family history from parents, were obtained. Although some subjects in this group were coping with problems other than their short stature (e.g., other medical and psychosocial problems), their intelligence and academic achievement were found to be positively correlated with socioeconomic status and independent of the condition of hypopituitarism. This study supports others that have found these children vulnerable to problems of emotional adjustment in middle and late childhood. Because of the heterogeneity of the group, findings must be interpreted cautiously. However, the consistent finding of disturbance in visual-motor integration is thought to be significant and demonstrates the need for further research that will examine possible neurological sequelae of long-term growth hormone deficiency.
Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed i... more Elevated plasma growth hormone (GH) and peripheral catecholamine levels are frequently observed in poorly controlled, insulin-dependent diabetes. Since the alpha adrenergic system plays an important role in hypothalamic regulation of G H secretion, we tested the hypothesis that altered central adrenergic activity contributes to the increased G H concentrations in diabetes. Clonidine, an a-adrenergic agonist, was administered to nine poorly controlled, young diabetic patients (age 12-19 yr) before and after 1 wk of continuous subcutaneous insulin infusion pump therapy. As expected, continuous subcutaneous insulin infusion lowered mean 24-h plasma glucose (from 203 f 21 to 112 f 7 mg/dl, p < 0.01) and G H (from 17.7 f 2.1 to 9.2 f 1.2 ng/ml, p < 0.01) to values observed in
Recessive and domiAant inheritance of IGHD are associated wit stinct phenotypes. Type I is more c... more Recessive and domiAant inheritance of IGHD are associated wit stinct phenotypes. Type I is more common, autosomal recessive owth hormone (GH) responsive, and insulin sensitive with pica1 facies. Type I1 is autosomal dominant and insulin and resistant. Dominant father-child inheritance of a type I enotype has, however, been suggested in three families, all th very short fathers. Two pairs of brothers, first cousins, presented with IGHD in rly childhood. The mother of one pair (KG height 147 cm) and r brother (RT height 176 em), the father of the others, showed sent or grossly subnormal GH responses to L-Dopa and insulin poglycemia. Pituitary function was otherwise normal. Neither rriage was consanguinous and the spouses of KG and RT were related. All 4 cousins respbnded remarkably well to GH This pedigree is most consistent with dominant inheritance of GHD type I in which variable expressivity is manifest by the ormal stature of RT. The existence of autosomal dominant ransmission of IGHD through individuals of normal stature may ave implications for genetic counselling in familial short
Two teenaged children born of normal parents in a consanguineous family had evidence of abnormal ... more Two teenaged children born of normal parents in a consanguineous family had evidence of abnormal neurological, endocrine, and ectodermal development. They had mental retardation, hearing loss, ocular dysmetria, hyperreflexia, and ataxia consistent with olivopontocerebellar degeneration. They had hypogonadotrophic hypogonadism and extremely short stature despite normal serum growth hormone and somatomedin-C. There was also hypodontia with peg shaped teeth and mid-face hypoplasia. This syndrome of hypoplasia of mid-line structures appeared to be inherited as an autosomal recessive trait. Ectodermal dysplasia is a general term for hereditary disorders which are characterised by abnormal skin, hair, nails, or teeth. A recent review has delineated approximately 55 different syndromes with anomalous development of ectodermal elements.' Olivopontocerebellar degeneration is one of the hereditary spinocerebellar degeneration syndromes with ataxia and tremor, as well as various other motor and sensory deficits.2 3 We have had the opportunity to investigate two children from a consanguineous family who have a unique syndrome characterised by abnormal ectodermal and neurological development as well as short stature and absence of sexual maturation. Case reports The index case was the 3488 g product of an uncomplicated term pregnancy and was delivered by caesarean section for cephalopelvic disproportion. Developmental milestones appeared normal to the parents, but he was referred to a children's hospital at the age of 3 years for failure to thrive. Physical examination revealed a proportionately small child. Laboratory evaluation showed normal serum calcium, phosphate, and protein bound iodine, and *Patients were studied in the Children'
ABSTRA CT Previous studies based on work in the rat and preliminary experiments with human intest... more ABSTRA CT Previous studies based on work in the rat and preliminary experiments with human intestine have suggested that two 8l-galactosidases are present in small intestine, and it is believed that only one of these enzymes is a lactase important for the digestion of dietary lactose. The high prevalence of intestinal lactase deficiency in man prompted more complete study of these enzymes. A portion of this study was presented at the Western Section of the American Federation for Clinical Research, 1 February 1968 and was published as an abstract (Clin. Res. 16: 117).
testicular defect in testosterone secretion has been documented in a pubertal male with a congeni... more testicular defect in testosterone secretion has been documented in a pubertal male with a congenital adrenal hyperplasia due to hereditary deficiency of the A5-isomerase-3fi-hydroxysteroid dehydrogenase enzyme complex (AY-3j-HSD). Diagnosis of the enzymatic defect is based on the clinical picture of ambiguous genitalia and salt-losing crisis in infancy, together with high urinary A5-pregnenetriol and plasma dehydroepiandrosterone when the patient was taken off replacement corticoid treatment. No hormonal response to ACTH or salt deprivation was demonstrable. In addition, in vivo studies revealed a partial enzymatic defect in the testis. Although plasma testosterone was low-normal (250 ng/100 ml), plasma A5-androstenediol was markedly elevated and rose to a greater extent than testosterone after human chorionic gonadotropin administration. In vitro testicular incubation studies suggested a testicular A5-3%-HSD enzyme defect with less A4 products formed from A5 precursors than in a control testis. Histochemical studies of the testis were also consistent with this defect. Testicular biopsy revealed spermato
A 54-year-old woman was referred to hospital because of poor metabolic control. Clinical examinat... more A 54-year-old woman was referred to hospital because of poor metabolic control. Clinical examination revealed marked acanthosis nigricans, and a striking lack of adipose tissue on the limbs, and excess fat deposits on the neck and face. She had been treated for diabetes since 2001 with high doses of insulin along with metformin. Clinical tests showed hypertriglyceridaemia with low high density lipoprotein (HDL) cholesterol, and cholestasis with mild cytolysis. Dunnigan syndrome (familial partial lipodystrophy type 2) was suspected and confirmed by molecular genetics. Pioglitazone was added to her treatment, and follow-up showed improvement of metabolic control 7 months after introducing pioglitazone, and improvement of insulin sensitivity 2 years later. Diabetes related to mutations of the lamin A/C gene is difficult to treat because of severe insulin resistance. Nevertheless, therapy with pioglitazone resulted in marked and sustained improvements in metabolic control and insulin sensitivity.
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