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1.
Nat Commun ; 9(1): 2105, 2018 05 29.
Article in English | MEDLINE | ID: mdl-29844444

ABSTRACT

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.


Subject(s)
Genetic Predisposition to Disease/genetics , Germ-Line Mutation/genetics , Human Growth Hormone/metabolism , Laron Syndrome/genetics , STAT5 Transcription Factor/genetics , Adolescent , Cell Line , Child , Eczema/genetics , Female , HEK293 Cells , Humans , Immunoglobulin E/blood , Infant , Insulin-Like Growth Factor I/biosynthesis , Male , Mutation, Missense/genetics , Response Elements/genetics
2.
J Pediatr ; 155(2): 183-9.e1, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19394043

ABSTRACT

OBJECTIVES: To describe the insulin regimens used to treat type 1 diabetes mellitus (T1DM) in youth in the United States, to explore factors related to insulin regimen, and to describe the associations between insulin regimen and clinical outcomes, particularly glycemic control. STUDY DESIGN: A total of 2743 subjects participated in the SEARCH for Diabetes in Youth study, an observational population-based study of youth diagnosed with T1DM, conducted at 6 centers. Data collected during a study visit included clinical and sociodemographic information, body mass index, laboratory measures, and insulin regimen. RESULTS: Sociodemographic characteristics were associated with insulin regimen. Insulin pump therapy was more frequently used by older youth, females, non-Hispanic whites, and families with higher income and education (P = .02 for females, P < .001 for others). Insulin pump use was associated with the lowest hemoglobin A1C levels in all age groups. A1C levels were >7.5% in >70% of adolescents, regardless of regimen. CONCLUSIONS: Youth using insulin pumps had the lowest A1C; A1C was unacceptably high in adolescents. There is a need to more fully assess and understand factors associated with insulin regimens recommended by providers and the influence of race/ethnicity, education, and socioeconomic status on these treatment recommendations and to develop more effective treatment strategies, particularly for adolescents.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/epidemiology , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Adolescent , Age Factors , Blood Glucose Self-Monitoring/statistics & numerical data , Child , Educational Status , Female , Glycated Hemoglobin/analysis , Hospitalization/statistics & numerical data , Humans , Income , Infusion Pumps, Implantable , Injections , Male , Sex Factors , United States/epidemiology , White People
3.
J Clin Endocrinol Metab ; 94(5): 1740-7, 2009 May.
Article in English | MEDLINE | ID: mdl-19240156

ABSTRACT

BACKGROUND: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R), a widely expressed, cell surface tyrosine kinase receptor. Five cases of heterozygous mutations in the IGF1R gene have been identified in patients with varying degrees of intrauterine and postnatal growth retardation. OBJECTIVE: The objective of the study was the analysis of the IGF1R gene in a short-statured patient and his affected family members. PATIENT: The male patient, with a height of -3.1 sd score (SDS; aged 12 yr), had normal circulating levels of GH binding protein, IGF-I, and IGF binding protein-3. His mother (-4.6 SDS), one of his siblings (-1.94 SDS), and several other maternal family members were also short statured. RESULTS: The patient, his mother, and the short-statured sibling carry a novel heterozygous 19-nucleotide duplication within exon 18 of the IGF1R gene, which introduces a premature termination codon at codon 1106 of the IGF1R open reading frame on one allele. Analyses of the primary dermal fibroblasts derived from the patient and family members indicated that the IGF1R mRNA expressed from the mutant allele was degraded through the nonsense-mediated mRNA decay pathway, resulting in reduced amount of wild-type IGF1R protein and, subsequently, diminished activation of the IGF1R pathway. CONCLUSIONS: The mutation results in haploinsufficiency of IGF1R protein due to nonsense-mediated mRNA decay and is associated with familial short stature.


Subject(s)
Body Height/genetics , Codon, Nonsense/genetics , RNA, Messenger/genetics , Receptor, IGF Type 1/genetics , Alleles , Base Sequence , Blotting, Western , Carrier Proteins/blood , Carrier Proteins/genetics , Cells, Cultured , Child , Codon, Nonsense/physiology , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Exons/genetics , Fetal Growth Retardation/genetics , Fibroblasts/metabolism , Growth Disorders/genetics , Haplotypes , Heterozygote , Humans , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 3/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Receptor, IGF Type 1/physiology , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics
4.
Pediatrics ; 121(5): e1258-66, 2008 May.
Article in English | MEDLINE | ID: mdl-18450868

ABSTRACT

OBJECTIVE: The purpose of this work was to determine the prevalence and predictors of diabetic ketoacidosis at the diagnosis of diabetes in a large sample of youth from the US population. PATIENTS AND METHODS: The Search for Diabetes in Youth Study, a multicenter, population-based registry of diabetes with diagnosis before 20 years of age, identified 3666 patients with new onset of diabetes in the study areas in 2002-2004. Medical charts were reviewed in 2824 (77%) of the patients in a standard manner to abstract the results of laboratory tests and to ascertain diabetic ketoacidosis at the time of diagnosis. Diabetic ketoacidosis was defined by blood bicarbonate <15 mmol/L and/or venous pH < 7.25 (arterial/capillary pH < 7.30), International Classification of Diseases, Ninth Revision, code 250.1, or listing of diabetic ketoacidosis in the medical chart. RESULTS: More than half (54%) of the patients were hospitalized at diagnosis, including 93% of those with diabetic ketoacidosis and 41% without diabetic ketoacidosis. The prevalence of diabetic ketoacidosis at the diagnosis was 25.5%. The prevalence decreased with age from 37.3% in children aged 0 to 4 years to 14.7% in those aged 15 to 19 years. Diabetic ketoacidosis prevalence was significantly higher in patients with type 1 (29.4%) rather than in those with type 2 diabetes (9.7%). After adjusting for the effects of center, age, gender, race or ethnicity, diabetes type, and family history of diabetes, diabetic ketoacidosis at diagnosis was associated with lower family income, less desirable health insurance coverage, and lower parental education. CONCLUSION: At the time of diagnosis, 1 in 4 youth presents with diabetic ketoacidosis. Those with diabetic ketoacidosis were more likely to be hospitalized. Diabetic ketoacidosis was a presenting feature of <10% of youth with type 2. Young and poor children are disproportionately affected.


Subject(s)
Diabetes Mellitus/diagnosis , Diabetic Ketoacidosis/diagnosis , Adolescent , Adult , Child , Child, Preschool , Diabetes Mellitus, Type 1/diagnosis , Educational Status , Emergency Service, Hospital , Female , Hospitalization , Humans , Infant , Insurance, Health , Male , Parents , Socioeconomic Factors , United States
5.
J Clin Endocrinol Metab ; 93(3): 823-31, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18165285

ABSTRACT

CONTEXT: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. OBJECTIVE: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. METHODS: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. RESULTS: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8+/-0.1 vs. +2.7+/-0.1 yr, P<0.0001) and after 3 yr (+2.5+/-0.2 vs. +4.1+/-0.1 yr, P<0.0001). This resulted in a net increase in predicted adult height of +4.5+/-1.2 cm in the anastrozole group at 24 months and +6.7+/-1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. CONCLUSIONS: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2-3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.


Subject(s)
Aromatase Inhibitors/therapeutic use , Body Height/drug effects , Growth Disorders/drug therapy , Growth Hormone/therapeutic use , Nitriles/therapeutic use , Triazoles/therapeutic use , Adolescent , Adult , Age Determination by Skeleton , Anastrozole , Blood Glucose/analysis , Body Composition , Bone Density , Follow-Up Studies , Growth Disorders/blood , Growth Disorders/physiopathology , Humans , Lipids/blood , Male , Puberty , Testosterone/blood
8.
J Pediatr ; 148(1): 128-31, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16423613

ABSTRACT

We report the successful use of oral urea in the management of children with chronic syndrome of inappropriate antidiuretic hormone secretion (SIAD). We performed a retrospective review of four children with chronic SIAD. After initial attempts at management with fluid restriction, each was started on a 30% to 50% oral urea solution, and the dose was titrated until normal serum sodium was achieved. Fluid intake was liberalized after serum sodium normalization. All four children normalized their serum sodium. No side effects or toxicities were experienced. Oral urea is a safe, effective treatment for chronic SIAD in children.


Subject(s)
Inappropriate ADH Syndrome/drug therapy , Urea/therapeutic use , Administration, Oral , Chronic Disease , Dose-Response Relationship, Drug , Female , Humans , Hyponatremia/drug therapy , Hyponatremia/etiology , Inappropriate ADH Syndrome/complications , Infant , Male , Retrospective Studies , Syndrome , Treatment Outcome , Urea/administration & dosage
12.
BMC Pediatr ; 2: 4, 2002 Apr 25.
Article in English | MEDLINE | ID: mdl-12014995

ABSTRACT

BACKGROUND: Disaccharide Intolerance Type I (Mendelian Interance in Man database: *222900) is a rare inborn error of metabolism resulting from mutation in sucrase-isomaltase (Enzyme Catalyzed 3.2.1.48). Usually, infants with SI deficiency come to attention because of chronic diarrhea and nutritional evidence of malabsorption. CASE PRESENTATION: We describe an atypical presentation of this disorder in a 10-month-old infant. In addition to chronic diarrhea, the child displayed severe and chronic hypercalcemia, the evaluation of which was negative. An apparently coincidental right orbital hemangioma was detected. Following identification of the SI deficiency, an appropriately sucrose-restricted, but normal calcium diet regimen was instituted which led to cessation of diarrhea, substantial weight gain, and resolution of hypercalcemia. CONCLUSIONS: This case illustrates that, similar to congenital lactase deficiency (Mendelian Interance in Man database: *223000, Alactasia, Hereditary Disaccharide Intolerance Type II), hypercalcemia may complicate neonatal Sucrase-Isomaltase deficiency. Hypercalcemia in the presence of chronic diarrhea should suggest disaccharide intolerance in young infants.


Subject(s)
Calcium/blood , Carbohydrate Metabolism, Inborn Errors/diagnosis , Failure to Thrive/etiology , Nephrocalcinosis/etiology , Sucrase-Isomaltase Complex/deficiency , Sucrose/metabolism , Female , Humans , Infant
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