Papers by Mitchell Geffner
The Journal of pediatrics, 1990
Pediatric endocrinology reviews: PER
With the availability of recombinant human (rh) IGF-I as a new therapeutic agent, the criteria fo... more With the availability of recombinant human (rh) IGF-I as a new therapeutic agent, the criteria for diagnosis and strategies for management of growth deficiencies continue to evolve. This supplement provides a clinical update on molecular, therapeutic, and metabolic aspects of the management of short stature associated with insulin-like growth factor-I deficiency (IGFD). Several distinct, single-gene defects associated with primary IGFD now have been identified. The first section of this supplement focuses on selecting certain patients for specific genetic testing of the GH/IGF-I axis, based on previously obtained clinical and biochemical assessments. Management of short stature in children responding poorly to rhGH and definitions of a good and poor response are discussed in the next section. In addition, the authors further address different methods to help practicing clinicians predict and assess GH response, review the effect of rhGH on final adult height, and discuss the role IGF-I may have in the therapeutic approach to short stature. Finally, the metabolic aspects related to the treatment of short stature are discussed in the third part of this supplement.
American journal of diseases of children (1960)
Germ cell tumors may cause various aberrations in pubertal development. In prepubertal boys, thes... more Germ cell tumors may cause various aberrations in pubertal development. In prepubertal boys, these tumors may secrete human chorionic gonadotropin, resulting in precocious puberty. Human chorionic gonadotropin and alpha-fetoprotein are both useful as germ cell tumor markers in the diagnosis and detection of recurrence. Pregnancy-specific beta 1-glycoprotein, another oncoplacental antigen, has been used as a tumor marker for trophoblastic neoplasms, but not previously for human chorionic gonadotropin-producing tumors associated with precocious puberty. Patients with germ cell tumors may also have abnormal karyotypes. Herein, we describe six male pediatric patients with germ cell tumors and pubertal derangements seen during an 8-year period. We confirm the high incidence of associated sexual precocity, the usefulness of alpha-fetoprotein, human chorionic gonadotropin, and pregnancy-specific beta 1-glycoprotein as tumor markers in the diagnosis and follow-up of these patients, and the occurrence of sex chromosomal abnormalities.
Pediatric endocrinology reviews: PER
Persistent Müllerian Duct Syndrome (PMDS) is a 46,XY disorder of sex development (DSD) in which M... more Persistent Müllerian Duct Syndrome (PMDS) is a 46,XY disorder of sex development (DSD) in which Müllerian structures are found in genotypic males with normally virilized external genitalia and unilateral or bilateral cryptorchidism. It is usually diagnosed incidentally during surgical repair of cryptorchidism or inguinal hernia. The majority of cases are due to a mutation of the anti-Müllerian hormone (AMH) gene or the AMH receptor, type II (AMH-RII) gene. Management of patients with PMDS requires a multidisciplinary approach. Long-term prognosis is good although fertility appears to be decreased and there may be a risk of malignancy due to cryptorchidism and retained Müllerian remnants. We describe 8 new cases of PMDS diagnosed in Southern California in the past 10 years and review the literature.
Background : Chronic HIV or antiretrovirals (ARV) can cause mitochondrial (mt) dysfunction, a pot... more Background : Chronic HIV or antiretrovirals (ARV) can cause mitochondrial (mt) dysfunction, a potential mechanism for insulin resistance (IR) which is common in perinatally HIV-infected children (HIV+). Mt dysfunction is also seen in non-HIV+ individuals with exogenous obesity. In a cross-sectional study, we compared mt function (mtfxn) in HIV+ and HIV-exposed, uninfected (HEU) children, and evaluated the association between mtfxn, BMI z-scores (BMIz), and IR. Methods : HIV+ and HEU were enrolled from the Adolescent Master Protocol of PHACS. Demographics, BMIz, venous lactate, and mtfxn (oxidative phosphorylation [OXPHOS] as measured by NADH dehydrogenase Complex I [CI] enzyme activity, OD/min/g e3) in peripheral blood mononuclear cells were evaluated. ARV use and fasting plasma glucose and insulin were recorded in HIV+. HOMA-IR score was calculated to define IR. Unadjusted differences in mtfxn by HIV status and IR (HIV+ only) were evaluated using Wilcoxon rank sum test. Linear regr...
The Journal of clinical endocrinology and metabolism, Jan 2, 2015
Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism a... more Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants. To understand the relationship(s) between mitochondrial fuel utilization [assessed via acylcarnitines (ACs) and branched-chain amino acids (BCAAs)] and pre-prandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine (AZT) or nevirapine (NVP) compared to HIV /ARV-unexposed uninfected (HUU) infants. Prospective cohort study with 3 groups: 1) intrauterine HIV/ARV/postnatal AZT-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal NVP-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between in utero HIV/ARV exposure and infant insulin. ...
The Journal of Clinical Endocrinology & Metabolism, 2015
Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in nor... more Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in normal children, potentially increasing their risk of cardiovascular disease (CVD). Abdominal adiposity, in particular visceral adipose tissue (VAT), is strongly associated with metabolic syndrome and CVD. However, it remains unknown whether VAT is increased in CAH. The objective of the study was to determine whether adolescents and young adults with classical CAH have more VAT and sc adipose tissue (SAT) than matched controls and whether VAT and SAT are associated with biomarkers of metabolic syndrome, inflammation, and hyperandrogenism in CAH. This was a cross-sectional study at a tertiary center. CAH subjects (n = 28; 15.6 ± 3.2 y; 15 females) were matched for age, sex, ethnicity, and body mass index to healthy controls (n = 28; 16.7 ± 2.3 y; 15 females). VAT and SAT, using computed tomography imaging and serum biomarkers associated with CVD risk, were measured. Data are reported as mean ± SD. Both VAT (43.8 ± 45.5 cm(2)) and SAT (288.1 ± 206.5 cm(2)) were higher in CAH subjects than controls (VAT 26.4 ± 29.6 cm(2) and SAT 226.3 ± 157.5 cm(2); both P<.001). The VAT to SAT ratio was also higher in CAH subjects (0.15 ± 0.07) than controls (0.12 ± 0.06; P<.05). Within CAH, measures of obesity (waist to height ratio, fat mass) and inflammation (plasminogen activator inhibitor-1, high-sensitivity C-reactive protein, leptin) correlated strongly with VAT and SAT. In addition, homeostasis model assessment of insulin resistance, and low-density lipoprotein correlated with abdominal adiposity. There were no sex differences for VAT or SAT in CAH subjects. CAH adolescents and young adults have increased abdominal adiposity, with a higher proportion of proinflammatory VAT than SAT. An improved understanding of the mechanism of obesity in CAH maylead to targeted prevention and therapeutics in this high-risk population.
Hormone Research in Paediatrics, 2015
Hormone Research in Paediatrics, 2015
Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short statu... more Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens. © 2015 S. Karger AG, Basel.
Hormone research in pædiatrics, 2014
Children receiving stimulants for attention deficit hyperactivity disorder (ADHD) frequently pres... more Children receiving stimulants for attention deficit hyperactivity disorder (ADHD) frequently present to pediatric endocrinology clinics for evaluation and treatment of growth disorders. The worldwide prevalence of stimulant use in children with ADHD also receiving recombinant human growth hormone (rhGH) and the impact on response to rhGH are unknown. Data on children enrolled in the KIGS® (Pfizer International Growth Study) registry were evaluated for the associated diagnosis of ADHD prior to initiation of Genotropin® rhGH. Concomitant stimulant medications and auxological information were captured. Response to rhGH was evaluated using established growth prediction models. The prevalence of ADHD in KIGS was 2.3% (1,748/75,251), with stimulants used in 1.8% (1,326/75,251). Children with idiopathic growth hormone deficiency (IGHD) who received stimulants grew significantly less (1.1 cm) in the first year of rhGH therapy than expected for rhGH-treated non-ADHD IGHD children. After one ...
Current diabetes reports, 2015
Youth-onset type 2 diabetes (T2D) is increasingly recognized as a disorder with substantial risk ... more Youth-onset type 2 diabetes (T2D) is increasingly recognized as a disorder with substantial risk for long-term metabolic, cardiovascular, and renal morbidity and mortality, as well as individual and societal burden. Recent studies suggest that the disorder differs from adult-onset T2D in a variety of ways and that there is an urgent need for an expanded set of treatment options. However, demographic, economic, and social challenges limit the number of eligible candidates for clinical trials in youth-onset T2D, and a growing number trials mandated by regulatory agencies have created a circumstance in which too many trials are chasing too few eligible participants. A solution to this situation will require novel approaches to clinical trial design incorporating collaboration among clinical investigators, pharmaceutical sponsors, and regulatory agencies. If successful, this approach could also serve as a model for clinical trials in other rare and understudied pediatric disorders.
Advances in pediatrics, 2006
In summary, much progress has been made in our understanding of childhood craniopharyngiomas. The... more In summary, much progress has been made in our understanding of childhood craniopharyngiomas. These histologically benign but "geographically malignant" tumors are challenging to treat and require experienced clinicians from multiple disciplines including neurosurgery, radiology, hematology/oncology, ophthalmology, endocrinology, and general pediatrics to address the multiple issues that arise with diagnosis, treatment, and long-term follow-up of affected children. The study and close observation of patients who have craniopharyngiomas may also be beneficial for our general understanding of pathophysiologic processes such as the observed "growth without growth hormone" phenomenon or the well-described and studied hypothalamic obesity phenotypes.
Pediatric nephrology (Berlin, Germany), 2003
Hypertension has been anecdotally reported in children with familial hypophosphatemic rickets (XL... more Hypertension has been anecdotally reported in children with familial hypophosphatemic rickets (XLH). To better identify and characterize the clinical and laboratory features of hypertensive XLH children, we reviewed the medical records of 41 XLH children, all treated with phosphate and vitamin D analogues. Eight children, who were originally normotensive, developed hypertension during the 2nd decade of life. At diagnosis of hypertension all had persistent secondary/tertiary hyperparathyroidism (HPTD), defined as high serum parathyroid hormone (PTH) for 12 months or longer. Seven had nephrocalcinosis (NC). Analysis of data showed that of 11 children with HPTD, 8 developed hypertension compared with 0 among 30 without HPTD (P<0.001). Of 40 children studied, 18 had NC that was significantly associated with both HPTD (P<0.01) and hypertension (P<0.025). At diagnosis of hypertension, serum calcium was elevated in 2. Plasma renin activity was high in 3 of 4 patients in whom it wa...
The Western journal of medicine, 2000
Pediatric Diabetes, 2015
The objectives were to (i) describe the characteristics of a large ethnically/racially and geogra... more The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.
Fertility and sterility, 1986
Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, co... more Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.
The Journal of pediatrics, 1990
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Papers by Mitchell Geffner