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Clinical Pediatric Endocrinology : Case... Apr 2013Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and...
Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease.
PubMed: 23990696
DOI: 10.1292/cpe.22.33 -
The Journal of Clinical Endocrinology... Nov 2013Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very... (Clinical Trial)
Clinical Trial
CONTEXT
Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes.
OBJECTIVE
Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients.
DESIGN AND SETTING
We conducted an open-label nonrandomized study at the National Institutes of Health.
PATIENTS
Patients were adolescents with RMS and poorly controlled diabetes.
INTERVENTION
Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied.
OUTCOME MEASURES
Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months.
RESULTS
HbA1c decreased from 11.4% ± 1.1% at baseline to 9.3% ± 1.9% after 6 months and 9.7% ± 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001).
CONCLUSIONS
Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets.
Topics: Adolescent; Blood Glucose; Child; Donohue Syndrome; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin Resistance; Leptin; Male; Receptor, Insulin; Treatment Outcome
PubMed: 23969187
DOI: 10.1210/jc.2013-2317 -
Journal of Clinical Research in... 2013Syndrome of extreme insulin resistance (SEIR) is a rare spectrum disorder with a primary defect in insulin receptor signalling, noted primarily in children, and is often...
Syndrome of extreme insulin resistance (SEIR) is a rare spectrum disorder with a primary defect in insulin receptor signalling, noted primarily in children, and is often difficult to diagnose due to the clinical heterogeneity.SEIR was diagnosed in an adolescent girl with facial dysmorphism,exuberant scalp and body hair, severe acanthosis, lipoatrophy, dental abnormalities, and short stature (Rabson-Mendenhall phenotype). She had elevated fasting (422.95 pmol/L) and post-glucose insulin levels(>2083 pmol/L). Total body fat was decreased (11%; dual-energy X-ray absorptiometry). Basal growth hormone (GH) was increased (7.9 μg/L)with normal insuline-like growth factor 1 (37.6 nmol/L) suggestive of GH resistance. She had fatty liver and polycystic ovaries. Echocardiography revealed ostium secundum type atrial septal defect (ASD). Blood glucose normalized with pioglitazone (30 mg/day). Delayed development, severe insulin resistance, mild hyperglycemia, absence of ketosis, and remarkable response of hyperinsulinemia and hyperglycemia to pioglitazone which persisted even after 1 year of diagnosis are some of the notable features of this patient. This is perhaps the first report of occurrence of congenital heart disease (ASD) in a patient of SEIR (Rabson-Mendenhall phenotype). This report highlights the clinical features of SEIR and the role of insulin sensitizers like pioglitazone in the management of such patients.
Topics: Adolescent; Donohue Syndrome; Female; Heart Septal Defects, Atrial; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Thiazolidinediones; Treatment Outcome
PubMed: 23367497
DOI: 10.4274/Jcrpe.857 -
Endocrine Journal 2013Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a...
Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.
Topics: Child, Preschool; Donohue Syndrome; Humans; Hypoglycemic Agents; Infant; Insulin, Short-Acting; Insulin-Like Growth Factor I; Male; Mutation; Receptor, Insulin; Recombinant Proteins
PubMed: 22972224
DOI: 10.1507/endocrj.ej12-0289 -
HIV Medicine Feb 2013The objective of the study was to conduct a within-cohort assessment of risk factors for incident AIDS-defining cancers (ADCs) and non-ADCs (NADCs) within the Australian...
OBJECTIVES
The objective of the study was to conduct a within-cohort assessment of risk factors for incident AIDS-defining cancers (ADCs) and non-ADCs (NADCs) within the Australian HIV Observational Database (AHOD).
METHODS
A total of 2181 AHOD registrants were linked to the National AIDS Registry/National HIV Database (NAR/NHD) and the Australian Cancer Registry to identify those with a notified cancer diagnosis. Included in the current analyses were cancers diagnosed after HIV infection. Risk factors for cancers were also assessed using logistic regression methods.
RESULTS
One hundred and thirty-nine cancer cases were diagnosed after HIV infection among 129 patients. More than half the diagnoses (n = 68; 60%) were ADCs, of which 69% were Kaposi's sarcoma and 31% non-Hodgkin's lymphoma. Among the NADCs, the most common cancers were melanoma (n = 10), lung cancer (n = 6), Hodgkin's lymphoma (n = 5) and anal cancer (n = 5). Over a total of 21021 person-years (PY) of follow-up since HIV diagnosis, the overall crude cancer incidence rate for any cancer was 5.09/1000 PY. The overall rate of cancers decreased from 15.9/1000 PY [95% confidence interval (CI) 9.25-25.40/1000 PY] for CD4 counts < 100 cells/μL to 2.4/1000 PY (95% CI 1.62-3.39/1000 PY) for CD4 counts > 350 cells/μL. Lower CD4 cell count and prior AIDS diagnoses were significant predictors for both ADCs and NADCs.
CONCLUSIONS
ADCs remain the predominant cancers in this population, although NADC rates have increased in the more recent time period. Immune deficiency is a risk factor for both ADCs and NADCs.
Topics: Acquired Immunodeficiency Syndrome; Adult; Aging; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Anus Neoplasms; Australia; CD4 Lymphocyte Count; Databases, Factual; Female; Follow-Up Studies; Hodgkin Disease; Humans; Logistic Models; Lung Neoplasms; Lymphoma, AIDS-Related; Male; Melanoma; Middle Aged; Prospective Studies; Risk Factors
PubMed: 22934689
DOI: 10.1111/j.1468-1293.2012.01038.x -
Journal of Korean Medical Science May 2012Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth...
Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 µIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 µIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.
Topics: Asian People; Base Sequence; Blood Glucose; C-Peptide; Codon, Nonsense; Donohue Syndrome; Heterozygote; Humans; Hypoglycemic Agents; Infant; Insulin; Male; Mutation, Missense; Receptor, Insulin; Republic of Korea; Sequence Analysis, DNA
PubMed: 22563226
DOI: 10.3346/jkms.2012.27.5.565 -
AJNR. American Journal of Neuroradiology Aug 2012RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental...
RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental vasoconstriction in multiple cerebral arteries. The angiographic appearance resembles vasculitis, except that the abnormalities resolve during the course of several months. Because the treatment of RCVS differs from that for vasculitis, radiologists must understand the clinical and radiologic features so as to better guide imaging algorithms and facilitate diagnosis. We present a series of 6 cases of RCVS that highlight the imaging features across multiple modalities.
Topics: Adult; Cerebral Arteries; Cerebrovascular Disorders; Female; Headache; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Recurrence; Tomography, X-Ray Computed; Young Adult
PubMed: 22422190
DOI: 10.3174/ajnr.A2964 -
Endocrine Journal 2011Rabson-Mendenhall syndrome (RMS) is a rare disorder that presents as severe insulin resistance as a result of mutations present in the insulin receptor (INSR). A Chinese...
Rabson-Mendenhall syndrome (RMS) is a rare disorder that presents as severe insulin resistance as a result of mutations present in the insulin receptor (INSR). A Chinese girl with RMS presented with profound diabetes, hyperinsulinemia, acanthosis nigricans, hirsutism, and abnormalities of teeth and nails. Direct sequencing of the patient's INSR detected heterozygote mutations at Arg83Gln (R83Q) and Ala1028Val (A1028V), with the former representing a novel mutation. Functional studies of Chinese hamster ovary (CHO) cells transfected with wild-type (WT) and mutant forms of INSR were performed to evaluate the effects of these mutations on receptor expression and activation. Receptor expression, insulin binding activity, and phosphorylation of the R83Q variant were comparable to WT. In contrast, expression of the A1028V receptor was much lower than that of WT INSR, and impairment of insulin binding and autophosphorylation were nearly commensurate with the decrease in expression detected. Reductions in the phosphorylation of IRS-1, Akt, and Erk1/2 (60%, 40%, and 50% of WT, respectively) indicate that the A1028V receptor contributes to impaired signal transduction. In conclusion, INSR mutations associated with RMS were identified. Moreover, the A1028V mutation associated with a decrease in expression of INSR potentially accounts for loss of function of the INSR.
Topics: Amino Acid Sequence; Animals; Asian People; Base Sequence; CHO Cells; Child; Cricetinae; Donohue Syndrome; Female; Genetic Variation; Humans; Insulin; Insulin Resistance; Male; Molecular Sequence Data; Pedigree; Polymorphism, Single Nucleotide; RNA; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection
PubMed: 21869538
DOI: 10.1507/endocrj.ej11-0032 -
Anales de Pediatria (Barcelona, Spain :... May 2011
Topics: Child; Donohue Syndrome; Humans; Male
PubMed: 21376683
DOI: 10.1016/j.anpedi.2010.12.013 -
The Journal of Clinical Endocrinology... Apr 2011In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway.
OBJECTIVE
This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women.
DESIGN
We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women.
SETTING
The study was conducted in a General Clinical Research Center in an academic medical center.
PARTICIPANTS
Women with PCOS (age, 18-37 yr; n = 10) and normal ovulatory controls (age, 18-37 yr; n = 11) were recruited.
INTERVENTIONS
For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 μg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 μg of recombinant hCG.
MAIN OUTCOME MEASURE(S)
We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration.
RESULTS
In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women.
CONCLUSION
In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway.
Topics: Adolescent; Adult; Body Mass Index; Chorionic Gonadotropin; Dehydroepiandrosterone; Dose-Response Relationship, Drug; Estradiol; Female; Humans; Hyperandrogenism; Injections, Intravenous; Oligomenorrhea; Polycystic Ovary Syndrome; Recombinant Proteins; Steroids; Up-Regulation; Young Adult
PubMed: 21270326
DOI: 10.1210/jc.2010-2200