Sayali A. Ranadive

Lessons from extreme human obesity: monogenic disorders.

Human obesity has a strong genetic component. Most genes that influence an individuals predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

Bariatric surgery in a patient with complete MC4R deficiency

Bariatric surgery is often successful for treatment of severe obesity. The mechanisms of weight loss after bariatric surgery and the role of central energy homeostatic pathways in this weight loss process are not well understood. The study of individuals with complete loss of function of genes important in the leptin–melanocortin system may help establish the significance of these pathways for weight loss after bariatric surgery. We describe the outcome of bariatric surgery in an adolescent with compound heterozygosity and complete functional loss of both alleles of the melanocortin 4 receptor (MC4R). The patient underwent laparoscopic adjustable gastric banding and truncal vagotomy at years of age, which resulted in initial, but not long-term weight loss. Our experience with this patient suggests that complete MC4R deficiency impairs response to gastric banding and results in poor weight loss after this surgery.

Identification, characterization and rescue of a novel vasopressin-2 receptor mutation causing nephrogenic diabetes insipidus

Objective  X‐linked nephrogenic diabetes insipidus (XNDI), caused by mutations in the V2 vasopressin receptor (V2R), is clinically distinguished from central diabetes insipidus (CDI) by elevated serum vasopressin (AVP) levels and unresponsiveness to 1‐desamino‐8‐d‐arginine vasopressin (DDAVP). We report two infants with XNDI, and present the characterization and functional rescue of a novel V2R mutation.

The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus.

The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans. We here describe the eighth individual with complete proopiomelanocortin (POMC) deficiency and the first with coincidental concomitant type 1 diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated adrenocorticotropic hormone deficiency identified a homozygous 5′ untranslated region mutation −11C>A, which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient’s insulin requirements were as expected for his age and pubertal development. This unique patient suggests that in humans the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity.

Pediatric Disorders of Water Balance

Fluid homeostasis requires adequate water intake, regulated by an intact thirst mechanism and appropriate free water excretion by the kidneys, mediated by appropriate secretion of arginine vasopressin (AVP, also known as antidiuretic hormone). AVP exerts its antidiuretic action by binding to the X chromosome-encoded V2 vasopressin receptor (V2R), a G protein-coupled receptor on the basolateral membrane of renal collecting duct epithelial cells. After V2R activation, increased intracellular cyclic adenosine monophosphate mediates shuttling of the water channel aquaporin 2 to the apical membrane of collecting duct cells, resulting in increased water permeability and antidiuresis. Clinical disorders of water balance are common, and abnormalities in many steps involving AVP secretion and responsiveness have been described. This article focuses on the principal disorders of water balance, diabetes insipidus, and the syndrome of inappropriate antidiuretic hormone secretion.

Letrozole vs Anastrozole for Height Augmentation in Short Pubertal Males: First Year Data

CONTEXT Aromatase inhibitors are used off-label to treat short stature in peripubertal boys. OBJECTIVE To investigate short- and long-term hormonal and auxologic differences in short pubertal boys treated with letrozole (L) or anastrozole (A). DESIGN PATIENTS are seen for laboratory evaluation and physical examination every 6 months, bone age yearly, DEXA and spine film every 2 years. They will be followed until they reach their final height. This is a preliminary report after 1 year of treatment. SETTING A single academic childrens hospital outpatient clinic. PATIENTS Boys with age >10 years, bone age ≤ 14 years, clinical and hormonal evidence of central puberty, and either height < fifth percentile or predicted adult height (PAH) more than 10 cm below mid-parental height (MPH). INTERVENTION Letrozole (2.5 mg) or anastrozole (1 mg) was administered orally each day. MAIN OUTCOME MEASURES Hormonal and clinical parameters, growth velocity, and change in bone age and PAH. RESULTS Thirty-nine boys have completed 1 year of treatment. Baseline means were age 14.1 years, PAH 166 cm, and testosterone 198 ng/dL. At 1 year, letrozole resulted in higher LH (L 6.1 ± 2.5 vs A 3.2 ± 1.7 IU/L) and testosterone (1038 ± 348 vs 536 ± 216 ng/dL) with lower estradiol (2.8 ± 2.8 vs 5.6 ± 2.9 pg/mL) and IGF-1 (237 ± 51 vs 331 ± 79 ng/mL). First year growth velocities were identical (7.2 cm/year), but an increase in PAH was greater in the anastrozole group (4.2 ± 3.5 vs 1.4 ± 4.4 cm, p = 0.03) after 1 year. CONCLUSIONS We present first-year data from a direct comparison of anastrozole and letrozole for height augmentation in short pubertal boys. Letrozole was more potent in hormonal manipulation than anastrozole. First-year growth velocities were comparable, but improvement in PAH was greater in the anastrozole group. It remains to be seen if positive PAH trends will translate to increase in final height in either group.

Outpatient transition of an infant with permanent neonatal diabetes due to a KCNJ11 activating mutation from subcutaneous insulin to oral glyburide

Abstract:  Neonatal diabetes mellitus is rare, may either be transient or permanent, and may be caused by mutations in any of the several different genes. Until recently, most forms of permanent neonatal diabetes required lifelong subcutaneous insulin for management; however, permanent neonatal diabetes due to activating mutations in the KCNJ11 gene, which encodes the Kir6.2 protein subunit of the ATP‐sensitive K+ (KATP) channel, may be amenable to oral sulfonylurea therapy. We describe a case of an 18‐month‐old infant with permanent neonatal diabetes due to an activating KCNJ11 mutation successfully transitioned from subcutaneous insulin therapy to oral sulfonylurea therapy in the outpatient setting.

Isolated adrenocorticotropic hormone deficiency presenting as an acute neurologic emergency in a peripubertal girl.

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is extraordinarily rare, and the clinical manifestations of its accompanying adrenal insufficiency are diverse. Early-onset forms of IAD have been linked to mutations in the Tpit transcription factor gene TPIT; however, the genetic basis of juvenile- or late-onset IAD is unknown. Herein, we describe a case of a peripubertal girl with IAD and a normal TPIT gene who presented with an acute neurologic emergency, demonstrating both the variable clinical presentation of IAD and the need for continued investigation into the molecular mechanisms underlying juvenile- and late-onset IAD.

Persistent elevation of urine aquaporin-2 during water loading in a child with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a R137L mutation in the V2 vasopressin receptor.

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a novel disease caused by a gain-of-function mutation in the V2 vasopressin receptor (V2R), which results in water overload and hyponatremia. We report the effect of water loading in a 3-year old boy with NSIAD, diagnosed in infancy, to assess urine aquaporin-2 (AQP2) excretion as a marker for V2R activation, and to evaluate the progression of the disease since diagnosis. The patient is one of the first known NSIAD patients and the only patient with a R137L mutation. Patient underwent a standard water loading test in which serum and urine sodium and osmolality, serum AVP, and urine AQP2 excretion were measured. The patient was also evaluated for ad lib fluid intake before and after the test. This patient demonstrated persistent inability to excrete free water. Only 39% of the water load (20 ml/kg) was excreted during a 4-hour period (normal ≥ 80-90%). Concurrently, the patient developed hyponatremia and serum hypoosmolality. Serum AVP levels were detectable at baseline and decreased one hour after water loading; however, urine AQP2 levels were elevated and did not suppress normally during the water load. The patient remained eunatremic but relatively hypodipsic during ad lib intake. In conclusion, this is the first demonstration in a patient with NSIAD caused by a R137L mutation in the V2R that urine AQP2 excretion is inappropriately elevated and does not suppress normally with water loading. In addition, this is the first longitudinal report of a pediatric patient with NSIAD diagnosed in infancy who demonstrates the ability to maintain eunatremia during ad lib dietary intake.

Monogenic Disorders Within the Energy Balance Pathway

The hypothalamus plays a major role in the long-term regulation of body weight in humans. Within the hypothalamus, the leptin–melanocortin system is critical for energy balance, as animal and human studies have shown that disruption of this pathway, which senses peripheral energy stores and signals satiety, leads to the most severe forms of human obesity. The monogenic causes of obesity identified so far in this pathway are very heterogeneous and account for less than 5% of severe obesity. The genetic basis of the remaining 95% of obesity is likely to be even more heterogeneous and polygenic. The melanocortin 4-receptor (MC4R) is the most specialized molecule for body weight maintenance within this system as the clinical phenotype of MC4R deficiency is limited to obesity. Indeed, heterozygous MC4R mutations are the most common cause of monogenic obesity. In addition, novel mechanisms are emerging as important for pathogenicity of obesity, such as abnormal hypothalamic development, alterations in neuronal plasticity, and dysfunction of the primary cilium. This chapter focuses on obesity caused by mutations in genes that have a physiologic role in the hypothalamic leptin–melanocortin system of energy balance.