Lindsey A. Loomba-Albrecht

Effect of puberty on body composition.

Purpose of reviewHere we examine the effect of puberty on components of human body composition, including adiposity (total body fat, percentage body fat and fat distribution), lean body mass and bone mineral content and density. New methods and longitudinal studies have expended our knowledge of these remarkable changes. Recent findingsHuman differences in adiposity, fat free mass and bone mass reflect differences in endocrine status (particularly with respect to estrogens, androgens, growth hormone and IGF-1), genetic factors, ethnicity and the environment. During puberty, males gain greater amounts of fat free mass and skeletal mass, whereas females acquire significantly more fat mass. Both genders reach peak bone accretion during the pubertal years, though males develop a greater skeletal mass. Body proportions and fat distribution change during the pubertal years as well, with males assuming a more android body shape and females assuming a more gynecoid shape. Pubertal body composition may predict adult body composition and affects both pubertal timing and future health. SummarySexual dimorphism exists to a small degree at birth, but striking differences develop during the pubertal years. The development of this dimorphism in body composition is largely regulated by endocrine factors, with critical roles played by growth hormone and gonadal steroids. It is important for clinicians and researchers to know the normal changes in order to address pathologic findings in disease states.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in three siblings having the same genetic lesion but different clinical presentations

BackgroundThis article summarizes the varying clinical manifestations of three siblings with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by the same genetic lesion.MethodsThe medical records of three siblings with FHHNC (one girl and two boys, aged 6 to 12 years) were reviewed and the clinical manifestations and treatment of their disease were described.ResultsDespite varying phenotypes, each sibling had the same genetic lesion—a novel homozygous mutation in CLDN16 (c.211A>G, M71V).ConclusionAlthough FHHNC is a rare disorder, this report is significant for the following reasons: (i) it describes a novel CLDN16 mutation causing FHHNC, adding to the literature of FHHNC-causing CLDN16 mutations; (ii) it suggests that genes other than CLDN16 or epigenetic factors are involved in the clinical spectrum of FHHNC; and (iii) it reinforces the variability of disease manifestation and genotype-phenotype correlations.

The Physiology of Puberty and its Disorders

Puberty is a complex process of developmental change regulated by multiple genetic and endocrine controls. Abnormal pubertal development (both precocious and delayed puberty) can cause significant distress to the patient and may in some instances be a sign of life-threatening pathology. Delayed puberty is often due to constitutional delay of growth and puberty, but will also occur in cases of primary gonadal failure and in patients with disorders leading to diminished gonadotropin levels (ie, central nervous system [CNS] tumors). Precocious puberty may occur due to CNS disorders, certain genetic disorders, ectopic gonadotropin secretion or autonomous sex steroid secretion. Treatment is directed toward the underlying pathology, and may include agents to either stimulate or block pubertal development. Health care providers require knowledge of the normal onset of timing and rate of progression of puberty, and must be able to identify patients with abnormal pubertal development, as well as initiate the appropriate laboratory workup.

An Oral Sulfonylurea in the Treatment of Transient Neonatal Diabetes Mellitus

BACKGROUND Neonatal diabetes mellitus (NDM) is rare, with a prevalence of approximately 1 in 500,000 infants worldwide. NDM may be caused by several different genetic abnormalities, and might either be transient (TNDM) or permanent. Until recently, clinical management of most permanent types of NDM required lifelong subcutaneous insulin treatment. However, due to activating mutations in the genes that encode the adenosine triphosphate-sensitive K(+) channel, some permanent types of NDM have been found to be amenable to oral sulfonylurea therapy. TNDM can last for a median of 12 weeks and completely resolve by 18 months. Although TNDM is typically treated with subcutaneous insulin, this mode of therapy might be difficult for some caregivers. CASE SUMMARY A small for gestational age male infant born at term developed NDM on day of life (DOL) 3. No other factors, such as sepsis, infection, or dextrose-containing intravenous fluids, that could have accounted for the hyperglycemia were present. In addition, there was no family history of DM or hyper-glycemic disorders. The patient was initially treated with subcutaneous regular insulin (0.25 U at a concentration of 10 U/L) q4h PRN for blood glucose concentrations >200 mg/dL. However, due to persistent blood glucose concentration fluctuations, a continuous insulin infusion (0.05 U/kg/h) was started on DOL 7. Because subcutaneous insulin injections could not be administered by the parents outside of the hospital, oral sulfonylurea therapy was attempted. A glyburide oral suspension, prepared by dissolving half of a 1.25-mg tablet in 1 mL of preservative-free, sterile water, was started at 0.2 mg/kg/d in 2 divided doses. The suspension was prepared immediately prior to each dose and was administered via syringe during feedings. On DOL 21, the patients NDM was managed solely with an oral sulfonylurea, target blood glucose concentrations of 150 to 250 mg/dL were achieved with glyburide 0.7 mg/kg/d in 2 divided doses, and insulin administration was no longer required. On DOL 25, the glyburide dosage was decreased to 0.5 mg/kg/d in 2 divided doses. On DOL 27, the patient was discharged on the same dosage. The patients NDM subsequently resolved by DOL 49. CONCLUSION An oral sulfonylurea was a useful treatment option in the management of TNDM in this patient.

High frequency of cardiac and behavioral complaints as presenting symptoms of hyperthyroidism in children.

Abstract Objective: Descriptive data characterizing the frequency of various chief complaints and presenting symptomatology in children with hyperthyroidism are lacking. Furthermore, difficulties in recognizing atypical presentations may delay diagnosis and increase morbidity. Methods: We performed a retrospective review of the medical records of 76 children with hyperthyroidism to characterize their chief complaints at initial presentation to care and document other presenting symptomatology. Results: Cardiac symptoms were the most frequent chief complaint, accounting for 23% of presenting complaints. Major mood and behavior disturbances were also frequently present (21%), but were infrequently cited as the chief complaint (6%). Conclusions: This study is the first to describe chief complaints separately from the other signs and symptoms of hyperthyroidism noted at the time of presentation to medical attention. Cardiac complaints were the most common; however, complaints associated with behavioral and mood disorders also occurred frequently. Clinicians should be aware of these presentations so that hyperthyroidism is diagnosed promptly to avoid morbidity associated with delayed diagnosis.

Neonatal cholestasis caused by hyperthyroidism.

A 1670-g male infant was born by emergent cesarean section at 32 and 5/7 weeks’ gestation caused by nonreassuring fetal heart rate tracings. The patient’s mother was a 25-year-old gravida 1 woman with a history of Graves disease (antithyroid peroxidase [APO] antibody positive at 208 IU/mL) and hypothyroidism secondary to radioiodine ablation performed 2 years before the delivery. Her thyroid studies were normal throughout pregnancy, with the exception of a mildly elevated thyroid-stimulating hormone level of 12 mIU/mL obtained during the third trimester. The pregnancy was further complicated by type 1 diabetes mellitus and drug, tobacco, and alcohol use. A fetal echocardiogram revealed a constricted ductus arteriosus, right ventricular hypertrophy, right atrial enlargement, and tricuspid regurgitation. After birth, the infant was intubated for poor respiratory effort and concern for underlying heart disease. He also developed early thrombocytopenia requiring platelet transfusion. Other early laboratory values showed hypoglycemia, evidence of disseminated intravascular coagulopathy, and elevated neonatal bilirubin (Table 1). On day of life (DOL) 2, the patient was jaundiced (conjugated bilirubin level of 11.2 mg/dL). Liver enzymes and alkaline phosphatase concentrations were elevated (Table 1). Doppler ultrasound excluded anatomic anomalies of the biliary tree and gallbladder. Serum tests for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus were negative, as were bacterial cultures of urine and blood. Metabolic studies, including those for a1-antitrypsin deficiency, were normal. The patient received fresh frozen plasma and platelet concentrate and his coagulopathy resolved, as did respiratory distress. On DOL 4, the patient became hypertensive and tachycardic (heart rate 235 bpm), prompting evaluation of his thyroid status. On DOL 5, he was diagnosed with thyrotoxicosis (Table 1). He was started on propylthiouracil (PTU) and propranolol on DOL 6, and heart rate and blood pressure normalized within 24 hours. His conjugated bilirubin concentration decreased following initiation of therapy on DOL 6. Given the lower incidence of hepatatoxicity with methimazole (MMI) compared with PTU in children (1), PTU was discontinued after 6 doses and therapy with MMI initiated on DOL 7; however, the patient’s transaminase levels increased further while on MMI therapy, peaking at an aspartate aminotrans-

Pseudohypoaldosteronism Type 1 due to a Novel Mutation in the Mineralocorticoid Receptor Gene

Background/Aims: Autosomal dominant pseudohypoaldosteronism type 1 is caused by mutations in the mineralocorticoid receptor (NR3C2) gene, often leading to life-threatening hyponatremia and hyperkalemia in the newborn period. We report a novel mutation in the NR3C2 gene, and report, for the first time, the association of well-treated pseudohypoaldosteronism with failure to thrive. This report additionally highlights the importance of aldosterone-sensitive sodium transport in the neonatal period. Patient and Methods: The patient presented with salt loss, hyperkalemia and a mild metabolic acidosis in the neonatal period (day of life 8). Further evaluation revealed significantly elevated levels of 18-hydroxycorticosterone, aldosterone and plasma renin activity, suggesting the diagnosis of pseudohypoaldosteronism. Results: Analysis of the patient’s NR3C2 gene revealed a novel missense mutation (c.1817G>C), which was subsequently analyzed in his parents and sister. Interestingly, the patient’s mother was found to have an identical mutation. Conclusion: We report a novel mutation in the gene for the mineralocorticoid receptor and an unusual clinical course of pseudohypoaldosteronism type 1 in an adequately treated patient.

Sexual precocity and its treatment

BackgroundPuberty is a complex and dynamic period in development during which individuals transition from the juvenile to adult state. Regulated by multiple genetic and endocrine controls, it is characterized by somatic growth and sexual maturation. Sexual precocity is defined as the appearance of secondary sexual characteristics before the lower limit of the normal age for pubertal onset.Data sourcesBased on recent publications and the experience with the disease of our group, we reviewed the normal timing and order of puberty, the definition of sexual precocity, the classification of sexual precocity, the differential diagnosis of sexual precocity, variations in pubertal development, the diagnosis of sexual precocity, and the treatment of sexual precocity.ResultsSexual precocity can be classified as either gonadotropin-releasing hormone (GnRH)-dependent or GnRH-independent. Regardless of the etiology, sexual precocity causes increased height velocity, somatic development, and skeletal maturation, which may have profound physical and psychological implications.ConclusionsThe treatment of sexual precocity is focused on its cause and must address both its psychosocial and clinical implications. For GnRH-dependent precocious puberty, GnRH agonists are the main pharmacological agents used. Alternatively, the treatment of disorders causing GnRH-independent sexual precocity is directed toward the underlying abnormality.

A novel glucokinase gene mutation and its effect on glycemic/C-peptide fluctuations in a patient with maturity-onset diabetes of the young type 2

Maturity-onset diabetes of the young (MODY) is a group of disorders accounting for 2-5% of diabetes; MODY2 is caused by inactivating GCK mutations. We report a case of MODY2 caused by a novel GCK mutation and demonstrate differential glycemic/C-peptide responses to treatment with insulin, no medication, and an oral sulfonylurea.

Endocrinopathies in Children Infected with Human Immunodeficiency Virus

Endocrine changes (including adrenal insufficiency, disorders of growth and puberty, thyroid dysfunction, metabolic abnormalities and osteopenia) accompany human immunodeficiency virus (HIV) infection in pediatric patients. The cause of these changes is multifactorial and includes direct viral effects of HIV, and effects of antiretroviral therapy. These effects may be of particular importance in childhood given the critical developmental processes that occur during this time period and the likelihood of prolonged exposure to the virus and medications.