Concise Review: Canine Diabetes Mellitus as a Translational Model for Innovative Regenerative Medicine Approaches.

Diabetes mellitus (DM) is a common spontaneous endocrine disorder in dogs, which is defined by persistent hyperglycemia and insulin deficiency. Like type 1 diabetes (T1D) in people, canine DM is a complex and multifactorial disease in which genomic and epigenomic factors interact with environmental cues to induce pancreatic ß-cell loss and insulin deficiency, although the pathogenesis of canine DM is poorly defined and the role of autoimmunity is further controversial. Both diseases are incurable and require life-long exogenous insulin therapy to maintain glucose homeostasis. Human pancreatic islet physiology, size, and cellular composition is further mirrored by canine islets. Although pancreatic or isolated islets transplantation are the only clinically validated methods to achieve long-term normoglycemia and insulin independence, their availability does not meet the clinical need; they target a small portion of patients and have significant potential adverse effects. Therefore, providing a new source for ß-cell replacement is an unmet need. Naturally occurring DM in pet dogs, as a translational platform, is an untapped resource for various regenerative medicine applications that may offer some unique advantages given dogs' large size, longevity, heterogenic genetic background, similarity to human physiology and pathology, and long-term clinical management. In this review, we outline different strategies for curative approaches, animal models used, and consider the value of canine DM as a translational animal/disease model for T1D in people. Stem Cells Translational Medicine 2019;8:450-455.

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.

Sexual precocity and its treatment.

BACKGROUND: Puberty 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 SOURCES: Based 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. RESULTS: Sexual 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. CONCLUSIONS: The 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.

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.

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

BACKGROUND: This article summarizes the varying clinical manifestations of three siblings with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by the same genetic lesion. METHODS: The 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. RESULTS: Despite varying phenotypes, each sibling had the same genetic lesion-a novel homozygous mutation in CLDN16 (c.211A>G, M71V). CONCLUSION: Although 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.

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

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.

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.

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.

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 patient's 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 patient's NDM subsequently resolved by DOL 49. CONCLUSION: An oral sulfonylurea was a useful treatment option in the management of TNDM in this patient.

Effect of puberty on body composition.

PURPOSE OF REVIEW: Here 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 FINDINGS: Human 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. SUMMARY: Sexual 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.