pituitrin and Growth-Disorders

Advances in genetic engineering will make possible treatment of many pediatric endocrine disorders with replacement therapy. Some of these conditions include short stature, precocious puberty, and diabetes mellitus. Although the availability of such hormonal replacement offers new treatment modalities, an understanding of their mechanism of action and pharmacologic characteristics is crucial to maximize their effectiveness while minimizing possible untoward effects. The clinician must evaluate potential risks and benefits as these substances come to market without definitive answers being available as to their long-term effects.

Topics: Child; Child, Preschool; Diabetes Mellitus, Type 1; Growth Disorders; Growth Hormone; Hormones; Humans; Infant; Insulin; Pituitary Diseases; Pituitary Hormone-Releasing Hormones; Prolactin; Puberty, Precocious; Recombinant Proteins; Somatostatin; Thyrotropin-Releasing Hormone; Vasopressins

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the vasopressin (AVP)-neurophysin II (NPII) gene, manifests gradually during early childhood with progressive polyuria and polydipsia. Patients are usually treated with synthetic AVP analog. If unlimited access to water is provided, prognosis is usually good even in the absence of specific treatment. In this study, we describe three families with adFNDI, in which growth failure was a prominent complaint, on the clinical and molecular level.. Histories from affected and unaffected family members were taken. Height and weight of index patients were recorded longitudinally. Patients underwent water deprivation tests, magnetic resonance imaging, and genetic analysis. One mutant was studied by heterologous expression in cell culture.. A total of ten affected individuals were studied. In two of the three pedigrees, a novel mutation in the AVP-NPII gene was found. The index children in each pedigree showed growth retardation, which was the reason for referral in two. In these cases, water intake was tightly restricted by the parents in an attempt to overcome suspected psychogenic polydipsia and to improve appetite. Once the children were treated by hormone replacement, they rapidly caught up to normal weight and height.. Genetic testing and appropriate parent counseling should be enforced in adFNDI families to ensure adequate treatment and avoid chronic water deprivation, which causes failure to thrive.

Topics: Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Growth Disorders; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Neurophysins; Pedigree; Polyuria; Vasopressins; Water Deprivation

Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant trait in which expression of a mutant vasopressin prohormone reduces vasopressin production. We investigated the NP85 Cys-->Gly mutant vasopressin prohormone in a large kindred in The Netherlands. We demonstrate that growth retardation is an important early sign in two children from this kindred, which recuperates by substitution therapy with 1-desamino-8-D-arginine vasopressin. To obtain clues about the basis for the dominant inheritance of FNDI, we analyzed the trafficking and processing of the mutant vasopressin prohormone in cell lines by metabolic labeling and immunoprecipitation. The mutant vasopressin prohormone was retained in the endoplasmic reticulum and thus was not processed to vasopressin. This defect was not caused by dimerization of the vasopressin prohormone via its unpaired cysteine residue. High level expression of the mutant vasopressin prohormone in cell lines resulted in strong accumulation in the endoplasmic reticulum and an altered morphology of this organelle. We hypothesize that disturbance of the endoplasmic reticulum results in dysfunction and ultimately cell death of the cells expressing the mutant prohormone. Our data support the hypothesis that FNDI is a progressive neurodegenerative disease with delayed onset of symptoms. Its treatment requires early detection of symptoms for which growth parameters are useful.

Topics: Adult; Animals; Cell Death; Child; Child, Preschool; Diabetes Insipidus; Dimerization; Endoplasmic Reticulum; Female; Fluorescent Antibody Technique; Growth Disorders; Humans; Immunosorbent Techniques; Male; Mice; Mutation; Netherlands; PC12 Cells; Pedigree; Pituitary Neoplasms; Protein Precursors; Rats; Transfection; Tumor Cells, Cultured; Vasopressins

Somatomedin serum levels of congenitally vasopressin-deficient Brattleboro rats were determined postnatally between day 1 and 55, and compared with heterozygous control values. Assays were performed with a radioimmunoassay of insulin-like growth factor 1 (IGF-1). A transient enhancement of immunoreactive IGF-1 levels between day 8 and 21 of age and a reduction in adulthood was found. This observation shows that the early growth impairments of the Brattleboro mutant are not due to a deficiency of IGF-1.

Topics: Animals; Body Weight; Female; Growth Disorders; Male; Radioimmunoassay; Rats; Rats, Brattleboro; Somatomedins; Vasopressins; Weaning

Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Catecholamines; Child; Child, Preschool; Diabetes Insipidus; Emotions; Endocrine System Diseases; Growth Disorders; Hormones; Humans; Hyperthyroidism; Hypopituitarism; Hypothyroidism; Infant; Infant, Newborn; Protein-Energy Malnutrition; Vasopressins

The Medical Research Council of Canada has initiated human growth hormone (hGH) therapy in 151 patients with documented complete hGH deficiency that was idiopathic in 76% of cases, secondary to craniopharyngioma (organic) in 17% and of varied cause in 7%. Approximately 50% of the patients with idiopathic disease had isolated hGH deficiency; during therapy thyroid deficiency developed in five patients and cortisol deficiency in three. A similar increase in mean height velocity occurred in the first treatment phase for patients less than 12 years old (0.93 plus or minus 0.30 cm/mo) and those 12 years and older (0.86 plus or minus 0.29 cm/mo). Although subsequent courses of hGH therapy yielded significantly diminished response in both age groups, this diminution was not progressive: the height velocity of the younger patients returned to 0.82 plus or minus 0.26 cm/ml in the fifth therapy phase. The mean height velocity attained at the optimal dosage (0.20 to 0.29 units/kg three times per week) for each age group did not differ significantly. Despite therapy being carried out for only 6 months of the year, normal increment ratios for height age and bone age against chronologic age were observed in the patients with idiopathic disease. In only four patients did treatment failure occur, and three of these were more than 20 years old. The addition of fluoxymesterone (10 mg/d) to the hGH therapeutic regimen (15 units/wk), when diminished response to hGH alone became evident, promoted an enhanced growth response in 9 of 11 older patients. These data indicate that age of the patient and dosage of hGH, but not diagnostic category, were important influences on the response to therapy. Younger patients responded best and maintained a higher mean growth velocity than older patients during intermittent hGH therapy

Topics: Adolescent; Age Determination by Skeleton; Antibodies; Body Height; Brain Neoplasms; Canada; Child; Cortisone; Craniopharyngioma; Female; Fluoxymesterone; Growth Disorders; Growth Hormone; Humans; Hypopituitarism; Male; Pituitary Hormones; Prolactin; Puberty; Thyroxine; Vasopressins

Topics: Aldosterone; Alkalosis; Angiotensin II; Biopsy; Blood Pressure; Child, Preschool; Diet Therapy; Female; Follow-Up Studies; Growth Disorders; Humans; Hyperaldosteronism; Hyperplasia; Hypertrophy; Hypokalemia; Juxtaglomerular Apparatus; Kidney Concentrating Ability; Kidney Diseases; Norepinephrine; Potassium; Renin; Secretory Rate; Sodium Chloride; Spironolactone; Syndrome; Vasopressins

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Anthropometry; Arginine; Arm; Body Height; Body Weight; Eunuchism; Gigantism; Glucagon; Gonadotropins; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Hypopituitarism; Insulin; Male; Pituitary Hormones; Thyrotropin; Vasopressins

Topics: Adolescent; Diabetes Insipidus; Growth; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Pituitary Function Tests; Skin Manifestations; Thyroxine; Vasopressins

Topics: 17-Hydroxycorticosteroids; Adolescent; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Blood Glucose; Child; Child, Preschool; Female; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Infant; Insulin; Male; Metyrapone; Obesity; Pituitary Diseases; Pituitary-Adrenal Function Tests; Psychosexual Development; Puberty; Puberty, Precocious; Urine; Vasopressins; Virilism

Topics: Arginine; Child; Deficiency Diseases; Endocrine System Diseases; Fasting; Growth; Growth Disorders; Growth Hormone; Humans; Hypoglycemia; Hypothyroidism; Insulin; Radioimmunoassay; Stimulation, Chemical; Turner Syndrome; Vasopressins