Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Recombinant human insulin-like growth factor-I therapy for children with growth disorders.

Until recently, the only possible therapy available for treatment of children with significant short stature was recombinant human growth hormone (rhGH). However, recombinant human insulin-like growth factor-I (rhIGF-I) has now become commercially available as a therapeutic option to treat children of short stature caused by severe primary IGF-I deficiency, defined as: height standard deviation score (SDS) less than or equal to -3.0, basal IGF-I SDS less than or equal to -3.0, and normal or elevated levels of GH. Published data demonstrate that rhIGF-I therapy in patients with primary IGF-I deficiency accelerates growth significantly during the first year of treatment, but progressive attenuation is likely in subsequent years. The growth response to rhIGF-I is neither as intense nor as well sustained as the growth response to rhGH among children with GH deficiency. Despite increasing interest in the possibility for broader use of rhIGF-I for growth promotion, especially in children with idiopathic short stature (ISS), it is necessary to wait for studies assessing the efficacy and safety of rhIGF-I therapy in this condition. In this particular population (ISS patients), the combination of rhIGF-I and rhGH, compared with either hormone used alone, may have theoretical advantages. Hypoglycemia has been the most common side effect reported with use of rhIGF-I and is reasonably controlled with adequate food intake. Most of the other (long-term) adverse effects appear to be related to hyperstimulation of lymphoid tissue growth. Little is known about the long-term effects of IGF-I therapy in growing children, but caution and long-term, controlled, prospective trials of rhIGF-I-treated children and adolescents are needed.

Growth hormone deficiency in children.

The foundation for the diagnosis of growth hormone (GH) deficiency in childhood must be auxology, that is, the comparison of the child's growth pattern to that of established norms for gender and ethnicity. It is only in those growing considerably more slowly than average that testing for GHD makes sense. Assessment of laboratory tests, whether static, for example, the measurement of growth factors or their binding proteins, or dynamic, for example, secretagogue-stimulated GH secretion is confirmatory. One must be cognizant of the assay used to determine GH, for there may be a 3-fold difference in the concentration of GH among commercially-available assays. Controversy still exists concerning the measurement of spontaneous GH release and whether sex-steroid priming is appropriate in prepubertal children. Imaging analysis may prove helpful in some children with congenital GHD or to detect a space-occupying lesion in the area of the hypothalamus and pituitary. The final diagnosis is based on multiple parameters and occasionally on a therapeutic trial of GH therapy to determine if there is a significant acceleration of growth velocity.

Male pubertal development and the role of androgen therapy.

In boys, the hormonal changes that accompany normal puberty are well defined, as are the physical signs of pubertal development and the kinetics of the growth spurt. Most androgens are derived from the testes, although adrenal androgens may also contribute; testosterone can also be aromatized to estrogen to exert important effects during puberty. Androgens, but especially their conversion to estrogens by aromatase, have a major role in the dramatic changes in linear growth, secondary sexual characteristics, and changes to bone, muscle and fat distribution that occur during puberty. Androgen therapy for delayed puberty should permit full normal pubertal development and thereby also address some of the associated psychosocial problems. Adolescent boys with conditions of permanent hypogonadism (hypogonadotropic or hypergonadotropic) or transient hypogonadotropic hypogonadism (constitutional delay of growth and puberty) can benefit from testosterone therapy. Long-term testosterone therapy should be given for hypothalamic or pituitary gonadotropin deficiency, or for primary hypogonadism such as for adolescents with Klinefelter syndrome, if endogenous testosterone levels drop or levels of luteinizing hormone rise. Intramuscular administration every few weeks is effective, but newer cutaneous forms, for example, gels or patches, also show promise in permitting adolescent males to reach adult body composition.

Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition.

Integrative neuroendocrine control of the gonadotropic and somatotropic axes in childhood, puberty, and young adulthood proceeds via multiple convergent and divergent pathways in the human and experimental animal. Emerging ensemble concepts are required to embody independent, parallel, and interacting mechanisms that subserve physiological adaptations and pathological disruption of reproduction and growth. Significant advances in systems biology will be needed to address these challenges.

Individualized therapy for growth hormone deficiency.

The use of human growth hormone to treat children with short stature resulting from growth hormone deficiency or insufficiency has now accrued over 40 years of clinical experience with a satisfactory safety and efficacy record. Growth hormone deficiency is the primary indication for growth hormone treatment in childhood. It is basically a clinical diagnosis, based upon auxologic features, and confirmed by biochemical testing. For assurance of compliance, dosing and, perhaps, safety considerations, a dosing algorithm based upon insulin-like growth factor-I response seems to be appropriate. Current data suggest that such algorithms reflect the true growth hormone needs of a patient, and allow optimization of growth hormone treatment. For patients who display a suboptimal growth response or in whom the insulin growth factor levels remain low with assurance of adherence to the injection schedule, it is reasonable to increase the growth hormone dose. The availability of recombinant human insulin-like growth factor-I treatment may provide an alternative for massively increasing the dose of growth hormone. Dose reductions should be considered for patients with serum insulin-like growth factor-I levels substantially above the normal range.

Endocrine control of body composition in infancy, childhood, and puberty.

Body composition exhibits marked variations across the early human lifetime. The precise physiological mechanisms that drive such developmental adaptations are difficult to establish. This clinical challenge reflects an array of potentially confounding factors, such as marked intersubject differences in tissue compartments; the incremental nature of longitudinal intrasubject variations in body composition; technical limitations in quantitating the unobserved mass of mineral, fat, water, and muscle ad seriatim; and the multifold contributions of genetic, dietary, environmental, hormonal, nutritional, and behavioral signals to physical and sexual maturation. From an endocrine perspective (reviewed here), gonadal sex steroids and GH/IGF-I constitute prime determinants of evolving body composition. The present critical review examines hormonal regulation of body composition in infancy, childhood, and puberty.