All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.
Mutations in multiple genes of the growth hormone/IGF‐I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high‐affinity IGF‐binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy‐associated plasma protein A2 (PAPP‐A2) that is hypothesized to increase IGF‐I bioactivity by specific proteolytic cleavage of IGFBP‐3 and ‐5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF‐I, IGFBP‐3, and ‐5, acid labile subunit, and IGF‐II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP‐A2 proteolytic activity. Size‐exclusion chromatography showed a significant increase in IGF‐I bound in its ternary complex. Free IGF‐I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP‐A2 in releasing IGF‐I from its BPs.
Caloric-protein malnutrition can slow growth and cause pubertal delay. This chapter focuses on endocrine abnormalities and pubertal alterations in patients with eating disorders, childhood obesity, the female athlete triad and children cancer survivors. Patients with anorexia nervosa (AN) exhibit multiple endocrine abnormalities, including isolated hypogonadotropic hypogonadism. The delay in pubertal development and reduction in growth seen in AN patients may be a direct result of malnutrition. Appropriate psychiatric, nutritional and hormonal therapy is necessary. It is suggested that obesity during childhood can accelerate pubertal onset and these children usually exhibit accelerated linear growth during puberty. In girls the relationship between childhood obesity and early pubertal onset could be related to their insulin resistance and/or hyperinsulinemia. The female athlete triad is often observed in physically active girls and women in whom low energy availability with or without disordered eating, menstrual dysfunction and low bone mineral density can be present. In prepubertal girls excess exercise can cause delayed menarche with no effects on adult height, while in postpubertal females it results in menstrual cycle irregularities. The consequences of childhood cancer depend on the type of cancer, its location, the age at which the disease was diagnosed, the dose of radiotherapy, and the type and dose of chemotherapy.
Introduction: Ballet dancers (BDs) have a negative energy balance related to physical training that results in alterations in body composition, sexual development, and adipokine secretion. Our aims were to study anthropometric parameters, body composition, and their relationship with adipokines throughout pubertal development. Subjects and methods: We carried out a prospective follow-up study of 22 female Caucasian BDs (Tanner II stage) followed throughout puberty. Nutritional status was determined by measurement of height, weight, and body mass index (BMI). We calculated growth velocity, bone maturity, and body composition at Tanner stages II, III, and V by dual energy X-ray absorptiometry. Circulating leptin, adiponectin, and soluble leptin receptor (sObR) levels were determined. Results: BDs presented a delay in skeletal maturation during puberty, without affectation of final height. Energy intake was deficient according to their physical exercise, and they had a delay of 1 year in the mean age of menarche. Leptin levels were decreased, whereas sObR and adiponectin levels were increased throughout puberty. The percentage of trunk fat, total fat mass, and fat of the extremities was decreased throughout the study period (P!0.01). Lean mass was increased in the lower extremities, and bone mineral density was normal. Conclusion: A negative energy balance together with maintained physical exercise induced modifications in body composition in BDs. Changes in leptin and adiponectin levels appear to be more related to total fat content than to BMI. Furthermore, the onset and delayed progress of puberty may be related with an inadequate energy balance due to increased exercise.
Objective: This study addresses the influence of the duration of malnutrition and the effect of weight recovery on regional fat mass distribution in moderately malnourished adolescents with anorexia nervosa (AN). Study design: We measured total and regional fat mass and leptin levels in 42 restrictive AN female adolescents and 23 controls. AN patients, followed over 2 years, were divided into three groups: prolonged moderate malnutrition (PM; secondary amenorrhea for over 1 year, nZ14); SM, short period of moderate malnutrition (secondary amenorrhea for less than 1 year, nZ13); and R, recovered from AN (BMI, body mass index and menses recovered for over 6 months, nZ15). Results: Total, trunk, and extremity fat mass were reduced in the PM and SM groups (P!0.05), whereas only PM patients showed altered regional fat distribution with a low trunk to extremity fat ratio (P!0.05). BMI increased after 12 months only in the SM group (P!0.05), with menses resumption in 69% of these patients and BMI normalization at 24 months. Their regional fat distribution was similar to controls throughout the study. No difference in any parameter was found between the R group and the controls. Conclusion: Prolonged malnutrition, but not weight recovery, is associated with an abnormal regional fat distribution pattern in moderately malnourished AN adolescents.European Journal of Endocrinology 157 473-479
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