[Puberty in chronic disease].
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There has been much recent interest in the relationship between androgens and bone mineralization in men. Increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood is important for the maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. The administration of testosterone to androgen-deficient men leads to an increase in bone mass, particularly in the trabecular bone compartment, and a reduction in levels of surrogate markers of bone turnover, suggesting that androgens have a dampening effect on bone remodelling. In addition, the administration of androgens to eugonadal men with idiopathic osteoporosis, with resulting supraphysiological testosterone concentrations, may lead to increases in bone mineral density. The risk of osteopenia due to androgen deficiency and the benefits of testosterone substitution therapy or supraphysiological administration on bone will be reviewed.
The consequences of IBD during childhood and adolescence may be devastating in terms of loss of growth potential, particularly if there has been a clinical course of frequent relapses resulting in inadequate nutrition and associated with repeated courses of steroid treatment. There is to date, however, a paucity of data recording final adult heights in such patients. The anticipation of relapse should become easier with increasing awareness of the importance of parameters of growth and pubertal development. Early and intensive nutritional support, and the use of steroid-sparing agents should help reduce the frequency and severity of any height deficit. The performance and timing of surgery must take into account the child's status in terms of height velocity and pubertal development. The importance of inducing the remission before the onset of puberty is stressed and this remission should be sustained at all costs during the pubertal years so that valuable height is not lost as a consequence of a missed pubertal growth spurt. Thus, increasing awareness of the issues of growth and development in these patients should improve the accuracy of initial diagnosis and early recognition of relapse, such that these children are ensured the best possible provision for achieving their full height potential.
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The number of women of all ages participating in physical activity is consistently increasing. Although there are numerous benefits to physical activity, specific problems may occur along the various stages of the female athlete's life, which need special attention. A remarkably late menarche, exaggerated beyond the expected genetic predisposition and a high prevalence of abnormal or absent menstrual cycles is seen in athletes, especially in dancers and long distance runners. Reproductive system dysfunction is associated with multiple factors, of which nutritional intake and caloric balance seem to be of a special importance. A high proportion of athletes suffer from pathological eating behaviours and there is an overlap between many features of anorexic patients and highly active athletes. The pathophysiology seen in most cases is hypo-oestrogenism due to suppression of the GnRH pulse generator. The mechanism(s) causing this reversible hypothalamic dysfunction are yet unknown. Of major concern are the skeletal abnormalities, including failure to reach peak bone mass, reduced bone density, scoliosis and stress fractures as a result of prolonged hypo-oestrogenism. Hormone replacement may be indicated in cases in which reduction of exercise or weight gain is not feasible or unsuccessful. Other populations that need special precautions are pregnant athletes and older women.
PURPOSE: To evaluate the growth of premenarchal patients with anorexia nervosa. METHODS: Growth parameters were measured semi-annually in 16 subjects with anorexia nervosa until 1 year post-menarche. RESULTS: Despite the accelerated growth that followed nutritional rehabilitation, the patients did not achieve their genetic height potential.
We describe a recently identified new form of dwarfism due to isolated growth hormone (GH) deficiency, secondary to inactivating mutations in the GH-releasing hormone receptor (GHRHR) gene. The identical nonsense mutations in the extracellular domain of the GHRHR (E72X or E50X, depending on whether the signal peptide is included in the numbering) has been independently described in three families residing on or originating from the Indian subcontinent (Pakistan, the Bombay region, and Delft near Sri Lanka). Another inactivating mutation, involving the donor splice site of intron 1, has been identified in a population in north-eastern Brazil. Genetic transmission is autosomal recessive; the gene is located on the short arm of chromosome 7. Affected subjects have severe isolated GH deficiency and postnatal growth failure, with a mean adult height of 130 cm for men and 114 cm for women (7-8 standard deviations below the norm). Dwarfism is proportional; a characteristic feature is relative microcephaly, which results in a 'miniaturized adult', eumorphic aspect. Bone age and puberty are delayed, but fertility appears normal. This new syndrome corresponds to the human homologue of the previously identified 'little mouse'.
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Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive disorder, characterized by disproportionately short stature and degenerative joint disease, which manifests in the early teens. The gene responsible for SED tarda, SEDL, has been identified in Xp22. We report on three novel SEDL mutations. The first mutation is in the rare, non-canonical 5' splice site of intron 4 (IVS4+4T>C) in an Italian family. Reverse transcription-polymerase chain reaction (RT-PCR) analysis has revealed that this mutation causes alternative splicing of exon 5, and, as a consequence, inclusion of exon 4b sequence. This gives rise to an altered, truncated SEDL protein. We also describe two new deletions: one is a 4-bp deletion in exon 6 [333-336del(GAAT)], identified in a Slovak patient with SEDT, and one is a 1.335-kb deletion (in5/ex6del), found in a Belgian patient. The identification of these novel mutations in SEDL adds to the spectrum of 30 mutations previously identified. A short summary of all currently known SEDL gene mutations is presented.
We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.
Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.
OBJECTIVE: Nutritional status is an important marker of overall health and linear growth retardation has serious long-term physiological and economic consequences. Approximately 35 and 29% of preschool children in sub-Saharan Africa are stunted and underweight, respectively. There is relatively little information available about the nutritional status in adolescents, the age group with the highest growth velocity after infancy. We conducted a series of cross-sectional surveys to determine the prevalence and main risk groups for malnutrition and to describe the associations between age, sexual maturation and nutritional status in adolescent schoolgirls in western Kenya. DESIGN: Three cross-sectional surveys; one in Mumias, using random sampling in all schools, and two surveys in Asembo, using a multi-stage random sample design. SETTING: Public primary schools in two different rural malaria endemic areas in western Kenya with high levels of malnutrition in preschool children. SUBJECTS: In all, 928 randomly selected adolescent schoolgirls aged 12-18 y. RESULTS: Overall prevalence of stunting and thinness was 12.1 and 15.6%, respectively. Of the total, 2% were severely stunted. Menarche and start of puberty were delayed by approximately 1.5-2 y compared to a US reference population. The prevalence of stunting and thinness decreased with age and mean height for age z-scores converged towards the median of the US reference curve. Girls who had not yet started menstruating were more likely to be stunted than the girls of the same age who were post-menarche. CONCLUSIONS: Stunting and thinness are common in young adolescent schoolgirls in these poor rural settings in western Kenya, but the prevalence decreases with age, providing observational support that children catch up on incomplete growth attained earlier in life due to a maturational delay of 1.5-2 y allowing prolonged growth.
Five cases of Kallmann's syndrome are presented, out-patients with microtestes, hypogonadotropic hypogonadism and complete anosmia. The final diagnosis was made only when they were aged between 17 and 26 (mean 21 years), although they had been seen by several physicians before: 3 for cryptorchidism and 3 for absence of spontaneous puberty; 2 had a positive family history, and 4 of the 5 patients or their parents admitted that they were aware of the fact that their sense of smell was completely absent, but they did not mention it spontaneously.
Little is known about the incidence of and risk factor for late effects of infant leukemia. We evaluated 19 children with acute lymphoblastic leukemia and 15 with acute myeloid leukemia who were diagnosed at age 12 months or younger and have survived for more than 5 years after the diagnosis (median length of follow-up, 13 years; range, 5.7-29 years). Ten patients received chemotherapy alone (group A), 17 received chemotherapy and CNS-directed radiation therapy (CRT) (group B), and seven received chemotherapy, CRT and bone marrow transplantation (group C). The most frequently observed late sequelae included problems in growth (66% of survivors), learning (50%), hypothyroidism (15%), and pubertal development (12%). Cataract, cardiac and hearing abnormalities occurred in 6% of patients. Only eight patients (24%) survive without late effects. In comparison to patients in group A, patients in groups B and C had a higher incidence of having at least one late complication (P = 0.009), a greater decrease in height Z score at 5 years after diagnosis (P = 0.023), and a higher incidence of academic difficulties (P = 0.004). The estimated odds of academic difficulties increased by 18% (P = 0.032) for each month younger in age at the time of CRT. These results indicate that late sequelae are common in longterm survivors of infant leukemia and are often related to CRT and the patient's age at the time of CRT.
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Reduction of bone density and its associated morbidity is recognized in young adults with beta-thalassaemia major, but the aetiology is not clear. This study used dual X-ray absorptiometry (DXA) to look at bone mineral apparent density (BMAD) in children and young adults with thalassaemia in a predominantly Asian population, in the context of sexual maturation. Fifty-five patients were scanned (mean age 13.8 years, range 5.9-37.5) and BMAD z-scores were calculated using normal data from locally recruited control subjects. Eighteen patients had undergone bone marrow transplantation (BMT) and the remainder were on a transfusion/chelation regimen. BMAD z-scores ranged from -3.3-1.6 with a mean of -0.92. No difference in BMAD was found between those patients treated conventionally and those who had undergone BMT. When comparing mean BMAD z-score according to sexual maturation, there was a highly significant difference (P < 0.0001) between those whose pubertal maturation was age appropriate (mean z-score -0.22), when compared with those who had disordered puberty (mean z-score -1.82). We have shown that failure to progress normally through puberty is highly significant in the failure of adequate bone mineralization and achievement of peak bone mass in thalassaemic patients. The management of these patients should therefore be pro-active to anticipate problems and facilitate normal sexual maturation.
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