Management of Wilms tumors in Drash and Frasier syndromes.

BACKGROUND: Children with WT1 gene-related disorders such as Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end-stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron-sparing surgery was beneficial. PROCEDURE: We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007. RESULTS: We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate-risk tumors and one high-risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron-sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft-tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end-stage renal disease-related complications. The median follow-up time for the 18 survivors was 136 months (range, 17-224 months). CONCLUSION: Most Wilms tumors in children with WT1-related disorders were early-stage and intermediate-risk tumors, with a young age at diagnosis. In patients without end-stage renal disease, nephron-sparing surgery should be considered for delaying the onset of renal failure.

[Turner syndrome]. / Le syndrome de Turner.

Turner syndrome occurs in 1:5000 live births (1:2,500 females) and is caused not only by X-chromosome monosomy, but also in a large degree, by the presence of a mosaicism (45,X) and/or an abnormal X or Y chromosome (deletion, isochromosome X, dicentric chromosome). Clinical features are heterogeneous and typical physical anomalies are often mild or absent. In all cases, patients are short but final height has been improved by growth hormone therapy. Ovarian failure, with variable onset depending on the chromosomal anomalies, is frequent. Others visceral diseases (bone anomalies, lymphedema, deafness, and cardiovascular, thyroid, gastrointestinal diseases) are less common and need a screening at diagnosis, then a survey during adolescence and adulthood. During gestation, typical forms can be diagnosed by ultrasound examination, but mild forms are discovered incidentally during amniocentesis for unrelated reasons (advanced maternal age) and prenatal advice is difficult. The quality of life and social life is better when puberty is not induced too late, and in absence of cardiac disease or deafness. Deafness can lead to learning difficulties and, during adulthood, sterility can have a negative effect on quality of life. The prognosis depends on heart diseases, obesity, arterial hypertension and osteoporosis. Therefore, a long-term follow-up is necessary.

[Postembolic pulmonary hypertension]. / Hypertension pulmonaire postembolique.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease characterized by the persistence of thromboemboli obstructing the pulmonary arteries as an organized tissue. The consequence is an increase in pulmonary vascular resistance resulting in pulmonary hypertension (PH) and progressive right heart failure. BACKGROUND: It is difficult to recognize the postembolic nature of PH because there is no known history of thromboembolic disease in more than 50% of cases. Diagnosis is based on the presence of mismatched segmental defects in the ventilation-perfusion scanning. When CTEPH is suspected, pulmonary angiography and high-resolution CT scan are required to establish the diagnosis and to assess the operability. Pulmonary angiography is always performed in conjunction with a diagnostic right heart catheterization, which is required to confirm the diagnosis of PH and to determine the degree of hemodynamic impairement. If there is a good correlation between the pulmonary vascular resistance and the anatomical obstruction, pulmonary endarterectomy (PEA) must be proposed. Otherwise, vasodilator and antiproliferative treatments and lung transplantation represent interesting alternatives. VIEWPOINT AND CONCLUSION: PEA remains the treatment of choice for eligible patients. Nevertheless, there is a need to conduct randomized trials to assess the efficacy of novel medical therapies in some situations: (1) in inoperable CTEPH due to distal lesions, (2) before PEA (therapeutic bridge) in patients who are considered "high risk" due to extremely poor hemodynamics, (3) in patients with persistent pulmonary hypertension after surgery.

CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development.

CONTEXT: CHARGE (coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities, and/or hearing loss defect) syndrome consists of a combination of congenital malformations including genital hypoplasia and retarded growth. OBJECTIVE: The objective of the study was to study gonadotropic axis function and growth parameters in CHARGE syndrome. DESIGN: This was a retrospective study. PATIENTS: The study included 32 children with CHARGE syndrome. RESULTS: Nineteen of 20 affected boys had micropenis and/or cryptorchidism, consistent with hypogonadotropic hypogonadism during fetal life. None of the boys was of pubertal age. Seven of nine boys tested before the age of 5 months during the neonatal peak period had extremely low testosterone levels. LH response to GnRH stimulation was variable during the first year of life and not correlated with existing clinical abnormalities. None of the girls over the age of 12 yr (n = 7) had begun puberty spontaneously, and a lack of response to GnRH stimulation was documented in five of them. Olfactory evaluation (n = 10) and magnetic resonance imaging (n = 18) of the forebrain revealed defective sense of smell and abnormal olfactory bulbs in all cases. Cardiorespiratory and nutritional problems were corrected, but the mean height of the 25 children who had reached 5 yr of age was -2 +/- 0.2 sd score. Height was not correlated with birth length or body mass index. GH deficiency was diagnosed in only three children. CONCLUSION: These findings suggest that CHARGE syndrome includes the main features of Kallmann syndrome, which is defined by hypogonadotropic hypogonadism combined with a defective sense of smell and abnormal olfactory bulb development. This forebrain abnormality, if confirmed in a larger group of patients, could serve as a major new criterion for the diagnosis of CHARGE syndrome.

A point mutation in the second zinc finger of the DNA-binding domain of the androgen receptor gene causes complete androgen insensitivity in two siblings with receptor-positive androgen resistance.

We have analyzed the nucleotide sequence of complementary and genomic DNAs of the human androgen receptor (AR) gene in two siblings (patients 9006 and 9030) with receptor-positive complete androgen insensitivity (Rec(+)-CAI). Northern analysis indicated that mRNA of the AR was normal in size. However, its expression was relatively reduced in both patients. Consistent with the normal androgen-binding capacity (496 and 552 fmol/mg DNA for patients 9006 and 9030, respectively) but decreased DNA-binding ability (168 fmol/mg DNA) measured in genital skin fibroblasts, no mutation was found in both N-terminal and ligand-binding domains of the AR. However, a single base substitution (G-->A) was found in the second zinc finger of the DNA-binding domain at nucleotide 2372 of the AR cDNA in both cases. This resulted in the replacement of a highly conserved arginine residue (amino acid 614) by a histidine. When the mutated receptor plasmid was cotransfected into PC-3 cells together with the reporter chloramphenicol acetyltransferase gene, chloramphenicol acetyltransferase activity was not induced by 5 alpha-dihydrotestosterone treatment, confirming that the mutation renders the AR nonfunctional and can, therefore, be held responsible for the clinical features in these patients. These results highlight the importance of Arginine-614 in the second zinc finger of the DNA-binding domain of the AR in the protein-DNA interaction.

[Treatment of pulmonary arterial hypertension]. / Traitement de l'hypertension artérielle pulmonaire.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis, and vascular remodeling of small pulmonary arteries. It induces a fixed pulmonary arterial obstruction, persistent elevation of pulmonary arterial resistance, and eventually right heart failure. Conventional therapy is based on simple measures (exercise limitation) and nonspecific treatments (warfarin, diuretics, and oxygen). Pure vasodilators, such as calcium channel blockers, are effective only in a minority of patients who have an acute response to vasodilator testing. Intravenous prostacyclin (epoprostenol) and endothelin receptor blockers have vasodilator and antiproliferative properties. Epoprostenol therapy has significantly improved PAH prognosis and remains the first-line treatment for patients with the most severe disease. Bosentan is an interesting first-line treatment for NYHA functional class III patients. Availability of novel specific drugs (endothelin receptor type A antagonists, prostacyclin analogues, type 5 phosphodiesterase inhibitors) is opening new perspectives in PAH treatment. The long-term benefit of these drugs remains to be evaluated and their respective place in treatment of these patients is still uncertain. The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension.

Assessment of Turner's syndrome by molecular analysis of the X chromosome in growth-retarded girls.

Turner's syndrome (TS) is a common disorder (1/2500 to 1/5000 female births) which is diagnosed at birth in approximately 20% of patients and during childhood or at puberty for the rest. Growth retardation is the most frequent clinical feature of TS, so we systematically searched for TS in female patients referred to our center because of short stature. Three hundred seventy-five female patients, 1 month to 18 yr old (mean +/- SD = 9(7/12) +/- 3(9/12), with growth retardation (less than -2 SD) and/or decreased height velocity were included in the study. Mean growth retardation was -2.57 SD +/- 0.79 (range: -1 to -7). Thirty-two percent of the patients had reached puberty. GH provocative tests were performed in 329 patients (87.7%), and 36 of these patients (11%) had impaired GH secretion (5 complete and 31 partial GH deficiency). TS was evaluated by Southern blot analysis of leukocyte DNA using a multiallelic polymorphic X chromosome marker (88% heterozygosity rate). Y chromosome PCR analysis was carried out if a pattern indicative of TS was obtained. Leukocyte DNA analysis produced an abnormal restriction pattern for 20 of the 375 cases (5.3%). There was a single hybridizing band in 13 cases, an allelic disproportion indicative of mosaicism in 6 cases, and 3 hybridizing bands in 1 case. One patient tested positive in the Y chromosome PCR analysis. Cytogenetic analysis showed 47 XXX trisomy in the patient with a 3-hybridizing-band pattern and confirmed the diagnosis of TS for 17 of the 19 suspected cases: 45 X: n = 7; 45 X/46 Xi(Xq): n = 4; 45 X/46 XX: n = 2; 46 Xi(Xq): n = 1; 45 X/46 Xr(X): n = 1; 45 X/46 XX/47 XXX: n = 1; 45 X/46 XY: n = 1. Cytogenetic analysis was normal (46 XX) for the 2 other patients. The TS phenotype is variable: dysmorphism is often missing or mild (particularly in cases of mosaicism), but growth is reduced in virtually all patients. Screening of 375 growth-retarded girls identified 18 cases of TS, of which 17 were diagnosed by molecular analysis. This incidence (4.8%) was significantly higher than the expected incidence in this population (0.8-1.6%: P < 0.001).

IGF type 1 receptor ligand binding characteristics are altered in a subgroup of children with intrauterine growth retardation.

The IGFs, IGF-I and IGF-II, regulate fetal growth by activating IGF type 1 receptors (IGF-IR). We aimed to quantify the binding of IGF-I to its cognate receptors in intrauterine growth-retarded children (IUGR). We measured the affinity of the erythrocyte IGF-IR and the number of IGF-IR receptors in 17 children with retarded growth (mean height, -2.7 SD), normal levels of GH, and a history of idiopathic intrauterine growth retardation (height at birth, -10 to -2 SD; mean, -3.1 SD). These children had reduced receptor affinity (Kd = 0.47 nM; P < 0.01) and more receptors per cell [binding capacity (Bmax) = 11.7 binding sites/cell; P < 0.05)] compared with control children (Kd = 0.32 nM; Bmax = 7.8 binding sites/cell). Moreover, the distributions of Kd and Bmax suggested that there were two groups of IUGR children. Group 1 included subjects with normal receptor binding function (Kd = 0.36 nM; Bmax = 8.2 sites/cell) and normal levels of circulating IGF-I. Group 2 comprised children with low receptor affinity (Kd = 0.56 nM) and increased receptor number (Bmax = 14.7 sites/cell). This group showed significantly decreased IGF-I levels (-2.1 SD; P < 0.01). We investigated these IGF-IR binding parameters in two additional groups of growth-retarded children (Turner syndrome and patients with chronic renal failure), in whom the IGF-I axis was not believed to be the primary cause, and found that Kd and Bmax were normal or nearly normal. We also measured IGF-IR binding parameters in 4 Seckel syndrome patients with IUGR and severely retarded growth (mean height, -7.9 SD). Their receptor affinity was reduced, but not statistically different, from that in controls, and their receptor number was normal, whereas IGF-I levels were elevated. Our results suggest heterogeneous alterations in IGF-IR binding function in IUGR patients.

New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes.

Classical 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3betaHSD) deficiency is a form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting from mutations in the HSD3B2 gene and causing various degrees of salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. To identify the molecular lesion(s) in the HSD3B2 gene in the 11 patients from the seven new families suffering from classical 3betaHSD deficiency, the complete nucleotide sequence of the whole coding region and exon-intron splicing boundaries of this gene was determined by direct sequencing. Five of these families were referred to Morel's molecular diagnostics laboratory in France, whereas the two other families were investigated by Peter's group in Germany. Functional characterization studies were performed by Simard's group in Canada. Following transient expression in 293 cells of each of the mutant recombinant proteins generated by site-directed mutagenesis, the effect of the 25 mutations on enzyme activity was assessed by incubating intact cells in culture with 10 nM [14C]-DHEA as substrate. The stability of the mutant proteins has been investigated using a combination of Northern and Western blot analyses, as well as an in vitro transcription/translation assay using rabbit reticulocyte lysates. The present report describes the identification of 8 mutations, in seven new families with individuals suffering from classical 3betaHSD deficiency, thus increasing the number of known HSD3B2 mutations involved in this autosomal recessive disorder to 31 (1 splicing, 1 in-frame deletion, 3 nonsense, 4 frameshift and 22 missense mutations). In addition to the mutations reported here in these new families, we have also investigated for the first time the functional significance of previously reported missense mutations and or sequence variants namely, A82T, A167V, L173R, L205P, S213G and K216E, P222H, T259M, and T259R, which have not previously been functionally characterized. Furthermore, their effects have been compared with those of the 10 previously reported mutant enzymes to provide a more consistent and comprehensive study. The present results are in accordance with the prediction that no functional 3betaHSD type 2 isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form of CAH due to classical 3betaHSD deficiency. Whereas the nonsalt-losing form also results from missense mutation(s) in the HSD3B2 gene, which cause an incomplete loss in enzyme activity, thus leaving sufficient enzymatic activity to prevent salt wasting. The functional data described in the present study concerning the sequence variants A167V, S213G, K216E and L236S, which were detected with premature pubarche or hyperandrogenic adolescent girls suspected to be affected from nonclassical 3betaHSD deficiency, coupled with the previous studies reporting that no mutations were found in both HSD3B1 and/or HSD3B2 genes in such patients strongly support the conclusion that this disorder does not result from a mutant 3betaHSD isoenzyme. The present study provides biochemical evidence supporting the involvement of a new molecular mechanism in classical 3betaHSD deficiency involving protein instability and further illustrates the complexity of the genotype-phenotype relationships of this disease, in addition to providing further valuable information concerning the structure-function relationships of the 3betaHSD superfamily.

Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement.

Fetal male sexual differentiation is driven by two testicular hormones: testosterone (synthesized by interstitial Leydig cells) and antimüllerian hormone (AMH; produced by Sertoli cells present in the seminiferous tubules). Intersex states result either from gonadal dysgenesis, in which both Leydig and Sertoli cell populations are affected, or from impaired secretion or action of either testosterone or AMH. Until now, only Leydig cell function has been assessed in children with ambiguous genitalia, by means of testosterone assay. To determine whether serum AMH would help in the diagnosis of intersex conditions, we assayed serum AMH levels in 107 patients with ambiguous genitalia of various etiologies. In XY patients, AMH was low when the intersex condition was caused by abnormal testicular determination (including pure and partial gonadal dysgenesis) but was normal or elevated in patients with impaired testosterone secretion, whereas serum testosterone was low in both groups. AMH was also elevated during the first year of life and at puberty in intersex states caused by androgen insensitivity. In 46,XX patients with a normal male phenotype or ambiguous genitalia, in whom the diagnosis of female pseudohermaphroditism had been excluded, serum AMH levels higher than 75 pmol/L were indicative of the presence of testicular tissue and correlated with the mass of functional testicular parenchyma. In conclusion, serum AMH determination is a powerful tool to assess Sertoli cell function in children with intersex states, and it helps to distinguish between defects of male sexual differentiation caused by abnormal testicular determination and those resulting from isolated impairment of testosterone secretion or action.

Vitamin D-dependent seasonal variation of PTH in growing male adolescents.

Twenty-eight young male adolescents (age from 13 years 6 months to 15 years 9 months) from a horseback-riding school were studied. They were studied at the end of summer (September of 1993) and, six months later, at the end of winter (March of 1994). At each timepoint their height and weight were measured and their pubertal status determined. Blood was collected and 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (PTH1-84), and 1,25-dihydroxy-vitamin D [1,25(OH)2D] were measured. After winter, weight and height had increased by a mean of 2.9 +/- 1.3 kg and of 3.3 +/- 1.2 cm, respectively. 25(OH)D concentrations which were 29.96 +/- 7.46 micrograms/L in September had significantly (p = 0.0001) fallen by a mean of 23.31 +/- 6.6 micrograms/L in March (6.61 +/- 2.04 micrograms/L). March and September concentrations of 25(OH)D were significantly correlated (r = 0.536, p = 0.0039). March values were negatively correlated with the pubertal status (r = 0.41; p = 0.03). In the meantime, PTH had significantly (p = 0.0001) increased by a mean of 8.59 +/- 8.53 ng/L (22.8 +/- 7.44 ng/L in September vs. 30.33 +/- 8.05 ng/L in March). A statistically significant correlation between PTH and 25(OH)D concentrations (r = 0.493; p = 0.0001) was obtained. Serum 1,25(OH)2D concentrations measured in September (37.7 +/- 12.94 ng/L) and in March (38.2 +/- 7.8 ng/L) were not different. March values were positively correlated with pubertal status (r = 0.49; p = 0.008). Modulation of PTH secretion by vitamin D appears to be a physiological mechanism occurring during adolescence. In spite of a marked depletion of vitamin D stores after winter, PTH values remained within normal range. Nevertheless, we cannot exclude that a more prolonged vitamin D deficiency could adversely affect bone metabolism during this critical period of life characterized by an increased need of vitamin D.

Anxiety and depressive disorders in fathers and mothers of anxious school-refusing children.

OBJECTIVE: To examine anxiety and depressive disorders in the mothers and fathers of children with anxious school refusal and to test for the existence of differences in familial aggregation between children suffering from school refusal related to separation anxiety disorder and those suffering from phobic disorder-based school refusal. METHOD: Using a blind standardized diagnostic evaluation (Schedule for Affective Disorders and Schizophrenia-Lifetime version, modified for the study of anxiety disorders; Diagnostic Interview for Genetic Studies; and Schedule for Affective Disorders and Schizophrenia for School-Age Children), the authors compared parental lifetime psychiatric illness for the 2 groups of anxious school refusers. RESULTS: Relationships between specific anxiety disorders in children and their parents revealed increased prevalence of simple phobia and simple and/or social phobia among the fathers and mothers of phobic school refusers, and increased prevalence of panic disorder and panic disorder and/or agoraphobia among the fathers and mothers of school refusers with separation anxiety disorder. Simple and/or social phobia in the father, simple phobia in the mother, and age of the father were associated with the group of phobic school refusers. CONCLUSIONS: The data show the high prevalence of both anxiety and depressive disorders in fathers and mothers of anxious school refusers. Significant differences were observed in familial aggregation considering the subgroups of anxious school-refusing children.

Insulin-like growth factor-I (IGF-I), insulin-like growth factor binding proteins (IGFBP) and insulin-like growth factor type I receptor in children with various status of chronic renal failure.

Chronic renal failure in childhood causes severe growth retardation. The aim of the study was to identify whether changes in the IGF system could account for the growth retardation observed in children with chronic renal failure. Insulin-like growth factor (IGF-I) serum concentrations, insulin-like growth factor binding proteins (IGFBP) and/or IGF-I binding to erythrocyte type I receptor of IGF were analysed in 69 children (mean age 11.6 +/- 4.3 years) with chronic renal failure and growth retardation (mean height -2.6 +/- 1.8 SD). The study population was separated into three groups, according to their renal status, children on conservative treatment (CRF group: n = 30), on haemodialysis (ESRD group: n = 26) and those transplanted (RT group: n = 13). Nineteen of these children, some from each of the three groups, received recombinant growth hormone therapy (rhGH). Mean basal IGF-I serum concentrations were -0.7 +/- 1.2 SD in the CRF group, + 2.1 +/- 3 SD in the ESRD group and + 1.1 +/- 2 SD in the RT group. Under rhGH therapy, as height velocity improved, mean IGF-I concentrations increased up to + 3.1 +/- 0.6 SD in the CRF group, to + 6.9 +/- 2.8 SD in the ESRD group and to + 3.9 +/- 2 SD in the RT group. Basal IGFBP-3 levels, studied by Western Ligand Blot were low in the CRF group and high in the ESRD and normal in the RT groups, whereas IGFBP-2 and a 30-32 kDa IGFBP were always high in all cases. Western immunoblot analysis showed that this 30-32 kDa IGFBP was mostly composed of IGFBP-1 and IGFBP-6 in all three groups, but IGFBP-6 was particularly abundant in the ESRD group. IGFBP-6 concentrations assessed by RIA were moderately increased in CRF children (392 +/- 177 ng/mL) and very high in children on ESRD (2094 +/- 1525 ng/mL) when compared to normal values (131 +/- 42 ng/mL). Binding studies of IGF type I receptor showed that there was no particular difference in IGF-I binding between renal failure patients and normal children. In poorly growing children, especially in ESRD children and to a lesser extent in RT children, high concentrations of IGF-I and IGFBP-1, 2, 3 and 6, suggest a resistance mainly by a sequestration mechanism. Moreover, in the CRF group, especially in the younger children, low levels of IGF-I and IGFBP-3 are evocative of an associated resistance at the GH receptor level.

[Severe hyponatremia associated with anorexia nervosa: role of inappropriate antidiuretic hormone secretion?]. / Hyponatrémie sévère associée à une anorexie mentale: rôle d'une sécrétion inappropriée d'hormone antidiurétique?

BACKGROUND: Anorexia nervosa may be revealed by hyponatremia or associated with it. This hyponatremia can be due to diuretics or laxatives abuse, potomania or inappropriate secretion of antidiuretic hormone as in the case reported here. CASE REPORT: A 15 year-old girl was admitted for anorexia nervosa. She had secondary amenorrhea and asthenia and had lost 14 kg during the preceding 4 months. Her natremia ranged from 112 to 130 mEq/l with normal urinary sodium excretion, serum hypoosmolality (252 mosm/kg) and inappropriately elevated urinary osmolality (698 mosm/kg). Renal, adrenal and thyroid functions were normal. After water loading, patient remained euvolemic, with a negative free water clearance and an increased plasma ADH level with concomitant hyposmolality. A diagnosis of inappropriate secretion of antidiuretic hormone was made, after excluding other conditions such as potomania, drug abuse, vomiting, tumor and chronic lung disease. CONCLUSIONS: Hyponatremia sometimes seen in anorexia nervosa must lead to the search of inappropriate antidiuretic hormone secretion.

[Physiopathology of the somatotropin axis in chronic renal insufficiency]. / Physiopathologie de l'axe somatotrope dans l'insuffisance rénale chronique.

Many factors contribute to the growth failure of chronic renal failure: water and electrolytes disturbances, hypertonicity, phosphate or calcium wasting, secondary hyperparathyroidism, anemia, hypertension, metabolic acidosis, and malnutrition. In addition, the pubertal growth spurt is usually stunted. Growth hormone (GH) resistance is observed with low GH binding protein (GHBP) level, and normal or low IGF I levels despite elevated GH level. Elevated IGFBP levels may contribute to a reduced IGF activity, especially in dialysed patients. Glucocorticoid therapy in transplanted patients further contribute to poor growth and inhibited IGF I activity. As conventional treatments have a limited effect to improve growth, adult height is often far below -2 SD. GH therapy has proved to be successful, especially in young children, overpassing the hormonal resistance so that an adult height within the normal range may be reached.

[Vitamin D status in the adolescent: seasonal variations and effects of winter supplementation with vitamin D3]. / Statut vitaminique D de l'adolescent: variations saisonnières et effets d'une supplémentation hivernale par la vitamine D3.

BACKGROUND: Recently, 25 hydroxyvitamin D (25 OHD) blood concentrations measured in adolescents during or at the end of winter were found very low. A concomitant stimulation of parathyroid function was observed. The aim of the present study was to test the biological effects of a treatment with vitamin D3 during winter. POPULATIONS AND METHODS: The effects of vitamin D3 supplementation (100,000 IU, twice, at the end of November and of January) were assessed in 24 male Caucasian adolescents (mean age +/- SD: 14 y 6 m +/- 9 m). They were pupils in a lad-jockeys training center located in the countryside near Chantilly (49 degrees northern latitude). Blood concentrations of 25 OHD, calcium and intact parathormone (PTH) were measured three times: before each oral intake of vitamin D3 and 2 months after the last intake (March). A group of 32 male adolescents (mean age +/- SD: 14 y 9 m +/- 6 m), pupils in the same center, receiving no vitamin D and sampled in November and in March, served as controls. RESULTS: In March, mean concentrations of 25 OHD (8.36 +/- 2.73 micrograms/L) were very low in vitamin D-not supplemented adolescents since 34% had levels less than 6 micrograms/L. In March, PTH concentrations (40.5 +/- 12.2 ng/L) were significantly (P = 0.0001) higher than in November (28.8 +/- 9.9 ng/L). In boys receiving vitamin D3 25 OHD serum concentrations measured in January (17.5 +/- 3.2 micrograms/L) and in March (18.7 +/- 4.0 micrograms/L) remained at a level not very different from that measured in November (16.6 +/- 3.8 micrograms/L). During the same period, calcium and PTH concentrations (32.2 +/- 11.7 ng/L in November; 32.4 +/- 14.3 in January and 32.9 +/- 13.5 ng/L in March) remained at their basal level as well. CONCLUSIONS: The observation that, after winter, a relatively large number of adolescents presented low concentrations of 25 OHD suggests that, during winter, usual dietary intakes and/or vitamin D stores are not sufficient to provide for their needs. Administration of two oral doses of 100,000 IU of vitamin D3 could maintain the vitamin D status at its initial level. The efficiency of such a prophylactic treatment is also assessed by its effect on parathyroid function.

[Basedow disease in children: clinical and evolutive aspects]. / Maladie de Basedow chez l'enfant: aspects cliniques et évolutifs.

PATIENTS AND METHODS: The initial symptomatology and long-term effects of antithyroid drug treatment are reported in children aged 11.7 +/- 3.2 years (52 girls, 16 boys) with hyperthyroidism due to Graves' disease. RESULTS: A family history of thyroid pathology was found in half of the cases: 7% (five out of 68) of our patients have had another autoimmune disorder associated with hyperthyroidism. The most frequent and permanent clinical symptoms at diagnosis were goiter and tachycardia. Antithyroid drug treatment was always proposed at first line and resulted in a rapid decrease in clinical and biological signs of hyperthyroidism. Subtotal thyroidectomy (n = 19) was mostly performed because of non-compliance or recurrence of hyperthyroidism after medical treatment withdrawal. Significant adverse reaction (leukoneutropenia) was observed in only one patient. Survival remission times analysis (remission being defined as clinical and biological euthyroidism for more than 1 year after antithyroid drug withdrawal) realised in 50 subjects followed up for at least 2.5 years showed complete remission in 55% of the patients treated exclusively medically (n = 27), when lost to follow-up or surgically treated subjects were considered as incomplete observations. On the whole studied population (n = 50), the remission rate was of 30% (n = 15) with an average follow-up period after medical therapy withdrawal of 5.2 +/- 3.0 years (range: 1.4-12.3 years). At present, ten out of 15 can be considered as healed (remission time for at least 2.5 years). Moreover, according to survival analysis, 75% of the remissions have a probability to occur in a delay of 4.6 +/- 1.0 years after the beginning of medical treatment. CONCLUSION: In this population, no remission after 7 years of antithyroid drug therapy was observed. Remission predictive factors remain to be defined.

[Turner syndrome: spontaneous growth of stature, weight increase and accelerated bone maturation]. / Syndrome de Turner: croissance staturopondérale et maturation osseuse spontanées.

BACKGROUND: Since growth hormone is effective in increasing the height of girls with Turner's syndrome, it is important to dispose of growth and bone maturation curves in a large number of untreated patients. POPULATION AND METHODS: Data on growth and bone maturation were collected from 160 patients with Turner's syndrome (50 have reached final height), born 1965-1991, untreated with growth hormone or anabolic steroids. X monosomy was found in half of the patients, mosaicism or X abnormality was present in the other half. Spontaneous puberty occurred in 25% (n = 25) of patients older than 13 years, 38 patients received estrogen after 13 years. Final heights were compared to predicted height according to Lyon's method. RESULTS: Forty-five percent of patients were small for date. Height velocity decreased from 2 years of age and decreased faster during adolescence, when gonadal dysgenesis occurred. Bone maturation velocity decreased also during adolescence. Excessive weight appeared after the age of 5 years. Patients with partial deletion of the long arm of X (n = 6) were taller than the other girls (n = 44) (mean +/- DS) 152.5 +/- 3.1 cm, range 150-158 cm versus 142.5 +/- 4.9 cm, 130-150 cm (P < 0.0001). Final height was not modified by spontaneous puberty. Final height was correlated with birth weight (r = 0.7), maternal height (r = 0.5) and mid parental height (r = 0.5). Finally, the Lyon's method for predicted final height seemed to be suitable for this population, (r = 0.8, P < 0.001). CONCLUSION: Appropriate growth curve is an essential clinical tool in evaluating treatment aimed at increasing final stature in patients with Turner's syndrome.

[Myocardiopathy and isolated glucocorticoid deficit with ACTH resistance: a fortuitous association?]. / Myocardiopathie et déficit isolé en glucocorticoïdes par résistance à l'ACTH: une association fortuite?

UNLABELLED: Hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by an isolated glucocorticoid deficiency which is exceptionally associated to regressive cardiomyopathy. CASE REPORT: A male newborn had iterative episodes of hypoglycemia since the first hours of life. Acute bronchiolitis at the age of 14 days was associated with transitory dilated cardiomyopathy. Hypoglycemia was due to glucocorticoid deficiency secondary to ACTH insensitivity. Molecular biology showed a composite heterozygotism for the ACTH receptor gene. CONCLUSION: Any congenital glucocorticoid deficiency should lead to search for cardiomyopathy.

[Massive hemoptysis during sarcoidosis]. / Hémoptysies graves au cours de la sarcoïdose.

Hemoptysis is a rare but often severe event in sarcoidosis. It usually occurs in patients with advanced, fibrotic lung disease. We herein report the case of a 36-year old female patient with type II pulmonary sarcoidosis who presented with abundant hemoptysis very early during the course of her disease. Two attempts to embolize bronchial arteries remained unsuccessful and surgery was eventually required to stop the bleeding. Clinical, microbiological, radiological and pathological data indicate that haemoptysis was caused by systemic hypervascularization around sarcoidosis granuloma.