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Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations. © 2004 Wiley-Liss, Inc.

Objective To analyze glycemic profile in children with congenital central hypoventilation syndrome, which is characterized by autonomic nervous system dysfunction. Study design We carried out a university hospital–based observational study. Participants included 14 patients assessed from 2007 to 2009 with a median age of 7.6 (25th-75th percentiles, 1.5-9.6) years at the time of the study. Glucose metabolism was assessed by calculating 24-hour plasma glucose (before and after meals) and fasting insulin concentrations and carrying out an oral glucose tolerance test (OGTT). The main outcome measure was the proportion of patients with abnormal glucose concentrations. Results Abnormal plasma glucose concentrations were found in 6 (43%) of the 14 patients with high fasting (n = 1) or postprandial (n = 5) hyperglycemia. OGTT was performed in 8 patients, of whom 3 (38%) had impaired glucose tolerance. Indices of insulin resistance and secretion were normal. No difference in clinical aspects relating to the presence of affected organs and/or systems related to central nervous system dysfunction, age, or auxology findings was found between patients with normal (43%) and abnormal (57%) glucose homeostasis over a 24-hour glycemia cycle or OGTT. Conclusion This study provides new information about glucose homeostasis in congenital central hypoventilation syndrome, revealing a high incidence of hyperglycemia and expanding the spectrum of the disease. It highlights the link between autonomic nervous system dysfunction and glycemic dysregulation. Regular, long-term monitoring of glucose metabolism is recommended in these patients.

We report the detection of a homozygous G to A mutation converting codon Gly15 into Asp15 in the type II 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) gene in a male pseudo-hermaphrodite born from consanguineous parents and suffering from severe salt-losing 3 beta-HSD deficiency. To investigate further the potential involvement of residue 15 in the beta alpha beta dinucleotide-binding fold, we have studied the effect of substituting Gly15 for Ala15. We assessed the effect of the G15D and G15A missense mutations on enzymatic activity by analyzing mutant enzymes generated by site-directed mutagenesis of type II 3 beta-HSD cDNA after their transient expression in COS-1 cells. In intact transfected cells, after a 2-h incubation, the percentage of conversion of [3H]pregnenolone (PREG) into [3H]progesterone (PROG) was 35% and 50% for the G15A and native type II 3 beta-HSD enzymes, respectively, whereas no detectable activity was observed in cells expressing the G15D protein. This finding is in agreement with the severity of the disease in the homozygote G15D index case. On the other hand, in homogenates from cells transfected with the normal pCMV-type II 3 beta-HSD plasmid or with the mutated pCMV-G15D or pCMV-G15A plasmid, the Km values for PREG were 0.72 microM, 3.2 microM, and 3.4 microM, respectively, when incubated for 1 h in the presence of excess (1 mM) NAD+. Moreover, the expressed G15D and G15A proteins had decreased affinities for NAD+ with Km values of 113 microM and 148 microM, respectively, compared with 22 microM for normal type II 3 beta-HSD.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is Inherited in an autosomal dominant, male-limited pattern. A heterozygous mutation encoding substitution of Asp578 with Gly in transmembrane helix 6 of the G protein-coupled receptor for luteinizing hormone (LHR) has been found in affected males from nine American FMPP families. Cells expressing the mutant LHR exhibit markedly increased cyclic adenosine monophosphate (cAMP) production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LHR. We have now analyzed genomic DNA from affected males from six additional FMPP families. PCR was used to amplify a fragment of the LHR gene encoding amino acid residues 441–594. None of the six new samples contained the Asp578→Gly mutation, as indicated by absence of digestion with Mspl. PCR products were then screened for heterozygous mutations using temperature-gradient gel electrophoresis. DNA fragments from two of the patients migrated abnormally. Direct sequencing of PCR product from one affected German male revealed a heterozygous mutation (ATG→ATA) encoding Met571→lle at the cytoplasmic end of hellx 6, the same mutation that has been reported In another European FMPP kindred. Affected males in the second family had a novel Thr577→lle mutation (ACC→ATC). Mutations in different portions of the LHR or in a different gene may be responsible for disease In the other FMPP kindreds. Agonist binding and functional coupling of the mutant receptors to the cAMP and inositol phosphate pathways were studied by transiently expressing them in COS-7 cells. Agonist affinity was unaffected by the mutations. Like the Asp578→Gly mutant receptor, the two newly identified mutant receptors triggered agonist-Independent production of cAMP, but not of inositol phosphates, suggesting that autonomous testosterone production in FMPP can be explained by constitutive activation of thecAMP pathway alone.

Nonobese diabetic (NOD) mice spontaneously develop an autoimmune form of diabetes associated with insulitis. A number of immunomodulatory therapies have been investigated as a treatment for the disease process. Oral administration of the autoantigens myelin basic protein and collagen type II suppresses experimental models of encephalomyelitis and arthritis. We have now found that oral administration of insulin delays the onset and reduces the incidence of diabetes in NOD mice over a 1-year period in animals administered 1 mg of porcine insulin orally twice a week for 5 weeks and then weekly until 1 year of age. As expected, orally administered insulin had no metabolic effect on blood glucose levels. The severity of lymphocytic infiltration of pancreatic islets was also reduced by oral administration of insulin. Furthermore, splenic T cells from animals orally treated with insulin adoptively transfer protection against diabetes, demonstrating that oral insulin administration generates active cellular mechanisms that suppress disease. These results show that oral insulin affects diabetes and the pancreatic cellular inflammatory process in the NOD mouse and raise the possibility that oral administration of insulin or other pancreatic autoantigens may provide a new approach for the treatment of autoimmune diabetes. Type I diabetes or insulin-dependent diabetes mellitus (IDDM) is thought to be an autoimmune disease in humans (1-3). The nonobese diabetic (NOD) mouse spontaneously develops IDDM that has many immunological and pathological similarities to human insulin-dependent diabetes. The autoimmune nature of the disease is suggested by the lymphocytic infiltration of the islets of Langerhans, which precedes the destruction of insulin-producing beta cells (4). As such, the NOD mouse has served as one of the primary models for IDDM and a model in which new approaches for immunotherapy have been investigated. A variety of immunomodulatory treatments have been studied in the NOD mouse. In general, treatments that affect T-cell function or are immunosuppressive have been effective, such as neonatal thymectomy and in vivo treatment with anti-CD4 monoclonal antibody and cyclosporine A (5-7). A major impetus behind such studies has been to develop approaches that may be utilized to treat human IDDM. Clinical trials in humans have demonstrated that antigen nonspecific immunosuppression with drugs such as cyclosporine A and azathioprine can affect beta-cell destruction after diabetes onset, but such therapy is not curative and is associated with drug-related toxicities (8, 9). The ability to identify patient populations at risk for diabetes (10, 11) makes the development of disease-specific nontoxic forms of therapy that can be administered to prediabetics to prevent or reduce the incidence of diabetes a major therapeutic goal. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. ?1734 solely to indicate this fact. We have been investigating antigen-driven peripheral immune tolerance as a means to suppress autoimmune processes, using the oral route of antigen exposure. Orally administered antigen stimulates the immune system in a physiologic fashion and has long been recognized to produce systematic immunologic hyporesponsiveness or tolerance (12-14). We and others have found that oral administration of autoantigens suppresses animal models of autoimmunity including experimental autoimmune encephalomyelitis (EAE) (15-17), adjuvantand collagen-induced arthritis (1820), and experimental autoimmune uveitis (21). Oral tolerance as a means to treat diabetes is especially attractive because of its virtual lack of toxicity and its inherent clinical applicability. In addition, such therapy cotild be applicable to pancreatic islet transplantation. In the present report, we have found suppression of diabetes in the NOD mouse by oral administration of insulin. MATERIALS AND METHODS Animals. NOD mice were purchased from Taconic Farms, maintained in our animal facility, and fed regularly with Purina Mouse Chow 5015 or 5008. The animals studied in experiments in Table 1 and Fig. 4 were housed in a conventional room, and those studied in all other experiments were housed in a virus antibody-free (VAF) facility. Female NOD mice were used for all experiments except for recipients in adoptive transfer experiments. Assessment of Diabetes. Mice were monitored for development of diabetes weekly by urinary glucose testing with test strips (Eli Lilly). Glycosuric mice were then bled to check for glycemia by using a glucose analyzer (Beckman). Diabetes was confirmed by hyperglycemia (>13.8 mM) for 2 consecutive weeks. Antigens. Porcine monocomponent insulin was purchased from Novo Biolabs (Danbury, CT). Myelin basic protein (MBP) was prepared as described (15). Oral Administration of Antigen. Insulin or MBP in phosphate-buffered saline (PBS; 1.7 mM KH2PO4/5 mM Na2HPO4/150 mM NaCl) was administered to mice orally through a syringe fitted with a ball-type feeding needle in a volume of 0.5 ml per mouse per feeding. Histopathology. The animals were sacrificed by cervical dislocation, and the pancreases were taken and immediately frozen. Cryosections (3 or 4 sections per mouse) were fixed with acetone and double-stained with (i) biotinylated monoclonal anti-thy-1.2 antibody plus avidin-peroxidase conjugate and (ii) monoclonal anti-beta-cell antibody (A2B5) plus alkaline phosphatase-conjugated anti-mouse IgM. The degree of insulitis was scored blindly by two independent observers using a semiquantitative scale ranging from 0 to 4: 0, normal islet with no sign of T-cell infiltration; 1, focal peri-islet T-cell infiltration; 2, more extensive peri-islet infilAbbreviations: NOD, nonobese diabetic; IDDM, insulin-dependbnt diabetes mellitus; MBP, myelin basic protein; EAE, experimental autoimmune encephalomyelitis; VAF, virus antibody-free.

Cushing's disease is the most common cause of Cushing's syndrome in children and is almost always related to over secretion of ACTH by the pituitary gland. It is important to identify a secreting adenoma prior to surgery. Seven cases studied with MRI are reviewed. In five cases the MRI findings suggested adenoma. Three secreting adenomas were confirmed at surgery. One case was in fact a cyst of the pars intermedia, and nothing could be found in the last case. Two patients presented with apparently normal findings on MRI, which was confirmed. There is a close correlation between identifying an adenoma and the success of surgery.

Objectifs Evaluer la fonction testiculaire apres la puberte chez le jeune adulte opere dans l’enfance d’un hypospade associe a 46 XY DSD idiopathique. Materiels et Methodes Les patients 46XY DSD idiopathique (hypospade et cryptorchidie ou micropenis), nes avant 1994, eleves en garcon, ont ete inclus (n = 30). Dix ont ete perdus de vue et 20 ont eu une evaluation de la fonction testiculaire (FSH, LH, inhibine B et testosterone) a un âge median de 16,6 ans (14-20). Au diagnostic, 7 garcons (35 %) ont une dysgenesie testiculaire (testosteronemie 3 groupes ont ete definis a la puberte: 1 : fonction testiculaire normale, 2 : insuffisance testiculaire exocrine (inhibine B Resultats Groupe 1 (n = 7, 35 %) : puberte spontanee. Groupe 2 (n = 4, 20 %) : puberte spontanee, testosterone normale et inhibine B basse. Groupe 3 (n = 9, 45 %) : puberte induite, inhibine B effondree. Conclusion Le risque d’insuffisance testiculaire est tres eleve (65 %). Ces resultats, inconnus auparavant, soulignent l’importance du suivi a long terme.

Introduction La transition des soins chez les jeunes diabetiques de type 1 (DT1) a la periode critique de l’adolescence comporte des enjeux medicaux majeurs. Patients et Methodes Les risques de rupture de suivi et de complications ont ete evalues longitudinalement dans une etude multicentrique en Ile de France (6 centres de pediatrie et 9 centres de diabetologie pour adultes). Des auto-questionnaires ont ete remplis par les patients et un questionnaire par leurs medecins a la derniere visite en pediatrie (T1), puis en diabetologie pour adultes 0,5-2 ans apres (T2). Resultats 61 patients (60 % du taux regional) âges de 18,6 ans DT1 depuis 8,8 ans, ont ete inclus a T1. Les donnees ont ete recueillies a T2 chez 57 patients (93 %), en moyenne 1 an apres T1. Le taux moyen d’HbA1c ne differe pas entre T2 et T1 (9 ± 2,2 % vs 8,9 ± 1,8 %), malgre l’augmentation du nombre d’injections (3,7 vs 3,3 inj/jour). Le nombre d’acidocetoses/an tend a etre plus eleve a T2 qu’a T1 (p = 0,06). 6 patients ont developpe une retinopathie minime (RD) a T2 (HbA1c = 9,7 ± 1,2 %, duree du DT1 = 11,2 ± 3,9 ans). Par comparaison avec les patients sans RD, ils sont significativement plus âges (20,2 vs 19,4 ans, p = 0,05) et ont un IMC plus eleve (25,7 vs 22,6, p = 0,025). A la fin de l’etude, 14 patients (23 %) sont en rupture de suivi : 7 n’ont jamais ete pris en charge en diabetologie adultes apres T1 malgre une transition organisee ; 7 autres patients ont rompu leur suivi en diabetologie pour adultes. Conclusion Cette etude montre les risques de la transition des soins chez les adolescents DT1 malgre une organisation de cette transition. Le mauvais controle glycemique, l’apparition de complications, et le taux eleve de ruptures de suivi font insister sur la necessite de developper 1) des soins et des strategies specifiques, 2) une supervision etroite des patients au moment de la transition et dans les 2 annees apres, par une collaboration active entre pediatres et diabetologues pour adultes, 3) l’identification de patients a haut risque de rupture de suivi lors de la transition.

L’hypothyroidie congenitale (HC) est l’une des maladies endocriniennes les plus frequentes chez l’enfant (1/3500). Si les athyreoses et les ectopies en representent la cause principale, les troubles de l’organification de l’iode (TOID) en sont une cause non negligeable (incidence inconnue). Leur physiopathologie reste mal elucidee et seuls quelques genes codant pour des facteurs cles de l’hormonosynthese (thyroperoxydase, DUOX2 oxidase, pendrin) ont ete incrimines sans qu’aucune correlation genotype- phenotype n’ait plus etre clairement etablie a ce jour. Le but de cette etude a donc ete de 1) determiner l’incidence des TOID. 2) decrire le phenotype precis d’une large cohorte de patients atteints, ceci afin ulterieurement de tenter une correlation genotype- phenotype apres etude moleculaire. Patients 71 enfants nes entre 1980 et 2006 atteints d’HC due a un TOID et suivis dans 3 hopitaux pediatriques parisiens ont ete retrospectivement inclus dans cette etude. Resultats Un TIOD a ete identifie chez 13.6 % des enfants atteints d’HC depistes dans la periode 2003-2006 (incidence 1 : 20.660). Parmi les 71 enfants porteurs d’un TIOD etudies, 61 avaient un TIOD partiel (defini par un taux de captage thyroidien a la scintigraphie, 1h apres administration de perchlorate entre 10 et 85 %) et 10 avaient un trouble total (taux > 90 %). Dans l’ensemble, les enfants porteurs d’un TIOD total presentaient une symptomatologie relativement uniforme et significativement plus severe que les patients avec TIOD partiel (hypotonie, ictere prolonge, distension abdominale, cri rauque) (p Conclusion La symptomatologie severe et uniforme des sujets atteints d’HC due un TIOD total suggere un defaut unique dans un facteur cle de l’hormonosynthese. Inversement, la presentation tres variable des enfants atteints d’HC due a un TIOD partiel suggere la responsabilite de plusieurs facteurs impliques dans l’organification de l’iode.

Introduction L’augmentation recente et importante d’incidence du diabete chez le tres jeune enfant represente un defi en diabetologie pediatrique. Patients et methodes L’analyse des differentes typologies du diabete et des caracteristiques du diabete de type 1 (DT1) de la naissance a 3 ans a ete menee dans un centre de diabetologie pediatrique de 2003 a 2006. Resultats Sur une periode de 4 ans, les enfants de moins de 3 ans (âge moyen = 19,5 mois) representent 21 % de tous les nouveaux cas de revelation de diabete de 0 a 15 ans (74/350). L’analyse des differentes etiologies de diabete chez ces tres jeunes enfants revele 78 % (n = 54) de DT1 autoimmun, 14,5 % (n = 10) de diabete non-type 1 de 5 etiologies genetiques differentes (diabete neonatal, lipoatrophique congenital, leprechaunisme, MODY, mitochondrial), et 7,5 % (n = 5) d’hyperglycemies transitoires. Les caracteristiques cliniques, biologiques, immunogenetiques sont analysees pour les 54 cas de DT1. Le plus jeune enfant atteint de diabete de DT1 est âge de 7 mois. Le DT 1 represente dans notre serie, 53 % des diabetes de moins de 1 an, 96 % des 1-2 ans et 79 % des 2-3 ans. Ils sont caracterises par : une duree de la symptomatologie courte ( Conclusion Cette etude precise sur une large serie, la frequence elevee du diabete du tres jeune enfant, les caracteristiques du DT1 temoignant d’une destruction plus agressive et plus rapide des cellules beta du pancreas, et indique l’importance de l’analyse du bilan etiologique du diabete avant l’âge de 3 ans.

Introduction La transition des soins a l'adolescence comporte des enjeux medicaux (risque de rupture de suivi et de complications) et psycho-sociaux, et doit etre evaluee. Patients et methodes Une etude de la transition des soins est menee dans la region Ile de France aupres de patients diabetiques suivis dans 6 services de pediatrie et 9 structures de diabetologie pour adultes. La phase 1 est une etude de suivi de cohorte qui comporte 2 temps (fin de pediatrie, puis 1 an apres) et repose sur des auto-questionnaires remplis par les patients et un questionnaire rempli par le medecin. Resultats Soixante et un patients âges de 18,6 ans (16,9-21,7 ans) diabetiques de type 1 depuis 8.8 ans ont ete inclus dans l'etude a leur derniere consultation en pediatrie en 2006. Ils representent 60 % des passages annuels dans la region. 68 % recoivent un traitement par multi-injections. La mediane de l'HbA1c est de 8,9 % (6,1 a 15,6 %), 3 patients sur 4 ont une HbA1c > 7,6 %. Ils n'ont pas de complications sauf 2 cas de micro-albuminurie et 2 cas d'hypertension arterielle. Concernant leurs comportements a risque : 20 % sont fumeurs, 20 % consomment alcool et cannabis, et 10 % ont eu au moins une tentative de suicide. Le taux de depression est de 18 % (echelle ADRS). Les patients percoivent une bonne alliance therapeutique avec leur pediatre (score moyen=78 % du score max de l'echelle de Consoli). La majorite d'entre eux juge que la transition se fait au bon moment (88,5 %), mais 13 patients (21 %) estiment ne pas avoir ete prepares au passage. Le suivi 8 mois apres indique que 85 % des patients se sont bien presentes en diabetologie pour adultes ; 7 patients ont une rupture de suivi au passage. L'etude se poursuit avec une 2 e enquete chez tous ces patients 1 an apres la fin du suivi pediatrique. Conclusion L'etude portant sur un large echantillon regional de jeunes diabetiques permet de decrire leur etat de sante medical et psychologique en fin de suivi pediatrique au moment de la transition des soins, et indique la necessite d'une vigilance et d'une organisation commune entre les pediatres et les diabetologues pour reperer les ruptures de suivi et identifier les patients a risque ou necessitant une prise en charge specifique de la transition.

Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean ± SE duration of 316 ± 21 days (range 31–850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of β-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18–24 mo of treatment were within normal limits. We conclude that this immunosuppressive regimen given to patients with overt type I diabetes maintains a residual insulin secretion, which, however, does not allow >2-yr remissions of insulin dependency. It remains to be studied whether some preservation of β-cell function will thereafter be retained and whether this can improve the management and prognosis of the disease. It will also be necessary to test whether earlier diagnosis can ameliorate and prolong our results.

Culture of rat islets of Langerhans for 1 week at 37 degrees C with recombinant transforming growth factor beta prolonged the survival of islet xenografts transplanted into diabetic mouse recipients. Treatment of diabetic recipients with a neutralizing monoclonal antibody to murine interferon gamma did not affect the survival of islet xenografts cultured 7 days in control medium. However, treatment of donor islets with transforming growth factor beta in combination with treatment of diabetic recipients with interferon gamma antibody produced a 75% survival of the islet xenografts at 100 days. Fifty percent of the recipients who had accepted their graft for more than 100 days were immune unresponsive to a transplant of freshly isolated islets from the same donor strain.

The use of growth hormone (GH) has progressively moved from a substitution therapy to a pharmacological agent promoting growth when it is otherwise considered insufficient. This process has progressed

Editor—We were surprised that in his editorial to our paper Saenger challenged our conclusions that most patients treated for growth hormone deficiency do not have this condition, and that controlled trials should be organised to evaluate the long term effects of growth hormone in most of the patients currently treated.1 Saenger supports the use of an integrated approach to diagnosing growth hormone deficiency and the wider use of IGF-1 measurements, as suggested by the Growth Hormone Research Society. However, his recent publications, as coauthor or senior author, do not reflect his plea.2,3 This contradiction reflects the widespread contrast between the recommendations in consensus guidelines and current practice or clinical research protocols. In the absence of a gold standard, how can growth hormone deficiency be defined? We propose using long term results of treatment in comparison with spontaneous outcome. The results of our observational study indicate that most patients had no clear benefit. Saenger argues that the patients in our paper were not treated for long enough and therefore do not provide long term results of growth hormone treatment. He contrasts our results with those reported by Blethen et al in 121 patients from the national cooperative growth study database, who were treated for a mean of 6.2 years compared with 3.2 years in our report.4 We included all patients who had started treatment to calculate its mean duration, whereas the 121 patients analysed represent less than 1% of around 14 000 patients in the national cooperative growth study. If we had selected only the 1% of patients with the longest treatment duration, our mean treatment duration would have been 7.9 years. We thought that we had made it clear in our paper that reports focusing on patients with longer treatments give a biased and overoptimistic view of the results. Obviously not clearly enough. We agree with Saenger that you can draw an analogy between the real estate business and use of growth hormone: better location in real estate and longer duration of growth hormone treatment both mean higher costs. However, a good location in real estate generally results in a good long term investment whereas the result of long term growth hormone treatment is still debatable.

Prenatal diagnosis of the classic forms of the congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency has progressed at the same time as the advances made in the field of both endocrinology and molecular genetics. In 1975, prenatal diagnosis of CAH was first made in the second trimester on the basis of raised levels of 17-hydroxyprogesterone (17-OHP) in the amniotic fluid (AF). Later an indirect prenatal diagnosis based on the genetic tracking of CAH was greatly facilitated by its linkage to HLA. By 1979, to obviate the need for corrective genital surgery the virilized genitalia in CAH female fetuses, a prenatal treatment was proposed by giving dexametfiasone to the mother in early pregnancy, and later was shown to be successful. Rapidly, there was a demand for an early prenatal diagnosis of the affection. This was rendered possible by the advances in molecular biology associated with the practice of chorionic villus biopsy. Prenatal diagnosis was then done in the first trimester of the pregnancy, by either HLA typing using HLA-DNA probes or direct studies of the genetic abnormalities of the C4-CYP21 locus. In practice, four methods have been, and can still be used : measurement of AF levels of 17-OHP, HLA typing, molecular studies of the C4-CYP21 genes, all in association with fetal sex determination (measurement of AF testosterone levels, karyotype and more recently detection of Y-chromosome specific sequences). Steroid analysis remains a simple and safe method in the absence of prenatal treatment and the only informative method when there is no previous family study. Nowadays, an early and accurate prenatal diagnosis can be achieved by molecular genetic studies on DNA extracted from chorion villus samples, but it requires the previous study of the nuclear family. The choice between HLA typing and direct C4-CYP21 loci studies depend on the possibilities and expertise of a given laboratory. HLA typing is still more often used with the improvement of using molecular studies instead of serological methods because almost all families are then informative. Nevertheless, HLA typing is unreliable in some circumstances: in case of a recombination event (1 % in our studies of over 250 families) or de novo mutation(s) and when the index case is deceased or not available. Studies of the C4-CYP21 gene locus by Southern blotting and the CYP21B gene mutations by PCR method have not these disadvantages. In our hands, Southern blotting study of the duplicated C4-CYP21 region has shown some complex genetic rearrangements and is fully informative method for prenatal diagnosis in about 60% of CAH families. The 9 most common point mutations of the CYP21B gene causing CAH (and also present in the CYP21A pseudogene) can be detected after specific PCR amplification of the functional CYP21B gene. In these conditions, almost all families are informative in our experience. Moreover, using this direct genetic analysis associated with the possibility to detect the heterozygotes in a non related-CAH population, a prenatal diagnosis could be done in a family without a previous CAH affected child. A prenatal diagnosis in the first trimester is required in order to stop unnecessary prenatal treatments (if unaffected female fetuses and all males fetuses), or when the parents wish to interrupt the pregnancy in case of a CAH affected fetus. In our experience using molecular genetics of the CYP21-C4 loci and sex determination by PCR method (SRY, Y-chromosome repeated sequences) or karyotype, prenatal diagnosis has been successfully done in 23 pregnancies at risk 1:4. In one case, there was no previous family study because the index c;>se was dead; in an other family, the only informations were the state of heterozygoty of the parents: one being a relative of a characterized CAH family, the other being detected by a systematic ACTH test and confirmed by mutation studies.

We studied the POMC gene in 3 cases (1 boy, 2 girls) of isolated ACTH deficiency with manifestations of hypocortisolism before 6 months of age, undetectable ACTH after stimulation with LPH and/or CRF, normal secretion of the other pituitary hormones and normal appearance of the pituitary on C.T. scan or M.R.I. One patient was born to consanguineous parents and one girl had an affected brother who died in the neonatal period. DNA from the 3 patients digested with EcoRI, BgIII and Pstl revealed a normal pattern after hybridization with POMC-genomic probes encompassing exons 1 and 3. After digestion with Sacl and hybridization with an exon 1 probe, a 10/15 kb polymorphism was detected and compatible with linkage of the disease to the POMC gene in the two families studied. PCR amplification of exons 1, 2 and 3 using primers in the flanking intronic sequences gave products of the expected size in the 3 patients. Direct sequencing of exon 2 which contains the transcription initation site and 15% of the coding sequence revealed no difference with controls and with the published sequence. Sequencing of exon 1 and 3 is under progress. We conclude that these 3 cases of congenital ACTH deficiency are not due to deletions in the POMC gene or point mutations in exon 2.

In order to determine immune and possibly non immune factors determining first phase insulin response to glucose (FPIRG) in siblings of type I diabetic patients, we performed a simplified intravenous glucose tolerance test in 170 normal children, 98 ICA negative and 12 ICA positive siblings of type I diabetic children. Normal children (age 3-16, 9.8±0.3 years) were patients hospitalized for reasons not interferring with glucose homeostasis and investigators' and colleagues' children. ICA negative siblings were similar to controls in respect to age (2-16, 9.3±0.4 years) and body mass index. Insulin was measured 1 and 3 minutes after i.v. injection of 0.5 mg/kg b.w. of 50% dextrose in 2.5 minutes. In normal children, FPIRG (1 + 3 minutes insulin measurements) increased with age, giving a linear regression curve of insulin 1 + 3 = 10.5*age + 11.3 (r=0.45). In comparison ICA negative siblings had a significantly lower FPIRG (86±6 vs 115±6 μU/ml, p

To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.

Summary Background Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. Methods This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). Findings The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9–1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1–1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3–4·4; and 17·1, 15·6–18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. Interpretation In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. Funding European Union.

Several conditions characterised by short fingers, reduced joint mobility, short stature, and muscular build with or without mental retardation have been delineated during the past 30 years: Moore-Federman syndrome, Myhre syndrome, acromicric dysplasia, geleophysic dysplasia, GOMBO syndrome, and LAPS (Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature) syndrome. In 1980 Myhre et al 1 reported two unrelated males with mental retardation, facial dysmorphism (short palpebral fissures, maxillary hypoplasia, prognathism, short philtrum, small mouth), short stature, brachydactyly, muscle hypertrophy, decreased joint mobility, mixed hearing loss, and cleft lip and palate in one of them. X rays showed a thickened calvarium, hypoplastic iliac wings, broad ribs, and large, flattened vertebrae with large pedicles. Five further cases were reported. Mental retardation of variable severity was present in all patients. Three of the older patients had hypertension. We report here four new unrelated patients who fit a diagnosis of Myhre syndrome, expanding the behavioural profile of the disorder, and discuss the differential diagnosis. ### Patient 1 Patient 1, a male, was the second child of healthy, non-consanguineous parents. The father was 181 cm tall and the mother was 165 cm tall. They were aged 40 and 34 years, respectively, at time of delivery. Birth weight was 2130 g, length 44.5 cm, and OFC 36 cm at 36 weeks’ of gestation based on LMP (40 weeks based on morphological score of maturity). Recurrent hypoglycaemia requiring glucose infusion was recorded during the first weeks. Psychomotor development was normal, but dysarthria required long term speech therapy. He had bilateral deafness, with loss of 40 dB in low frequencies to 20 dB on the right side, and from 60 dB to 35 dB on the left side. MRI and CT showed bilateral dysplasia of the external semicircular canal. The stapedial footplate was bilaterally thick and, on the right side, fused with the …

Deciphering mechanisms involved in failure of self tolerance to preproinsulin-2 is a key issue in type 1 diabetes. We used nonautoimmune 129SV/Pas mice lacking preproinsulin-2 to study the immune response to preproinsulin-2. In these mice, a T cell response was detected after immunization with several preproinsulin-2 peptides and confirmed by generating hybridomas. Activation of some of these hybridomas by wild-type (wt) islet cells or recombinant murine proinsulin-2 demonstrated that two epitopes can be generated from the naturally expressed protein. Although T cells from wt mice responded to preproinsulin-2 peptides, we could not detect a response to the naturally processed epitopes in these mice. Moreover, after immunization with recombinant whole proinsulin-2, a T cell response was detected in preproinsulin-2-deficient but not in wt mice. This suggests that islet preproinsulin-2-autoreactive T cells are functionally eliminated in wt mice. We used a transplantation model to evaluate the relevance of reactivity to preproinsulin-2 in vivo. Wild-type preproinsulin-2-expressing islets transplanted in preproinsulin-2-deficient mice elicited a mononuclear cell infiltration and insulin Abs. Graft infiltration was further increased by immunization with preproinsulin-2 peptides. Preproinsulin-2 expression thus shapes the immune response and prevents self reactivity to the islet. Moreover, islet preproinsulin-2 primes an immune response to preproinsulin-2 in deficient mice.

Among 40 children with recent type 1 IDDM treated with cyclosporin A (CyA), 27 interrupted insulin injections 48 ± 5 days after the onset of therapy and thereafter maintained their HbA1C level below 7.5% [N: 4.8 ± 0.7 (sd)%]. We compared this group with the 13 patients who could not maintain such glucose control without insulin. No differences were detected in terms of age (10.2 vs 9.8 yrs), sex, initial blood glucose (3.9 vs 5.1 g/l), presence of islet cell antibodies (ICA: 72 vs 80%; S-ICA: 84 vs 93%; CF-ICA: 60 vs 43%), insulin autoantibodies (36 vs 25%), DR3 (61 vs 77%), DR4 (74 vs 69%), DR3,4 (39 vs 46%). Clearcut differences were observed for the duration of polyuria (27 vs 48 days, p < 0.01), weight loss (3.2 vs 10.1% BW, p < 0.001), ketoacidosis (11 vs 62%, p < 0.001) and C peptide response to iv glucagon (0.5 vs 0.1 nmol/l, p < 0.02). Mean CyA dose (8.3 mg kg−1 d−1) and 12 hr trough levels (RIA) in blood were similar (273 ng/ml vs 299 ng/ml) in both groups. These data indicate that the early response to CyA depends primarily on the precocity of immunointervention and the persistence of sufficient beta cell function. Selection of patients based on these parameters should further increase the frequency of early remissions in future trials of immunosuppression in recent IDDM.

Although short term health on growth hormone treatment has been extensively studied, little is known of the long-term health of subjects treated with growth hormone in childhood. Approximately 40 000 children are treated with growth hormone in the European Union and several hundred thousands in the world and it is essential to address this important question. SAGhE is an European consortium aimed at addressing this question as well as to gain further insight in the long term effect of growth hormone both in terms of height and of significance on quality of life. Eight countries participate in SAGhE: Belgium, France, Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom and have recruited approximately 25 000 patients who were treated for the most part in the late 80's and 90's and who are currently adults. The results of the SAGhE study as a whole are expected to be available to the investigators at the end of 2012 and will be disseminated in 2013. However, the study did not start synchronously in all countries and results from France and from 3 other countries have been made disseminated in late 2010 and published in early 2012. In the report from France, 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534) idiopathic short stature (n = 871) or born short for gestational age (n = 335) who started treatment between 1985 and 1996 were followed on vital status up to September 2009 for 94.7% of the patients. In this population of patients, all-cause mortality was increased with a standardized mortality ratio (SMR) of 1.33. 95% CI 1.08–1.64). In multivariate analysis adjusted for height, the use of GH doses >50 µg/kg/day was associated with mortality rates using external and internal references (SMR 2.94, 95%CI 1.22–7.07, HR 2.79, 95%CI 1.14–6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95%CI 1.01–14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95%CI 1.40–5.83), subarachnoid or intracerebral hemorrhage (SMR 6.66, 95%CI 1.79–17.05) was observed. Mortality rates were therefore increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. In a parallel report, 3 additional countries (Belgium, Netherlands, Sweden) the cause of death from a cohort of 2543 patients could be identified and no cancer- or cardiovascular disease-related deaths were found. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood but do not change the risk benefit balance of growth hormone treatments, after careful evaluation by Medicine Agencies. Consolidated results of the SAGhE study are expected to be available at the end of 2012 and to be disseminated during 2013.

The literature is scarce regarding the long term effect of synthetic growth hormone (GH) treatment. The objective of this thesis was to analyse the morbidity of 6874 patients from the French SAGhE study treated by GH for short stature, focusing on three themes: Neurovascular risk: Using two population-based registries, we showed an increase in the risk of stroke (SIR 3.5 to 4.4 according the registry used), more specifically for the subarachnoid hemorrhage (SIR 5.7 or 6.3). Risk of diabetes : Using the antidiabetic drugs deliveries obtained from the French national health insurance database, no difference in the risk of treated diabetes was found (SPR 1.0). Risk of cancer : Compared with the French population-based registries of cancer, no significant difference in the risk of cancer was found (SIR 0.7), but the excess risk for bone tumor is 3.5 . Events were identified from three sources : a) Information on vital status collected from the Répertoire National d’Identification des Personnes Physiques and cause of death as indicated on death certificate, b) Health questionnaire sent to all living patients, c) Data extracted from the French national health insurance information, including the French hospital discharge database, also called Programme de Médicalisation des Systèmes d’Information from 2008 to December 2010, long-lasting affection statements, and antidiabetics drugs deliveries.; Les données de la littérature concernant la tolérance à long terme du traitement par hormone de croissance (GH) recombinante sont très réduites. L’objectif du travail rapporté dans cette thèse porte sur l’analyse de la morbidité chez 6874 patients de l’étude SAGhE traités en France dans le cadre d’un déficit idiopathique en GH ou d’une petite taille constitutionnelle, avec les 3 axes de travail suivants : Risque neurovasculaire : Utilisant des données de référence issues de 2 registres de population, nous avons montré une augmentation du risque d’accident vasculaire cérébral (SIR à 3.5 ou 4.4 selon le registre considéré), et plus particulièrement d’hémorragies sous-arachnoïdiennes (SIR 5.7 ou 6.3). Risque de diabète : Utilisant les prescriptions d’antidiabétiques fournies par le SNIIRAM au sein de notre cohorte, nous n’avons pas mis en évidence d’augmentation de la prévalence du diabète traité (SPR 1.0). Risque de cancer : En comparaison au registre de référence du réseau FRANCIM, il n’y a pas de différence significative dans le risque de survenue d’un cancer (SIR 0.7). En revanche, le risque de développer une tumeur osseuse est 3.5 fois plus élevé chez les sujets exposés à l’hormone de croissance dans l’enfance. Les évènements ont été identifiés à partir de trois sources : a) RNIPP et CépiDC pour la connaissance du statut vital et les causes de décès si le sujet est décédé, b) Questionnaire de santé envoyé aux sujets non décédés, c) Données SNIIRAM à partir d’une extraction spécifique basée sur les identifiants des sujets de notre cohorte, permettant d’obtenir les codes CIM-10 des déclarations d’Affection Longue Durée, les codages PMSI entre 2008 et 2010 correspondant aux hospitalisations, et les prescriptions d’antidiabétiques.