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Aunque podria pensarse erroneamente que el hipotiroidismo ha desaparecido desde que se instauro la deteccion selectiva en neonatos, hay que conocer bien los signos de la enfermedad en el periodo neonatal, dado que hay formas que pueden pasar desapercibidas en el proceso de deteccion o en los ninos nacidos fuera de Europa. Ademas, existen algunas formas, entre las que predominan las adquiridas, que aparecen tras un intervalo libre de sintomas despues del nacimiento. Despues de participar en la valoracion del paciente, el pediatra debe conocer las formas de deteccion selectiva neonatal y el tratamiento establecido. Entre los cuadros de hipertiroidismo infantil predomina la enfermedad de Basedow, cuyo diagnostico es facil fuera del periodo neonatal. La principal dificultad es de tipo terapeutico, ya que la afeccion se caracteriza por su elevado riesgo de recidiva, por lo que conviene elegir, entre los tres tratamientos clasicos (antitiroideos de sintesis [ATS], cirugia y yodo radiactivo), aquel que ofrezca la mayor probabilidad de exito, teniendo en cuenta la edad del paciente, la intensidad de los signos y el volumen del bocio. Parece que existe un amplio consenso respecto a la necesidad de comenzar el tratamiento con los ATS. El cancer de tiroides es infrecuente en los ninos, pero este diagnostico debe sospecharse sistematicamente ante cualquier nodulo tiroideo, sobre todo en ninos pequenos, si ha habido una exposicion a radiaciones o si existen antecedentes familiares. Debe seguirse de forma rigurosa una conducta diagnostica y terapeutica bien sistematizada.

La pubertad se caracteriza por el desarrollo de los caracteres sexuales secundarios, la aceleracion de la velocidad de crecimiento, la aparicion de la menstruacion (menarquia) y la adquisicion de la capacidad reproductiva. Los mecanismos de su puesta en marcha todavia estan poco claros, pero recurren a senales hipotalamicas y a la retroalimentacion negativa de los estrogenos. La secrecion de GnRH hipotalamica estimula la secrecion de FSH y de LH hipofisarias y, por tanto, la secrecion de esteroides sexuales ovaricos. Los estrogenos estan implicados en el desarrollo de las mamas, en el crecimiento de la vagina y del utero y en el pico de crecimiento puberal. Permiten la fusion de los cartilagos de crecimiento. Los androgenos ovaricos y suprarrenales provocan el desarrollo de la pilosidad pubica.

Resume Patients et methodes. Nous avons etudie le devenir scolaire de 73 eleves hypothyroidiens depistes a l'hopital Saint-Vincent-de-Paul, en comparant leurs resultats a la moyenne nationale obtenue aux tests nationaux d'evaluation de CE2 et de 6 e . Notre etude regroupait 29 tests de 6 e et 44 tests de CE2, qui ont ete divises en trois groupes: les plus jeunes, n'ayant passe que le test de CE2; ceux d'âge moyen, ayant passe les deux tests; et les plus âges, qui n'ont pu passer que le test de 6 e . Resultats. Les resultats des plus jeunes des CE2 montrent une bonne reussite globale puisque ceux-ci obtiennent de meilleurs scores en francais (note differentielle positive statistiquement significative) et des scores equivalents en mathematiques. Ceux d'âge moyen ont des resultats comparables aux notes nationales aux deux tests. Les resultats des plus âges des eleves de 6 e montrent des differences marquees en mathematiques (note differentielle negative statistiquement significative) et des scores legerement moins bons en francais. Discussion. Selon la classe, les facteurs de pronostic sont differents, mais les facteurs de suivi du traitement, conditionnes par le niveau socioeconomique de la famille, sont predominants par rapport aux facteurs prenatals. On retiendra surtout la date de debut de traitement et la normalisation de la TSH. En revanche, la cause ne constitue pas un facteur de pronostic, du moins en CE2, les athyreotiques etant plus performants que les ectopiques. Conclusion. Pour les enfants depistes depuis 15 ans, la scolarite parait normale. Ces resultats sont encourageants. Ils representent une reelle victoire en comparaison des resultats obtenus avant le depistage. Si on ne peut agir sur les facteurs prenatals, une vigilance particuliere doit s'operer sur la qualite de la prise en charge, dans sa globalite, a la fois medicale et familiale.

Growth hormone levels rise steadily through normal puberty, in parallel with the pubertal stages but decline rapidly at the end of puberty (stage V). The general evolution of the secretory profile of GH is parallel to the growth velocity curve. The frequency of GH pulses remains unchanged; however, their amplitude, mean integrated concentrations, area under the curve, and urinary growth hormone are elevated at midpuberty. The main action of GH is to ensure, together with sex steroids, the pubertal growth spurt. However, the role of pubertal GH is not confined to inducing the pubertal growth spurt. It also participates, together with sex steroids, in the acquisition of adult bone mineral density.

In Turner patients, the presence of a Y chromosome or derivative Y is correlated with the risk of gonadoblastoma induction. "Marker" chromosomes originating from Y, may not show characteristic fluorescence and then be very difficult to identify by conventional cytogenetic techniques, although they still predispose the patients to gonadal tumors. Using polymerase chain reaction of the gene from the sex-determining region of the Y chromosome, we screened 40 Turner patients (thirty seven 45X and three 45X,46XX) for the presence of Y chromosomal DNA. We were able to identify karyotypically unrecognized Y chromosome material in 1 patient out of the 40 studied. In this patient mild clinical and biological hyperandrogenism was observed. Reliability of our technique was ascertained by the detection of the expected 648 base pairs amplified DNA fragment in all normal male controls as well as in 3 Turner patients with confirmed 45X,46XY mosaicism. Despite the low frequency of unrecognized Y chromosome material (1 case over 40 in our experience), our data suggest that polymerase chain reaction of the gene from the sex-determining region of the Y chromosome is worthy of being performed in Turner patients considering the potential risk of the presence of a Y chromosome.

Resume Les auteurs presentent une experience de pres de 14 ans qui traite de la prise en charge des enfants hypothyroidiens congenitaux, de l'etiopathogenie de l'hypothyroidie, des modalites therapeutiques adoptees par l'equipe et du devenir des enfants apres depistage.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Assessment of school performance provides an excellent index of adequacy of therapy of congenital hypothyroidism.Scholarly achievement of 73 children with congenital hypothyroidism screened and followed-up in our clinic was evaluated by comparison to national tests calculated from a wide random sample. The 73 children were divided into three groups: 31 patients belonging to the CE2 class (third primary school class) (group 1); 13 patients belonging to the 6th class (first secondary school class) having already passed CE2 tests (group 2); and 16 patients also belonging to the 6th class but not having passed CE2 tests (group 3).The youngest patients showed better results in French than national means, with similar results in mathematics. The intermediate aged patients showed comparable scores to the national mean in both tests. The oldest patients showed significantly less achievement in mathematics, and somewhat (but not markedly) less achievement in French. Etiology of hypothyroidism did not seem to be a prognostic factor, with the athyreotic patients having better results in CE2 than ectopic ones. Age at onset of treatment and the duration of treatment before normalization of thyroid stimulating hormone (TSH) seemed to represent the main prognostic factors as does compliance to treatment, which depends on socioeconomic levels of families.Encouraging results are now obtained in those patients who have been screened in the neonatal period and treated very early. Compliance to the treatment remains an important factor of prognosis.

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c., during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GH deficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/y; p0.001) and with the first year of observation in Group 2 (p0.001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 +/- 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3 y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.

Results of an inquiry in adults patients (18-53 years of age) coming from three centers (1 in Rouen2 in Paris), 213 questionnaires were sent. 105 answers were received. Scholar achievement: only secondary cycle in 6%, Secondary cycle + professional course in 22% and tertiary cycle in 44%. No scholar ship in 2%, 26% were still ongoing studies. Professions: 18% are unemployed (24%), Secretary jobs: 10%, Health professions (altogether): 18%, Teachers: 8%, Clerks: 7%, Executive jobs: 8% and Miscellaneous jobs: 5%. 3% have an handicapped status. The small height was a career obstacle in 29%. Affective life. Age of first sexual intercourse was 19-22 years. 17 are or were married and 15% are living in couple. But 58% have not any sexual life whatsoever. These women are divided on the ways to cure the sterility. Few among the oldest have attempted adoption or medically assisted procreation, with each time low rate of success. 26% have psychological disturbances which were serious in 6% mainly due to depression.

The adequate L-thyroxine dosage for the initial treatment of infants with congenital hypothyroidism is a subject of controversy. Some recommend higher dosages (10 micrograms/kg/day) to ensure adequate levels, while others advocate lower dosages to permit normalisation of thyroid status. The aim of this study was to evaluate the results of a treatment strategy using an initial dosage of 7.5-8.0 micrograms/kg per day, TSH measurements being taken at 15 and 30 days of treatment. Fifty one newborns infants with primary congenital hypothyroidism detected by neonatal screening were treated with the same therapeutic strategy. A mean L-thyroxine dosage of 7.9 micrograms/kg per day at the onset of treatment and 6.6 micrograms/kg/d at 2 months, normalised the FT4 and FT3 levels at 15 days in 100% and TSH levels at 2 months in 90% of cases. Many patients showed elevated levels of FT4 and a systematic higher initial dosage could expose many infants to a dangerous hyperthyroidism. Patients with abnormal TSH levels at 2 months already had higher TSH levels in the first 8 weeks of life and, despite higher L-thyroxine dosage, also exhibited lower FT4 and FT3 levels. These patients who needed an early increase in dosage had already shown a more profound ante and neonatal hypothyroidism. This subgroup of patients require a higher dosage of thyroxine and early assessment of FT4, FT3 and TSH levels are required for optimum dosage choice.Even though a subgroup of patients may require a higher dosage of L-thyroxine, an initial dosage of 7.5-8.0 micrograms/kg per day, with an early assessment of FT4, FT3, and TSH levels, is adequate for the treatment of the majority of infants with congenital hypothyroidism.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324--Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546--Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.

Screening for congenital hypothyroidism (CH) is an opportunity to investigate maturation by measuring alphafetoprotein (AFP).Blood AFP was measured in 73 full-term infants (controls), 22 infants with permanent CH and 19 with a transient form (FT) of hypothyroidism. It was also measured in mothers of the two groups with hypothyroidism. AFP was measured by RIA and its value was compared to those of FT4, TSH and bilirubin.Blood AFP was higher in patients with CH with significant differences between patients who had jaundice or not, but AFP was not significantly different in FT patients and controls. Initial values of AFP in both CH and FT population was correlated to the levels of AFP in their mothers. Under treatment with 7.5 micrograms/kg/day of l-T4, AFP levels remained increased at T15, then gradually normalized at T30-T60. The log of AFP was correlated to TSH levels between T15 and T60 but was not correlated to FT4 levels. Preliminary results at one year of age show that IQ seems better in infants with early normalization of AFP.Prolonged follow-up is necessary to assess the possibility that initial kinetics of AFP under therapy have a prognostic value for estimating the quality of outcome.

Occurrence of any pubertal sign before eight years of age defines premature sexual development but does not always mean precocious puberty (PP); one should distinguish borderline physiological situations which need only a follow-up and frankly pathological situations which need very precise investigations and suitable treatment. The first situations are premature thelarche, pubarche and menarche in which the height and bone maturation, pelvic ultrasonography (US) are normal for age, avoiding hormonal investigations. Conversely in the second situation, the bone age is more advanced than the height age and the pelvic US displays ovarian activity and uterine development. The next step is the characterization of the level of the mechanism of puberty: hypothalamohypophysal or ovarian: in the first case gonadotropin levels are elevated after GnRH infusion, in the second case, depressed. The aetiological diagnosis are in true PP: brain tumors malformations or hamartoma even if negative idiopathic. At ovarian level: ovarian tumors or McCune Albright syndrome or recurrent cysts. The first etiology leads to use GnRH analog in the second the treatment is more delicate.

During mammalian embryogenesis, the presence of the SRY gene determines the bipotential gonad to develop as a testis. 46,XY sex reversal has been described in man. It is associated with an essentially female phenotype and a streak gonad. In a collaborative study, we analysed 36 patients with a 46,XY sex reversal. The testis determining region of the Y chromosome was analysed by Southern blotting and by DGGE analysis of the SRY open reading frame (orf). We found a total of 7 mutations in the testis determining region including the SRY gene. This brings to 19 the total number of mutations in SRY associated with sex reversal. No relationship was found between the SRY status and the presence or absence of gonadoblastoma. However, a correlation was observed between the SRY genotype and the histology of the gonad. A mutant in SRY is associated with a completely dysgenetic gonad. The presence of immature testicular tubules is usually observed when SRY is normal. These latter results suggest the existence of as yet unidentified testis determining genes.

The actual worldwide incidence of congenital hypothyroidism (CH) is based on the results of screening in parts of the world where screening is mandatory, i.e. most of Europe, USA, Canada, Cuba, Australia, New Zealand and Japan. In other parts of the world, some indications are given by the results of pilot studies. In Europe, mean overall incidence (1985-1990) for the countries included in our inquiry is 1/3801--in each country for the same period: Austria 1/3,930, Belgium 1/3,750, Czechoslovakia 1/6,037, Denmark 1/3,777, Finland 1/3,969, France 1/4,132, FRG 1/3,827, Greece 1/3,314, Hungary 1/5,632, Israel 1/3,152, Italy 1/3,150, The Netherlands 1/3,723, Norway 1/3,069, Portugal 1/3,139, Spain 1/3,216, Switzerland 1/3,913, UK 1/3,398 and Turkey (pilot study 1989-1992) 1/2,943. In comparison, the figures for the USA for the whole country are similar for the mean overall incidence (1988-1990): 1/4,119. But large variations exist between the states, the reasons of which are perhaps related either to technical problems or to the ethnic background in each state. In Canada and Japan, modifications of screening procedures have led to similar figures for the last years in our possess, Canada (1986-1988) 1/3,884 and Japan (1990) 1/3,856. The figures (mean overall incidence) for Cuba (1987-1991) 1/2,325, for Australia (1985-1990) 1/1/3,331 and for New Zealand (1987-1990) 1/4,496 are quite comparable. So in these countries where the screening is established, no great variations are noted as in certain parts of the world with pilot studies: Argentine (Buenos Aires; 1985-1990) 1/4,407, Chile (1991-1992) 1/2,514, Brazil (Porto Alegre; 1987-1991) 1/4,429.(ABSTRACT TRUNCATED AT 250 WORDS)

Four cases of XX patients with testis development are reported. The aim of this study was to describe their clinical features and to see if there was any relationship between phenotypes and the presence of Y material. Several human Y-derived sequences including the SRY probe were used to analyze the DNA of the patients. Yp material including the pseudo-autosomal region and SRY was detected. The cases reported in this study confirm that XX true hermaphrodites cannot be distinguished from XX males on the basis of their genotypes. There is no relationship between clinical and anatomical phenotypes and the presence of Y material. SRY does not warrant a complete and normal testis differentiation. Although similar in some features with Klinefelter's syndrome patients, XX males exhibit specific clinical manifestations due to the lack of Y-specific genes.

Antibody-dependent cell mediated cytotoxicity (ADCC) and thyroid growth immunoglobulin blocking (TGI block) which have been found in autoimmune thyroiditis in adults, as well as TSH receptors binding inhibitory antibodies (TBI ab) and antimicrosomal (Mc ab) and antithyroglobulin (Tg ab) antibodies were search in 42 mothers-infants pairs called at hospital after a positive screening for congenital hypothyroidism. The etiologic diagnoses were: 12 athyreosis, 12 ectopies, 7 anatomically normal glands and 11 transients. Tg ab and Mc ab were measured by commercial hemagglutination tests, TBI ab were determined using a radio ligand assay. ADCC in a 51Cr release assay by human thyroid cells in culture and TGI block by incorporation of 3H-thymidine using the same cells. Results were 38% for TBI ab in infants mainly in patients with dysgenesis without any concordance between mothers and infants. ADCC were found in 24% and TGI block in 24% with respectively mothers-infants concordance of 90% and 84%. Five mothers had autoimmune diseases (2 thyroiditis, 2 Graves' diseases and 1 insulin-dependent diabetes). Beside these rare cases of maternal diseases, the significantly high number of antibodies without any expression in the mothers suggests that autoimmunity plays a role in the etiology of congenital hypothyroidism.

Follow-up was obtained for at least 4 years in 52 children (40 F, 12 M) who presented with congenital hypothyroidism, detected by TSH screening at 5 days of age and persisting at the 3th-5th postnatal week. Eight had athyreosis, 33 an ectopic thyroid gland and 11 an anatomically normal thyroid. Treatment began at day 29 +/- 12 (1 SD) with I-T4 solution, 5-7 micrograms/kg/day and was followed in order to obtain immediately T4 and FT4 blood levels in the high normal range, with normal TSH at least from age 6 months. Mental development was evaluated at age 0.5, 1 and 2 years with the Brunet-Lézine scale, and at 4 years with the Termann-Merill test. Thirty of them were reevaluated at age 7 years with the WISC-R test. The results of these tests were all in the normal range, with individual differences, the range being 85 to 145 at 4 years and 95 to 133 at 7 years, not different from those obtained in age-matched controls and in the normal siblings of the patients at 4. The WISC-R test at 7 years did not show differences between verbal and performance levels. Its results were correlated with those of the TM test performed at age 4 years in the same 30 patients: r = 0.75, p less than 0.01. School level at 7 years was normal for age in these 30 hypothyroid children.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied nine patients aged 1 month to 16 years with 46, XX karyotypes and testicular tissue. Some of these patients were followed through puberty. Phenotypically, two presented normal and seven abnormal external genitalia (AG). Among this latter group, four showed hypospadias and three true hermaphroditism (TH). The endocrine data were similar in all three groups: testosterone levels were within normal limits during puberty, decreasing in adulthood; gonadotrophin levels were above the control values at mid puberty. Histologies of the two sub groups of AG patients were identical up to 5 years of age and presented differences when compared with controls, regardless of the ovarian part of the ovotestis. However, in patients older than 8 years, germ cells disappeared and dysgenesis became obvious. In one patient, the ovarian zone of the gonad was detected only after complete serial sections of the removed gonad were examined. Southern blot analysis with Y-DNA probes displayed Y-specific material for the classic 46 XX males and a lack of such sequences for all patients with AG and TH. Based on these findings, we postulate that 46, XX males with AG and 46, XX TH may represent alternative manifestations of the same genetic defect. These data together with those concerning familial cases of 46, XX males with AG and 46, XX TH suggest an autosomally (or pseudoautosomally) determined mechanism.

Long term administration of GnRH agonists is currently considered as the treatment of choice for precocious puberty. For the first time, we have at our disposal an efficacious and specific treatment of the disorder responsible for the syndrome called precocious puberty. Whether of idiopathic or neurogenic origin, true precocious puberty is primarily a hypothalamo-pituitary disorder. It is at this location that the GnRH agonists exert their effect. Knobil’s experiments in monkeys [1] provided a rationale for agonist treatment by showing that continuous infusion of GnRH caused suppression of gonadotropin release. Our understanding of the mechanism of action of GnRH agonists is however incomplete and many questions arise when the gonadotropin secretory patterns during agonist treatment are considered.

Introduction. Most XX males, SRY positive, have a normal male phenotype. I some cases, XX males, SRY negative, are associated with ambiguous genitalia (AG). The aim of this study was to find out whether, in these patients, AR amount is diminished in target cells and whether partial androgen resistance is relevant to molecular abnormalities of the AR gene. Patients and Method. Three XX males with AG were studied. PCR of the SRY gene, known to be equated to the testis determining gene, was negative. AR binding capacity (Bmax) and dissociation constant (Kd) of the A-AR complex were determined on genital skin fibroblasts by Scatchard analysis. PCR coupled with SSCP analysis was performed on all exons (4-8) encoding for the androgen-binding domain (ABD) of AR. Results. Receptor-binding capacity was respectively 243, 206 and 162 fmol/mg DNA (N = 650 ± 200 fmol/mg DNA). Kd was respectively 1, 0.66 and 0.4 nM (N = 0.6 ± 0.3 nM). No band shifts were detected on the 5 exons studied. Known mutated exons of AR detected by SSCP were used as control. Discussion. In patients with partial androgen insensitivity syndrome and diminished receptor binding capacity, a mutation has been reported within the ABD. In the 3 XX males, AG seems to be due to a low level of AR, without any detected mutation in the ABD. In these XX males, SRY negative, AG is relevant to a low level of expression of the AR gene. We suggest that the product of the SRY gene could thus be a transcriptional factor of the AR gene. Production of AR by AR-negative COS cells transfected by SRY gene is now under investigation.

Introduction. AR belongs to a family of ligand-induced transcription factors, and its normal function is to control the differentiation, development and maintenance of male reproductive function. Complete (CAIS) and partial (PAIS) androgen insensitivity syndrome are X-linked disorders occuring in 46,XY patients and leading respectively to a female phenotype and an undermasculinized male. We have determined the AR binding capacity on genital skin fibroblasts and studied the AR gene in the DNA of 5 patients with CAIS and one patients with PAIS. Families. All patients with CAIS were characterized by a referred to our clinic for genital bud, cryptorchidism and perineal hypospadias. Two maternal uncles had ambiguous genitalia. Methods. AR binding capacity was determined on genital skin fibroblasts (GSF) using [3H]-R 1881. Point mutations were detected by SSCP analysis of exons 2-7 of the AR gene on DNA from white blood cells and identified after direct DNA sequencing. Results. AR binding capacity (Bmax). dissociation constant (Kd) and detected mutations are reported in the table below. Normal Bmax = 65 ± 200 fmol/mg DNA. Normal Kd = 0.6 ± 0.3 nM. Discussion. In these families, we detected only amino acid substitution. In two cases (indicated by †), a new restriction site was created which made possible the carrier diagnosis of patients's sisters. Patients 3 presented a de novo mutation. In 2 cases (indicated by 0) a restriction site was abolished and carrier diagnosis was possible. In family 6, we found a mutation reported threefold indicating a hot-spot amino acid. As expected, the mutation described within the DNA-binding domain did not alter the AR binding capacity (patients 1 and 2). Further receptor studies are currently underway to support the potential androgen-AR and DNA-AR affinity changes.

ABSENCE OF MUTATION IN THE G PROTEIN a s SUBUNIT GENE IN PATIENTS WITH Mc CUNE ALBRIGHT SYNDROME (MAS)

We have attempted to document in cryptorchid children that there is an LH deficiency and a secondary deficiency of testosterone. We have shown a diminished LH peak after LH-RH in cryptorchid versus normal infants (P less than 0.05). The postnatal surge of testosterone is significantly low (P less than 0.001) in permanent cryptorchids versus infants with secondary testicular descent, whose levels are similar to those in controls. In permanent cryptorchids during the same period (0-4 months), LH and testosterone levels were significantly lower (P less than 0.01 and P less than 0.05 respectively) than in infants with secondary descent, and the levels of testosterone and LH were correlated in both populations. In children, a low basal level of LH was observed at pubertal stage P2, and LH peak after LH-RH was significantly reduced at stages P1 and P2 (P less than 0.01 and P less than 0.05 respectively). The post-stimulatory levels of testosterone after hCG were reduced at the same stages (P less than 0.01, P less than 0,05), and the two levels were correlated (P less than 0.01). No differences are seen for LH and testosterone afterwards. It has been possible to show by immunofluorescence on pituitary cells the occurrence of antigonadotropin cell antibodies (AGCA) in more than 50% of our patients, with no relation to age and no correlations between endocrinological data and the presence or absence of AGCA. The relatively low success rate of hCG treatment, mainly in young children, and of GnRH irrespective of the regimen of treatment, does not exclude the role of primary LH deficiency in cryptorchidism.

The effects of LH-RH on FSH and LH were studied in 39 prepuberal boys with undescended testes and in 18 normal prepuberal boys. The mean basal levels of LH and FSH and the mean peak level of FSH after administration of LH-RH did not differ significantly between the two groups but the mean peak level of LH was significantly (p≤0.01) lower in those with undescended testes. This may correlate with a delay of gonadotropic secretion in boys with undescended testes. But, as two boys among the 39 studied had undetectable LH and FSH serum levels which failed to increase after LR-RH, inclusion of hypogonadotropic patients in the group must be considered as an alternative hypothesis.

The final height of patients treated with growth hormone for isolated growth hormone deficiency has, up to now, been subnormal, with a mean below −2 sd in the series reported, an insufficient height at the onset of puberty and a more or less accelerated bone maturation during puberty being two important factors of the poor results. A long-acting analogue of gonadoliberin, Trp6-GnRH, has been given to GH-treated patients with isolated growth hormone deficiency at the time they reached pubertal stage 2, in combination with unchanged doses of GH, for one year in 11 and for two years in 7 of them. It resulted in an increase in the height age/bone age ratio and a reduction of the height insufficiency for bone age. The increase was slight but significant after one year, and fair after two years, in spite of a reduced annual growth rate. Post-analogue follow-up in 5 patients with continued GH treatment showed a good development of growth and of puberty. It is concluded that combination of the long-acting Trp6-GnRH analogue and GH for 1–2 years in patients with isolated growth hormone deficiency whose puberty starts with a very insufficient height may be an appropriate way to improve their growth parameters. Studies with increased doses of GH or increased frequency of injections could help to optimize the results. Several years of follow-up are needed for demonstrating the results on final height.

In congenital rubella an acid-labile alpha-interferon was present in sera collected from fetuses between weeks 21 and 29 of gestation and from children with active congenital rubella. This interferon was different from the interferon detected in normal amniotic fluid and was not found in sera from uninfected fetuses or from children with postnatally acquired rubella. The fetal interferon is of interest as a complementary marker to confirm the virus contamination of the fetuses during maternal rubella. The role of the prolonged synthesis of this interferon in congenital rubella disease and its immune defects are discussed.

The paradoxical association of female pseudohermaphroditism and androgen deficiency was observed in two 46,XX subjects with high corticosterone plasma levels. Subject 1 has been declared a boy due to clitoris enlargement; she had no vagina and uterus. Subject 2 had ambiguous external genitalia. In both, at age 27 and 17 years, fusion of outer labia, impuberism, ovarian cysts, and histologically normal ovarian tissue were observed. Blood pressure was normal. Basal cortisol levels were normal but unresponsive to ACTH. Progesterone levels were 40 and 62 ng/ml and rose after ACTH (50 and 79 ng/ml). 17-hydroxyprogesterone levels were 25 and 21 ng/ml and did not rise after ACTH. Corticosterone levels were 70 and 92 ng/ml and rose after ACTH (110 and 180 ng/ml). All three steroids were suppressed by dexamethasone. Androgen and estrogen levels were at or below the lower limit for normal women. The sex steroid levels obtained by radioimmunoassay in plasma and a follicular cyst fluid were confirmed by isotope dilution-mass spectrometry. We suggest that the sexual ambiguousness resulted from an excessive production of gestagenic steroids during fetal life, and that the enzyme defect is either a partial 17 alpha-hydroxylase defect combined with a peripheral production of 17-hydroxyprogesterone, or else a partial 17-20-desmolase defect with a secondary 21-hydroxylase defect limited to the cortisol pathway.

Hemoglobin electrophoresis realised as a routine screening test on 1 500 gabonese individuals revealed the existence of a sickle cell abnormality n 24.40% cases (22.27% were AS heterozygotous and 2.1% were SS homozygotous). Bapounov and Fang ethnies appeared to be the most involved. The importance of such disturbance (I gabonese individual out of 4 is concerned) could justify the creation of Prenatal Counseling Centers mainly dealing with this genetic problem.

Base levels of estrone (E1), estradiol-17-beta (E2) and testosterone (T) were measured by radio-immunoassay. Results were classified according to the stages of puberty (Tanner scale) in 89 normal girls ranging from 1 to 22 years of age. Fourty-three pathological cases were studied. In 22 cases of ovarian agenesis E2 and T were most often low. In 7 cases of isolated breast prococity, 4 cases of isolated pilous precocity, one case of isolated genital hemorrhage and 5 cases of hypopituitarism, E1, E2 and T levels were similar to those of impuberal girls. Levels of oestrogens were increased in 4 cases of true precocious puberty.

The authors report the results of treatment with human growth hormone (hGH) (for 3 1/2 years to 11 3/4 years, mean: 5 years 4 months) in 34 children presenting with complete growth hormone deficiency and an average growth failure reaching 3.9 standard deviations (SD). Treatment was discontinued, after spontaneous or induced puberty, when bone age reached or was beyond 15 years in boys, and 13 years in girls. A partial correction was obtained in almost all cases. However, average height remained at -2.4 SD with respect to age and -1.75 with respect to bone age, reaching normal limits in only half of the patients. School and professional performances were not appreciably different from those which are observed in normal adolescents. Although the acceptance of the diagnosis and therapy was not always good, the medical support associated with the supervision of the treatment seems to have had a favourable psychological effect.

Delayed puberty is defined as the total or almost total absence of development of sex characteristics at an age exceeding the mean by two standard deviations: approximately 15 years in boys and 13 years in girls. A double sense has been given to this term, which is usually applied to permanent hypogonadism as well as to normal but delayed maturation. In practice, certain signs can assist formulation of a prognosis, and if necessary the type of therapy required. Data on which can be based the diagnosis, surveillance, and medical conduct in sexually immature adolescents are discussed. Their interpretation is simple when elevated gonadotrophins levels indicate a primary gonadal lesion, or when the delayed puberty results from a general disease disturbing body maturation. In other cases, interpretation of data is often very difficult and is sometimes a very slow process. Because of these difficulties, the diagnosis between simple delay and gonadotrophic insufficiency is discussed in this report on the basis of a retrospective study conducted for a long enough period to have arrived at a definite conclusion.

Blood levels of gonadotropins (FSH and LH) and gonadal steroids (testosterone or estradiol) have been evaluated in 72 children and adolescents with primary gonadal defects (45 agonadal patients, 7 with asymetrical gonadal dysgenesis, 9 with Klinefelter syndrome, 4 with partial testicular dysgenesis and 7 with partial ovarian dysgenesis) and in 17 cases of male pseudohermaphrodism. A LH-RH test has been performed in most cases, and a testicular stimulation test with chorionic gonadotropin in patients with testicular tissue. Agonadal subjects had increased blood and pituitary releasable gonadotropins: very high in infants and young children, much less from 7 to 11 years, a high spurt being observed at 12 years. This diphasic pattern relates to the varying sensitivity of hypothalamic receptors and suggests that adrenal steroids may restrain gonadotropic secretion at 7-8 years. As a diagnostic tool, the increase of gonadotropins may be missing in the 7-11 years group. In the 1-12 years patients with partially defective gonads, blood and pituitary releasable gonadotropins and blood steroids are usually normal, but testosterone response to chorionic gonadotropin may be already blunted. From 13 years the gonadotropic secretion is usually increased, even when testosterone secretion and reserve are within normal range. Most male pseudohermaphrodites showed normal gonadotropic and testicular secretions. But four patients had highly increased responses to LH-RH, suggesting a defect of testicular secretion or of receptors, and demonstrating some heterogeneity in the male pseudohermaphrodism group.

A direct measurement of free thyroxine (FT4) by a radio-immunologic method using an analogue of thyroxine as tracer allowed to establish the normal values in 341 children from birth to puberty. These values were used as reference for the determination of free T4 in the diagnosis and management of treatment for congenital hypothyroidism. In 44 treated hypothyroid children, there was a positive correlation between the serum concentration of free T4 and the amount of levothyroxine given daily (r = 0.46, p less than 0.01). There was also a negative correlation between free T4 and serum TSH (r = 0.59, p less than 0.001). Thus, the measurement of free thyroxine seems to be a more reliable, more accurate and more sensitive parameter than that of total thyroxine or TSH for controlling the treatment of congenital hypothyroidism.