197 results on '"Otten BJ"'
Search Results
2. A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty
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Kremer, H, Martens, Jwm, VAN REEN, M, VERHOEF POST, M, Wit, Jm, Otten, Bj, Drop, Sls, DELEMARRE VAN DE WAAL HA, POMBO ARIAS, M, DE LUCA, Filippo, Potau, N, Buckler, Jmh, Jansen, M, Parks, Js, Latif, Ha, Moll, Gw, Epping, W, Saggese, G, Mariman, Ecm, Themmen, Apn, and Brunner, Hg
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Male ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,DNA Mutational Analysis ,Puberty, Precocious ,Luteinizing Hormone ,Receptors, LH ,Biochemistry ,Endocrinology ,Mutation ,Mechanistische en klinisch genetische aspecten van gonadotropine receptor mutaties ,Cyclic AMP ,Humans ,Amino Acid Sequence ,Mechanistic and clinical genetic aspects of gonadotropin receptor mutations ,Child - Abstract
Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.
- Published
- 1999
3. Pubarche and serum dehydroepiandrosterone sulphate levels in children with Prader-Willi syndrom
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Siemensma, Elbrich, Lind van Wijngaarden, Roderick, Otten, BJ, Jong, Frank, Hokken - Koelega, Anita, Pediatrics, and Internal Medicine
- Published
- 2011
4. Het syndroom van Turner
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Schrama, Sabine, Otten, BJ, and Pediatrics
- Published
- 2002
5. Diagnose en behandeling van eht syndroom van Turner, conclusies en aanbevelingen
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Otten, BJ, Schrama, Sabine, and Pediatrics
- Published
- 2002
6. Genotype versus phenotype in families with androgen insensitivity syndrome
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Boehmer, Annemie, Brüggenwirth, Hennie, van Assendelft, C, Otten, BJ, Mooijman, Marja, Niermeijer, Martinus, Brunner, HG, Rouwe, CW, Waelkens, J, Oostdijk, W (Wilma), Kleijer, W, Kwast, Theodorus, de Vroede, MA, Drop, Sten, Pediatrics, Developmental Biology, and Clinical Genetics
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RECEPTOR GENE-MUTATIONS ,DOMAIN ,CELLS ,17-BETA-HYDROXYSTEROID DEHYDROGENASE-3 DEFICIENCY ,NOVO MUTATIONS ,STEROID BINDING ,MOSAICISM - Abstract
Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (IS patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.
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- 2001
7. 17 beta-hydroxysteroid dehydrogenase-3 deficiency: Diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations
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Boehmer, ALM, Brinkmann, AO, Sandkuijl, LA, Halley, DJJ, Niermeijer, MF, Andersson, S, de Jong, FH, Kayserili, H, de Vroede, MA, Otten, BJ, Rouwe, CW, Mendonca, BB, Rodrigues, C, Bode, HH, de Ruiter, PE, Delemarre-van de Waal, HA, Drop, SLS, and Faculteit Medische Wetenschappen/UMCG
- Subjects
ANDROGEN INSENSITIVITY ,ARABS ,17-KETOSTEROID REDUCTASE DEFICIENCY ,MOLECULAR-GENETICS ,TESTICULAR FEMINIZATION ,MALE PSEUDOHERMAPHRODITISM - Abstract
17 beta-Hydroxysteroid dehydrogenase-3 (17 beta HSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17 beta HSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17 beta HSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo. In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17 beta HSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655-1;G-->A. The minimal incidence of 17 beta HSD3 deficiency in The Netherlands was shown to be 1:147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655-1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo mutations. 17 beta HSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic Variation can occur between families with the same homozygous mutations. The incidence of 17 beta HSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.
- Published
- 1999
8. Comments: A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty
- Author
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Kremer, H, Martens, John, van Reen, M, Verhoef-Post, M, Wit, JM, Otten, BJ, Drop, Sten, Delemarre- van de Waal, HA, Pombo-Arias, M, de Luca, F, Potau, N, Buckler, JMH, Jansen, M, Parks, JS, Latif, HA, Moll, GW, Epping, W, Saggese, G, Mariman, ECM, Themmen, Axel, Brunner, HG, and Developmental Biology
- Published
- 1999
9. Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome
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van Teunenbroek, A (Arne), Schrama, Sabine, Stijnen, T (Theo), Jansen, M, Otten, BJ, Delemarre-van de Waal, HA, Vulsma, T, Wit, JM, Rouwe, CW, Reeser, HM, Gosen, JJ, Westerlaken, C, Drop, Sten, Faculteit Medische Wetenschappen/UMCG, Pediatrics, Epidemiology, and Erasmus School of Health Policy & Management
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DEFICIENCY ,HEIGHT ,SECRETION ,CHILDREN ,PROFILES ,BINDING PROTEIN ,FREQUENCY ,THERAPY ,GH - Abstract
To optimize the growth promoting effect of growth hormone (GH), 65 previously untreated girls with Turner syndrome (TS), chronological age (CA) 2-11 yr, were randomized into 3 dosage regimen groups: A, B, and C, with a daily recombinant-human GH dose during 4 study years of 4-4-4-4, 4-6-6-6, and 4-6-8-8 IU/m(2) b.s. The first GH dosage increase in groups B and C resulted in a significantly higher mean height velocity (HV) compared with constant dose group A. During the third year, when the dose was raised again only in group C, mean HV was significantly higher in groups B and C than in group A, and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA (Dutch-Swedish-Danish Turner references) was identical; however, in year 4 mean Delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment, the following was determined. 1) The mean Delta HSDSCA was significantly higher for groups B and C compared with group A, but not significantly different between groups B and C. 2) Although significantly higher compared with estimated values for untreated Dutch girls with TS, bone maturation of the GH treated girls was not significantly different between groups. 3) It was positively related with the degree of bone age (BA) retardation at start of study and negatively with baseline CA. 4) Both the modified Index of Potential Height (mIPH(RUS)) and a recently developed Turner-specific final height (FH) prediction method (PTSRUS), based on regression coefficients for H, CA, and bone age, showed significant increases in mean FH prediction, without significant differences between groups. PTSRUS values were markedly higher than the mIPH(RUS) values. Dose dependency could be shown for the area under the curve (AUC) for GH, but Delta HSDSCA was not linearly related with AUC. Baseline GH binding protein (BP) levels were in 84% of the cases within the normal age range; the decrease in mean levels after 6 months GH was not significant. Mean insulin-like growth factor I (IGF-I) and IGFBP-3 plasma levels increased significantly, without significant differences between groups. Delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period, beta-0.002 and beta-0.0004. Thus, a stepwise GH-dosing approach reduced the ''waning'' effect of the growth response after 4 yr treatment without undue bone maturation. FH prediction was not significantly different between treatment groups. Irrespective of the GH dose used, initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction, but was not statistically significant when expressed as Delta HSDSCA over the study period.
- Published
- 1996
10. Final height in girls with turner syndrome after long-term hormone treatment in three dosages and low dose estrogens
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van Pareren, YK (Yvonne), Schrama, Sabine, Stijnen, T (Theo), Sas, Theo, Jansen, M, Otten, BJ, Hoorweg - Nijman, JJG, Vulsma, T, Stokvis-Brantsma, WH, Rouwé, CW, Reeser, HM, Gerver, WJ, Gosen, JJ, Rongen - Westerlaken, C, Drop, Sten, van Pareren, YK (Yvonne), Schrama, Sabine, Stijnen, T (Theo), Sas, Theo, Jansen, M, Otten, BJ, Hoorweg - Nijman, JJG, Vulsma, T, Stokvis-Brantsma, WH, Rouwé, CW, Reeser, HM, Gerver, WJ, Gosen, JJ, Rongen - Westerlaken, C, and Drop, Sten
- Published
- 2003
11. Differential inhibition of 17-x hydroxylase and 17,20-lyase activities by three novel missende CYP17 mutations identified in patients with P450c17 deficiency
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van den Akker, Erica, Koper, Frans, Boehmer, Annemie, Themmen, Axel, Verhoef-Post, M, Timmerman, MA (Marianna), Otten, BJ, Drop, Sten, Jong, Frank, van den Akker, Erica, Koper, Frans, Boehmer, Annemie, Themmen, Axel, Verhoef-Post, M, Timmerman, MA (Marianna), Otten, BJ, Drop, Sten, and Jong, Frank
- Published
- 2002
12. RESULTS OF LONG-TERM THERAPY WITH GROWTH-HORMONE IN 2 DOSE REGIMENS IN TURNER SYNDROME
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NIENHUIS, HE, RONGENWESTERLAKEN, C, WIT, JM, OTTEN, BJ, KEIZERSCHRAMA, SMPFD, DRAYER, NM, DELEMARREVANDEWAAL, HA, VULSMA, T, OOSTDIJK, W, and WAELKENS, JJJ
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ADULT HEIGHT ,TURNER SYNDROME ,DEFICIENT CHILDREN ,HGH ,INJECTION FREQUENCY ,GIRLS ,HEIGHT VELOCITY ,GROWTH HORMONE DOSE ,BONE AGE ,WEEKLY IM - Abstract
Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/M2/week, with an increase in height velocity, though in the older girls, the response was comparatively poor. Therefore, the dose regimens in groups B1 and B2 were increased to 36 IU/M2/week given as six injections in both groups. This change resulted in an increase in height velocity only in group B1. During the first 2 years only, the height velocity was greater in group A2 than group A1. The conclusion is that a regimen of six injections/week is more effective than one of three injections/week in terms of initial height gain and change in predicted adult height. In girls with Turner syndrome aged over 16 years, GH therapy has no significant effect.
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- 1993
13. Testicular Adrenal Rest Tumours in Congenital Adrenal Hyperplasia
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Claahsen-van der Grinten, HL, primary, Hermus, ARMM, additional, and Otten, BJ, additional
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- 2009
- Full Text
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14. Case 2: A 6‐year‐old boy with precocious puberty (Discussion and Diagnosis)
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Mattheij, MAC, primary and Otten, BJ, additional
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- 2008
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15. Case 2: A 6‐year‐old boy with precocious puberty (Case Presentation)
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Mattheij, MAC, primary and Otten, BJ, additional
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- 2008
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16. Testicular Adrenal Rest Tumours in Congenital Adrenal Hyperplasia
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Otten BJ, Hermus ARMM, and Claahsen-van der Grinten HL
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endocrine system ,lcsh:RC648-665 ,urogenital system ,lcsh:RJ1-570 ,food and beverages ,lcsh:Pediatrics ,lcsh:Diseases of the endocrine glands. Clinical endocrinology - Abstract
In adult patients with congenital adrenal hyperplasia (CAH), the presence of testicular adrenal rest tumours (TART) is an important complication leading to gonadal dysfunction and infertility. These tumours can be already found in childhood and puberty. In this paper, we review the embryological, histological, biochemical, and clinical features of TART and discuss treatment options.
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- 2009
17. A visual pitfall: Persistent Mullerian duct syndrome (PMDS)
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Marcus, KA, primary, Halbertsma, FJJ, additional, Picard, JY, additional, and Otten, BJ, additional
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- 2007
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18. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial
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Sas, Theo, Schrama, Sabine, Stijnen, T (Theo), Jansen, M, Otten, BJ, Hoorweg - Nijman, JJG, Vulsma, T, Massa, GG, Rouwé, CW, Reeser, HM, Gerver, WJ, Gosen, JJ, Rongen - Westerlaken, C, Drop, Sten, Sas, Theo, Schrama, Sabine, Stijnen, T (Theo), Jansen, M, Otten, BJ, Hoorweg - Nijman, JJG, Vulsma, T, Massa, GG, Rouwé, CW, Reeser, HM, Gerver, WJ, Gosen, JJ, Rongen - Westerlaken, C, and Drop, Sten
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- 1999
19. 17 Bèta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, pheontypic variability, population genetics, and worldwide distribution of ancient and de novo mutations
- Author
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Boehmer, Annemie, Brinkmann, Albert, Ayuningtyas, Wireni, Halley, Dicky, Niermeijer, Martinus, Andersson, S, Jong, Frank, Kayserili, H, de Vroede, MA, Otten, BJ, Rouwé, CW, Mendonça, BB, Rodrigues, C, Bode, HH, Ruiter, Petra, Delemarre - van de Waal, H, Drop, Sten, Boehmer, Annemie, Brinkmann, Albert, Ayuningtyas, Wireni, Halley, Dicky, Niermeijer, Martinus, Andersson, S, Jong, Frank, Kayserili, H, de Vroede, MA, Otten, BJ, Rouwé, CW, Mendonça, BB, Rodrigues, C, Bode, HH, Ruiter, Petra, Delemarre - van de Waal, H, and Drop, Sten
- Published
- 1999
20. Treatment of tall stature in boys with somatostatin analogue 201–995: effect on final height
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Noordam, C, primary, van Daalen, S, additional, and Otten, BJ, additional
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- 2006
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21. Idiopathic precocious puberty versus puberty in adopted children; auxological response to gonadotrophin-releasing hormone agonist treatment and final height
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Kempers, MJ, primary and Otten, BJ, additional
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- 2002
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22. Growth hormone treatment in children with Noonan's syndrome: four year results of a partly controlled trial
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Noordam, C, primary, van der Burgt, I, additional, Sengers, RCA, additional, de Waal, HA Delemarre-van, additional, and Otten, BJ, additional
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- 2001
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23. Growth hormone therapy in pre‐pubertal children with Noonan syndrome: first year growth response and comparison with Turner syndrome
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Schepper, J De, primary, Otten, BJ, additional, François, I, additional, Bourguignon, J‐P, additional, Craen, M, additional, Van der Burgt, I, additional, and Massa, GG, additional
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- 1997
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24. Shortened and diminished pubertal growth in boys and girls treated for acute lymphoblastic leukaemia
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Groot-Loonen, JJ, primary, Setten, P van, additional, Otten, BJ, additional, van‘t Hof, MA, additional, Lippens, RJJ, additional, and Stoelinga, GBA, additional
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- 1996
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25. Effect of growth hormone treatment on craniofacial growth in Turner's syndrome
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Rongen-Westerlaken, C, primary, Born, E vd, additional, Prahl-Andersen, B, additional, Teunenbroek, A v, additional, Manesse, P, additional, Otten, BJ, additional, Tweel, I vd, additional, Kuijpers-Jagtman, AM, additional, Delemarre vd Waal, HA, additional, Drayer, NM, additional, Wit, JM, additional, and Brande, JL vd, additional
- Published
- 1993
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26. Case 2: A 6-year-old boy with precocious puberty (case presentation)
- Author
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Mattheij MA and Otten BJ
- Published
- 2009
- Full Text
- View/download PDF
27. A visual pitfall: Persistent Mullerian duct syndrome (PMDS)
- Author
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Marcus KA, Halbertsma FJ, Picard JY, and Otten BJ
- Abstract
Persistent Müllerian Duct Syndrome (PMDS) is a rare disorder of the anti-mullerian hormone (AMH) synthesis or receptor, which due to the visual contrast of normal masculine external genitalia and female internal genitalia can raise confusion, sometimes during surgery for cryptorchidism or hernia inguinalis. For an acute and accurate analysis of such a situation a thorough knowledge of gonadal embryology is mandatory. The diagnosis is made on finding Müllerian structures in an individual with complete virilization without signs of hypocortisolism or exposition to maternal androgens during foetal life. Karyotyping and gonadal biopsy provide additional information to confirm the diagnosis. As the risk of malignant transformation is not clear, orchidopexy is advised in patients with cryptorchidism, with lifelong palpatory follow-up. In case of urologic symptoms, surgical removal of the Müllerian remnants can be considered, with careful attention for the vulnerable ductus deferens. Despite optimal treatment the prognosis regarding fertility remain uncertain. [ABSTRACT FROM AUTHOR]
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- 2008
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28. Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
- Author
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Stikkelbroeck NMM, Hermus AR, Braat DDM, and Otten BJ
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- 2003
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29. Clinical note. Progressive sensorineural hearing loss and a widened vestibular aqueduct in Pendred syndrome.
- Author
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Cremers WRJ, Bolder C, Admiraal RJC, Everett LA, Joosten FBM, van Hauwe P, Green ED, and Otten BJ
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- 1998
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30. Case 2: A 6-year-old boy with precocious puberty (Discussion and Diagnosis).
- Author
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Mattheij, MAC and Otten, BJ
- Subjects
- *
CASE studies , *PRECOCIOUS puberty , *TUMORS in children , *RADIOTHERAPY - Abstract
A case study is presented where a six-year-old boy presented with precocious puberty. Partial excision of the patient's tumor revealed a germinoma. The patient was treated with radiotherapy, and remained dependent of hormone replacement therapy. A the age of 21, he is reportedly continuing cortisone and thyroxine treatment. He is said to be doing well with a height of 1.84 meters and normal levels of 1GF-1, and germinoma has not recurred since.
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- 2009
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31. Letter. Influence of peritoneal loss of GHBP, IGF-I and IGFBP-3 on serum levels in children with ESRD.
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van der Kamp, HD, Otten, BJ, Swinkels, LMJW, Sweeps, CGJ, Monnens, LAH, and Schröder, CH
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- 1999
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32. 151 DIACNOSIS OF 21HYDROXYLASE DEPFICIENCY 21HD BY DETERMINATION OF SALIVARY STEROIDS
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Otten, BJ., Rijken, JC., Stoelinga, CBA., and Benraad, THJ.
- Published
- 1988
33. Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty.
- Author
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Pijnenburg-Kleizen KJ, Thomas CMG, Otten BJ, Roeleveld N, and Claahsen-van der Grinten HL
- Subjects
- Adolescent, Adrenal Hyperplasia, Congenital metabolism, Adrenal Hyperplasia, Congenital pathology, Age Factors, Biomarkers analysis, Body Mass Index, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Longitudinal Studies, Male, Prognosis, Retrospective Studies, Adrenal Hyperplasia, Congenital drug therapy, Body Height drug effects, Hydrocortisone therapeutic use, Puberty drug effects, Sexual Maturation drug effects
- Abstract
Background In congenital adrenal hyperplasia (CAH), achieving the balance between overtreatment and undertreatment remains challenging. Final height (FH) can serve as a long-term outcome measure. We aimed to identify age-dependent factors that influence FH in CAH patients, resulting in age-specific treatment goals. Methods We retrospectively evaluated longitudinal data of 39 pediatric CAH patients born between 1980 and 1997 from the Radboudumc CAH database. We analyzed height and bone age (BA) at diagnosis or 4 years of age, at the start of puberty and at FH. Height data were corrected for parental height and secular trend. Hydrocortisone (HC) use and salivary steroid concentrations were studied longitudinally throughout childhood and puberty. Results Median FH standard deviation scores (SDSs) corrected for target height SDSs (THSDSs) was -1.63. Median height SDS corrected for THSDS (HSDS-THSDS) decreased from diagnosis/age 4 years to FH in both salt wasting (SW) CAH and simple virilizing (SV) CAH, and in both male and female patients. However, when height was corrected for BA, no height loss occurred from diagnosis/age 4 years to FH in any of the subgroups, while a height gain was seen in SV males. In the combined model analyzing both HC dose and salivary steroid concentrations, in childhood the androstenedione (A) concentration was negatively associated with FH, while in puberty the HC dose was negatively associated with FH. Conclusions In CAH, loss of growth potential already occurs in early childhood. In prepubertal children, exposure to elevated androgens is associated with decreased FH. In puberty, the growth suppressing effects of HC outweigh the negative effects of elevated androgens. Therefore, we suggest different treatment approaches in prepubertal and pubertal patients.
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- 2019
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34. A delayed diagnosis of salt-wasting congenital adrenal hyperplasia.
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Pijnenburg-Kleizen KJ, Noordam C, Otten BJ, and Claahsen-van der Grinten HL
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- Adrenal Hyperplasia, Congenital therapy, Age Factors, Child, Preschool, Humans, Infant, Newborn, Male, Sodium Chloride administration & dosage, Urogenital Abnormalities diagnosis, Adrenal Hyperplasia, Congenital diagnosis, Delayed Diagnosis
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- 2016
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35. Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.
- Author
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Freriks K, Verhaak CM, Sas TC, Menke LA, Wit JM, Otten BJ, de Muinck Keizer-Schrama SM, Smeets DF, Netea-Maier RT, Hermus AR, Kessels RP, and Timmers HJ
- Subjects
- Adolescent, Adult, Androgens administration & dosage, Depression drug therapy, Depression psychology, Estrogens administration & dosage, Female, Follow-Up Studies, Growth Hormone therapeutic use, Human Growth Hormone administration & dosage, Humans, Oxandrolone administration & dosage, Time Factors, Turner Syndrome psychology, Young Adult, Cognition drug effects, Emotional Intelligence drug effects, Emotions drug effects, Oxandrolone pharmacology, Quality of Life psychology, Turner Syndrome drug therapy
- Abstract
Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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36. Salivary morning androstenedione and 17α-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia.
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de Groot MJ, Pijnenburg-Kleizen KJ, Thomas CM, Sweep FC, Stikkelbroeck NM, Otten BJ, and Claahsen-van der Grinten HL
- Subjects
- Adolescent, Adrenal Hyperplasia, Congenital drug therapy, Child, Child, Preschool, Female, Glucocorticoids pharmacology, Glucocorticoids therapeutic use, Humans, Male, Retrospective Studies, Saliva drug effects, 17-alpha-Hydroxyprogesterone analysis, Adrenal Hyperplasia, Congenital metabolism, Androstenedione analysis, Puberty metabolism, Saliva chemistry
- Abstract
Background: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17α-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring., Methods: We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21-hydroxylase deficiency., Results: A-dione and 17OHP levels and its ratio 17OHP/A-dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46-4.41) during prepuberty; 2.36 nmol/L (0.63-8.89) for boys and 1.99 nmol/L (0.32-6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11-15 mg/m2/day. A-dione levels above the upper reference limit (URL), suggesting undertreatment, coincided with 17OHP levels ≥10 times URL. The percentage of A-dione levels above URL was 16% at ages 4-8 years, but increased to 31% for girls at 16 years and 46% for boys at 17 years., Conclusions: Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4-6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys.
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- 2015
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37. Growth hormone therapy, muscle thickness, and motor development in Prader-Willi syndrome: an RCT.
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Reus L, Pillen S, Pelzer BJ, van Alfen-van der Velden JA, Hokken-Koelega AC, Zwarts M, Otten BJ, and Nijhuis-van der Sanden MW
- Subjects
- Child, Preschool, Combined Modality Therapy, Female, Humans, Infant, Longitudinal Studies, Male, Muscle, Skeletal diagnostic imaging, Netherlands, Prader-Willi Syndrome diagnosis, Single-Blind Method, Ultrasonography, Exercise Therapy, Human Growth Hormone therapeutic use, Motor Skills drug effects, Muscle Strength drug effects, Muscle, Skeletal drug effects, Prader-Willi Syndrome drug therapy
- Abstract
Objective: To investigate the effect of physical training combined with growth hormone (GH) on muscle thickness and its relationship with muscle strength and motor development in infants with Prader-Willi syndrome (PWS)., Methods: In a randomized controlled trial, 22 infants with PWS (12.9 ± 7.1 months) were followed over 2 years to compare a treatment group (n = 10) with a waiting-list control group (n = 12). Muscle thickness of 4 muscle groups was measured by using ultrasound. Muscle strength was evaluated by using the Infant Muscle Strength meter. Motor performance was measured with the Gross Motor Function Measurement. Analyses of variance were used to evaluate between-group effects of GH on muscle thickness at 6 months and to compare pre- and posttreatment (after 12 months of GH) values. Multilevel analyses were used to evaluate effects of GH on muscle thickness over time, and multilevel bivariate analyses were used to test relationships between muscle thickness, muscle strength, and motor performance., Results: A significant positive effect of GH on muscle thickness (P < .05) was found. Positive relationships were found between muscle thickness and muscle strength (r = 0.61, P < .001), muscle thickness and motor performance (r = 0.81, P < .001), and muscle strength and motor performance (r = 0.76, P < .001)., Conclusions: GH increased muscle thickness, which was related to muscle strength and motor development in infants with PWS. Catch-up growth was faster in muscles that are most frequently used in early development. Because this effect was independent of GH, it suggests a training effect., (Copyright © 2014 by the American Academy of Pediatrics.)
- Published
- 2014
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38. Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.
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Verver EJ, Freriks K, Sas TC, Huygen PL, Pennings RJ, Smeets DF, Hermus AR, Menke LA, Wit JM, Otten BJ, van Alfen-van der Velden JA, de Muinck Keizer-Schrama SM, Topsakal V, Admiraal RJ, Timmers HJ, and Kunst HP
- Subjects
- Adolescent, Adult, Anabolic Agents administration & dosage, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Hearing, Hearing Loss genetics, Hearing Loss, Sensorineural genetics, Hearing Tests, Human Growth Hormone administration & dosage, Humans, Karyotype, Karyotyping, Oxandrolone administration & dosage, Turner Syndrome drug therapy, Turner Syndrome genetics, Young Adult, Anabolic Agents adverse effects, Hearing Loss epidemiology, Oxandrolone adverse effects, Turner Syndrome complications
- Abstract
Objective: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox)., Study Design: Double-blind follow-up study., Setting: University hospital., Patients: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years., Intervention: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level., Main Outcome Measures: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment., Results: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups., Conclusion: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.
- Published
- 2014
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39. Comparison of body surface area versus weight-based growth hormone dosing for girls with Turner syndrome.
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Schrier L, de Kam ML, McKinnon R, Che Bakri A, Oostdijk W, Sas TC, Menke LA, Otten BJ, de Muinck Keizer-Schrama SM, Kristrom B, Ankarberg-Lindgren C, Burggraaf J, Albertsson-Wikland K, and Wit JM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Insulin-Like Growth Factor I metabolism, Turner Syndrome blood, Turner Syndrome physiopathology, Body Surface Area, Body Weight, Drug Dosage Calculations, Human Growth Hormone administration & dosage, Turner Syndrome drug therapy
- Abstract
Background/aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS)., Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies., Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA., Conclusion: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
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40. Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.
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Sas TC, Gault EJ, Bardsley MZ, Menke LA, Freriks K, Perry RJ, Otten BJ, de Muinck Keizer-Schrama SM, Timmers H, Wit JM, Ross JL, and Donaldson MD
- Subjects
- Adolescent, Adult, Age Factors, Androgens adverse effects, Child, Child, Preschool, Double-Blind Method, Female, Human Growth Hormone adverse effects, Humans, Oxandrolone adverse effects, Randomized Controlled Trials as Topic, Androgens therapeutic use, Human Growth Hormone therapeutic use, Oxandrolone therapeutic use, Turner Syndrome drug therapy, Turner Syndrome physiopathology
- Abstract
There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3–4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03–0.05 mg/kg/day starting from the age of 8–10 years onward scan be considered., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
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41. Growth hormone combined with child-specific motor training improves motor development in infants with Prader-Willi syndrome: a randomized controlled trial.
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Reus L, Pelzer BJ, Otten BJ, Siemensma EP, van Alfen-van der Velden JA, Festen DA, Hokken-Koelega AC, and Nijhuis-van der Sanden MW
- Subjects
- Child Development drug effects, Child Development physiology, Developmental Disabilities physiopathology, Developmental Disabilities therapy, Female, Humans, Infant, Longitudinal Studies, Male, Regression Analysis, Treatment Outcome, Human Growth Hormone therapeutic use, Motor Skills physiology, Physical Therapy Modalities, Prader-Willi Syndrome drug therapy, Prader-Willi Syndrome physiopathology
- Abstract
Although severe motor problems in infants with Prader-Willi syndrome (PWS) are striking, motor development has never been studied longitudinally and the results of growth hormone (GH) treatment on motor development are contradictory. The authors studied whether GH treatment can enhance the effect of physical training on motor development in infants with PWS. Twenty-two infants were followed for two years during a randomized controlled trial. The treatment and control groups began GH after baseline or following a control period, respectively. Both groups followed a child-specific physical training program. Motor performance was measured every three months. Multi-level regression analysis revealed that motor development differed significantly between infants (p<.001), and this could be partially explained by baseline motor developmental level (p<.01). GH treatment enhanced the effects of child-specific physical training on both motor developmental rate and motor developmental potential. Moreover, this effect was more pronounced when GH treatment was initiated at a younger age., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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42. Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome.
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Freriks K, Timmers HJ, Netea-Maier RT, Beerendonk CC, Otten BJ, van Alfen-van der Velden JA, Traas MA, Mieloo H, van de Zande GW, Hoefsloot LH, Hermus AR, and Smeets DF
- Subjects
- Adult, Female, Genetic Predisposition to Disease, Gonadoblastoma diagnosis, Gonadoblastoma etiology, Humans, In Situ Hybridization, Fluorescence, Lymphocytes metabolism, Mouth Mucosa metabolism, Ovarian Neoplasms diagnosis, Ovarian Neoplasms etiology, Real-Time Polymerase Chain Reaction, Turner Syndrome complications, Turner Syndrome diagnosis, Chromosomes, Human, X genetics, Chromosomes, Human, Y genetics, Mosaicism, Turner Syndrome genetics
- Abstract
Turner syndrome (TS) is the result of (partial) X chromosome monosomy. In general, the diagnosis is based on karyotyping of 30 blood lymphocytes. This technique, however, does not rule out tissue mosaicism or low grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. We investigated different approaches to improve the detection of mosaicisms in 162 adult women with TS (mean age 29.9 ± 10.3). Standard karyotyping identified 75 patients (46.3%) with a non-mosaic monosomy 45,X. Of these 75 patients, 63 underwent additional investigations including FISH on buccal cells with X- and Y-specific probes and PCR-Y on blood. FISH analysis of buccal cells revealed a mosaicism in 19 of the 63 patients (30.2%). In five patients the additional cell lines contained a (derivative) Y chromosome. With sensitive real-time PCR we confirmed the presence of this Y chromosome in blood in three of the five cases. Although Y chromosome material was established in ovarian tissue in two patients, no gonadoblastoma was found. Our results confirm the notion that TS patients with 45,X on conventional karyotyping often have tissue specific mosaicisms, some of which include a Y chromosome. Although further investigations are needed to estimate the risk of gonadoblastoma in patients with Y chromosome material in buccal cells, we conclude that FISH or real-time PCR on buccal cells should be considered in TS patients with 45,X on standard karyotyping., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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43. Objective evaluation of muscle strength in infants with hypotonia and muscle weakness.
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Reus L, van Vlimmeren LA, Staal JB, Janssen AJ, Otten BJ, Pelzer BJ, and Nijhuis-van der Sanden MW
- Subjects
- Case-Control Studies, Child, Preschool, Female, Humans, Infant, Linear Models, Male, Muscle Strength Dynamometer, Reproducibility of Results, Child Development physiology, Muscle Hypotonia diagnosis, Muscle Strength physiology, Muscle Weakness diagnosis, Prader-Willi Syndrome diagnosis
- Abstract
The clinical evaluation of an infant with motor delay, muscle weakness, and/or hypotonia would improve considerably if muscle strength could be measured objectively and normal reference values were available. The authors developed a method to measure muscle strength in infants and tested 81 typically developing infants, 6-36 months of age, and 17 infants with Prader-Willi Syndrome (PWS) aged 24 months. The inter-rater reliability of the measurement method was good (ICC=.84) and the convergent validity was confirmed by high Pearson's correlations between muscle strength, age, height, and weight (r=.79-.85). A multiple linear regression model was developed to predict muscle strength based on age, height, and weight, explaining 73% of the variance in muscle strength. In infants with PWS, muscle strength was significantly decreased. Pearson's correlations showed that infants with PWS in which muscle strength was more severely affected also had a larger motor developmental delay (r=.75)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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44. Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II.
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Kempers MJ, van der Crabben SN, de Vroede M, Alfen-van der Velden J, Netea-Maier RT, Duim RA, Otten BJ, Losekoot M, and Wit JM
- Subjects
- Adult, Child, Preschool, Delayed Diagnosis, Female, Genetic Testing, Humans, Infant, Male, Mutation, Pedigree, Dwarfism, Pituitary diagnosis, Dwarfism, Pituitary genetics, Human Growth Hormone genetics, RNA Splice Sites genetics
- Abstract
Background: Congenital isolated growth hormone deficiency (IGHD) is a rare endocrine disorder that presents with severe proportionate growth failure. Dominant (type II) IGHD is usually caused by heterozygous mutations of GH1. The presentation of newly affected family members in 3 families with dominant IGHD in whom previous genetic testing had not demonstrated a GH1 mutation or had not been performed, prompted us to identify the underlying genetic cause., Methods: GH1 was sequenced in 3 Caucasian families with a clinical autosomal dominant IGHD., Results: All affected family members had severe growth hormone (GH) deficiency that became apparent in the first 2 years of life. GH treatment led to a marked increase in height SDS. So far, no other pituitary dysfunctions have become apparent. In the first family a novel splice site mutation in GH1 was identified (c.172-1G>C, IVS2-1G>C). In two other families a previously reported splice site mutation (c.291+1G>A, IVS3+1G>A) was found., Conclusion: These data show that several years after negative genetic testing it was now possible to make a genetic diagnosis in these families with a well-defined, clearly heritable, autosomal dominant IGHD. This underscores the importance of clinical and genetic follow-up in a multidisciplinary setting. It also shows that even without a positive family history, genetic testing should be considered if the phenotype is strongly suggestive for a genetic syndrome. Identification of pathogenic mutations, like these GH1 mutations, has important clinical implications for the surveillance and genetic counseling of patients and expands our knowledge on the genotype-phenotype correlation., (© 2013 S. Karger AG, Basel.)
- Published
- 2013
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45. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome.
- Author
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Freriks K, Sas TC, Traas MA, Netea-Maier RT, den Heijer M, Hermus AR, Wit JM, van Alfen-van der Velden JA, Otten BJ, de Muinck Keizer-Schrama SM, Gotthardt M, Dejonckere PH, Zandwijken GR, Menke LA, and Timmers HJ
- Subjects
- Adult, Breast drug effects, Breast growth & development, Child, Child, Preschool, Double-Blind Method, Female, Follow-Up Studies, Human Growth Hormone administration & dosage, Humans, Randomized Controlled Trials as Topic, Treatment Outcome, Virilism chemically induced, Body Height drug effects, Oxandrolone administration & dosage, Turner Syndrome drug therapy
- Abstract
Objective: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment., Design and Methods: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition., Results: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency., Conclusion: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.
- Published
- 2012
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46. Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.
- Author
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de Munnik SA, Otten BJ, Schoots J, Bicknell LS, Aftimos S, Al-Aama JY, van Bever Y, Bober MB, Borm GF, Clayton-Smith J, Deal CL, Edrees AY, Feingold M, Fryer A, van Hagen JM, Hennekam RC, Jansweijer MC, Johnson D, Kant SG, Opitz JM, Ramadevi AR, Reardon W, Ross A, Sarda P, Schrander-Stumpel CT, Sluiter AE, Temple IK, Terhal PA, Toutain A, Wise CA, Wright M, Skidmore DL, Samuels ME, Hoefsloot LH, Knoers NV, Brunner HG, Jackson AP, and Bongers EM
- Subjects
- Cell Cycle Proteins genetics, Child, Preschool, Cohort Studies, Congenital Microtia, Ear abnormalities, Female, Growth Disorders drug therapy, Growth Disorders genetics, Human Growth Hormone blood, Human Growth Hormone therapeutic use, Humans, Infant, Male, Micrognathism drug therapy, Micrognathism genetics, Mutation, Origin Recognition Complex genetics, Patella abnormalities, Urogenital Abnormalities, Growth Charts, Growth Disorders diagnosis, Micrognathism diagnosis, Sexual Development genetics
- Abstract
Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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47. Ovarian function and reproductive hormone levels in girls with Prader-Willi syndrome: a longitudinal study.
- Author
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Siemensma EP, van Alfen-van der Velden AA, Otten BJ, Laven JS, and Hokken-Koelega AC
- Subjects
- Adolescent, Aging physiology, Anti-Mullerian Hormone blood, Child, Child, Preschool, Cohort Studies, Enzyme-Linked Immunosorbent Assay, Estradiol blood, Estradiol therapeutic use, Female, Fertility, Follicle Stimulating Hormone blood, Humans, Infant, Inhibins blood, Longitudinal Studies, Luteinizing Hormone blood, Ovarian Function Tests, Prader-Willi Syndrome blood, Prader-Willi Syndrome drug therapy, Puberty physiology, Young Adult, Estrogens blood, Ovary physiopathology, Prader-Willi Syndrome physiopathology
- Abstract
Context: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain., Objectives: The aim of the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS., Measurements: We performed a longitudinal assessment of anti-müllerian hormone (AMH), gonadotropins, estradiol (E(2)), inhibin B and A, and pubertal development in girls and female adolescents with PWS., Patients and Methods: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E(2), and inhibin B and A levels were compared with reference values., Results: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E(2) and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P = 0.05) and M4 (P < 0.0001) were significantly higher in girls with PWS than in healthy references., Conclusion: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS.
- Published
- 2012
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48. The effect of growth hormone treatment or physical training on motor performance in Prader-Willi syndrome: a systematic review.
- Author
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Reus L, van Vlimmeren LA, Staal JB, Otten BJ, and Nijhuis-van der Sanden MW
- Subjects
- Animals, Body Composition drug effects, Humans, Prader-Willi Syndrome physiopathology, Treatment Outcome, Human Growth Hormone therapeutic use, Motor Activity drug effects, Prader-Willi Syndrome drug therapy
- Abstract
Although motor problems in Prader-Willi syndrome (PWS) are prominent in infants, and continue into childhood and adulthood, there is little insight into the factors important for clinical management. The literature was reviewed to: (1) provide an overview of the characteristics and prevalence of motor problems and (2) evaluate the effects of growth hormone (GH) treatment and physical training on motor performance. A systematic search revealed 34 papers: 13 on motor performance; 12 on GH treatment; and nine on physical training. In infants, motor development is 30-57% of the normal reference values, and children and adults also have significant problems in skill acquisition, muscle force, cardiovascular fitness, and activity level. GH treatment positively influenced motor performance in infants, children, and adults, although not all studies demonstrated an effect. All studies on physical training demonstrated beneficial effects in PWS patients. We suggest a combination of GH treatment and physical training to be started as soon as possible, especially in infants, to improve motor development as this will positively influence general development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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49. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study.
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Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Troeman ZC, van Alfen-van der Velden AA, Otten BJ, Rotteveel J, Odink RJ, Bindels-de Heus GC, van Leeuwen M, Haring DA, Oostdijk W, Bocca G, Mieke Houdijk EC, van Trotsenburg AS, Hoorweg-Nijman JJ, van Wieringen H, Vreuls RC, Jira PE, Schroor EJ, van Pinxteren-Nagler E, Willem Pilon J, Lunshof LB, and Hokken-Koelega AC
- Subjects
- Adolescent, Child, Child Development drug effects, Child Development physiology, Child, Preschool, Cognition physiology, Female, Humans, Intelligence Tests, Longitudinal Studies, Male, Prader-Willi Syndrome physiopathology, Prader-Willi Syndrome psychology, Research Design, Time Factors, Cognition drug effects, Human Growth Hormone pharmacology, Human Growth Hormone therapeutic use, Prader-Willi Syndrome drug therapy
- Abstract
Background: Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited., Methods: Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores., Results: During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores., Conclusions: Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.
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- 2012
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50. Cardiac evaluation in children with Prader-Willi syndrome.
- Author
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Marcus KA, van Alfen-van der Velden JA, Otten BJ, Weijers G, Yntema HG, de Korte CL, and Kapusta L
- Subjects
- Child, Female, Heart Function Tests, Humans, Male, Prospective Studies, Systole, Heart physiopathology, Myocardium pathology, Prader-Willi Syndrome pathology, Prader-Willi Syndrome physiopathology
- Abstract
Aim: To assess cardiac anatomy and myocardial systolic function in children with Prader-Willi syndrome (PWS)., Methods: Physical examination, electrocardiographic (ECG) recordings and transthoracic echocardiograms including two-dimensional speckle tracking echocardiography (2DSTE) were performed and evaluated in the Radboud University Hospital Nijmegen, the Netherlands. In total, 19 children diagnosed with PWS and 38 age-matched control subjects underwent cardiac evaluation., Results: Abnormal ECG findings were detected in nine PWS patients. Echocardiography revealed mild structural cardiac abnormalities in two patients. Conventional echocardiographic findings did not indicate systolic left ventricular dysfunction, in contrast to 2DSTE examination. Global peak systolic strain (rate) measurements, in all three directions of contraction, were significantly lower in children with PWS (p < 0.001) compared with healthy age-matched children. In two-thirds of the patients, 2DSTE revealed abnormal systolic deformation (peak systolic strain as well as strain rate). T2P values in PWS patients were similar to control subject. Systolic myocardial function appears more affected in case of maternal uniparental disomy., Conclusion: Cardiac evaluation, including 2DSTE, detects frequent alterations in myocardial systolic function in children diagnosed with PWS, whose conventional echocardiographic findings did not indicate ventricular systolic dysfunction. Because cardiovascular morbidity and mortality is substantial in PWS, especially adults, we emphasize the need for cardiac assessment in PWS., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)
- Published
- 2012
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