193 results on '"Wit, JM"'
Search Results
2. An analysis of intra-uterine growth retardation in rural Malawi
- Author
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Verhoeff, FH, Brabin, BJ, van Buuren, S, Chimsuku, L, Kazembe, P, Wit, JM, and Broadhead, RL
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- 2001
- Full Text
- View/download PDF
3. Short stature and the probability of coeliac disease, in the absence of gastrointestinal symptoms
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van Rijn, J C W, Grote, F K, Oostdijk, W, and Wit, JM
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- 2004
4. Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novel IGFALS mutations.
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Işık, E, Haliloglu, B, van Doorn, J, Demirbilek, H, Scheltinga, SA, Losekoot, M, Wit, JM, Işık, E, Haliloglu, B, van Doorn, J, Demirbilek, H, Scheltinga, SA, Losekoot, M, and Wit, JM
- Published
- 2017
5. Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novel IGFALS mutations.
- Author
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Genetica Sectie Metabole Diagnostiek, Other research (not in main researchprogram), Işık, E, Haliloglu, B, van Doorn, J, Demirbilek, H, Scheltinga , SA, Losekoot, M, Wit, JM, Genetica Sectie Metabole Diagnostiek, Other research (not in main researchprogram), Işık, E, Haliloglu, B, van Doorn, J, Demirbilek, H, Scheltinga , SA, Losekoot, M, and Wit, JM
- Published
- 2017
6. Determinants of Advanced Bone Age in Childhood Obesity
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de Groot, CJ, van den Berg, A, Ballieux, B, Kroon, HM, Rings, Edmond, Wit, JM, van den Akker, Erica, de Groot, CJ, van den Berg, A, Ballieux, B, Kroon, HM, Rings, Edmond, Wit, JM, and van den Akker, Erica
- Published
- 2017
7. Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density
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Hannema, Sabine, Wit, JM, Houdijk, Mecam, van Haeringen, A, Bik, E C, Verkerk, Annemieke, Uitterlinden, André, Kant, SG, oostdijk, W, Bakker, E, Delemarre-van de Waal, HA, Losekoot, M, Hannema, Sabine, Wit, JM, Houdijk, Mecam, van Haeringen, A, Bik, E C, Verkerk, Annemieke, Uitterlinden, André, Kant, SG, oostdijk, W, Bakker, E, Delemarre-van de Waal, HA, and Losekoot, M
- Published
- 2016
8. Mutations in TBL1X Are Associated With Central Hypothyroidism
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Heinen, CA, Losekoot, M, Sun, Y, Watson, P J, Fairall, L, Joustra, SD, Zwaveling-Soonawala, N, Oostdijk, W (Wilma), van den Akker, Erica, Alders, M, Santen, GWE, van Rijn, RR, Dreschler, WA, Surovtseva, O V, Biermasz, NR, Hennekam, RC, Wit, JM, Schwabe, J W R, Boelen, A, Fliers, E, van Trotsenburg, ASP, Heinen, CA, Losekoot, M, Sun, Y, Watson, P J, Fairall, L, Joustra, SD, Zwaveling-Soonawala, N, Oostdijk, W (Wilma), van den Akker, Erica, Alders, M, Santen, GWE, van Rijn, RR, Dreschler, WA, Surovtseva, O V, Biermasz, NR, Hennekam, RC, Wit, JM, Schwabe, J W R, Boelen, A, Fliers, E, and van Trotsenburg, ASP
- Published
- 2016
9. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation
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Kamp, GA, Mul, D (Dick), Waelkens, JJJ, Jansen, M, Delemarre-van de Waal, HA, Verhoeven-Wind, L, Frölich, M, Oostdijk, W (Wilma), Wit, JM, and Pediatrics
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Biochemistry - Published
- 2001
10. 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
11. PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation-In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations
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oostdijk, W, Idkowiak, J, Mueller, JW, House, PJ, Taylor, AE, O'Reilly, MW, Hughes, BA, de Vries, MC, Kant, SG, Santen, GWE, Verkerk, Annemieke, Uitterlinden, André, Wit, JM, Losekoot, M, Arlt, W, oostdijk, W, Idkowiak, J, Mueller, JW, House, PJ, Taylor, AE, O'Reilly, MW, Hughes, BA, de Vries, MC, Kant, SG, Santen, GWE, Verkerk, Annemieke, Uitterlinden, André, Wit, JM, Losekoot, M, and Arlt, W
- Abstract
Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c. 1371del, p. W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c. 809G>A, p. G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p. W462Cfs*3, showed increased 5 alpha-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.
- Published
- 2015
12. Adenomatous polyposis coli-mediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors
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Miclea, RL, Karperien, M, Bosch, CA, van der Horst, Bert, Valk, MA, Kobayashi, T, Kronenberg, HM, Rawadi, G, Akcakaya, P, Löwik, Clemens, Fodde, Riccardo, Wit, JM, Robanus-Maandag, EC, Molecular Genetics, Neurosciences, and Pathology
- Abstract
Background: During skeletogenesis, protein levels of beta-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of beta-catenin turnover by down-regulating intracellular levels of beta-catenin. Results: To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of beta-catenin was used, our approach resulted in the accumulation of wild type beta-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells. Conclusion: Our data indicate that a tight Apc-mediated control of beta-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.
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- 2009
13. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-1 receptor due to a terminal 15q26.2>qter deletion detected by multiplex ligation probe amplification
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Walenkamp, MJE, Schrama, Sabine, Kalf, ME, van Duyvenvoorde, HA, Boot, AM (Annemieke), Kant, SG, White, SJ, Losekoot, M, Dunnen, JT, Karperien, M, Wit, JM, and Pediatrics
- Published
- 2008
14. The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP
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Nikkel, SM, Dauber, A, de Munnik, S, Connolly, M, Hood, RL, Caluseriu, O, Hurst, J, Kini, U, Nowaczyk, MJM, Afenjar, A, Albrecht, B, Allanson, JE, Balestri, P, Ben-Omran, T, Brancati, F, Cordeiro, I, da Cunha, BS, Delaney, LA, Destree, A, Fitzpatrick, D, Forzano, F, Ghali, N, Gillies, G, Harwood, K, Hendriks, YMC, Heron, D, Hoischen, A, Honey, EM, Hoefsloot, LH, Ibrahim, J, Jacob, CM, Kant, SG, Kim, CA, Kirk, EP, Knoers, NVAM, Lacombe, D, Lee, C, Lo, IFM, Lucas, LS, Mari, F, Mericq, V, Moilanen, JS, Moller, ST, Moortgat, S, Pilz, DT, Pope, K, Price, S, Renieri, A, Sa, J, Schoots, J, Silveira, EL, Simon, MEH, Slavotinek, A, Temple, IK, van der Burgt, I, de Vries, BBA, Weisfeld-Adams, JD, Whiteford, ML, Wierczorek, D, Wit, JM, Yee, CFO, Beaulieu, CL, White, SM, Bulman, DE, Bongers, E, Brunner, H, Feingold, M, Boycott, KM, Nikkel, SM, Dauber, A, de Munnik, S, Connolly, M, Hood, RL, Caluseriu, O, Hurst, J, Kini, U, Nowaczyk, MJM, Afenjar, A, Albrecht, B, Allanson, JE, Balestri, P, Ben-Omran, T, Brancati, F, Cordeiro, I, da Cunha, BS, Delaney, LA, Destree, A, Fitzpatrick, D, Forzano, F, Ghali, N, Gillies, G, Harwood, K, Hendriks, YMC, Heron, D, Hoischen, A, Honey, EM, Hoefsloot, LH, Ibrahim, J, Jacob, CM, Kant, SG, Kim, CA, Kirk, EP, Knoers, NVAM, Lacombe, D, Lee, C, Lo, IFM, Lucas, LS, Mari, F, Mericq, V, Moilanen, JS, Moller, ST, Moortgat, S, Pilz, DT, Pope, K, Price, S, Renieri, A, Sa, J, Schoots, J, Silveira, EL, Simon, MEH, Slavotinek, A, Temple, IK, van der Burgt, I, de Vries, BBA, Weisfeld-Adams, JD, Whiteford, ML, Wierczorek, D, Wit, JM, Yee, CFO, Beaulieu, CL, White, SM, Bulman, DE, Bongers, E, Brunner, H, Feingold, M, and Boycott, KM
- Abstract
BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. METHODS AND RESULTS: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.
- Published
- 2013
15. Pubertal development in the Netherlands
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Mul, D (Dick), Fredriks, AM, van Buuren, S, Oostdijk, W (Wilma), Verloove-Vanhorick, SP, Wit, JM, and Pediatrics
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- 2001
16. 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
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- 1999
17. Should blood gas analysis be part of the diagnostic workup of short children? Auxological data and blood gas analysis in children with renal tubular acidosis
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Mul, D (Dick), Grote, FK (Floor), Goudriaan, JR, Schrama, Sabine, Wit, JM, oostdijk, W, Mul, D (Dick), Grote, FK (Floor), Goudriaan, JR, Schrama, Sabine, Wit, JM, and oostdijk, W
- Published
- 2010
18. The diagnostic workup of growth failure in secondary health care; An evaluation of consensus guidelines
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Grote, FK (Floor), Oostdijk, W (Wilma), Schrama, Sabine, van Dommelen, P, van Buuren, S, Dekker, FW, Ketel, AG, Moll, Henriette, Wit, JM, Grote, FK (Floor), Oostdijk, W (Wilma), Schrama, Sabine, van Dommelen, P, van Buuren, S, Dekker, FW, Ketel, AG, Moll, Henriette, and Wit, JM
- Published
- 2008
19. Referral patterns of children with poor growth in primary health care
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Grote, FK (Floor), Oostdijk, W (Wilma), Schrama, Sabine, Dekker, FW, van Dommelen, P, van Buuren, S, Kooij, AMLVD, Verkerk, PH, Wit, JM, Grote, FK (Floor), Oostdijk, W (Wilma), Schrama, Sabine, Dekker, FW, van Dommelen, P, van Buuren, S, Kooij, AMLVD, Verkerk, PH, and Wit, JM
- Published
- 2007
20. 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
21. The effect of pubertal delay by GnRH agonist in GH-deficient children on final height
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Mul, D (Dick), Wit, JM, Oostdijk, W (Wilma), Broeck, J, Mul, D (Dick), Wit, JM, Oostdijk, W (Wilma), and Broeck, J
- Published
- 2001
22. Psychosocial, cognitive, and motor functioning in patients with suspected Sotos syndrome: a comparison between patients with and without NSD1 gene alterations
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de Boer, L, primary, Röder, I, additional, and Wit, JM, additional
- Published
- 2006
- Full Text
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23. Inhibition of Gsk3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway.
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Miclea RL, Siebelt M, Finos L, Goeman JJ, Löwik CW, Oostdijk W, Weinans H, Wit JM, Robanus-Maandag EC, Karperien M, Miclea, R L, Siebelt, M, Finos, L, Goeman, J J, Löwik, C W G M, Oostdijk, W, Weinans, H, Wit, J M, Robanus-Maandag, E C, and Karperien, M
- Abstract
Objective: In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β (GSK3β) down-regulates transduction of the canonical Wnt signal by promoting degradation of β-catenin. In this study we wanted to further investigate the role of Gsk3β in cartilage maintenance.Design: Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3β inhibitor.Results: In E17.5 fetal mouse metatarsals, GIN treatment resulted in loss of expression of cartilage markers and decreased chondrocyte proliferation from day 1 onward. Late (3 days) effects of GIN included cartilage matrix degradation and increased apoptosis. Prolonged (7 days) GIN treatment resulted in resorption of the metatarsal. These changes were confirmed by microarray analysis showing a decrease in expression of typical chondrocyte markers and induction of expression of proteinases involved in cartilage matrix degradation. An intra-articular injection of GIN in rat knee joints induced nuclear accumulation of β-catenin in chondrocytes 72 h later. Three intra-articular GIN injections with a 2 days interval were associated with surface fibrillation, a decrease in glycosaminoglycan expression and chondrocyte hypocellularity 6 weeks later.Conclusions: These results suggest that, by down-regulating β-catenin, Gsk3β preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term β-catenin up-regulation in cartilage secondary to Gsk3β inhibition may be sufficient to induce osteoarthritis-like features in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2011
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24. Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders.
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Fredriks AM, van Buuren S, van Heel WJM, Dijkman-Neerincx RHM, Verloove-Vanhorick SP, and Wit JM
- Abstract
Aims: To obtain age references for sitting height (SH), leg length (LL), and SH/H ratio in the Netherlands; to evaluate how SH standard deviation score (SDS), LL SDS, SH/H SDS, and SH/LL SDS are related to height SDS; and to study the usefulness of height corrected SH/H cut-off lines to detect Marfan syndrome and hypochondroplasia.Methods: Cross-sectional data on height and sitting height were collected from 14 500 children of Dutch origin in the age range 0-21 years. Reference SD charts were constructed by the LMS method. Correlations were analysed in three age groups. SH/H data from patients with Marfan syndrome and genetically confirmed hypochondroplasia were compared with height corrected SH/H references.Results: A positive association was observed between H SDS, SH SDS, and LL SDS in all age groups. There was a negative correlation between SH/H SDS and height SDS. In short children with a height SDS <-2 SDS, a cut-off limit of +2.5 SD leads to a more acceptable percentage of false positive results. In exceptionally tall children, a cut-off limit of-2.2 SDS can be used. Alternatively, a nomogram of SH/H SDS versus H SDS can be helpful. The sensitivity of the height corrected cut-off lines for hypochondroplasia was 80% and for Marfan syndrome only 30%.Conclusions: In exceptionally short or tall children, the dependency of the SH/H ratio (SDS) on height SDS has to be taken into consideration in the evaluation of body proportions. The sensitivity of the cut-off lines for hypochondroplasia is fair. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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25. Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm.
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Euser AM, Finken MJJ, Keijzer-Veen MG, Hille ETM, Wit JM, Dekker FW, and Dutch POPS (Project On Preterm and Small-for-Gestational-Age Infants)-19 Collaborative Study Group
- Abstract
BACKGROUND: Increasing evidence indicates that adult body composition is associated with prenatal and infancy weight gain, but the relative importance of different time periods has not been elucidated. OBJECTIVE: The objective was to study the association between prenatal, early postnatal, and late infancy weight gain and body mass index (BMI), fat mass, and fat distribution in young adulthood. DESIGN: We included 403 men and women aged 19 y from a Dutch national prospective follow-up study who were born at <32 wk of gestation. BMI, waist circumference, and waist-to-hip ratio SD scores and subscapular-to-triceps ratio, percentage body fat, fat mass, and fat-free mass at age 19 y were studied in relation to birth weight SD scores, weight gain from preterm birth until 3 mo postterm (early postnatal weight gain), and weight gain from 3 mo until 1 y postterm (late infancy weight gain). RESULTS: Birth weight SD scores were positively associated with weight, height, BMI SD scores, and fat-free mass at age 19 y but not with fat mass, percentage body fat, or fat distribution. Early postnatal and late infancy weight gain were positively associated with adult height, weight, BMI, waist circumference SD scores, fat mass, fat-free mass, and percentage body fat but not with waist-to-hip ratio SD scores or subscapular-to-triceps ratio. CONCLUSIONS: In infants born very preterm, weight gain before 32 wk of gestation is positively associated with adult body size but not with body composition and fat distribution. More early postnatal and, to a lesser extent, late infancy weight gain are associated with higher BMI SD scores and percentage body fat and more Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]
- Published
- 2005
26. International child health. Measuring health-related quality of life in a child population.
- Author
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Verrips EGH, Vogels TGC, Koopman HM, Theunissen NCM, Kamphuis RP, Fekkes M, Wit JM, and Verloove-Vanhorick SP
- Abstract
Background: The 56-item TNO AZL Child Quality Of Life (TACQOL) questionnaire was developed to meet the need for a reliable and valid instrument for measuring health-related quality of life (HRQoL) in children. HRQoL was defined as health status in seven domains plus emotional responses to problems in health status. The TACQOL explicitly offers respondents the possibility of differentiating between their functioning and the way they feel about it. The aims of the study were threefold: to evaluate psychometric performance of the TACQOL in the general population, to evaluate the relationship between Parent Forms and Child Forms and to obtain additional information about validity. Methods: A random sample of 1,789 parents of 6-11 year olds completed the TACQOL (response rate 71%), as well as 1,159 8-11 year olds themselves (response rate 69%). Results: Multiple correspondence analyses showed that item response categories were ordinal and that the TACQOL scales may be regarded as metric. Cronbach's alpha ranged from 0.65 to 0.84. Only 57% of reported health status problems were associated with negative emotions. Intraclass correlation coefficients between Parents Forms and Child Forms ranged from 0.44 tot 0.61. Pearson's correlation coefficients between TACQOL and KINDL ranged from 0.24 to 0.60. Univariate analyses of variance showed that children with chronic diseases and children receiving medical treatment had lower TACQOL scores than healthy children. Conclusions: The study showed that with the TACQOL, children's HRQoL can be measured in a reliable and valid way. [ABSTRACT FROM AUTHOR]
- Published
- 1999
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27. Comparative effect of two doses of growth hormone for growth hormone deficiency.
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Keizer-Schrama SDM, Rikken B, Hokken-Koelega A, Wit JM, Drop S, and Dutch Growth Hormone Working Group
- Published
- 1994
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28. Comparative effect of two doses of growth hormone for growth hormone deficiency. The Dutch Growth Hormone Working Group.
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De Muinck Keizer-Schrama S, Rikken B, Hokken-Koelega A, Wit JM, Drop S, De Muinck Keizer-Schrama, S, Rikken, B, Hokken-Koelega, A, Wit, J M, and Drop, S
- Abstract
The comparative effect and safety of 2 IU compared with 4 IU/m2/day of recombinant human growth hormone (rhGH) was studied in 38 growth hormone deficient children regarding the impact of several factors on short term (one year) and long term (three year) growth response. In 21 newly diagnosed patients, three years of rhGH treatment resulted in a significant increase of height velocity SD score, height SD score, and predicted adult height SD score, irrespective of rhGH dose. In 17 transfer patients (previously treated with 12 IU rhGH/m2/week) 4 IU/m2/day resulted in a significantly higher height velocity SD score and height SD score for chronological age than 2 IU/m2/day, while more of them reached their target range or showed a substantial height SD score increment. Height SD score for bone age and predicted adult height SD score only increased significantly with 4 IU rhGH. After one year of rhGH treatment, new patients showed significant negative correlation between delta height SD score with age and baseline insulin-like growth factor I (IGF-I) SD score, and positive correlation with rhGH dose. After three years of treatment, delta height SD score for chronological age was significantly, negatively correlated with age and baseline 'corrected' height SD score (height SD score for chronological age minus target height SD score). There was no significant correlation with rhGH dose. Prolonged treatment with either dose had no adverse effect on IGF-I concentrations, carbohydrate or lipid metabolism. As early age and divergence between height SD score and target height SD score seem more important for growth response than rhGH dose, it is recommended that treatment starts early with 2 IU rhGH/m(2)/day and the dose is doubled if growth is insufficient after several years of treatment. [ABSTRACT FROM AUTHOR]
- Published
- 1994
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29. GASTRIC DRIP FEEDING IN PATIENTS WITH GLYCOGEN-STORAGE DISEASE TYPE-I - ITS EFFECTS ON GROWTH AND PLASMA-LIPIDS AND APOLIPOPROTEINS
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FERNANDES, J, ALAUPOVIC, P, WIT, JM, and University of Groningen
- Published
- 1989
30. METHIONYL GROWTH HORMONE (met-GH) IN A DOSAGE OF 4 IU/m2 DAY PROMOTES GROWTH IN TURNER SYNDROME
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Rongen-Westerlaken, C, primary, Wit, Jm, additional, Drop, Sls, additional, Otten, B J, additional, Oostdijk, W, additional, Delemarre-van de Wall, Ha, additional, and Gons, M, additional
- Published
- 1988
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31. Screening rules for growth to detect celiac disease: a case-control simulation study.
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van Dommelen P, Grote FK, Oostdijk W, Keizer-Schrama SM, Boersma B, Damen GM, Csizmadia CG, Verkerk PH, Wit JM, van Buuren S, van Dommelen, Paula, Grote, Floor K, Oostdijk, Wilma, Keizer-Schrama, Sabine M P F de Muinck, Boersma, Bart, Damen, Gerard M, Csizmadia, Cassandra G, Verkerk, Paul H, Wit, Jan M, and van Buuren, Stef
- Abstract
Background: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children.Methods: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion.Results: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group.Conclusion: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease. [ABSTRACT FROM AUTHOR]- Published
- 2008
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32. The diagnostic work up of growth failure in secondary health care; an evaluation of consensus guidelines.
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Grote FK, Oostdijk W, De Muinck Keizer-Schrama SM, van Dommelen P, van Buuren S, Dekker FW, Ketel AG, Moll HA, Wit JM, Grote, Floor K, Oostdijk, Wilma, De Muinck Keizer-Schrama, Sabine Mpf, van Dommelen, Paula, van Buuren, Stef, Dekker, Friedo W, Ketel, Arnoldus G, Moll, Henriette A, and Wit, Jan M
- Abstract
Background: As abnormal growth might be the first manifestation of undetected diseases, it is important to have accurate referral criteria and a proper diagnostic work-up. In the present paper we evaluate the diagnostic work-up in secondary health care according to existing consensus guidelines and study the frequency of underlying medical disorders.Methods: Data on growth and additional diagnostic procedures were collected from medical records of new patients referred for short stature to the outpatient clinics of the general paediatric departments of two hospitals (Erasmus MC - Sophia Children's Hospital, Rotterdam and Spaarne Hospital, Haarlem) between January 1998 and December 2002. As the Dutch Consensus Guideline (DCG) is the only guideline addressing referral criteria as well as diagnostic work-up, the analyses were based on its seven auxological referral criteria to determine the characteristics of children who are incorrectly referred and the adequacy of workup of those who are referred.Results: Twenty four percent of children older than 3 years were inappropriately referred (NCR). Of the correctly referred children 74-88% were short corrected for parental height, 40-61% had a height SDS <-2.5 and 21% showed height deflection (Delta HSDS < -0.25/yr or Delta HSDS < -1). In none of the children a complete detailed routine diagnostic work up was performed and in more than 30% no routine laboratory examination was done at all. Pathologic causes of short stature were found in 27 children (5%).Conclusion: Existing guidelines for workup of children with suspected growth failure are poorly implemented. Although poorly implemented the DCG detects at least 5% pathologic causes of growth failure in children referred for short stature. New guidelines for referral are required with a better sensitivity and specificity, wherein distance to target height should get more attention. The general diagnostic work up for short stature should include testing for celiac disease in all children and for Turner syndrome in girls. [ABSTRACT FROM AUTHOR]- Published
- 2008
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33. METHIONYL GROWTH HORMONE metGH IN A DOSAGE OF 4 IUm2DAY PROMOTES GROWTH IN TURNER SYNDROME
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Rongen-Westerlaken, C., Wit, JM., Drop, SLS., Otten, B. J., Oostdijk, W., Wall, HA. Delemarre-van de, and Gons, M.
- Published
- 1988
34. METHIONYL GROWTH HORMONE (met-GH) IN A DOSAGE OF 4 IU/m2DAY PROMOTES GROWTH IN TURNER SYNDROME
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Rongen-Westerlaken, C, Wit, Jm, Drop, Sls, Otten, B J, Oostdijk, W, Delemarre-van de Wall, Ha, and Gons, M
- Abstract
In a Dutch multi-center study 16 girls with Turner Syndrome were treated with met-GH in a dosage of 4 IU/m2body surface administered s.c. once a day. In girls older than 13 years low-dose ethinyl-estradiol (EE) therapy (0.1 ug/kg body weight o.d.) was added. Ages ranged from 7.9 to 15.2 years and bone age from 6.0 to 12 “years”. Heights, expressed as standard deviation scores, were between -2.5 and -5.1 (median -3.9). Endogenous GH secretion was assessed by arginine infusion, exercise test, GRF (1-29)-test and plasma SM-C/IGF-I. Mean ( ± S.D.) growth velocities were:During the first 6 months of therapy the mean ( ± S.D.) bone age (Greulich and Pyle) advanced from 9.1 (±1.2) to 9.4 (±1.2)“years” and the predicted adult height from 148.2 (±4.5) to 151.0 (±4.2) cm. The growth response (growth velocity during 9 months of therapy minus baseline) ranged from 0.8 to 7.0 cm/year and was negatively correlated with chronological age (r= -0.48, p<0.05). In the 4 girls older than 13 years, who also received EE, the growth response was 3.3 ± 0.9, compared to 4.0 ± 1.6 in younger girls. Growth response was not correlated with maximum plasma GH levels during provocation tests. Anti-GH antibodies with a binding capacity of > 0.2 U/l were found in 5 out of 10 patients. In one of them a very high value (3.7 U/l) was found.
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- 1988
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35. Identification of novel genes including NAV2 associated with isolated tall stature.
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Weiss B, Ott T, Vick P, Lui JC, Roeth R, Vogel S, Waldmüller S, Hoffmann S, Baron J, Wit JM, and Rappold GA
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- Animals, Humans, Male, Mice, Bone Development, Growth Plate, Tretinoin, Body Height genetics, DNA Helicases genetics
- Abstract
Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two ( Ift140, Nav2 ) of the six genes were well-expressed in the growth plate. Nav2 ( p -value 1.91E-62) as well as Ift140 ( p -value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140 , NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2 , in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Weiss, Ott, Vick, Lui, Roeth, Vogel, Waldmüller, Hoffmann, Baron, Wit and Rappold.)
- Published
- 2023
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36. A Novel Pathogenic IGSF1 Variant in a Patient with GH and TSH Deficiency Diagnosed by High IGF-I Values at Transition to Adult Care
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Kardelen AD, Karakılıç Özturan E, Poyrazoğlu Ş, Baş F, Ceylaner S, Joustra SD, Wit JM, and Darendeliler F
- Subjects
- Adolescent, Humans, Male, Immunoglobulins, Insulin-Like Growth Factor I, Membrane Proteins, Prolactin, Testosterone, Thyrotropin, Dwarfism, Pituitary, Hypothyroidism drug therapy, Transition to Adult Care
- Abstract
IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to pediatric endocrinology for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his insulin-like growth factor 1 level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of IGSF1 deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during long-term follow-up., Competing Interests: Conflict of interest: None declared, (©Copyright 2023 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)
- Published
- 2023
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37. A Novel Method for Adult Height Prediction in Children With Idiopathic Short Stature Derived From a German-Dutch Cohort.
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Blum WF, Ranke MB, Keller E, Keller A, Barth S, de Bruin C, Wudy SA, and Wit JM
- Abstract
Context: Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations., Objective: We aimed to develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting variables., Methods: Demographic and auxologic data were collected in childhood (1980s) and at AH (1990s). Data were collected by Dutch and German referral centers for pediatric endocrinology. A total of 292 subjects with ISS (219 male, 73 female) were enrolled. The population was randomly split into modeling (n = 235) and validation (n = 57) cohorts. Linear multi-regression analysis was performed with predicted AH (PAH) as response variable and combinations of chronological age (CA), baseline height, parental heights, relative bone age (BA/CA), birth weight, and sex as exploratory variables., Results: Ten models including different exploratory variables were selected with adjusted R² ranging from 0.84 to 0.78 and prediction errors from 3.16 to 3.68 cm. Applied to the validation cohort, mean residuals (PAH minus observed AH) ranged from -0.29 to -0.82 cm, while the conventional methods showed some overprediction (BP: +0.53 cm; RWT: +1.33 cm; projected AH: +3.81 cm). There was no significant trend of residuals with PAH or any exploratory variables, in contrast to BP and projected AH., Conclusion: This set of 10 multi-regression algorithms, developed specifically for children with ISS, provides a flexible tool for AH prediction with better accuracy than the conventional methods., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2022
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38. Should Skeletal Maturation Be Manipulated for Extra Height Gain?
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Wit JM
- Subjects
- Adolescent, Adrenal Hyperplasia, Congenital, Aromatase Inhibitors administration & dosage, Aromatase Inhibitors adverse effects, Child, Female, Gonadotropin-Releasing Hormone analogs & derivatives, Growth Disorders etiology, Growth Disorders genetics, Haploinsufficiency, Human Growth Hormone administration & dosage, Human Growth Hormone adverse effects, Human Growth Hormone deficiency, Humans, Infant, Small for Gestational Age, Male, Puberty, Puberty, Precocious, Recombinant Proteins, Body Height drug effects, Bone Development drug effects, Growth Disorders drug therapy
- Abstract
Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone or in combination with recombinant human growth hormone (rhGH). GnRHa is effective in attaining a normal adult height (AH) in the treatment of children with central precocious puberty, but its effect in short children with normal timing of puberty is equivocal. If rhGH-treated children with growth hormone deficiency or those who were born small-for-gestational age are still short at pubertal onset, co-treatment with a GnRHa for 2-3 years increases AH. A similar effect was seen by adding rhGH to GnRHa treatment of children with central precocious puberty with a poor AH prediction and by adding rhGH plus GnRHa to children with congenital adrenal hyperplasia with a poor predicted adult height on conventional treatment with gluco- and mineralocorticoids. In girls with idiopathic short stature and relatively early puberty, rhGH plus GnRHa increases AH. Administration of letrozole to boys with constitutional delay of growth puberty may increase AH, and rhGH plus anastrozole may increase AH in boys with growth hormone deficiency or idiopathic short stature, but the lack of data on attained AH and potential selective loss-of-follow-up in several studies precludes firm conclusions. GnRHas appear to have a good overall safety profile, while for aromatase inhibitors conflicting data have been reported., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wit.)
- Published
- 2021
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39. The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth
- Author
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Ghanny S, Zidell A, Pedro H, Joustra SD, Losekoot M, Wit JM, and Aisenberg J
- Subjects
- Adolescent, Humans, Male, Obesity, Morbid blood, Obesity, Morbid genetics, Pediatric Obesity blood, Pediatric Obesity genetics, Pedigree, Syndrome, Congenital Hypothyroidism blood, Congenital Hypothyroidism genetics, Gonadal Disorders blood, Gonadal Disorders genetics, Immunoglobulins deficiency, Immunoglobulins genetics, Membrane Proteins deficiency, Membrane Proteins genetics, Obesity blood, Obesity genetics, Prolactin blood, Testis growth & development, Thyroxine blood
- Abstract
Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband’s brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.
- Published
- 2021
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40. Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes.
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Weiss B, Eberle B, Roeth R, de Bruin C, Lui JC, Paramasivam N, Hinderhofer K, van Duyvenvoorde HA, Baron J, Wit JM, and Rappold GA
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Exome, Female, Gene Expression, Growth Plate metabolism, Humans, Infant, Infant, Newborn, Male, Mice, Netherlands, Pedigree, Body Height genetics, Carrier Proteins genetics, Cell Cycle Proteins genetics, Cytoskeletal Proteins genetics, Growth Disorders genetics, NIMA-Related Kinase 1 genetics, Thiosulfate Sulfurtransferase genetics
- Abstract
Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in CEP104, CROCC, NEK1, TOM1L2 , and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes ( CEP104, CROCC , and NEK1 ) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weiss, Eberle, Roeth, de Bruin, Lui, Paramasivam, Hinderhofer, van Duyvenvoorde, Baron, Wit and Rappold.)
- Published
- 2021
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41. Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature
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Labarta JI, Ranke MB, Maghnie M, Martin D, Guazzarotti L, Pfäffle R, Koledova E, and Wit JM
- Subjects
- Child, Humans, Artificial Intelligence, Dwarfism diagnosis, Endocrinology methods, Human Growth Hormone analysis, Human Growth Hormone therapeutic use, Pediatrics methods
- Abstract
Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.
- Published
- 2021
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42. Growth failure: 'idiopathic' only after a detailed diagnostic evaluation.
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Rapaport R, Wit JM, and Savage MO
- Abstract
The terms 'idiopathic short stature' (ISS) and 'small for gestational age' (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term 'SGA' was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms 'SGA' and 'ISS' as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
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- 2021
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43. Catch-up Growth in Prepubertal Children Treated for Juvenile Hypothyroidism and Growth Hormone Deficiency can be Modelled with a Monomolecular Function
- Author
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Wit JM, Sas TCJ, Ranke MB, and van Dommelen P
- Subjects
- Child, Female, Humans, Male, Body Height, Celiac Disease therapy, Growth Disorders therapy, Human Growth Hormone deficiency, Hypothyroidism therapy, Models, Theoretical
- Abstract
Objective: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD)., Methods: We used a monomolecular function for all available prepubertal data on height standard deviation score (HSDS) minus target height SDS (adjHSDS) in children with JHT (n=20) and GHD (n=18) on a conventional (CoD) or high GH dose (HD), based either on a national height reference with an age cut-off of 10 (girls) and 12 (boys) years (model 1) or prepubertal height reference values, if age (0) was ≥3, with no upper age limit (model 2)., Results: The models could be fitted in 83-90% of cases; in other cases the HSDS decreased after several measurements, which violated the assumption of an irreversible growth process. In JHT, the rate constant (k) and adjHSDS (0) were lower than in CD (p=0.02), but adjHSDS (end) was similar. In GHD (model 1), k was lower than for CD (p=0.004) but similar to JHT, while adjHSDS (0) and adjHSDS (end) were similar to CD and JHT. Thus, the shape of CUG is similar for children with JHT and GHD, while children with CD had less growth deficit at start and a faster CUG. The differences in CUG parameters between GH dose subgroups did not reach statistical significance., Conclusion: Modelling CUG of prepubertal children with JHT and GHD can be used for assessing the adequacy of CUG and the influence of clinical treatment modalities on its speed and magnitude.
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- 2021
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44. IGSF1 Does Not Regulate Spermatogenesis or Modify FSH Synthesis in Response to Inhibins or Activins.
- Author
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Brûlé E, Heinen CA, Smith CL, Schang G, Li Y, Zhou X, Wang Y, Joustra SD, Wit JM, Fliers E, Repping S, van Trotsenburg ASP, and Bernard DJ
- Abstract
Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 ( IGSF1 ) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male Igsf1 knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of Igsf1 -knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ ( Fshb/FSHB ) subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2021
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45. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.
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Lin YC, Niceta M, Muto V, Vona B, Pagnamenta AT, Maroofian R, Beetz C, van Duyvenvoorde H, Dentici ML, Lauffer P, Vallian S, Ciolfi A, Pizzi S, Bauer P, Grüning NM, Bellacchio E, Del Fattore A, Petrini S, Shaheen R, Tiosano D, Halloun R, Pode-Shakked B, Albayrak HM, Işık E, Wit JM, Dittrich M, Freire BL, Bertola DR, Jorge AAL, Barel O, Sabir AH, Al Tenaiji AMJ, Taji SM, Al-Sannaa N, Al-Abdulwahed H, Digilio MC, Irving M, Anikster Y, Bhavani GSL, Girisha KM, Haaf T, Taylor JC, Dallapiccola B, Alkuraya FS, Yang RB, and Tartaglia M
- Subjects
- Animals, Bone Morphogenetic Protein 2 metabolism, Bone Morphogenetic Protein 4 metabolism, Bone Morphogenetic Proteins metabolism, Cell Line, Cell Line, Tumor, Female, Gene Expression Regulation, Developmental physiology, HEK293 Cells, Hep G2 Cells, Humans, Intercellular Signaling Peptides and Proteins metabolism, MCF-7 Cells, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Bone and Bones metabolism, Calcium-Binding Proteins metabolism, Developmental Disabilities metabolism, Osteogenesis physiology, Signal Transduction physiology
- Abstract
Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3
-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
46. Identification of novel genetic variants associated with short stature in a Baka Pygmies population.
- Author
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Zoccolillo M, Moia C, Comincini S, Cittaro D, Lazarevic D, Pisani KA, Wit JM, and Bozzola M
- Subjects
- Adult, Alleles, Body Height genetics, Exome genetics, Female, Genome-Wide Association Study methods, Humans, Male, Black People genetics, Cell Adhesion Molecules genetics, GPI-Linked Proteins genetics, Growth Disorders genetics, Hyaluronoglucosaminidase genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) significantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5'-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was significantly increased compared to African and non-African populations. In vitro luciferase assay showed significant differences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.
- Published
- 2020
- Full Text
- View/download PDF
47. A Proposal for the Interpretation of Serum IGF-I Concentration as Part of Laboratory Screening in Children with Growth Failure
- Author
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Wit JM, Bidlingmaier M, de Bruin C, and Oostdijk W
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Netherlands, Societies, Medical standards, Young Adult, Growth Disorders blood, Growth Disorders diagnosis, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor I metabolism, Pediatrics standards, Reference Standards
- Abstract
The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.
- Published
- 2020
- Full Text
- View/download PDF
48. Response to Letter to the Editor: "IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction".
- Author
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Joustra SD, Roelfsema F, van Trotsenburg ASP, Schneider HJ, Kosilek RP, Kroon HM, Logan JG, Butterfield NC, Zhou X, Toufaily C, Bak B, Turgeon MO, Brûlé E, Steyn FJ, Gurnell M, Koulouri O, Le Tissier P, Fontanaud P, Bassett JHD, Williams GR, Oostdijk W, Wit JM, Pereira AM, Biermasz NR, Bernard DJ, and Schoenmakers N
- Subjects
- Animals, Humans, Mice, Immunoglobulins, Membrane Proteins
- Published
- 2020
- Full Text
- View/download PDF
49. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.
- Author
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Joustra SD, Roelfsema F, van Trotsenburg ASP, Schneider HJ, Kosilek RP, Kroon HM, Logan JG, Butterfield NC, Zhou X, Toufaily C, Bak B, Turgeon MO, Brûlé E, Steyn FJ, Gurnell M, Koulouri O, Le Tissier P, Fontanaud P, Duncan Bassett JH, Williams GR, Oostdijk W, Wit JM, Pereira AM, Biermasz NR, Bernard DJ, and Schoenmakers N
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Growth Hormone biosynthesis, Humans, Immunoglobulins deficiency, Insulin-Like Growth Factor I analysis, Intercellular Signaling Peptides and Proteins deficiency, Male, Membrane Proteins deficiency, Mice, Middle Aged, Immunoglobulins physiology, Intercellular Signaling Peptides and Proteins physiology, Membrane Proteins physiology, Neurosecretion physiology, Somatotrophs physiology
- Abstract
Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition., Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function., Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting., Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates., Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels., Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure., (© Endocrine Society 2019.)
- Published
- 2020
- Full Text
- View/download PDF
50. Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy
- Author
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Wit JM, Deeb A, Bin-Abbas B, Al Mutair A, Koledova E, and Savage MO
- Subjects
- Adolescent, Age Factors, Body Height genetics, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Growth Disorders genetics, Growth Disorders physiopathology, Human Growth Hormone adverse effects, Human Growth Hormone deficiency, Humans, Male, Time Factors, Treatment Outcome, Adolescent Development drug effects, Body Height drug effects, Child Development drug effects, Growth Disorders drug therapy, Hormone Replacement Therapy adverse effects, Human Growth Hormone administration & dosage
- Abstract
It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.
- Published
- 2019
- Full Text
- View/download PDF
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