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M J E Walenkamp and J M Wit

Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH–IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH–IGF-I axis in order to describe the role of the GH–IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH–IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH–IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH–IGF-I axis for the patient and the therapeutic options will be discussed.

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N van Montfoort, M J J Finken, S le Cessie, F W Dekker and J M Wit

Objective: Studies about the association between birth weight and circulating cortisol level have been published from 1998 onwards. However, their findings were inconsistent. To quantitatively assess the overall association between birth weight and circulating cortisol level, we aimed to perform a meta-analysis of the published literature.

Methods: A literature search was conducted in PubMed, and selected papers were systematically reviewed. A pooled regression coefficient was calculated for the entire group as well as for males and females separately.

Results: Data from 11 study populations were pooled (n = 2301). These populations differed with respect to geographical area, age, sex distribution, inclusion criteria and gestational age. We found a statistically significant inverse association between birth weight and circulating cortisol level: a 1 kg lower birth weight was associated with a 25.3 nmol/l (95% confidence interval (CI): 5.9–44.8) higher cortisol level. Separate results were reported for males and females in six study populations. The association in males was 20.6 nmol/l per kg (95% CI: 4.2–37.0) and in females it was 30.9 nmol/l per kg (95% CI: 7.4–54.4).

Conclusion: Differences between study populations hampered the comparability of the included studies. Although the majority of studies were underpowered, by using a meta-analytic approach we found an inverse association between birth weight and circulating cortisol level. Thus, our findings suggest that there is some evidence for a possible role of the hypothalamus–pituitary–adrenal axis in the epidemiological association between birth weight and cardiovascular disease. However, the strength of the overall association between birth weight and circulating cortisol level was weak.

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Christiaan L Meuwese, Anne M Euser, Bart E Ballieux, Huib A van Vliet, Martijn J J Finken, Frans J Walther, Friedo W Dekker and Jan M Wit

Background

The long-term effects of perinatal growth and corticosteroid exposure on adrenal steroid concentrations in adults born very preterm are uncertain.

Objectives

To examine the effect of birth weight, early postnatal growth, and pre- and postnatal corticosteroid administration on serum adrenal steroids in 19-year-old subjects born very preterm.

Design and methods

Subjects born before 32 weeks of gestation in The Netherlands participating in the Project on Preterm and Small for Gestational Age Infants (POPS) were investigated at 19 years of age. Serum cortisol, DHEA sulfate (DHEAS), and androstenedione (Adione) concentrations were measured in 393 out of 676 eligible subjects, compared with controls, and associated with perinatal growth and pre- and postnatal corticosteroids administration using multiple linear regression analyses.

Results

Serum DHEAS and Adione in men and women were higher than in controls. In the multiple regression analyses, birth weight SDS showed a statistically significant negative association with serum DHEAS concentrations in women (β: −0.865, 95% confidence interval (CI): −1.254 to −0.476) and in men (β: −0.758, 95% CI: −1.247 to −0.268) and with serum Adione concentrations in women (β: −0.337, 95% CI: −0.593 to −0.082). Early postnatal weight gain showed no association with any of measured adrenal markers. In women, serum Adione was associated with postnatal dexamethasone exposure (β: 0.932, 95% CI: 0.022 – 1.843).

Conclusions

Young adults born very preterm show elevated adrenal androgens, particularly when born small for gestational age. Postnatal corticosteroid administration is positively associated with serum Adione in young women.

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H A van Duyvenvoorde, M J E Kempers, Th B Twickler, J van Doorn, W J Gerver, C Noordam, M Losekoot, M Karperien, J M Wit and A R M M Hermus

Context

Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.

Objective

To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.

Subjects

Three short Kurdish brothers and their relatives.

Results

The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.

Conclusions

The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

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S H Donze, C R Meijer, S G Kant, G R J Zandwijken, A H van der Hout, R M L van Spaendonk, A M W van den Ouweland, J M Wit, M Losekoot and W Oostdijk

Objective

Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers.

Design

In this retrospective multi-center study (2002–March 2014) clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness).

Results

Patients with SEDs showed similar HtSDS to patients with SHI (−2.3 and −2.6, respectively, P=0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P<0.01) and extremities/trunk ratio 2.57 vs 2.43 (P=0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (n=3) was similar to the other groups.

Conclusions

Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.

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L De Boer, HA Van Duyvenvoorde, EC Willemstein-Van Hove, CM Hoogerbrugge, J Van Doorn, JA Maassen, M Karperien and JM Wit

OBJECTIVE: To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level. DESIGN: Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values. METHODS: IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR. RESULTS: NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls. CONCLUSIONS: NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.

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D Mul, S Wu, R A de Paus, W Oostdijk, A C Lankester, H A van Duyvenvoorde, C A L Ruivenkamp, M Losekoot, M J D van Tol, F De Luca, E van de Vosse and J M Wit

Objective

The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an I κ B mutation suggests that the NF-κB pathway may interact with STAT5B signaling.

Design

Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21–25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance.

Methods and results

In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that M AP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells.

Conclusions

We conclude that the 17q21–25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression.

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S A van Gool, G A Kamp, R J Odink, S M P F de Muinck Keizer-Schrama, H A Delemarre-van de Waal, W Oostdijk and J M Wit

Objective

To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS).

Design and methods

Forty children with no signs of puberty, age at start 4–8 years (girls) or 4–10 years (boys), height SDS <−2.0 SDS, and birth length >−2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m2 per day (equivalent to 75 μg/kg per day at start and 64 μg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (s.d.) age of 20.4 (2.3) years.

Results

GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2–5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (−1.3 (0.8) SDS versus −2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3–12 years, AH was −2.1 (0.7) and −1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain.

Conclusion

High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.

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Marie J E Walenkamp, Solrun Vidarsdottir, Alberto M Pereira, Marcel Karperien, Jaap van Doorn, Hermine A van Duyvenvoorde, Martijn H Breuning, Ferdinand Roelfsema, M Femke Kruithof, Jaap van Dissel, Riny Janssen, Jan M Wit and Johannes A Romijn

Objective: STAT5b is a component of the GH signaling pathway. Recently, we described a 31-year-old male patient (height, −5.9 SDS) with a novel homozygous inactivating mutation in the STAT5b gene. The purpose of this study is to describe the phenotype in detail, including GH secretion and immunological function. In addition, we report four family members of this patient, all heterozygous carriers of the mutation.

Design and methods: Twenty-four hour GH and prolactin secretion characteristics were assessed by blood sampling at 10-min intervals. An IGF-I generation test was performed. Monocyte function was tested by stimulation of whole blood with lipopolysaccharide (LPS) in the presence or absence of Interferon-γ (IFN-γ). In addition, T cell function was determined by measuring proliferative responses of peripheral blood mononuclear cells (PBMC) after stimulation by various polyclonal activators and Interleukin-2 (IL-2). Clinical and biochemical characteristics were determined in the carriers of the mutation.

Results: GH secretory parameters were comparable with that of healthy male controls (mean fat percentage 25), but likely increased in relation to the patient’s 40% body fat. The regularity of GH secretion was diminished. Prolactin secretion was increased by sixfold. The IGF-I generation test showed a small increase in IGF-I and IGF-binding protein-3 on lower GH doses and an increase in IGF-I to −2.4 SDS on the highest dose of GH. In vitro, IL-12p40, IL 10, and tumour necrosis factor-α (TNF-α) production rates by PBMC increased to values within the normal range upon stimulation of LPS. Heterozygous carriers of the mutation did not show abnormalities, although the height of the males was below the normal range.

Conclusions: This report shows that GH and prolactin secretion were increased in this patient homozygous for a new STAT5b mutation. Although STAT5b plays a role in signaling within immune cells, clinical immunodeficiency is not an obligatory phenomenon of STAT5b deficiency per se. Heterozygous carriers of a STAT5b mutation show no signs of GH insensitivity.

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S Kos, C M Cobbaert, T M Kuijper, W Oostdijk, S E Hannema, J M Wit, N Biermasz and B E P B Ballieux