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In this case series, we describe four children and adolescents with tall stature or growth acceleration to illustrate the diagnostic evaluation of tall stature according to the new Paediatric Association of the Netherlands (NVK) Guideline on growth disorders. A 14-year-old girl with tall stature and a relatively late onset of puberty was diagnosed with idiopathic familial tall stature, and the patient decided not to opt for epiphysiodesis. A 14-year-old boy with prepubertal growth acceleration and a history of behavioural problems was diagnosed with Klinefelter syndrome. A 7-year-old boy with tall stature, arachnodactyly, pectus excavatum and lumbar scoliosis was diagnosed with Marfan syndrome. Finally, a 16-year-old girl with isolated progressive tall stature was diagnosed with growth hormone excess caused by a pituitary somatotroph adenoma. The most clinically relevant conditions associated with tall stature are Klinefelter and Marfan syndrome, and secondary growth disorders such as precocious puberty and growth hormone excess.

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Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS.

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We present a 13-year-old boy who was admitted with complaints of a state of progressive sleepiness and a sudden headache with vomiting and fever. Laboratory testing showed hypoglycemia, multiple pituitary hormonal deficiencies, and an elevated C-reactive protein level. A cranial magnetic resonance imaging (MRI) showed an opaque sphenoid sinus and an intrasellar mass suggesting hemorrhage, so that we suspected pituitary apoplexy (PA) originating from a non-functioning adenoma, although a pituitary abscess could not completely be excluded. The boy was treated with antibiotics, hydrocortisone, and levothyroxine. Due to his rapid clinical improvement, no surgery was performed and we considered the diagnosis of PA as confirmed. At follow-up, the MRI scan showed a small residual lesion. Pituitary deficiencies of growth hormone, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, and vasopressin persisted. A literature search of all well-documented cases of PA in children or adolescents (n=30, 13 boys and 17 girls) indicated that this condition is rare below 20 years of age but must be considered when a patient experiences headache with or without visual disturbances, even in the presence of clinical and laboratory signals suggestive of pituitary abscess. MRI neuroimaging is helpful in the differential diagnosis. In both conditions, the possibility of ACTH deficiency should always be considered, investigated, and treated. In cases without severe neuro-ophthalmological deficits and/or with a rapid and positive response to acute medical management, one can abstain from surgical treatment.

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Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency.

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BACKGROUND: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. METHODS: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. RESULTS: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. CONCLUSION: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.

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OBJECTIVE: Short stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy. DESIGN AND METHODS: Adopted siblings (girl and a boy) of unknown family history were referred for assessment of short stature (-4.5 and -5.6 SDS) at the age of 10 and 8.1 years respectively. They had delayed bone ages (6.8 and 4.5 years), normal GH peaks at stimulation tests, and severely reduced IGF1 concentrations (-3.5 and -4.0 SDS). Genetic analysis of the GH1 gene showed a heterozygous P59S mutation at position involved in binding to GH receptor (GHR). RESULTS: Isoelectric focusing analysis of secreted GH in patient serum revealed the presence of higher GH-P59S peak compared with that of wt-GH. Furthermore, computational simulation of GH-P59S binding to GHR suggested problems in correct binding of the mutant to the GHR. In vitro GHR binding studies revealed reduced binding affinity of GH-P59S for GHR (IC50, 30  ng/ml) when compared with the wt-GH (IC50, 11.8  ng/ml) while a significantly decreased ability of the mutant to activate the Jak2/Stat5 signaling pathway was observed at physiological concentrations of 25-100  ng/ml. CONCLUSIONS: The clinical and biochemical data of our patients support the diagnosis of partial bioinactive GH syndrome. The higher amount of GH-P59S secreted in their circulation combined with its impact on the wt-GH function on GHR binding and signaling may alter GHR responsiveness to wt-GH and could ultimately explain severe short stature found in our patients.

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We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFß3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.

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In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.

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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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BACKGROUND AND OBJECTIVE: Coeliac disease is treated with a lifelong gluten-free diet (GFD). The aim of our study was to investigate whether the dietary (nondietary) compliance is associated with health-related quality of life (HRQoL) of coeliac patients. METHODS: Patients from our hospital, known with coeliac disease for more than 10 years, were invited to participate in a study on possible gluten tolerance. HRQoL was assessed by the Short Form-36 health survey, symptoms by the Gastrointestinal Symptom Rating Scale and dietary compliance by a food frequency questionnaire. HRQoL of coeliac patients was compared with that of the general population. RESULTS: Fifty-three biopsy-confirmed coeliac patients were divided into three groups according to gluten consumption: GFD (n = 33), gluten transgression (<10 g gluten/day; n = 8) and normal gluten-containing diet (>10 g gluten/day; n = 12). Compared with the general population, coeliac patients scored significantly worse on general health perception but significantly better on bodily pain and limitations due to physical problems. The results of the Gastrointestinal Symptom Rating Scale and the Short Form-36 health survey were similar in all three dietary groups. CONCLUSION: Although adhering to the GFD is strictly important to prevent future complications, patients who stop following GFD do exist and patients with partial or nonadherence report similar HRQoL compared with patients with strict adherence in this group of adult coeliac patients.

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Prader-Willi syndrome (PWS) is a neurogenetic disorder with hypotonia, psychomotor delay, obesity, short stature, and sleep-related breathing disorders. The aim of this study was to evaluate the association between psychomotor development and sleep-related breathing disorders in PWS infants. Bayley Scales of Infant Development were performed in 22 PWS infants, with a median (interquartile range, IQR) age of 1.8 (1.1-3.4) y, and a body mass index SD score (BMISDS) of -0.5 (-1.3 to 1.6). We evaluated psychomotor development in relation to results of polysomnography. Median (IQR) mental and motor development was 73.1% (64.3-79.6%) and 55.2% (46.5-63.1%) of normal children, respectively. All infants had sleep-related breathing disorders, mostly of central origin. The apnea hypopnea index was not associated with psychomotor development. Only four infants had obstructive sleep apnea syndrome (OSAS). They had a significantly delayed mental development of 65.5% (60.0-70.3%) of normal. They had a median BMISDS of 1.4 (0.1-1.6), which tended to be higher than in those without OSAS. Our data indicate that psychomotor development in PWS infants is not related to central sleep-related breathing disorders, but infants with OSAS have more severely delayed mental development, suggesting that PWS infants should be screened for OSAS.

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This study explored the opinions of (para)medical and nursing staff in two Dutch Neonatal Intensive Care Units (NICU's). A questionnaire was used that measured: a) the perceived impact of NIDCAP on several NICU conditions, b) attitudes, subjective norm, perceived behavioral control, knowledge and abilities of using the NIDCAP method (based on the Theory of Planned Behavior) and c) training interest, requirements, information sources and the relevance of the NIDCAP method for different groups of NICU patients. Respondents were positive about NIDCAP and felt that using NIDCAP is fulfilling and leads to improvement of the infant's development, health and well-being. However, NIDCAP was also thought to be time-consuming and might worsen job conditions. The nursing staff, compared to the medical staff, had a more positive attitude (p=.004), higher perceived behavioral control (p=.004) and perceived a more positive impact of NIDCAP on NICU conditions (p=.008).

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BACKGROUND: To promote early diagnosis and treatment of short stature, consensus meetings were held in the mid nineteen nineties in the Netherlands and the UK. This resulted in guidelines for referral. In this study we evaluate the referral pattern of short stature in primary health care using these guidelines, comparing it with cut-off values mentioned by the WHO. METHODS: Three sets of referral rules were tested on the growth data of a random sample (n = 400) of all children born between 01-01-1985 and 31-12-1988, attending school doctors between 1998 and 2000 in Leiden and Alphen aan den Rijn (the Netherlands): the screening criteria mentioned in the Dutch Consensus Guideline (DCG), those of the UK Consensus Guideline (UKCG) and the cut-off values mentioned in the WHO Global Database on Child growth and Malnutrition. RESULTS: Application of the DCG would lead to the referral of too many children (almost 80%). The largest part of the referrals is due to the deflection of height, followed by distance to target height and takes primarily place during the first 3 years. The deflection away from the parental height would also lead to too many referrals. In contrast, the UKCG only leads to 0.3% referrals and the WHO-criteria to approximately 10%. CONCLUSION: The current Dutch consensus guideline leads to too many referrals, mainly due to the deflection of length during the first 3 years of life. The UKCG leads to far less referrals, but may be relatively insensitive to detect clinically relevant growth disorders like Turner syndrome. New guidelines for growth monitoring are needed, which combine a low percentage of false positive results with a good sensitivity.

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AIM: Prevalences of overweight in The Netherlands, defined by international cut-off points, are presented in 14 500 children of Dutch origin, 2904 of Turkish and 2855 of Moroccan origin, aged 0-21 y. RESULTS: The mean prevalence for Turkish boys and girls was 23.4% and 30.2%, for Moroccans 15.8% and 24.5%, for Dutch youths in large cities 12.6% and 16.5%, and for other Dutch participants 8.7% and 11.3%, respectively. CONCLUSION: The development of adequate prevention strategies is urgently needed.

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BACKGROUND: Improved survival due to advances in neonatal care has brought issues such as postnatal growth and development more to the focus of our attention. Most studies report stunting in children born very preterm and/or small for gestational age. In this article we study the growth pattern of these children and aim to identify factors associated with postnatal catch-up growth. METHODS: 1338 children born with a gestational age <32 weeks and/or a birth weight of <1500 grams were followed during a Dutch nationwide prospective study (POPS). Subgroups were classified as appropriate for gestational age and <32 weeks (AGA) or small for gestational age (<32 wks SGA and > or =32 wks SGA). Data were collected at different intervals from birth until 10 years for the 962 survivors and compared to reference values. The correlation between several factors and growth was analysed. RESULTS: At 10 years the AGA children had attained normal height, whereas the SGA group demonstrated stunting, even after correction for target height (AGA: 0.0 SDS; SGA <32 wks: -0.29SDS and > or =32 wks: -0.13SDS). Catch-up growth was especially seen in the SGA children with a fast initial weight gain. BMI was approximately 1 SD below the population reference mean. CONCLUSION: At 10 years of age, children born very preterm AGA show no stunting. However, many children born SGA, especially the very preterm, show persistent stunting. Early weight gain seems an important prognostic factor in predicting childhood growth.

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Sex steroids, and particularly estrogens, are important regulators of bone growth and bone mass accrual. For a long time, it was thought that these effects were mainly caused by their modulatory effects on the somatotrophic axis. Data gathered in the past years have challenged this view and it is now widely accepted that many of the effects of sex steroids on growth and bone mass accrual are caused by direct effects on target cells in the growth plate and bone. This review summarizes and discusses some of our latest findings on the expression of sex steroid receptors in the growth plate, the source of the ligands activating these receptors, and their putatitive mechanism of action predominantly focusing on observations in the rat.

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OBJECTIVE: To determine changes in peri- and neonatal care concerning neonatal mortality and morbidity by comparing 2 cohorts of very prematurely born infants (gestational age [GA] <32 weeks), 1 from the 1980s and 1 from the 1990s. METHODS: The Leiden Follow-Up Project on Prematurity (LFUPP-1996/97), a regional, prospective study, includes all infants who were born alive after a GA <32 weeks in 1996 and 1997 in the Dutch health regions Leiden, The Hague, and Delft. The Project On Preterm and Small for Gestational Age Infants (POPS-1983), a national, prospective study from the presurfactant era, includes all liveborn infants <32 weeks' GA and/or <1500 g from 1983 (n = 1338). For comparison, infants from the POPS-1983 cohort with a GA <32 weeks from the same Dutch health regions were selected (n = 102). RESULTS: The absolute number of preterm births in the study region increased by 30%: 102 in 1983 to on average of 133 in 1996-1997. Centralization of perinatal care improved: the percentage of extrauterinely transported infants decreased from 61% in 1983 to 35% in 1996-1997. A total of 182 (73%) of the LFUPP-1996/97 infants were treated antenatally with glucocorticosteroids compared with 6 (6%) of the POPS-1983 infants. A total of 112 (42%) of the LFUPP-1996/97 infants received surfactant. In-hospital mortality decreased from 30% in the 1980s to 11% in the 1990s. Mortality of the extremely preterm infants (<27 weeks) decreased from 76% to 33%. The incidence of respiratory distress syndrome remained the same: approximately 60% in both groups. Mortality from respiratory distress syndrome, however, decreased from 29% to 8%. The incidence of bronchopulmonary dysplasia increased from 6% to 19%. For the surviving infants, the average length of stay in the hospital and the mean number of NICU days stayed approximately the same ( approximately 67 days total admission time and 44 NICU days in both groups); including the infants who died, the mean NICU admission time increased from 27 days in the 1980s to 41 days in the 1990s. Equal percentages of adverse outcome (dead or an abnormal general condition) at the moment of discharge from hospital were found (+/-40% in both groups). CONCLUSIONS: An increase in the absolute number of very preterm births in this study region was found, leading to a greater burden on the regional NICUs. Improvements in peri- and neonatal care have led to an increased survival of especially extremely preterm infants. However, increased survival has resulted in more morbidity, mainly bronchopulmonary dysplasia, at the moment of discharge from the hospital.

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UNLABELLED: The aim of this study was to present age references for waist circumference (WC), hip circumference (HC), and waist/hip ratio (WHR) in Dutch children. Cross-sectional data were obtained from 14,500 children of Dutch origin in the age range 0-21 years. National references were constructed with the LMS method. This method summarises the distribution by three smooth curves representing skewness (L curve), the median (M curve), and coefficient of variation (S curve). The correlations between body mass index-standard deviation score (BMI-SDS), the circumferences and their ratio, and demographic variables were assessed by (multiple) regression analysis for three age groups: 0-<5 years (1), 5-<12.5 years (2), and 12.5-<21 years (3). A cut-off for clinical use was suggested based on the International Obesity Task Force criteria for BMI. Mean WC and HC values increased with age. Mean WC was slightly higher in boys than in girls, and this difference was statistically significant from 11 years of age onwards. In contrast, HC was significantly higher in girls than in boys from 9 years onwards. The correlation between WC-SDS and BMI-SDS ( r =0.73, P <0.01) and between HC and BMI-SDS ( r =0.67, P <0.01) increased with age. With regard to WHR-SDS, a low correlation was found for 12.5-20 years of age ( r =0.2, P <0.01). WC-SDS correlated positively with height SDS ( r =0.35, P <0.01). CONCLUSION: Waist circumferences can be used to screen for increased abdominal fat mass in children, whereby a cut-off point of 1.3 standard deviation score seems most suitable.

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