Adult Height after Growth Hormone Treatment at Pubertal Onset in Short Adolescents Born Small for Gestational Age: Results from a Belgian Registry-Based Study.

OBJECTIVES: Information on the efficacy of GH treatment in short SGA children starting their treatment in adolescence is limited. Therefore, adult height (AH), total height gain, and pubertal height gain were evaluated in short SGA children who started GH treatment at pubertal onset. PATIENT AND METHODS: Growth data of 47 short SGA adolescents (22 boys) who started GH treatment at pubertal onset (PUB group) were compared with results from 27 short SGA patients (11 boys) who started GH therapy at least 1 year before pubertal onset (PrePUB group). RESULTS: The PUB group achieved a mean (±SD) total height gain of 0.8 ± 0.7 SDS and an AH of -2.5 ± 0.7 SDS after 4.1 ± 1.1 years of GH treatment with a dosage of 41.8 ± 8.4 µg/kg/day. These results were comparable with those in the PrePUB group, which was treated for a longer duration (5.8 ± 2.1 years), resulting in a total height gain of 1.1 ± 0.7 SDS and an AH of -2.1 ± 1.0 SDS. Multiple regression analysis showed a significantly lower height gain in pubertal patients, females, and patients weighing less at start of GH treatment. An AH above -2 SDS and above the parent-specific lower limit of height was, respectively, reached in 28% and 70% of PUB and 44% and 67% of PrePUB patients (NS). AH SDS was positively correlated with the height SDS at start of GH. CONCLUSIONS: Short SGA adolescents starting GH therapy at an early pubertal stage have a modest and variable height gain. A normal AH can be expected in one third of the patients, especially in those with a smaller height deficit at onset of GH treatment.

Clinical presentation and outcome of children with central diabetes insipidus associated with a self-limited or transient pituitary stalk thickening, diagnosed as infundibuloneurohypophysitis.

OBJECTIVE: Despite lymphocytic or autoimmune infundibuloneurohypophysitis (INH) is an increasingly recognized aetiology in children with central diabetes insipidus (CDI); clinical data on epidemiology (clinical evolution, predisposing factors, complications), diagnosis and management of this entity are limited and mostly based on published case reports. The aim of this study was to gain a broader insight in the natural history of this disease by analysing the clinical presentation, radiological pituitary stalk changes, associated autoimmunity and hormonal deficiencies in children with CDI and a self-limiting or transient stalk thickening (ST), diagnosed as autoimmune infundibuloneurohypophysitis, during the last 15 years in four Belgian university hospitals. DESIGN AND PATIENTS: The medical files of nine CDI patients with a ST at initial presentation and no signs of Langerhans cell histiocytosis or germinoma at presentation and/or during follow-up of more than 1.5 years were reviewed. RESULTS: Age at presentation ranged from 3 to 14 years. Two patients had a positive family history of autoimmunity. Three children presented with associated growth failure, two with nausea and one with long-standing headache. Median maximal diameter of the stalk was 4.6 mm (2.7-10 mm). Four patients had extra-pituitary brain anomalies, such as cysts. One patient had central hypothyroidism, and another had a partial growth hormone deficiency at diagnosis. Within a mean follow-up of 5.4 (1.5-15) years, stalk thickening remained unchanged in two patients, regressed in one and normalized in six children. CDI remained in all, while additional pituitary hormone deficiencies developed in only one patient. CONCLUSIONS: In this series of children INH with CDI as initial presentation, CDI was permanent and infrequently associated with anterior pituitary hormone deficiencies, despite a frequent association with nonstalk cerebral lesions.

Evaluation of the hypothalamic-pituitary-adrenal axis and its relationship with central respiratory dysfunction in children with Prader-Willi syndrome.

BACKGROUND: Children with Prader-Willi Syndrome (PWS) have been considered at risk for central adrenal insufficiency (CAI). Hypothalamic dysregulation has been proposed as a common mechanism underlying both stress-induced CAI and central respiratory dysfunction during sleep. OBJECTIVE: To evaluate CAI and sleep-related breathing disorders in PWS children. PATIENTS AND METHODS: Retrospective study of cortisol response following either insulin tolerance test (ITT) or glucagon test (GT) in 20 PWS children, and comparison with 33 non- Growth Hormone deficient (GHD) controls. Correlation between sleep related breathing disorders and cortisol response in 11 PWS children who received both investigations. RESULTS: In PWS children, the cortisol peak value showed a significant, inverse correlation with age (Kendall's τ = -0.411; p = 0.012). A similar though non-significant correlation was present between cortisol increase and age (τ = -0.232; p = 0.16). Similar correlations were found in controls. In only 1 of 20 PWS children (5 %), ITT was suggestive of CAI. Four patients had an elevated central apnea index but they all exhibited a normal cortisol response. No relationship was found between peak cortisol or cortisol increase and central apnea index (respectively p = 0.94 and p = 0.14) or the other studied polysomnography (PSG) parameters. CONCLUSIONS: CAI assessed by ITT/GT is rare in PWS children. Our data do not support a link between CAI and central respiratory dysregulation.

Human insulin polymorphism upon ligand binding and pH variation: the case of 4-ethylresorcinol.

This study focuses on the effects of the organic ligand 4-ethylresorcinol on the crystal structure of human insulin using powder X-ray crystallography. For this purpose, systematic crystallization experiments have been conducted in the presence of the organic ligand and zinc ions within the pH range 4.50-8.20, while observing crystallization behaviour around the isoelectric point of insulin. High-throughput crystal screening was performed using a laboratory X-ray diffraction system. The most representative samples were selected for synchrotron X-ray diffraction measurements, which took place at the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS). Four different crystalline polymorphs have been identified. Among these, two new phases with monoclinic symmetry have been found, which are targets for the future development of microcrystalline insulin drugs.

Short Stature in KBG Syndrome: First Responses to Growth Hormone Treatment.

BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.

Novel crystalline phase and first-order phase transitions of human insulin complexed with two distinct phenol derivatives.

The primary focus of the present work is the study of the effects that two ligands and the crystallization pH have on the crystalline forms of human insulin. For this purpose, human insulin (HI) was co-crystallized with two distinct phenolic derivatives: the organic ligands meta-cresol (m-cresol) and 4-nitrophenol. The formation of polycrystalline precipitates was then followed by means of structural characterization of the individual specimens in terms of unit-cell symmetry and parameters. In both cases, two different polymorphs were identified via X-ray powder diffraction measurements, the first of hexagonal symmetry (R3 space group) at higher pH values and the second of monoclinic symmetry (space group P21) with unit-cell parameters a = 87.4282 (5), b = 70.5020 (3), c = 48.3180 (4) Å, ß = 106.8958 (4)°, the latter of which to our knowledge has never been observed before.

Care delivery and outcomes among Belgian children and adolescents with type 1 diabetes.

UNLABELLED: We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0-18 years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77 %) and had at least one parent of Belgian origin (78 %). Nearly all patients (≥95 %) underwent determination of HbA(1c) and BMI. Screening for retinopathy (55 %) and microalbuminuria (73 %) was less frequent, but rates increased with age and diabetes duration. Median HbA(1c) was 61 mmol/mol (7.7 %) [interquartile range 54-68 mmol/mol (7.1-8.4 %)] and increased with age and insulin dose. HbA(1c) was higher among patients on insulin pump therapy. Median HbA(1c) significantly differed between centres [from 56 mmol/mol (7.3 %) to 66 mmol/mol (8.2 %)]. Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA(1c) and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care. CONCLUSION: Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA(1c) remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.

Adult final height after GH therapy for irradiation-induced GH deficiency in childhood survivors of brain tumors: the Belgian experience.

OBJECTIVES: The treatment of brain tumors in childhood is frequently complicated by growth retardation with a high proportion of irradiation (Irr)-induced GH deficiency (GHD) resulting in reduced adult final height (AFH) even after GH therapy (GHT). In order to optimize future GHT protocols, more information on the factors influencing the growth response to GH in these children is needed. This retrospective study evaluated AFH and influencing auxological and treatment factors of a standardized daily biosynthetic GHT in childhood survivors of brain tumors with documented GHD after brain Irr. DESIGN AND METHODS: From the Belgian GH Registry, 57 children survivors of a brain tumor outside the hypothalamo-pituitary area with available AFH were stratified into two groups depending on cranial (C-Irr; n=25) or craniospinal (CS-Irr; n=32) Irr. RESULTS: In the C-Irr patients, results showed an AFH of -0.8 (-2.5, 1.4) SDS (median (range)) and in the CS-Irr patients, results showed a significantly (P<0.001) lower AFH of -1.8 (-4.2, 0.0) SDS. AFH SDS corrected for mid-parental height (MPH) in the C-Irr group was -0.5 (-2.2, 0.9) and -1.5 (-3.6, 0.0) SDS in the CS-Irr group. AFH was positively correlated with age at end of tumor therapy, height SDS at start GHT, height gain SDS first year GHT, and negatively correlated with CS-Irr. CONCLUSIONS: GHT failed to restore adult height to MPH in nearly half of Irr-induced GHD patients for brain tumor, especially those receiving CS-Irr, irradiated at a younger age or shorter at start GHT.

Concerns, expectations and perception regarding stature, physical appearance and psychosocial functioning before and during high-dose growth hormone treatment of short pre-pubertal children born small for gestational age.

BACKGROUND/AIMS: Few data are available about parental concerns and psychosocial functioning of young children born small for gestational age (SGA) treated with growth hormone (GH). The present study focused on the perception of short stature and the concerns and expectations of the parents regarding GH treatment. METHODS: Forty prepubertal short SGA children, randomized into a GH-treated and a GH-untreated group, and their parents were evaluated by a questionnaire and a semi-structured interview at start and after 2 years of follow-up. RESULTS: Before start, 85% of the parents were concerned about short stature, 76% expected an increase in adult height of > or =10 cm and 81% expected a positive impact on well-being. Half of the parents expressed fears regarding GH treatment. After 2 years, more parents of treated children reported obvious growth and physical changes, and fewer parents reported teasing because of short stature. An improvement of well-being was reported by half of the parents of treated and untreated children. Fears about GH treatment disappeared almost completely. CONCLUSION: The perspective of GH treatment induced major adult height expectations. In treated children, the physical effects of GH treatment became obvious, teasing because of short stature decreased and initial concerns about short stature and GH therapy decreased.

Effect of 2 years of high-dose growth hormone therapy on cognitive and psychosocial development in short children born small for gestational age.

OBJECTIVE AND DESIGN: Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects of high-dose GH therapy on cognitive development and psychosocial functioning in 34 prepubertal (3-8 years) short SGA children, equally randomized into a GH-treated group (TRG) and an untreated group (UTRG). METHODS: At start and after 2 years, children underwent standardized tests measuring the intellectual abilities (Wechsler Preschool and Primary Scale of Intelligence-Revised, or Wechsler Intelligence Scale for Children-Revised); their parents completed a standardized questionnaire evaluating psychosocial functioning (Child Behavior Checklist; CBCL). RESULTS: At start, total IQ scores were significantly (P < 0.05) lower in the SGA group than in the general population: 32% of the SGA patients had scores below 85. After 2 years, IQ scores remained unchanged in the TRG, but increased significantly (P < 0.05) in the UTRG. After exclusion of children with developmental problems, however, no significant changes in IQ scores occurred in the UTRG as well as the TRG. At baseline, 24% (8/34) children had problematic CBCL total problems scores, equally distributed among the two groups; no significant changes in the different subscale scores occurred after 2 years. CONCLUSION: No beneficial effect of 2 years of GH therapy on cognitive and behavioral profile could be observed in a cohort of rather young short SGA children presenting a variable degree of developmental delay and behavioral problems. Subsequent follow-up could reveal potential long-term effects of GH therapy on development and behavior.

[Necrotizing pneumonia in children: apropos of 4 cases]. / Pneumonie nécrosante de l'enfant: à propos de 4 cas.

OBJECTIVES: To describe the necrotizing pneumonia in children, a severe affection which prevalence seems to increase; to review literature. PATIENTS AND METHODS: We report 4 cases of necrotizing pneumonia: symptoms, agents, diagnostic tools, treatment and long term evolution. RESULTS: In 2 cases, pneumatoceles could be seen at chest X-ray. Two patients presented a deficiency of anti-pneumococcal antibodies. Three needed insertion of a pleural chest tube of whom 1 had a resection of a small piece of necrotic lung. Duration of hospitalisation is longer than in uncomplicated pneumonias. CONCLUSION: Necrotizing pneumonia is a severe affection. Diagnosis has to be made by lung CT. Long term evolution is excellent in pediatric population with serious management at hospital.

Growth hormone (GH) secretion in patients with childhood-onset GH deficiency: retesting after one year of therapy and at final height.

BACKGROUND: Recent studies have shown that many patients treated with growth hormone (GH) during childhood because of idiopathic GH deficiency (GHD) are no longer GH deficient when retested after cessation of GH therapy when final height is achieved. These patients are labelled as transient GHD. We hypothesized that normalization of GH secretion in transient GHD could occur earlier during the course of GH treatment, which could allow earlier cessation of GH treatment. METHODS: In a retrospective study, GH secretion was re-evaluated after cessation of GH treatment at final height in 43 patients diagnosed during childhood as idiopathic GHD (10 with multiple pituitary hormonal deficiencies (MPHD) and 33 with isolated GHD (IsGHD)). In a prospective study, GH secretion was re-assessed after interruption of GH treatment given for 1 year in 18 children with idiopathic GHD (2 MPHD, 16 IsGHD). GH secretion was evaluated by glucagon or insulin stimulation tests. RESULTS: In the retrospective study, all the 10 patients with MPHD and 64% of the 33 patients with IsGHD were still deficient at re-evaluation using the paediatric criteria to define GHD (GH peak <10 ng/ml at provocative test). The proportion of persisting deficiency was greater in patients with complete IsGHD (86%, 12/14 patients) than in patients with partial IsGHD (47%, 9/19 patients). With the criteria proposed in adulthood (GH peak <3 ng/ml), all the 10 patients with MPHD were still considered to be deficient. In contrast, only 15% (5/33 patients) with IsGHD had a maximal GH value <3 ng/ml (36% of the 14 patients with complete IsGHD and none of the 19 patients with partial IsGHD). In the prospective study, after interruption of GH therapy given for 1 year, the 2 patients with MPHD were still GHD at re-evaluation and they resumed GH treatment. Among the 16 patients with IsGHD, 13 (81%) were still deficient (peak response <10 ng/ml) after 1 year. Two of the 3 patients in whom GHD was not confirmed at retesting after 1 year GH showed again a deficient response at second retesting. CONCLUSIONS: Although many patients diagnosed with IsGHD during childhood have a normalized GH secretory capacity when retested during adulthood, early retesting after interruption of GH treatment given for 1 year during childhood does not enable to determine if GH therapy has to be discontinued before cessation of growth.

Cotinine in meconium indicates risk for early respiratory tract infections.

1. In order to identify potential risks for lower respiratory tract symptoms during early infancy, the concentration of cotinine was measured in meconium of 91 newborns as a parameter of prenatal exposure to tobacco, and a questionnaire was performed with parents at birth. Infants were followed up for the first year of life by monthly telephone interviews. 2. Lower respiratory tract infections during the first 6 months of life were associated with a high concentration of cotinine in meconium (cotinine higher than median vs lower than median; odds ratio 4.9, 95% confidence interval 1.2 to 20.3), while none of the other variables tested including selfreport of parental, prenatal or postnatal tobacco consumption, parents history of atopy, maternal age, presence of siblings, socio-economic status, duration of gestation, birth weight, gender, and duration of breast feeding were identified as independent risks. The occurrence of a lower respiratory tract infection during the first 6 months of life was predicted correctly in 77% of the infants by a cotinine excretion in meconium exceeding the group median. 3. In conclusion, quantification of cotinine in meconium is preferred to historical parameters as an estimate of the risk for early respiratory tract infections.

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4alpha/MODY1/TCF14) on chromosome 20q, glucokinase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1alpha/MODY3/TCF1) on chromosome 12q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13q and hepatocyte nuclear factor-1 beta (HNF-1beta/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4alpha, HNF-1alpha and HNF-1beta genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T-->A) and one deletion mutation (P379fsdelT) were found in the HNF-1alpha gene, but no MODY-associated mutations were found in the HNF-4alpha and HNF-1beta genes. Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1alpha gene, and 11 (16%) have no mutations in the HNF-4alpha, IPF1 and HNF-1beta genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additional locus that can cause MODY.

Growth hormone treatment of short children born small for gestational age.

Short children born small-for-gestational-age (SGA) appear to be at an increased risk of having a poly-endocrinopathy, including a degree of growth hormone (GH) deficiency and/or insulin-like growth factor 1 (IGF-1) resistance. Among GH-deficient children, those born SGA present a lower growth response to GH therapy than those not born SGA. The growth response of short SGA children to GH treatment does not appear to depend significantly on the secretory status of GH (as judged by provocative testing), indicating that the SGA condition (IGF-1 resistance) predominates over the availability of endogenous GH in determining the short stature of the majority of these children. When a higher than replacement dose of GH is administered, the growth response of short SGA children matches that of GH-deficient non-SGA children, indicating that the IGF-1 resistance towards growth can be overcome, and that a normal stature can be obtained, at least throughout childhood. It is anticipated that, increasingly, the indications and the doses for GH therapy in children will become interlinked with the emerging principles of endocrine programming in early life.

[Evaluating the independence of paraplegic patients at the end of the first rehabilitation--a multicenter project of computer-assisted quality control in rehabilitation]. / Bewertung der Selbständigkeit von Querschnittsgelähmten am Ende der Erstrehabilitation--ein multizentrisches Projekt der computererfassbaren Qualitätskontrolle in der Rehabilitation.

Rehabilitation of patients who became handicapped due to illness or trauma is a difficult process, involving many therapeutic sections. The necessity to document the results of different rehabilitation programs led to the development of numerous scoring systems in the USA within the last 25 years, considering mainly functional results. The present functional assessment score (DMGP-Selbständigkeitserfassung für Tetraplegiker) for the documentation of self-sufficiency in tetraplegic patients after primary rehabilitation has been designed to record the quality of rehabilitation programs and has been exclusively designed for patients with quadriplegia, it there fore has the advantage of a better and more precise documentation over other general functional scoring systems, especially for the interests of different sections (occupational therapy, physiotherapy) being involved in this special rehabilitation program. The aim of the documentation is to record the degree of independence of tetraplegic patients after primary rehabilitation, considering the individual requirements of aids and the assumption of circumstances suitable for wheel-chairs. Since all data are collected on a computer-readable form each participating clinic has the opportunity for an individual analysis of the own results, as well as the opportunity of comparing it with the collective results.

Elution of blood group antibodies from red cells.

By slowly lowering the surface tension of the aqueous medium through the admixture of 47.5% dimethyl sulfoxide (DMSO) and 0.1% bovine serum albumin (BSA) and by raising the pH to 9, complete elution of A, D, and K antibodies from sensitized erythrocytes (RBC) could be achieved. The eluates comprising the antibodies were subjected to dialysis to remove the DMSO and to neutralize the pH, and to ultrafiltration to remove the excess water. Recovery of a sizeable proportion of the eluted RBC (of blood groups A and K) proved possible by slow and careful removal of the DMSO with phosphate-buffered saline containing 2% BSA.