Age-related changes in energy metabolism in peripheral mononuclear blood cells (PBMCs) and the brains of cognitively healthy seniors.

Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1H- and 31P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (- 15%) and ATP levels (- 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (- 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (- 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant.

Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program.

Context: Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective: To assess incidence of key safety outcomes. Design: Prospective, multinational, observational study (1999 to 2015). Setting: A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients: Children with growth disorders. Interventions: GH treatment. Main outcome measures: Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions: GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.

Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study.

Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood. Objective: To assess mortality in children receiving GH. Design: Prospective, multinational, observational study. Setting: Eight hundred twenty-seven study sites in 30 countries. Patients: Children with growth disorders. Interventions: GH treatment during childhood. Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results: Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non-GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65). Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions.

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial.

BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.

Assessment of Primary Cancer Incidence in Growth Hormone-Treated Children: Comparison of a Multinational Prospective Observational Study with Population Databases.

BACKGROUND/AIMS: Although results of the majority of clinical studies have shown no association between growth hormone (GH) treatment in childhood and risk of primary cancer, concerns remain regarding the potential influence of GH therapy on neoplastic cell growth. This study evaluated the incidence of primary malignancies in a large observational study of paediatric GH treatment. METHODS: Primary cancer incidence was assessed in a cohort of 19,054 GH-treated children without a reported prestudy history of malignancy in the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). The standardised incidence ratio (SIR) for primary cancer in GH-treated children was determined by comparing cancer incidence in the GeNeSIS study population with incidence rates for country-, age-, and sex-matched cohorts of the general population. RESULTS: During a mean follow-up of 3.4 years in GeNeSIS (64,705 person-years), 13 incident potential primary cancers were identified in GH-treated patients. The SIR (95% confidence interval) for all observed cancers was 1.02 (0.54-1.75), and the crude incidence was 20.1 (10.7-34.4) cases per 100,000 person-years. CONCLUSION: Acknowledging the relatively short follow-up in our study, GH-treated children without a history of previous malignancy did not have a higher risk of all-site primary cancer during the study when compared to general-population cancer registries.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.

OBJECTIVE: To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD). DESIGN: Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. METHODS: Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort). RESULTS: MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development. CONCLUSIONS: MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Radiological Features in Patients with Short Stature Homeobox-Containing (SHOX) Gene Deficiency and Turner Syndrome before and after 2 Years of GH Treatment.

BACKGROUND/AIMS: The short stature homeobox-containing (SHOX) gene is one of many genes that regulate longitudinal growth. The SHOX deficiency (SHOX-D) phenotype, caused by intragenic or regulatory region defects, ranges from normal stature to mesomelic skeletal dysplasia. We investigated differences in radiological anomalies between patients with SHOX-D and Turner syndrome (TS) and the effect of 2 years of growth hormone (GH) treatment on these anomalies. METHODS: Left hand/wrist, forearm and lower leg radiographs were assessed at baseline and after 2 years in children with genetically confirmed SHOX-D (GH-treated and untreated groups) and TS (GH-treated) in a randomised, controlled, multinational study. RESULTS: Radiological anomalies of hand, wrist and forearm were common in SHOX-D and TS. Radial bowing appeared more prevalent in SHOX-D, while lower leg anomalies were more common in TS. There were no significant differences in radiological findings between GH-treated and untreated patients with SHOX-D after 2 years. CONCLUSION: GH treatment had no systematic effect on skeletal findings in SHOX-D, based on limited radiological differences between the GH-treated and untreated groups at 2 years. Bone age radiographs allow assessment of radiological signs indicating a potential diagnosis of SHOX-D and may lead to earlier genetic confirmation and initiation of GH therapy.

Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study.

CONTEXT: Previous studies showed improvement in impaired quality of life (QoL) in adult patients with growth hormone (GH) deficiency (GHD) who were treated with GH; improvement was sustained over a few years after GH therapy. OBJECTIVE: To evaluate the QoL over 10 years. DESIGN: This was a prospective observational study. SETTING: The study was conducted in clinical practice. PATIENTS: 1436 adult patients with adult-onset (AO) GHD (mean age [standard deviation (SD)]: 49.0 [12.2] years; 49% female) and 96 with childhood-onset (CO) GHD (31.3 [10.0] years; 60% female) (total N = 1532). INTERVENTION: GH therapy. MAIN OUTCOME MEASURES: QoL was measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) in countries where validated questionnaires and normative data for calculation of Z-scores were available. Change in QoL was tested by Student's t test and predicted by mixed-model repeated measures (MMRM) analysis. RESULTS: At study entry, patients had diminished QoL Z-scores (mean [SD] AO, -1.55 [1.69]; CO -0.98 [1.32]). The largest QoL improvements were in the first year: mean (SD) increase 0.77 (1.37) for AO (P < .001) and 0.50 (1.37) for CO (P < .001). The initial improvement from study entry remained statistically significant throughout 10 years for AO and in years 1 to 4, 6, and 7 for CO (P < .05). MMRM analysis predicted a greater QoL improvement in those who were not depressed, lived in Europe, had poorer Z-scores at entry, had lower body mass index at entry, and had no impaired vision. CONCLUSION: These data suggest that GH replacement provides sustained improvement in QLS-H scores toward normality for up to 10 years.

High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency.

CONTEXT: PROP1 gene mutations cause multiple pituitary hormone deficiency (MPHD). OBJECTIVE: We sought to expand experience with PROP1 mutation carriers by studying a large cohort of Lithuanian patients. PATIENTS AND METHODS: Sixty-seven MPHD patients were tested for PROP1 defects. Perinatal and postnatal data were obtained from medical records. Hormonal investigations, pituitary imaging, and GH therapy were provided in a single center in Kaunas, Lithuania. RESULTS: A biallelic PROP1 gene mutation was found in 47 subjects (70.1%), of which 46 were homozygous for 296delGA. Positive finding rate among MPHD and population prevalence of PROP1 defects in Lithuania (15.8 per million) were the highest reported to date. Patients' birth lengths/weights were normal. Testicular retention was noted in 31% of boys. Median height SD scores declined over years 1-5: -1.56, -2.34, -3.43, -3.52, and -3.70. Mid-parental height predicted severity of growth retardation at diagnosis (r2=0.30; P=.0001). Deficiencies of GH, TSH, ACTH, and FSH/LH were diagnosed in 44/44, 44/44, 19/44, and 22/44 subjects at median age of 5.5, 5.6, 13.1, and 15.0 years, respectively. Pituitary height ranged from 16.6 mm (+20.2 SD) to 1.4 mm (-15.5 SD) and declined with age (r2=0.27, P=.001). GH replacement (dose 0.027 mg/kg/d) led to height velocities 12.2; 9.1; 6.9; 6.8; 6.7; 5.6; and 5.7 cm/y (medians) at years 1-7 and final height SD scores (17 patients) -0.98±1.77 (-1.04±1.41 below target height; P=.008 vs 0). CONCLUSIONS: High prevalence of PROP1 defects in Lithuania is due to 296delGA mutation, suggesting a founder effect.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency.

OBJECTIVE: We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). DESIGN: Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. METHODS: Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort). RESULTS: MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. CONCLUSIONS: MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study.

BACKGROUND/AIMS: Magnetic resonance imaging (MRI) is used to investigate the etiology of growth hormone deficiency (GHD). This study examined relationships between MRI findings and clinical/hormonal phenotypes in children with GHD in the observational Genetics and Neuroendocrinology of Short Stature International Study, GeNeSIS. METHODS: Clinical presentation, hormonal status and first-year GH response were compared between patients with pituitary imaging abnormalities (n = 1,071), patients with mutations in genes involved in pituitary development/GH secretion (n = 120) and patients with idiopathic GHD (n = 7,039). RESULTS: Patients with hypothalamic-pituitary abnormalities had more severe phenotypes than patients with idiopathic GHD. Additional hormonal deficiencies were found in 35% of patients with structural abnormalities (thyroid-stimulating hormone > adrenocorticotropic hormone > luteinizing hormone/follicle-stimulating hormone > antidiuretic hormone), most frequently in patients with septo-optic dysplasia (SOD). Patients with the triad [ectopic posterior pituitary (EPP), pituitary aplasia/hypoplasia and stalk defects] had a more severe phenotype and better response to GH treatment than patients with isolated abnormalities. The sex ratio was approximately equal for patients with SOD, but there was a significantly higher proportion of males (approximately 70%) in the EPP, pituitary hypoplasia, stalk defects, and triad categories. CONCLUSION: This large, international database demonstrates the value of classification of GH-deficient patients by the presence and type of hypothalamic-pituitary imaging abnormalities. This information may assist family counseling and patient management.

Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS.

OBJECTIVE: Childhood cancer survivors are commonly treated with GH for GH deficiency that develops either as a result of primary malignancy or its treatment. One study--the Childhood Cancer Survivor Study (CCSS)--demonstrated increased risk of second neoplasm (SN) in GH-treated childhood cancer survivors compared with non-GH treated, after adjusting for key risk factors. We assessed the incidence of SN in GH-treated childhood cancer survivors in outpatient observational studies of GH replacement. DESIGN: Retrospective analysis of two prospective cohort studies that collected data on safety of GH replacement as prescribed in clinical practice. METHODS: Childhood cancer survivors enrolled in Eli Lilly and Company's pediatric (Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS)) and adult (Hypopituitary Control and Complications Study (HypoCCS)) observational studies of GH treatment were assessed for incidence of SN. RESULTS: The percentage of childhood cancer survivors treated with GH who developed a SN was 3.8% in pediatric GeNeSIS participants and 6.0% in adult HypoCCS participants. The estimated cumulative incidence of SN at 5 years of follow-up in these studies was 6.2 and 4.8% respectively. CONCLUSIONS: The incidence of SN in GeNeSIS and HypoCCS GH-treated participants is similar to the published literature and is thus consistent with increased risk of SN in childhood cancer survivors treated with GH. As follow-up times were relatively short (<3 years), longer observation is recommended. Nevertheless, clinicians should be alerted to the possibility of increased risk of SN in childhood cancer survivors treated with GH and continue chronic surveillance.

Genotypes and phenotypes of children with SHOX deficiency in France.

CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

BACKGROUND/AIMS: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. METHODS: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds. RESULTS: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. CONCLUSION: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome.

BACKGROUND: Patients with mutations or deletions of the Short Stature Homeobox-containing(SHOX) gene have variable degrees of growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX deficiency remain short in adulthood. Growth hormone (GH) treatment improves short-term linear growth; however, there are no data on GH treatment effects on final height. PATIENTS: In a retrospective study, we assessed the relative effects of GH on final height gain in patients with SHOX deficiency (n = 14; 12 females) and Turner syndrome (TS) (n = 158). Patients were included if they fulfilled the following criteria: genetically-confirmed SHOX deficiency or TS, baseline height SDS <1.5, GH treatment started at Tanner stage < or =2, duration of GH treatment >2 years, and final height attained. RESULTS: Both groups of patients were short at baseline (height SDS [mean +/- SD]: SHOX deficiency, -3.3 +/- 0.9; TS, -2.9 +/- 0.8). Height SDS gain from baseline to final height was significant for each patient group (SHOX deficiency, 1.1 +/- 0.7; TS, 1.2 +/- 0.8; p < 0.001); however, it was not significantly different between groups (p = 0.708). CONCLUSIONS: Patients with SHOX deficiency receive similar final height benefit from GH treatment to those with TS.

Changing patterns of the adult growth hormone deficiency diagnosis documented in a decade-long global surveillance database.

BACKGROUND: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996. METHODS: Baseline demographics, reported cause of GHD, and diagnostic tests were available from 5893 GH-treated patients. Trends for change over time in diagnosis, GH stimulation test data, and IGF-I measurements were analyzed at 2-yr intervals by linear regression models, with entry year as the predictive variable. RESULTS: Over the decade, there was a decrease in patients enrolled with diagnoses of pituitary adenoma (50.2 to 38.6%; P < 0.001), craniopharyngioma (13.3 to 8.4%; P = 0.005) and pituitary hemorrhage (5.8 to 2.8%; P = 0.001); increases in idiopathic GHD (13.9 to 19.3%; P < 0.001), less common diagnoses (7.4 to 15.8%; P < 0.001), and undefined/unknown diagnoses (1.3 to 8.6%; P < 0.001) were observed. Use of arginine, clonidine, and L-dopa tests declined, whereas use of the GHRH-arginine test increased. Median values for peak GH from all tests except GHRH-arginine and for IGF-I SD scores increased significantly (P < 0.001). Over the decade (1996--2005), idiopathic GHD was reported for 16.7% of patients, and more than half of these had adult onset GHD. In the idiopathic adult onset group, 40.2% had isolated GHD; 18.3 and 4.4% had a stimulation test GH peak of at least 3.0 and 5.0 microg/liter, respectively. CONCLUSIONS: Significant shifts in diagnostic patterns have occurred since approval of the adult GHD indication, with a trend to less severe forms of GHD.

Hypoglycemia due to paraneoplastic secretion of insulin-like growth factor-I in a patient with metastasizing large-cell carcinoma of the lung.

CONTEXT: Nonpancreatic tumors may cause recurrent hypoglycemia known as nonislet cell tumor hypoglycemia. It is due to overproduction and secretion by the tumor of incompletely processed IGF-II, termed big IGF-II. We recently identified a patient with recurrent hypoglycemia and low insulin, but without elevated big IGF-II. Multiple small lung nodules were detected by computed tomography scan. An undifferentiated large-cell carcinoma was diagnosed from an axillary lymph node metastasis. OBJECTIVE: The objective was to investigate whether the patient's hypoglycemia was due to excessive IGF-I production by the tumor. METHODS: Serum IGF- I and IGF-II, insulin, and GH were measured by RIA; the distribution of IGFs between IGF binding protein complexes in serum was analyzed after neutral gel filtration. Tissue IGF-I was identified by immunohistochemistry and in situ hybridization, and by RT-PCR after RNA extraction. RESULTS: Total and free serum IGF-I, but not total, free, and big IGF-II, was increased, and the IGF-I content of the two IGF binding protein complexes was elevated. Immunohistochemistry demonstrated IGF-I peptide in situ hybridization IGF-I mRNA in the lymph node metastasis. Combined GH/glucocorticoid treatment prevented hypoglycemia, but did not lower IGF-I. After chemotherapy with carboplatinum/etoposide, the lung nodules largely regressed, and serum IGF-I and the IGF-I content of the two binding protein complexes became normal. Hypoglycemia did not recur despite discontinuation of GH/glucocorticoid treatment. CONCLUSION: Our findings are compatible with a new form of tumor hypoglycemia caused by circulating tumor-derived IGF-I.

IGF-I and IGF-II stimulate directed cell migration of bone-marrow-derived human mesenchymal progenitor cells.

Insulin-like growth factors (IGFs) are known to be key regulators of bone growth, remodeling, and repair. Since all these processes depend on the recruitment of cells with the potential to be committed to the osteoblastic lineage, we studied possible effects of IGF-I and -II on migration of human mesenchymal progenitor cells (MPC) using a modified Boyden chamber assay. The results were compared to those of primary osteoblasts and in vitro-osteogenic-differentiated MPC. IGF-I and -II stimulated cell migration of all these cell populations in a dose-dependent manner from 1 to 100ng/mL. The maximal chemotactic index (CI) was 4-5 for MPC and primary osteoblasts and about 3 for in vitro-differentiated MPC. Checkerboard analysis revealed that IGFs stimulated true directed cell migration (chemotaxis) and not simply chemokinesis. Addition of an antibody against the type I IGF receptor (alphaIR3) completely abolished (MPC) or markedly reduced (primary osteoblasts) the chemotactic effects of each of the IGFs. IGFBP-3 itself had no direct effect, while IGFBP-5 stimulated MPC migration at concentrations of 80 and 160ng/mL. Parallel application of IGFBP-3 had borderline inhibitory effects while the addition of 40ng/mL of IGFBP-5 enhanced the chemotactic effect of IGF-I on MPC. In conclusion, our results show that IGF-I and -II are chemotactic factors for MPC and indicate that IGFBP-5 both modulates the IGF-I effect and directly stimulates migration of human mesenchymal progenitor cells.

The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome.

OBJECTIVE: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS). STUDY DESIGN: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS. RESULTS: In the clinic sample LWD subjects, height standard deviation score ranged from -5.5 to +0.1 (-2.3 +/- 1.3, girls and -1.8 +/- 0.6, boys). Wrist changes related to Madelung deformity were present in 18 of 34 (53%) LWD subjects. In comparing the LWD and TS populations in the GeNeSIS sample, Madelung deformity, increased carrying angle, and scoliosis were more prevalent in the LWD population, whereas high arched palate was similarly prevalent in the two populations. CONCLUSIONS: Short stature is common in both LWD (girls and boys) and TS (girls). Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood include short stature, short limbs, wrist changes, and tibial bowing.