Height SDS Changes (ΔhSDS) in Healthy Children from Birth to 18 Years, with Correction Factors for Measurement Intervals of Less than One Year.

BACKGROUND: Growth is volatile and non-linear. Assessing the instantaneous speed of growth (momentary height velocity) depends on the precision and the number of measurements and the duration of the observation period. Measurements at short intervals reflect both the non-linearity of growth and the technical error of measurements (TEM). MATERIAL: We reanalyzed longitudinal measurements of body length at age 0, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months, from 1879 healthy infants (956 girls, 923 boys) from France (180 girls, 173 boys), Vilnius, Lithuania (507 girls, 507 boys), Lublin, Poland (67 girls, 56 boys), Zürich, Switzerland (94 girls, 102 boys) and Spain (108 girls, 95 boys); and longitudinal measurements of annual body height from age 2 to 18 years from 1528 healthy children and adolescents (774 girls, 754 boys) from France (41 girls, 47 boys), Vilnius, Lithuania (23 girls, 27 boys), Lublin, Poland (70 girls, 58 boys), Zürich, Switzerland (111 girls, 120 boys), Spain (94 girls, 74 boys), the Czech Republic (65 girls, 69 boys), Hungary (316 girls, 320 boys), and Berkeley, USA (54 girls, 39 boys). RESULTS: We calculated age - and sex-specific mean values for height and SD for height separately for each country. In addition, we defined the instantaneous speed of growth by the difference of two measures of hSDS Formulas References A1 , or in the case of multiple measurements, by the slope of the linear regression (ßhSDS(t)). Based on the longitudinal measurements of body length, we present reference values for annual growth velocity given in the form of SD of annual hSDS changes (ΔhSDS), from birth to maturity. Correction factors are added for validating measurements obtained at intervals of less than one year. The correction factors depend on number of measurements, and duration of the observation period.

Metabolic syndrome and endothelial dysfunction in a population born small for gestational age relationship to growth and Gh therapy.

UNLABELLED: Being born small for gestational age (SGA) and a rapid increase in weight during early childhood and infancy have been strongly linked to metabolic syndrome. A transversal study was conducted on 167 pre-pubertal and 102 pubertal subjects; auxological parameters, systolic and diastolic blood pressure, laboratory data, and carotid-wall thickness (CA-IMT) were measured. RESULTS: Patients born SGA with spontaneous catch-up growth have higher values of BMI, blood pressure, HOMA index, and CA-IMT than those treated with GH and the appropriate-for-gestational age (AGA) group. In conclusion, subjects born SGA are at high risk of developing chronic diseases, including obesity, hypertension, insulin resistant, and endothelial dysfunction, at an early age, mainly those with good catch-up growth compared with the receiving GH because of negative catch-up growth. Our data is compared with published results.

Children born small for gestational age: multidisciplinary approach.

The definition of a newborn SGA changes depending on which parameter is taken as reference. For the neonatologists who are the first to take care of these newborns the most used parameter in the past has been the weight that should be below the 10 centile for the reference standards. In the last years paediatric endocrinologists are more and more interested in the length of these newborns, a parameter more accurate to growth. This paper presents the last consensus statements regarding the definition of SGA newborns taken into consideration the length, the weight, both or them and even the head circumference.

Study of apoptosis and related proteins, CRH and hpGH in placentas of newborns small for gestational age (SGA).

UNLABELLED: The aim of this study is to quantify the expression of apoptotic genes and genes related to the development and growth in placentas of pregnancies with IUGR (intrauterine growth restriction) and normal placentas. We studied the expression of Bcl-2, Caspase3, hpGH (human placental growth hormone) and CRH (corticotropin releasing hormone) genes in normal and IUGR placentas. In addition we have demonstrated this expression by immunohistochemical techniques. MATERIAL AND METHODS: Placentas of newborns with intrauterine infections, complicated pregnancies, congenital malformations and birth asphyxia were excluded. RNA extraction and purification. Total RNA was extracted and cleansed from the lysate using RNA wiz (Ambion) and Qiagen Rneasy Mini (Qiagen). cDNA synthesis. This assay was performed using the Retroscript Kit, Ambion. RT-PCR was performed with the LightCycler System 2.0 (Roche Diagnostics) and the LightCycler FastStart DNA Master Plus SYBR Green I. An immunochemical study was performed using the Envision Plus Dako protocol. RESULTS: Bcl-2, hpGH and CRH are down regulated in the SGA group in comparison to the control group. Caspase3 is up regulated in the SGA group in comparison to the control group. We demonstrated that in placentas from pregnancies with IUGR, expression of Bcl-2is diminished and expression of caspase 3 is augmented compared to normal placentas.

Growth and growth hormone treatment in short stature children born small for gestational age.

Persistent short stature is one of the most frequent complications of being born small for gestational age (SGA) as almost 15% of such children have a low adult height. Additionally, individuals born SGA may have low lean body mass and increased central adiposity which put them at risk of long-term morbidity related to insulin resistance and metabolic disease. Onset of puberty appears at a normal age but comes relatively early for their actual height. There are studies that show that the pubertal growth spurt is moderately decreased in SGA and some girls may experience advanced pubarche and menarche. We have retrospectively analyzed 64 untreated SGA children and we have observed that adult height was lower than target height and positively correlated with maternal height, target height and height at onset of puberty; the tempo of puberty was very similar between SGA and controls but pubertal growth spurt was lower in SGA than in controls. The pathophysiology of postnatal growth failure is complex and different anomalies in the GH-IGF axis had been described. The effect of GH therapy on linear growth and adult height has been extensively studied in the last 15 years. In the short term, GH treatment produces an acceleration of growth with a significant increment of height which is dose dependent during the first 3-4 years. The long-term response is less dose dependent and the vast majority of short SGA children reach an adult height within normal standards and adequate for their target height. There is an important variation in the growth response of SGA children to GH indicating that SGA represents a heterogeneous condition in which response during the first year is the most important predictor of subsequent growth response. GH appears to be safe at the current doses employed but monitoring of IGF-I, IGFBP-3 and glucose metabolism is mandatory during therapy.

Psychomotor and intellectual development (Neurocognitive Function) of children born small for gestational age (SGA). Transversal and longitudinal study.

Although much is now known about the effects of intrauterine growth retardation (IUGR) on children born SGA with regard to anthropometric and biochemical parameters and their treatment, there are still many gaps associated with its impact on neurocognitive functions. In our experience published several years ago, IUGR has a negative effect on neurocognitive development, regardless of whether these children showed evidence of catch-up growth or not or of the socio-economic conditions that might contribute to the situation. We have now accumulated a large number of cases, many of whom have been followed longitudinally, some for up to 7 years, many having been treated with GH from the time when this therapy was first approved by the EMA. Apart from the cases mentioned, other confounding factors such as gestational age, Apgar score, neonatal comorbidity and the possible effects of GH treatment have also been included. In addition and using our own reference standards, we now present our experience, which confirms what we had already noted in the past, that IUGR is in itself a condition that often causes psychomotorintellectual impairment, may be extremely severe and tends to worsen. This negative impact of IUGR on neurocognitive development does not depend on how the child grows,spontaneous growth is better and when growth is not altered by GH therapy. Later studies will be able to confirm whether early treatment with GH throughout the 2nd year of life, or an early specific stimulation programme, or the sum of both, can improve the neurocognitive development of these children. IUGR prevention, acting on causal factors that are partly avoidable such as smoking, working conditions and stress during pregnancy (see the corresponding article in this supplement) proves once again to be the best way to stop this negative impact on the IQ of many children born SGA.

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas.

BACKGROUND: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS: Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION: Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.