Clinico-radiological correlation of pituitary stalk interruption syndrome in children with growth hormone deficiency.

PURPOSE: To analyze the clinical, hormonal, and radiological characteristics of Pituitary stalk interruption syndrome (PSIS) in children with growth hormone deficiency (GHD). METHODS: This is a prospective cross-sectional study, conducted over a period of three years in a short stature clinic of tertiary care referral hospital. 57 severe short stature children with proven GHD were included in the study. RESULTS: Among 57 children with GHD, 14 (24%) were diagnosed as PSIS. The mean age at diagnosis was 11.8 ± 2.6years. The male to female ratio was 2.5:1. Nine (64%) children had multiple pituitary hormone deficiency (MPHD) and 5 (36%) had isolated growth hormone deficiency (IGHD). In spite of absent or ectopic posterior pituitary (EPP)in Magnetic Resonance Imaging (MRI) of PSIS cohorts, only one had Arginine vasopressin (AVP) deficiency. EPP was seen near median eminence in 6 (44%), elsewhere in 4 (28%), and absent in 4 (28%)children. The height gain following growth hormone therapy was better in PSIS cohorts as compared to non-PSIS. CONCLUSION: Male gender, breech presentation, external congenital anomalies like cryptorchidism, midline defects and nystagmus were more common in children with PSIS. MPHD were more frequently seen in PSIS whereas IGHD in non-PSIS cohort. AVP deficiency is very rare in PSIS despite of absent or ectopic posterior pituitary in MRI. High index of clinical suspicion in all severe short stature may lead to early diagnosis and prompt initiation of growth hormone treatment for better outcome.

Reduced Bone Mineral Density in Middle-Aged Male Patients with Adult Growth Hormone Deficiency.

The aim of the work was to investigate the bone mineral density (BMD) in middle-aged male patients with both childhood-onset (CO) and adulthood-onset (AO) adult growth hormone deficiency (AGHD). In this retrospective cross-sectional study in a major medical center in China, dual X-ray absorptiometry was performed in 50 male AGHD patients (average age was 35.2±9.8 years) and 50 age- and BMI-matched non-athletic healthy men. BMD was compared between AGHD patients and controls. Compared with healthy controls, AGHD group had significantly decreased IGF-1 (p1<0.001) and IGF-1 SDS (p1<0.001). Serum testosterone levels were significantly lower in AGHD patients (p1<0.001), mainly in AO AGHD patients (p3<0.001). The BMD of the femoral neck, trochanter, femoral shaft, total hip, and lumbar spine were significantly lower in all AGHD patients compared with healthy controls (all p1<0.05), especially in CO AGHD patients (all p2<0.05). Multiple stepwise linear regression indicated AGHD was negatively correlated with BMD at each site (ß<0, p<0.05). Additionally, serum testosterone level was an independent influencing factor of BMD of the femoral neck (ß=0.256, p=0.018) and lumbar spine (ß=0.219, p=0.040). BMD was significantly reduced in AGHD patients, especially in CO AGHD patients. Our data suggested that the status of growth hormone deficiency and testosterone level were important for maintaining of bone mineral density in middle-aged male patients with AGHD.

Evidence of intrauterine growth restriction and growth hormone deficiency in 49,XXXXY syndrome.

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population.

Morphological changes of the cerebral cortex between children with isolated growth hormone deficiency and idiopathic short stature.

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis plays an important role in normal brain development, and GH deficiency inevitably affects the growth of the cerebral cortex. This study was designed to analyze morphological differences in gray matter volume, cortical surface area, and gray matter thickness between children with isolated growth hormone deficiency (IGHD) and children with idiopathic short stature (ISS). Twenty-four children with IGHD (mean age 9.42 years, peak GH < 5 µg/l) and 24 controls with ISS (mean age 9.21 years, peak GH > 10 µg/l) were included. High-resolution three-dimensional T1-weighted MRIs were acquired at participants' first visit. Measurements of gray matter volume, cortical surface area and gray matter thickness were obtained using FreeSurfer. The total and regional differences between groups were statistically analyzed. Correlations between the FreeSurfer results and GH and IGF-I levels were also obtained. The gray matter volume, cortical surface area and gray matter thickness of the total brain and of the bilateral hemispheres of children with IGHD were significantly smaller than those of children with ISS (all P values < 0.05). All the measurements had similar cortical distributions between groups but varied across regions. Cortical regions with significant differences in the mean gray matter volume and surface area were mainly distributed around the bilateral central sulci and the lateral and basal parts of the temporal lobes (all P values < 0.05). There were negative correlations between gray matter volume, cortical surface area and GH levels, and the right hemispheric and total cortical surface area correlated significantly with GH levels (all P values < 0.05) in children with IGHD. There were significant positive correlations between gray matter volume, cortical surface area and IGF-I levels (all P values < 0.05) in both groups, except for in left hemispheric gray matter volume in children with ISS. Children with IGHD have significant morphological changes in the cerebral cortex, which were partially influenced by GH and IGF-I levels. These cortical changes may be related to deficits in their relatively slower development in intelligence, motor performance, and other functions.

Questioning the Value of Brain Magnetic Resonance Imaging in the Evaluation of Children with Isolated Growth Hormone Deficiency.

BACKGROUND: Isolated growth hormone deficiency (IGHD) is a relatively common disorder. Current diagnostic protocol requires a brain magnetic resonance imaging (MRI) study of the hypothalamus and the hypophysis to determine the cause after establishment of the diagnosis. This study aimed to examine the yield of brain MRI in the evaluation of children with IGHD and to define clinical and laboratory parameters that justify its performance. METHODS: A retrospective chart review of all children (<18 years) diagnosed with IGHD was conducted at 3 pediatric endocrinology units between 2008 and 2018. RESULTS: The study included 192 children (107 boys) with confirmed IGHD. The mean age ± standard deviation (SD) at diagnosis was 8.2 ± 3.7 years (median 8.5 years, range 0.8-15.9). The mean height SD score (SDS) at diagnosis was -2.25 ± 0.73. The mean height deficit SDS (defined as the difference between height SDS at diagnosis and mid-parental height SDS) was -1.7 ± 0.9. Fifteen children (7.8%) had pathological MRI findings. No space-occupying lesion was detected. Children with pathological MRIs had greater height deficit SDS and lower peak growth hormone levels on provocative tests compared to children with normal MRIs: -2.3 ± 1.2 vs. -1.6 ± 0.8 (p = 0.02) and 4.4 ± 1.9 vs. 5.7 ± 1.3 (p = 0.01), respectively. CONCLUSION: Our preliminary data indicate that most brain MRIs performed for routine evaluation of children with IGHD are not essential for determining cause. Further studies with larger cohorts are needed in order to validate this proposed revision of current protocols.

Cerebral vasoreactivity, a surrogate marker of cerebrovascular disease, is not impaired in subjects with lifetime, untreated, congenital isolated GH deficiency.

OBJECTIVES: Cerebrovascular disease (CeVD) is a major cause of death and disability. The role of the GH/IGF-I axis on CeVD risk is controversial. Patients with GH deficiency (GHD) in the setting of hypopituitarism often exhibit CeVD predisposing factors, like low nitric oxide generation, endothelial dysfunction, increased visceral fat mass, increased levels of LDL cholesterol, and increased intima-media thickness, a surrogate marker of atherosclerosis. However, several confounders such as the primary hypothalamic-pituitary lesion, hormonal replacement therapies, consequences of surgery and radiotherapy, may influence this relationship. Therefore, we decided to assess cerebral vasoreactivity, a surrogate marker of CeVD, in adult subjects with untreated isolated GHD (IGHD) due to the same homozygous null mutation in the GHRH receptor gene. METHODS: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, intima-media thickness measurement, and transcranial Doppler were performed. The intracranial hemodynamics (mean flow velocity, pulsatility and resistance indexes) were measured, and the response to the vasodilatory stimulus by breath-holding maneuver (breath-holding index) was calculated. RESULTS: IGHD and control groups were similar in Framingham risk score and intima-media thickness. Similarly, there was no difference in mean flow velocity, pulsatility, resistance, and breath-holding index. CONCLUSIONS: Lifetime, untreated IGHD does not cause impaired cerebral vasoreactivity.

Short stature and growth hormone deficiency in a subset of patients with Potocki-Lupski syndrome: Expanding the phenotype of PTLS.

Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well.

Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors.

Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence. Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors. Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set. Results: In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6-100%). Conclusions: This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.

Differences between patients with isolated GH deficiency based on findings in brain magnetic resonance imaging.

INTRODUCTION: Protocol for prescribing hormone replacement therapy in isolated growth hormone (GH) deficiency includes magnetic resonance imaging of the brain. There is controversy on the frequency of structural pituitary abnormalities and on the importance of abnormal MRI findings on prognosis and response to GH replacement. METHODS: A descriptive, retrospective study of children of both sexes aged 0-14 years, who had undergone brain MRI, diagnosed with isolated GH deficiency at a tertiary hospital in the past 14 years, aimed at reporting the frequency of abnormal MRI findings in isolated GH deficiency, and to establish whether differences exist in height diagnosis and evolution according to MRI findings. MRI findings were also compared with the findings reported in healthy children in order to establish incidence. RESULTS: 96 patients were studied, of whom 74/96 (77%) reached adult age. Abnormal MRI findings were seen in 11.5% of them (8/11 of pituitary origin). No brain or pituitary tumor was seen in any case. Patients with abnormal images had a mean age at treatment start of 8 years, a target height of -0.8SD, and a final height of 1.04SD, while patients with normal MRI findings had an age at treatment start of 10 years old, a target height of -1.44SD, and a final height of -1.75SD, with statistically significant differences. CONCLUSIONS: Patients with abnormal MRI findings show a more favorable response to GH replacement therapy.

Relevance of Pituitary Gland Magnetic Resonance Imaging Results with Clinical and Laboratory Findings in Growth Hormone Deficiency.

BACKGROUND The present study investigated the relationship between detection of organic pathologies with magnetic resonance imaging of the pituitary gland, clinical and laboratory findings, and treatment response. MATERIAL AND METHODS The study included a total of 183 patients who had isolated growth hormone deficiency, received at least 1 year of treatment, returned regularly for follow-ups, and whose pituitary magnetic resonance images were available. The patients were divided into 2 groups: those with and without pathological evidence with magnetic resonance imaging. Clinical and laboratory features and treatment responses were compared between patients with and without pathological evidence with magnetic resonance imaging. RESULTS Of the 183 patients, 105 were females and 78 were males, and 114 patients (62.2%) were prepubertal and 69 patients (37.8%) were pubertal. Their mean age was 10.01±3.25 years (1-17.6 years). Pituitary images of 153 (83.6%) patients were normal. Of the patients with detected pathologies (16.4%), 19 (10,4%) had pituitary hypoplasia, 5 (2.7%) had partial empty sella, 3 (1.7%) had ectopic neurohypophysis and 3 (1.7%) had empty sella, pineal, and arachnoid cyst. A statistically significant increase was observed in the height increase rate after treatment compared to before treatment in both groups (p<0.001). However, the group with pathology had a statistically significant (p=0. 007) post-treatment increase height rate. Although in the group with pathology there was a lower L-DOPA and clonidine peak GH response, there was not any statistically significant difference between the 2 groups (p=0.051, p=0.113). Pituitary gland length was also shorter in the group with pathology compared to the group without pathology (P<0.001). CONCLUSIONS Magnetic resonance imaging is a useful tool in assessing GH deficiency pathogenesis and in predicting treatment response.

Pituitary height at magnetic resonance imaging in pediatric isolated growth hormone deficiency.

BACKGROUND: Magnetic resonance imaging (MRI) is used for neuroradiologic evaluation of patients with idiopathic growth hormone deficiency (IGHD). OBJECTIVES: To compare pituitary height and morphology at MRI between patients with IGHD and controls. MATERIALS AND METHODS: This retrospective study was conducted in pediatric patients, 3 years-15 years old, who had had brain MRI with non-contrast-enhanced midsagittal T1-weighted images. These images were measured for pituitary height and morphology of the pituitary gland including shape, stalk and posterior pituitary bright spot was evaluated. RESULTS: One hundred and nineteen patients were included, with 49 and 70 patients assigned to the study and control groups, respectively. Mean pituitary height was significantly less in the IGHD group than in the control group (3.81 mm±1.38 vs. 4.92 mm±1.13, retrospectively; P<0.001). Subgroup analysis revealed a significant difference in the pituitary height between groups in the prepubertal (8-10 years) and pubertal (11-13 years) periods (P=0.039 and P=0.006, respectively) and a trend toward significance in the postpubertal period (P=0.053). There was a significant difference in pituitary shape between IGHD and controls when combining grades III, IV and V (P=0.007). Other abnormal MRI findings of the pituitary stalk and posterior bright spot were significantly more often observed in the IGHD group (P<0.05). CONCLUSION: Pituitary height was significantly smaller in patients with IGHD than in controls during prepuberty and puberty. Abnormal concave superior contour, hypoplastic stalk and absent/ectopic posterior bright spot were observed significantly more often among patients with IGHD.

Retinal Neural and Vascular Structure in Isolated Growth Hormone Deficiency Children and Evaluation of Growth Hormone Treatment Effect

OBJECTIVE: To evaluate neural and vascular retinal morphology of children with isolated growth hormone deficiency (GHD) and to determine any retinal changes due to GH treatment. METHODS: Twenty-eight children with isolated GHD and 53 age-, gender- and body mass index-matched healthy volunteers were enrolled in this prospective study. The retinal nerve fibre layer (RNFL) and macular thickness (MT) were measured, as well as intraocular pressure (IOP). The number of retinal vascular branching points were calculated. Effect of GH treatment on the retina and IOP was evaluated after one year of treatment. Measurements were also made in the control group at baseline and following the initial examination. Pre- and post-treatment changes were compared. The findings were also compared with those of the controls. The correlation between ocular dimensions and insulin-like growth factor-I (IGF-1) levels were also analysed. RESULTS: The number of branching points was significantly lower in GHD patients as compared with control subjects (15.11±2.67 and 19.70±3.37, respectively, p=0.05 for all comparisons). No statistically significant differences were found in mean RNFL, MT and IOP values between GHD patients and control subjects. GH treatment did not create any significant changes in the retinal vascularization or other retinal neural parameters and IOP either within the patient group or when compared with the control group. No correlations were observed between ocular dimensions and IGF-1 levels. CONCLUSION: Our findings suggest that isolated GHD may lead to decreased retinal vascularization. However, retinal neural growth and differentiation were not affected by GHD. These findings may be related to the fetal development process of pituitary somatotropic cells and the retina. Additionally, GH treatment did not cause any changes in retinal neural and vascular tissues.

How to deal with giant pituitary adenomas: transsphenoidal or transcranial, simultaneous or two-staged?

Giant pituitary adenomas (diameter >4 cm) are a challenge to treat, and there is no consensus on the optimal surgical strategy. We report here our experience in surgical management of these lesions. Adult patients with giant pituitary adenomas (n = 62; 54 non-functioning and eight hormone-secreting adenomas) who underwent surgical resection at our hospital from 2009 to 2015 were retrospectively reviewed. Surgical and clinical outcomes were analyzed. Single transsphenoidal and transcranial approaches were used in 43 (69.4%) and four (6.5%) patients, respectively. A combined transsphenoidal and transcranial approach was used in 13 patients (20.9%) and in two patients (3.2%), a transcranial procedure was followed 3 months later by a transsphenoidal approach. Greater than 90% resection was achieved in 47 cases (75.8%). During a mean follow-up period of 46.9 months, 49 patients (79%) showed improved visual impairment scores, while none experienced visual deterioration. There was no post-operative hemorrhage or mortality. A total of 27 patients (43.5%) received adjuvant medical and/or radiation therapy. At last follow-up, eight patients (12.9%) had recurrence. For giant pituitary adenoma, the transsphenoidal and transcranial approaches should be combined flexibly based on the characteristics of the tumor. In certain cases, a simultaneous combined approach can maximize tumor extirpation and lower the risk of swelling and bleeding of the residual tumor.

Diagnosis of growth hormone deficiency in the paediatric and transitional age.

Growth hormone deficiency is a rare cause of childhood short stature, but one for which treatment exists in the form of recombinant human growth hormone. A diagnosis of growth hormone deficiency is made based on auxology, biochemistry and imaging. Although no diagnostic gold standard exists, growth hormone provocation tests are considered the mainstay of diagnostic investigations. However, these must be interpreted with caution in view of issues with variability and reproducibility, as well as the limited evidence-base for cut-off values used to distinguish growth hormone deficient and non-growth hormone deficient subjects. In addition, nutritional and pubertal status can affect results, with no consensus on the role of priming with sex steroid hormones. Difficulties with assays exist both for growth hormone as well as insulin-like growth factor-1. Pituitary magnetic resonance imaging is a useful diagnostic, and possibly prognostic, aid. Although genetic testing is not routine, the discovery of more relevant mutations makes it an increasingly important investigation. Children with growth hormone deficiency are retested biochemically on completion of growth, to assess whether they remain so into adulthood.

Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency.

CONTEXT: Adult-onset GH deficiency (GHD) increases visceral adiposity and the activity of the enzyme 11ß-hydroxysteroid dehydrogenase, which converts cortisone (E) to cortisol (F), both linked to insulin resistance and increased cardiovascular risk. Conversely, we reported that adults with congenital isolated GHD (IGHD) have increased insulin sensitivity. OBJECTIVE: To assess the type of fat distribution and the amount of visceral and sc fat and to correlate them to the F/E ratio in adults with untreated IGHD due to a mutation in the GHRH receptor gene. METHODS: Body composition was assessed by dual-energy x-ray absorptiometry, thickness of sc and visceral fat was measured by sonography, and serum F and E were measured in 23 IGHD subjects and 21 age-matched controls. RESULTS: Waist/hip ratio (WHR), trunk fat, and trunk/extremity fat (TR/EXT) ratio were higher in IGHD subjects. Visceral fat index (VFI) (but not sc fat index [SFI]) was higher in IGHD. F and F/E ratio were also higher in IGHD. In all 44 individuals, WHR correlated with TR/EXT ratio, thickness of visceral fat, VFI/SFI ratio, F, and F/E ratio. TR/EXT ratio correlated with visceral fat thickness, VFI/SFI ratio, and F. Age had a significant effect on VFI and on F/E ratio. Body mass index SD score and WHR have a similar significant effect on TR/EXT ratio and on F/E ratio. CONCLUSIONS: Lifetime congenital untreated IGHD causes increased visceral adiposity with a high F/E ratio. However, the increased insulin sensitivity suggests that visceral adiposity needs a minimal GH secretion to translate into increased insulin resistance.

Isolated GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum, and reduces size but not density of trabecular and mixed bone.

CONTEXT: The GH/IGF-I axis is important for bone growth, but its effects on joint function are not completely understood. Adult-onset GH-deficient individuals have often reduced bone mineral density (BMD). However, there are limited data on BMD in adult patients with untreated congenital isolated GH-deficient (IGHD). We have shown that adult IGHD individuals from the Itabaianinha, homozygous for the c.57+1G>A GHRHR mutation, have reduced bone stiffness, but BMD and joint status in this cohort are unknown. OBJECTIVE: The goal is to study BMD, joint function, and osteoarthritis score in previously untreated IGHD adults harboring the c.57+1G>A GHRHR mutation. DESIGN: This is a cross-sectional study. METHODS: Areal BMD by dual-energy X-ray absorptiometry was measured in 25 IGHD and 23 controls (CO). Volumetric BMD (vBMD) was calculated at the lumbar spine and total hip. Joint function was assessed by goniometry of elbow, hips, and knees. X-rays were used to measure the anatomic axis of knee and the severity of osteoarthritis, using a classification for osteophytes (OP) and joint space narrowing (JSN). RESULTS: Genu valgum was more prevalent in IGHD than CO. The osteoarthritis knees OP score was similar in both groups, and knees JSN score showed a trend to be higher in IGHD. The hips OP score and JSN score were higher in IGHD. Areal BMD was lower in IGHD than CO, but vBMD was similar in the two groups. Range of motion was similar in elbow, knee, and hip in IGHD and CO. CONCLUSIONS: Untreated congenital IGHD due to a GHRHR mutation causes hip joint problems and genu valgum, without apparent clinical significance, reduces bone size, but does not reduce vBMD of the lumbar spine and hip.

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.

Cardiac functions in children with growth hormone deficiency before and during growth hormone-replacement therapy.

Childhood growth hormone deficiency (GHD) decreases left-ventricular (LV) mass, but impairment of cardiac function has never been documented. The objective of this study was to assess the cardiac effects of GHD and recombinant human growth hormone (rhGH) treatment using conventional echocardiography and tissue Doppler imaging. Complete two-dimensional, M-mode, pulse-wave Doppler echocardiography and pulse-wave tissue Doppler imaging were performed in 12 children (6 male and 6 female patients) with GHD at baseline and at 5.86 ± 1.61 months after rhGH therapy. Recombinant human growth hormone treatment was associated with a significant increase in LV mass index (63.8 ± 27.1 to 79.3 ± 30.3 g/m(2); P < 0.01) and LV internal dimensions (21.4 ± 2.63 to 24.0 ± 4.13 mm in systole [P = 0.03] and 36.5 ± 3.90 to 39.5 ± 4.94 mm in diastole [P < 0.01]). There were statistical differences of parameters, such as deceleration time of early peak velocity of mitral, isovolumic relaxation time, and myocardial performance index (103 ± 15.4 to 139 ± 21.2 ms [P < 0.01], 55.5 ± 9.24 to 69.2 ± 3.74 ms [P < 0.01], and 37.8 ± 4.46 to 44.9 ± 5.44% [P < 0.01], respectively). Before and during rhGH therapy, there were no significant differences in fractional shortening of the left ventricle, peak mitral, and tricuspid wave velocities with ratios determined using conventional echocardiography and tissue Doppler imaging. In children, GHD affects heart morphology by inducing a decrease in cardiac size, but it does not modify cardiac function. Recombinant human growth hormone treatment increases cardiac mass, deceleration time of early peak velocity of the mitral valve, isovolumic relaxation time, and myocardial performance index, but it does not make a difference in other parameters of conventional echocardiography and tissue Doppler imaging.

MRI findings and genotype analysis in patients with childhood onset growth hormone deficiency--correlation with severity of hypopituitarism.

AIM: To evaluate the relationship between pituitary size, PIT1 and PROP1 genotype, and the severity of childhood onset growth hormone deficiency (coGHD). PATIENTS: Forty-four patients with coGHD (34 M; 9.7 +/- 4.1 years): severe isolated (SI) GHD (n = 14); partial isolated (PI) GHD (n=13); multiple pituitary hormone deficiencies (MPHD) (n=17). RESULTS: Pituitary abnormalities were found in 7/14 patients with SIGHD (50%), 16/17 patients with MPHD (94.1%), and no patient with PIGHD. Mean pituitary height (PHT SDS) was significantly lower in MPHD than in SIGHD and PIGHD. Pituitary height SDS and pituitary volume (PV) SDS correlated with IGF-I SDS and stimulated GH peaks in the SIGHD and MPHD groups. No PIT1 mutation was identified. The PROP1 AG deletion (301-302) was present in five related patients with MPHD and more severe phenotype than the other patients with MPHD. CONCLUSIONS: Pituitary abnormalities corresponded to the severity of coGHD. Genetic alterations were identified in five related patients with MPHD.

[Ultrasonographic evaluation of atherosclerotic changes in carotid and brachial arteries in children with growth hormone deficiency before GH replacement therapy]. / Ocena zaawansowania procesu miazdzycowego za pomoca badania ultrasonograficznego tetnic szyjnych wspólnych i ramiennych u dzieci z niedoborem hormonu wzrostu przed wdrozeniem leczenia substytucyjnego.

BACKGROUND: According to very well documented onset of atherosclerosis in early childhood, scientists are looking for good diagnostic methods for evaluating first changes in arterial blood vessels non-invasively. We want to know more about pathogenetic mechanisms and about changes in vessels especially in the group of young people with risk factors of premature atherosclerosis. The role of endothelial dysfunction in the very early phase of this process is known very well so far. High resolution echocardiography seems to be a good method which allows to examine arteries in children and adolescents. Because of localization, brachial and carotid arteries are a very good field for this kind of examinations. OBJECTIVES: Evaluation with high resolution echocardiography, selected parameters of endothelial function in children with growth hormone deficiency before replacement therapy. We measured the intimal plus medial thickness in carotid communis arteries (IMT) also. MATERIAL AND METHODS: We examined a group of 24 children (19 boys and 5 girls) aged 8-16 yr (mean 12 yr) suffered from growth hormone (GH) deficiency. The control group consisted of 24 children in similar age and sex relation. Using high resolution echocardiography, B-mode images, we measured in end diastole, distance "m-m" in brachial arteries (distance between two "m" lines which are borders among media and adventitia of near and far wall of the artery) at rest, during reactive hyperaemia (with increased flow causing endothelium-dependent dilatation FMD), again at rest and after sublingual glyceryl trinitrate (causing endothelium-independent dilatation NTGMD). Using Doppler technique we evaluated baseline flow and calculated degree of reactive hyperemia. We also measured intimal plus medial thickness in every carotid artery three times and calculated mean value. In our analysis we estimated concentrations of cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides. RESULTS: In children with growth hormone deficiency the vessel size was smaller then in the control group and FMD was significantly impaired (10.05% v. 14.62%; p=0.058). NTGMD was similar to the control group (p=0.,371). We noticed higher IMT values in the whole examined group compared to the control group (0.52 mm v. 0.41 mm; p=0.0000). We noticed an important correlation between FMD and IMT in whole patients (examined plus control group) (p=0.004). The level of total cholesterol was higher in the examined group (p=0.039). CONCLUSIONS: 1. FMD evaluated in brachial artery, seems to be an useful sign of impaired endothelial function in children suffering from the risk factors of atherosclerosis. 2. The evaluation of IMT in carotid arteries in patients with growth hormone deficiency showed a more advanced degree of atherosclerotic changes in this group compared to healthy controls. 3. Ultrasonographic evaluation of premature atherosclerosis in children with growth hormone deficiency is a basis for the future estimation of positive effects of the replacement therapy.