Complete Growth Hormone Deficiency Research Articles

Optimal final adult height achieved by low-dose recombinant human growth hormone therapy.

Thailand has been administering the recombinant human growth hormone (rhGH) treatment for >20 years. Due to limited resources being available, efforts have been directed toward utilizing rhGH at the lowest feasible dose. However, there is currently a lack of evidence in terms of the efficacy and outcomes. To evaluate the auxological outcomes of growth hormone (GH) treatment and the GH secretion ability after reaching final adult height (FAH) and discontinuing rhGH. Data of 40 patients were retrospectively reviewed. The clinical characteristics, auxological data, and results of biochemical and endocrine investigations before and during rhGH treatment were evaluated. In addition, GH retesting was performed in 24 patients using the insulin tolerance test. Twenty patients (50%) had complete growth hormone deficiency (GHD), defined as peak stimulated GH level <5 ng/mL, and the remaining patients had partial GHD. Most patients were male (n = 25, 62.5%). The mean age at which rhGH was initiated was 8.9 years. Patients with partial GHD received a higher dose of rhGH than those with complete GHD (30.9 µg/kg/d vs. 26.2 µg/kg/d, P = 0.02). Patients with complete and partial GHD reached FAH at height standard deviation scores (SDSs) of -0.65 and -1.47, respectively. The factors associated with obtaining a good clinical response in terms of height gain included peak-stimulated GH level, age of puberty, and age of discontinuing rhGH. After completing the rhGH treatment, 13 of the 24 patients showed normal GH secretion. Patients with multiple pituitary hormone deficiency (MPHD) were likely to have persistent GHD through adulthood (n = 8, 88.9%). This study has demonstrated that the use of low-dose rhGH could result in healthy populations achieving optimal FAHs. Patients with MPHD might not require retesting as they were likely to have persistent GHD. The results obtained in this research highlight the benefits of the treatment. This treatment can be applied in resource-limited countries.

Electrocardiographic Findings in Children With Growth Hormone Deficiency.

Introduction It has been shown that cardiac functions begin to deteriorate in growth hormone (GH) deficiency even in childhood. However, little is known about how GH deficiency affects arrhythmogenesis. The aim of this study was to evaluate the parameters of P wave dispersion (Pd), QT dispersion (QTd), corrected QT (QTc) dispersion (QTcd), T wave peak-to-end (Tp-e) interval, Tp-e/QT ratio, and Tp-e/QTc ratio in children with GH deficiency. This study alsoaimed to evaluate the relationship of these parameters with insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3). Method In the study, records of children diagnosed with GH deficiency in Adana City Training and Research Hospital Pediatric Endocrine Outpatient Clinic between September 2021 and December 2022 were retrospectively reviewed. The control group consisted of children in the same age group who applied to the Emergency Outpatient Clinic with a complaint of chest pain and no pathological finding was detected. The electrocardiograms (ECGs) of all patients were retrospectively evaluated. Results There were a total of 82 children in the study, 41 of whom were diagnosed with GH deficiency and 41 in the healthy control group. The age and male/female ratio of children with GH deficiency were similar to those in the control group (p>0.05). There were 27 (66%) children with complete GH deficiency and 14 (34%) children with partial GH deficiency. P wave dispersion was similar in both GH-deficient children and control group children. It was also similar in children with complete and partial GH deficiency (p>0.05). QT and QTc dispersions were found to be increased in children with GH deficiency, although not statistically significant, compared to the control group (p>0.05). Tp-e interval, Tp-e/QTmax (longest QT interval), and Tp-e/QTcmax (longest QTc interval) ratios were increased in children with GH deficiency compared to the control group (p=0.001, p=0.003, and p=0.001, respectively). QT and QTc dispersion, Tp-e interval, Tp-e/QTmax, and Tp-e/QTcmax ratios were found to be increased in children with complete GH deficiency compared to children with partial GH deficiency, but the difference was not significant (p>0.05). No correlation was found between these ECG parameters and IGF-1, IGFBP-3, and peak GH levels after stimulation tests (p>0.05). Conclusion We found in our study that the Tp-e interval was longer and Tp-e/QT and Tp-e/QTc ratios were increased in children with GH deficiency. These results suggest that the risk of ventricular arrhythmias in children with GH deficiency may start to increase from childhood. However, further prospective studies are needed to confirm our results.

Evaluation of cardiac structure, exercise capacity and electrocardiography parameters in children with partial and complete growth hormone deficiency and their changes with short term growth hormone replacement therapy.

To evaluate cardiac structure, exercise capacity and electrocardiography (ECG) parameters of children with complete and partial growth hormone (GH) deficiency (GHD) and the effect of 12 months GH treatment on these. M-mode echocardiography, ECG and exercise test expressed as metabolic equivalent (MET) were performed in children with GHD, aged 9-14 years, divided into those with a peak GH response < 7µg/L (complete GHD; n = 30) and 7-10µg/L (partial GHD; n = 17) after two GH stimulation tests, at baseline and 12 months after GH initiation. Forty-eight healthy peers underwent the same tests once. Left ventricular mass (LVM) was significantly lower before treatment in both groups with GHD compared to healthy peers (p = 0.015 and p = 0.032) but LVM in the GHD groups was similar to controls after 12 months of treatment. The increase in LVM in the complete GHD group was significant (p = 0.044). LVM index was significantly reduced with treatment in children with partial GHD (p = 0.035). Max METs, VO2max and exercise duration were significantly increased in children with complete GHD after treatment (p = 0.022, p = 0.015 and p = 0.002, respectively). Significant changes in P wave and QTc dispersion on ECG between groups were within physiological limits. This study showed that children with both partial and complete GHD had smaller cardiac structures and less exercise capacity compared to their healthy peers prior to GH treatment but this improved with 12 months of treatment. The cardiac trophic effect of GH, as well as the effect of increasing exercise capacity, is greater in those with complete GHD than in those with partial GHD.

Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer.

Since its discovery nearly a century ago, over 100,000 studies of growth hormone (GH) have investigated its structure, how it interacts with the GH receptor and its multiple actions. These include effects on growth, substrate metabolism, body composition, bone mineral density, the cardiovascular system and brain function, among many others. Recombinant human GH is approved for use to promote growth in children with GH deficiency (GHD), along with several additional clinical indications. Studies of humans and animals with altered levels of GH, from complete or partial GHD to GH excess, have revealed several covert or hidden actions of GH, such as effects on fibrosis, cardiovascular function and cancer. In this Review, we do not concentrate on the classic and controversial indications for GH therapy, nor do we cover all covert actions of GH. Instead, we stress the importance of the relationship between GH and fibrosis, and how fibrosis (or lack thereof) might be an emerging factor in both cardiovascular and cancer pathologies. We highlight clinical data from patients with acromegaly or GHD, alongside data from cellular and animal studies, to reveal novel phenotypes and molecular pathways responsible for these actions of GH in fibrosis, cardiovascular function and cancer.

Leydig Cell Hypoplasia and Pituitary Stalk Agenesis: Genetic Link or Coincidence

Leydig cell hypoplasia illustrates a rare category of 46, XY DSD "disorders of sex development". We report a case of a patient assigned to the female sex carrying a DSD with 46 XY karyotype on Leydig cell hypoplasia associated with pituitary stalk agenesis. This association has not been described yet in the literature. The patient was first admitted at the age of five for failure to thrive (FTT) with an abnormality of sexual development. The FTT was related to complete GH deficiency on pituitary stalk agenesis. Upon investigation, the patient was diagnosed as carrying a DSD 46, XY. The endocrine evaluation revealed low testosterone, FSH, and LH levels with a negative HCG test. The abdominopelvic ultrasound objectified two testicles in the inguinal folds. ²After discussing the case in a multidisciplinary consultation meeting, and taking into account the wishes of the family and the psychiatric expertise, the selected sex that was assigned to the patient was female. At the age of 19, the patient underwent a bilateral gonadectomy and the anatomopathological examination confirmed the diagnosis of Leydig cell hypoplasia. Leydig cell hypoplasia is a rare autosomal recessive syndrome, diagnosed by clinical, biological, radiological, histological, and genetic evidence. Its association with pituitary stalk agenesis has not been described in the literature. This syndrome is characterized by the inability of the chorionic gonadotropin luteinizing hormone receptor in Leydig cells to respond to luteinizing hormone, thereby causing feminization of a male fetus. The treatment has three components: hormonal treatment, surgical treatment, and psychological care.

Acute lymphoblastic leukemia in a child with Weiss-Kruszka syndrome: Casual or causal association?

Weiss-Kruszka syndrome is a recently described genetic disorder characterized by craniofacial features, ptosis, dysgenesis of the corpus callosum, and neurodevelopmental impairment. It is caused by heterozygous loss-of-function variantsin ZNF462 gene.During the time, the original phenotype was expanded, including several complications, sensorineural hearing loss, congenital hypogonadotropic hypogonadism with anosmia and complete growth hormone deficiency associated with empty sella syndrome.Here we report the first case of Weiss-Kruszka syndrome, associated to a de novo 9q31.1q31.3 microdeletion showing an acute lymphoblastic leukemia.A speculation on the contribution of our case to the phenotypic expansion of WSKA is here discussed. More clinical and functional studies are needed to elucidate this association. A possible expansion of the WSKA phenotype is discussed.

Response to growth hormone according to provocation test results in idiopathic short stature and idiopathic growth hormone deficiency.

Purpose To investigate growth response in children with either idiopathic short stature (ISS) or growth hormone (GH) deficiency (GHD).Methods The data of prepubertal GHD or ISS children treated using recombinant human GH were obtained from the LG Growth Study database. GHD children were further divided into partial and complete GHD groups. Growth response and factors predicting growth response after 1 and 2 years of GH treatment were investigated.Results This study included 692 children (98 with ISS, 443 partial GHD, and 151 complete GHD). After 1 year, changes in height standard deviation score (ΔHt-SDS) were 0.78, 0.83, and 0.96 in ISS, partial GHD, and complete GHD, respectively. Height velocity (HV) was 8.72, 9.04, and 9.52 cm/yr in ISS, partial GHD, and complete GHD, respectively. ΔHt-SDS and HV did not differ among the 3 groups. Higher initial body mass index standard deviation score (BMI-SDS) and midparental height standard deviation score (MPH-SDS) were predictors for better growth response after 1 year in ISS and the partial GHD group, respectively. In the complete GHD group, higher Ht-SDS and BMI-SDS predicted better growth response after 1 year. After 2 years of GH treatment, higher BMI-SDS and MPH-SDS predicted a better growth outcome in the partial GHD group, and higher MPH-SDS was a predictor of good growth response in complete GHD.Conclusions Clinical characteristics and growth response did not differ among groups. Predictors of growth response differed among the 3 groups, and even in the same group, a higher GH dose would be required when poor response is predicted.

Аналіз показників росту дівчаток із синдромом Шерешевського — Тернера залежно від каріотипу в українській популяції

Мета дослідження: визначення показників зросту та кісткового віку дівчаток із синдромом Шерешевського — Тернера (СШТ) в українській популяції залежно від віку та каріотипу, кінцевого зросту порівняно зі здоровими дівчатами, а також визначення стану соматотропної функції гіпофіза дівчаток із СШТ.Матеріали і методи. Проведено ретроспективний аналіз за період з 2005 по 2014 рік 502 реєстраційних карт дівчаток із СШТ, віком від 11 місяців до 17 років включно. Поглиблене обстеження проводилось дітям, які проходили амбулаторне чи стаціонарне лікування в НДСЛ «ОХМАТДИТ» та Українському науково-практичному центрі ендокринної хірургії, трансплантації ендокринних органів і тканин. Визначали фізичний розвиток дитини, кістковий вік, наявність соматотропної недостатності, рівень інсуліноподібного фактора росту 1 (ІФР-1). Для порівняння показників зросту дітей із СШТ та здорових дівчаток загальної популяції ми використовували результати обстеження фізичного розвитку 525 соматично здорових дівчаток із нормальнім жіночим каріотипом віком від 10 місяців до 17 років включно (контрольна група). Результати. Різниця показників зросту в дівчаток із СШТ та соматично здорових дівчаток з нормальним жіночим каріотипом була вірогідною (p &lt; 0,05) в усіх вікових групах старше одного року, збільшується з віком, максимальна в пубертатному віці. Ступень затримки зросту в дівчаток із СШТ у середньому становить –3,1 ± 1,1 SD з максимальним ступенем затримки в 14 років. Кістковий вік у дівчаток із СШТ затриманий в усіх вікових групах з максимальною різницею з паспортним віком у 17 років. Відсутня вірогідна різниця показників зросту, кісткового віку, рівня стимульованого СТГ та ІФР-1 у дівчаток із СШТ з різним каріотипом (p &gt; 0,05), що свідчить про те, що формула каріотипу не впливає на ці показники. Більшість дівчаток із СШТ мають нормальну соматотропну функцію, однак у 35,7 % наявний частковій або повний дефіцит соматотропного гормона.

Clinical and auxological characteristics of growth hormone deficiency in children of the southern region of Ukraine

Anotation. Regional clinical and auxological studies of growth hormone deficiency (GHD) in children contribute to a realistic assessment of the severity of the problem and prevent underdiagnostics of the disease. The aim of the study is to analyze the features of various forms of GHD in children of the Odessa region on the basis of the clinicians’ integrated assessment of history, physical examination, auxology, stature, growth velocity, bone age (BA), 2 growth hormone (GH) stimulation tests, insulin-like growth factor, magnetic resonance imaging in 92 children with GHD in the Odessa region. Parametric variables were assessed using criteria t-test and хі-square (χ2). The p value &lt;0,05 was considered statistically significant. Decrease in SDS height from - 2,1 tо - 6,6 was found. Isolated GHD (IGHD) was diagnosed in 65,2% of diseases, multiple pituitary hormone deficiency (MPHD) in 34,8% cases. IGHD was more often idiopathic and MPHD was more often arose on an organic basis. Chronological age (CA), BA and height of children with MPHD were lower at the start of therapy compared with IGHD. Complete GH deficiency was more common in children with MPHD (62,7%), while partial GH deficiency was more common in children with IGHD (81,7%). Very low values of the coefficient CA/BA (less than 0,55) were significantly more often detected in children with MPHD compared with IGHD. The regional clinical and auxological characteristics of GHD in children in the Odessa region can be considered in further study of population aspects and patterns of growth.

Gene polymorphisms in leptin and its receptor and the response to growth hormone treatment in patients with idiopathic growth hormone deficiency.

This study aimed to investigate the relationships between genetic polymorphisms of leptin/receptor genes and clinical/biochemical characteristics in children with growth hormone deficiency (GHD). Ninety-three GHD children and 69 age-matched normal controls were enrolled. Anthropometric measurements, bone age, and laboratory test results were obtained. Polymorphisms in the LEP gene promoter locus (LEP-2548, rs7799039) and LEPR genes (K109R, rs1137100 and Q223R, rs1137101) were analyzed using PCR-RFLP. The serum leptin levels were measured using an ELISA kit. The median height and BMI z-scores of all GHD subjects were -2.20 and -0.26, respectively, and those of normal controls were -0.30 and -0.13, respectively. The serum leptin levels were similar between GHD subjects and normal controls (p = 0.537), but those were different between the complete GHD (6.97 ng/mL) and partial GHD (4.22 ng/mL) groups (p = 0.047). There were no differences in the genotypic distributions of LEP-2548, LEPR K109R, and Q223R between GHD subjects and normal controls. However, GHD subjects with the G allele at LEP-2548 showed higher IGF-1 (p = 0.047) and IGFBP-3 SDSs (p = 0.027) than GHD subjects with the A allele. GHD subjects with the G allele at LEPR Q223R showed lower stimulated GH levels (p = 0.023) and greater height gain after 1 year of GH treatment (p = 0.034) than GHD subjects with the A allele. In conclusion, leptin/leptin receptor genes are suggested to have the role of growth-related factors, which can affect various growth responses in children who share the same disease entity.

Abnormal amplitude of spontaneous low-frequency fluctuation in children with growth hormone deficiency: A resting-state functional magnetic resonance imaging study

Growth hormone deficiency (GHD) is a developmental disorder caused by the partial or complete deficiency of growth hormone secreted by the pituitary gland, or its receptor. Patients with GHD are characterized by short stature, slow growth, and certain cognitive and behavioral abnormalities. Previous behavioral and neuroimaging studies indicate that GHD might affect the brain functional activity associated with cognitive and behavioral abilities. We thus investigated the spontaneous neural activity in children with GHD using amplitude of low-frequency fluctuation (ALFF) analysis. ALFF was calculated based on resting-state functional magnetic resonance imaging (rs-fMRI) data in 26 children with GHD and 15 age- and sex-matched healthy controls (HCs). Comparative analysis revealed that the ALFF of the right lingual gyrus and angular gyrus were significantly increased, while the ALFF of the right dorsolateral superior frontal gyrus, the left postcentral gyrus, superior parietal gyrus and middle temporal gyrus were significantly decreased in children with GHD relative to HCs. These findings support the presence of abnormal brain functional activity in children with GHD, which may account for the abnormal cognition and behavior, such as aggression, somatic complaints, attention deficits, and language withdrawal. This study provides imaging evidence for future studies on the pathophysiological mechanisms of abnormal behavior and cognition in children with GHD.

Complete growth hormone deficiency associated with solitary median maxillary central incisor syndrome (SMMCI)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-077 A Case of Growth Hormone Deficiency in Sturge-Weber Syndrome

Introduction: Sturge-Weber syndrome (SWS) is a congenital neurocutaneous disorder characterized by a port wine stain on the skin in the distribution of the ophthalmic branch of the trigeminal nerve (vascular malformation of skin), glaucoma, and leptomeningeal angiomas. Central nervous system abnormalities may increase the risk of hypothalamic-pituitary dysfunction. One previous study showed that SWS patients had higher prevalence of growth hormone deficiency than the general population although the etiology is unclear. This case report describes a patient who was initially diagnosed with SWS and later confirmed with complete growth hormone deficiency.Case: A 7-year-and-11-month-old boy who had been diagnosed with SWS visited a tertiary center for the evaluation of short stature [111.1cm (<3 percentile)]. He was born at 37 weeks of gestational age with birth weight of 3230g by cesarean section and had a port wine nevus on the right side of the face since birth. He had a history of epilepsy first occurring at 6 months of age when he was diagnosed with SWS. There were two more attacks of seizure till 32 months of age. Brain magnetic resonance imaging revealed leptomeningeal angioma, choroidal hemangioma, and diffuse brain atrophy. He was diagnosed with glaucoma and had been managed with surgery and medication. There was no family history of SWS or any other brain anomaly. His mid-parental height was 167.7cm. All blood tests were normal including complete blood count, chemistry, and thyroid function test. Hand x-ray showed delayed bone age. Cocktail test was performed for the evaluation of short stature. As a result, he was diagnosed with complete growth hormone deficiency (peak GH on L-dopa test: 2.46 ng/mL, peak GH on glucagon test: 3.71 ng/mL). The recombinant growth hormone therapy was started at the age of 8 years and 1 month. He showed good response to GH treatment. His height became 125.8cm at the age of 9 years and 5 months (height velocity 9.2 cm/year), and 134.3cm at the age of 10 years and 6 months.Conclusion: We experienced a case with Sturge-Weber syndrome and complete growth hormone deficiency which was successfully managed by recombinant growth hormone therapy. It may be better to consider the possibility of GH deficiency even if there are certain conditions that affect the growth itself.

Morphological changes of the central sulcus in children with complete growth hormone deficiency: a 3.0 T MRI study

Objective: To analyze morphological changes in central sulcus of the cerebral cortex in children with complete growth hormone deficiency (CGHD). Methods: Patients attending the Shandong Provincial Hospital who were diagnosed with CGHD or idiopathic short stature were recruited from January 2015 to January 2019. Thirty children with CGHD (18 males and 12 females, 5 to 14 years old) and 30 children with idiopathic short stature (22 males and 8 females, 5 to 14 years old) were included. Measurements of the central sulcus, including the average width, maximum depth, average depth, top length, bottom length and depth position-based profiles (DPP), were obtained using Brain VISA software. The significant differences between groups were statistically analyzed. Results: The average width of bilateral central sulci in children with CGHD (left: (2.26±0.41) mm; right: (2.19±0.34) mm) were significantly higher than those in children with idiopathic short stature (left: (2.10±0.27) mm; right: (2.02±0.18) mm) (P<0.05) ; The maximum depth of the left central sulcus ((19.67±1.29) mm) and the average depth of the right central sulcus ((14.18±1.41) mm) were significantly lower than those in children with idiopathic short stature (left maximum depth: (20.69±1.43) mm; right average depth: (14.92±1.21) mm) (P<0.05) . Children with CGHD had significantly lower DPP at the middle part of the left central sulcus (sites: 46-54) and the inferior part of the right central sulcus(sites: 91-98). Conclusion: There are significant morphological changes of the central sulcus in children with CGHD, which may represent the structural basis of their relatively slower development in motor, cognitive and linguistic functional performance.

Recombinant GH treatment in a case of Costello syndrome with a 5-year follow-up

.Costello syndrome (CS) is a rare member of the group of neuro-cardio-facio-cutaneous diseases known as RASopathies. CS involves characteristic dysmorphic craniofacial features, cardiac defects, and increased cancer susceptibility, depending on the heterozygous activating germline mutations in HRAS. Polyhydramnios and high birth weight are the most common presentations in the perinatal and neonatal periods; while poor postnatal growth, short stature, and failure to thrive are significant issues in infancy. Possible mechanisms of short stature in CS include GH deficiency and feeding difficulties. Only a few reported cases of CS with GH deficiency exist in literature. Here, we describe the 5-yr follow-up of a CS patient with complete GH deficiency treated with recombinant human GH (rhGH) from the age of four years. No significant adverse events regarding progression of hypertrophic cardiomyopathy and tumor development were observed. She has been responsive to treatment with improved growth velocity and height standard deviation scores. She is still under continuous monitoring for concerns on the possible development of cardiac events and malignancies. This case indicated that rhGH therapy is effective for improving the height and growth velocity of CS patients with GH deficiency under close cardiac and oncological monitoring.

Impact of BMI on peak growth hormone responses to provocative tests and therapeutic outcome in children with growth hormone deficiency

This study investigated the relationship between peak stimulated growth hormone (GH) and body mass index (BMI), as well as the impact of BMI on therapeutic response in patients with GH deficiency (GHD). A total of 460 patients were enrolled in the study. The patients were divided into four groups as per the etiology and peak GH values: idiopathic (n = 439), organic (n = 21), complete (n = 114), and partial (n = 325) GHD groups. Subsequently, they were classified as normal, overweight, or obese based on their BMI. There was no difference in BMI between complete and partial GHD. A significant negative relationship between peak GH and BMI were found. Moreover, obese GHD children had a considerably better therapeutic response in height increase and BMI decrease during 2 years of GH treatment compared to non-obese children with GHD. There was no difference between peak GH and type of GH stimulation test (GHST), except the clonidine test, which showed a much lower peak GH in obese GHD children. In conclusion, BMI had a negative impact on peak GH response, and therapeutic outcome was more favorable in the obese group. Despite no difference in GH response by type of GHST, the degree of obesity differentially affected the results.

Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.

MON-248 Impact of Body Mass Index on Peak Growth Hormone Response to Provocative Testing and Therapeutic Outcome in Children with Growth Hormone Deficiency

Introduction: The growth hormone (GH) stimulation test can be influenced by various factors, including type of GH stimuli, age, body mass index (BMI), and pubertal state. It is known that GH secretion is inversely related to BMI, but there is no available BMI - specific cut off value in children with growth hormone deficiency (GHD). The purpose of the study was to evaluate the therapeutic response according to obesity and relationship between GH secretion and BMI in children with GHD Methods: Among the GHD patients met the inclusion criteria, 460 patients conducted insulin stimulation test in common were enrolled for this study. Of these, the group were divided into idiopathic GHD (n=439), organic GHD (n=21), complete GHD (n=114), and partial GHD (n=325). We compared the variables including age, peak GH level, bone age, height standard deviation score (SDS), BMI SDS, and insulin-like growth factor-1 (IGF-1) SDS of each group. Results: Of the 439 patients with idiopathic GHD, 385 patients were normal (88%), 28 patients were overweight (6%), and 26 patients were obese (6%). The peak GH for the insulin stimulation test was 4.7 in obese group and 5.1 in non-obese group. The peak GH in organic GHD was 1.6 for obesity and 3.1 for non-obese group. According to the multiple regression analysis, the peak GH was significantly reduced by 1.06 as BMI SDS was increased by 1 in patients with complete GHD (p=0.03). The cutoff value of complete GHD in obese children was lower than that of non-obese group [response to insulin: obese group ≤ 4.7 (area under the curve AUC= 0.87, 95% CI 0.7-1.0), non-obese group ≤ 4.92 (AUC= 0.83, 95% CI 0.80-0.87); response to L-dopa: obese group ≤ 4.3 (AUC= 0.90, 95% CI 0.76-1.0), non-obese group ≤ 4.9 (AUC= 0.83, 95% CI 0.79-0.87)]. IGF-1 SDS and height SD at initiation of GH therapy of obese group were higher than those of non-obese group, but the height gain during GH therapy between two groups was similar. Regardless of obesity, therapeutic response of the first year of GH therapy was better than the second year of treatment. Conclusion: The BMI and GH peak of obese children with GHD shows inverse correlation, with a relatively low cutoff value. Further comparative research to better understand of the relationship between BMI and GH secretion with simple obese children is needed to expand clinical application.

Increased transactivation and impaired repression of β-catenin-mediated transcription associated with a novel SOX3 missense mutation in an X-linked hypopituitarism pedigree with modest growth failure.

SOX3, a transcription factor of the SRY-related high mobility group box family, has been implicated in the etiology of X-linked hypopituitarism. Here, we report a Chinese pedigree of X-linked hypopituitarism with variable phenotypes. Despite the complete growth hormone deficiency, the growth failure of the patients was relatively modest. A rare point variant of SOX3 (c.424C > A; p. P142T) was identified in the pedigree via target panel sequencing. An in vitro study showed that both the expression and nuclear targeting of SOX3 remained unaffected by the variant. However, increased transcriptional activation and impaired repression of β-catenin-mediated transcription were noticed as a result of the SOX3 variant. This is the first study to report that the rare SOX3 missense variant associated with hypopituitarism possibly due to increased activation of SOX3 target genes and disregulation of β-catenin target genes. In addition, we have expanded the phenotypic spectrum associated with SOX3 mutations.

Сlinical and genetic variants of Turner syndrome and the rationale for the choice of their treatment

Background. The main clinical manifestation of Turner syndrome (TS) is short stature, which is observed in 98-100% of patients. In cases of karyotype 45,X girls do not develop puberty, different degrees of developmental delay can also occur in cases of mosaicism. The phenotype of TS have different variants that makes it difficult to diagnose, especially in case of mosaicism. In the available literature there is no data on the individual approach to the therapy with recombinant growth hormone (rGH) in girls with TS. Objective . To determine the clinical and genetic variants of TS girls before puberty and of puberty age, and especially their physical and pubertal development, growth hormone function in order to determine the individual indications for hormonal treatment of growth and puberty disorders. Materials and methods . We performed analysis of registry, which includes 566 children with TS during 12 years. Also we carried out a detailed survey of 150 girls with TS, during which the phenotypic features, parameters of physical and sexual development, growth hormone status of function, efficiency of treatment with rGH in children of different ages were assessed. Results and discussion . We identified clinical and genetic variants of girls with TS before puberty and of puberty age. The largest proportion of patients with TS before puberty age have dwarfism in conjunction with phenotypic features of high importance and karyotype 45,X, the smallest share – growth retardation in combination with phenotypic features of low significance and karyotype 45,X/46,XX. The greatest proportion of patients with TS of puberty age have dwarfism and lack of signs of the spontaneous pubertal development and karyotype 45,X, and the lowest – delayed growth and spontaneous puberty. Partial or complete deficiency of growth hormone was detected in 35,65% of patients with TS of different ages belonging to the clinical and genetic variants with dwarfism. Conclusions . Clinical and genetic variants of TS can be used for early diagnosis, as well as the choice of individual approach to rGH therapy. In girls with TS of puberty age in the presence of dwarfism and without spontaneous pubertal development as well as with dwarfism and spontaneous puberty appointment rGH for the treatment of short stature is justified, even in the case of late initiation. In contrast, it is inappropriate to start rGH treatment in puberty age patients with TS in cases of normal function of the pituitary growth hormone with dwarfism and with spontaneous pubertal development as well as those with growth retardation in presence or without of spontaneous pubertу because delayed initiation of rGH does not lead to effective increase in growth.