Isolated Growth Hormone Research Articles

Two cases of immunoglobulin G4 (IgG4)-related hypophysitis diagnosed without pituitary biopsy.

Background:Immunoglobulin G4-related hypophysitis (IgG4-RH) is a rare disease, diagnosis of which typically depends on histopathology following an invasive pituitary biopsy, possibly leading to permanent hypopituitarism. Herein, we report two cases of IgG4-RH with favorable responses to glucocorticoids. One of them was multiple organs involved and treated with glucocorticoids and methotrexate.Methods:We retrospectively review clinical features, radiological images, and treatment of two cases with IgG4-RH. In addition, literature on IgG4-RH was comprehensively reviewed and a new therapeutic strategy for IgG4-RH was provided.Results:A 45-year-old man presented with diabetes insipidus for 6 months. Pituitary magnetic resonance imaging (MRI) indicated thickening of pituitary stalk. His serum IgG4 was 13,500 mg/l and hormonal evaluation revealed isolated growth hormone deficiency. Pituitary biopsy was denied by the patient due to fears of permanent pituitary damage. Treatment with prednisone and methotrexate (MTX) for 1 week led to improvement in sellar images and reduction in IgG4 level. His IGF1 (insulin-like growth factor-1) recovered after a 4-month treatment. The second case is a 43-year-old woman presenting with diabetes insipidus and amenorrhea for 20 months. Her pituitary MRI was similar to the patient above. Her serum IgG4 level was 5980 mg/l and hormonal measurement confirmed isolated hypogonadotropic hypogonadism. After 2 weeks of prednisone, the sellar images improved. After 3 months of treatment, her pituitary MRI was normal, IgG4 level had decreased to near normal range, and menstruation resumed. Literature review found additional patients with IgG4-RH, who were treated successfully without invasive pituitary biopsy in a manner similar to our cases. Therefore, we discuss the necessity of invasive pituitary biopsy for IgG4-RH.Conclusion:For suspected IgG4-RH with pituitary hormone deficiency, biopsy-induced hypopituitarism may be avoided by using diagnostic glucocorticoid treatment. Impaired pituitary hormone secretion may be recovered in response to steroid therapy. Improved pituitary MRI after 1–2 weeks of glucocorticoid treatment may provide diagnostic evidence of IgG4-RH.

P.R209H GH1 variant challenges short stature assessment

Objective: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. Design: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. Results: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. Conclusions: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

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

IntroductionProtocol 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. MethodsA 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. Results96 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. ConclusionsPatients with abnormal MRI findings show a more favorable response to GH replacement therapy.

Macrophages From Subjects With Isolated GH/IGF-I Deficiency Due to a GHRH Receptor Gene Mutation Are Less Prone to Infection by Leishmania amazonensis.

Isolated growth hormone (GH) deficiency (IGHD) affects approximately 1 in 4,000 to 1 in 10,000 individuals worldwide. We have previously described a large cohort of subjects with IGHD due to a homozygous mutation in the GH releasing hormone (GHRH) receptor gene. These subjects exhibit throughout the life very low levels of GH and its principal mediator, the Insulin Growth Factor-I (IGF-I). The facilitating role of IGF-I in the infection of mouse macrophages by different Leishmania strains is well-known. Nevertheless, the role of IGF-I in Leishmania infection of human macrophages has not been studied. This study aimed to evaluate the behavior of Leishmania infection in vitro in macrophages from untreated IGHD subjects. To this end, blood samples were collected from 14 IGHD individuals and 14 age and sex-matched healthy controls. Monocytes were isolated and derived into macrophages and infected with a strain of Leishmania amazonensis. In addition, IGF-I was added to culture medium to evaluate its effect on the infection. Cytokines were measured in the culture supernatants. We found that macrophages from IGHD subjects were less prone to Leishmania infection compared to GH sufficient controls. Both inflammatory and anti-inflammatory cytokines increase only in the supernatants of the control macrophages. Addition of IGF-I to the culture medium increased infection rates. In conclusion, we demonstrated that IGF-I is crucial for Leishmania infection of human macrophages.

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

A Case of Syringomyelia Presenting With Isolated Growth Hormone Deficiency

A Case of Syringomyelia Presenting With Isolated Growth Hormone Deficiency

A Case of Syringomyelia Presenting With Isolated Growth Hormone Deficiency

Introduction: An association between isolated growth hormone deficiency (GHD) and syringomelia as pathologic entities has previously been described in pediatric and adult populations. In these cases, patients often have progressive motor or sensory disturbances and are noted to have a Chiari I Malformation (CIM). We report a case of an otherwise asymptomatic male presenting with short stature due to isolated GHD with an associated large holocord syrinx and obstructed cerebral spinal fluid (CSF) without a classic CIM. Case Report: An otherwise healthy 4.5 year old male presenting for upper respiratory …

Isolated growth hormone deficiency – a rare, but treatable cause of low stature

Growth hormone deficiency is a rare cause of low stature. Early recognition of the disease results in effective treatment, leading to a final height as closely as possible to the genetic target. The authors present the case of a 1 year 2 months old girl admitted for growth evaluation in our department. She had been previously diagnosed with isolated growth hormone deficiency in an Endocrinology Unit and was now sent to complete the investigations and undergo imaging studies. The laboratory investigations excluded other pathologies. The MRI showed adenohypophysis hypoplasia, thin hypophyseal stalk. Se is started on growth hormone substitution treatment with good results.

Systematic profiling of clinical missence mutation effects on the intermolecular interaction between human growth hormone and its receptor in isolated growth hormone deficiency

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and can result from congenital or acquired causes. Among the known factors, genetic mutations in human growth hormone (hGH) remain the most frequent cause of IGHD, which influence the binding of hGH to its cognate receptor (hGHbp). Although previous studies have systematically investigated the residue importance at hGH–hGHbp complex interface, the molecular role of IGHD-associated residue mutations in the complex function still remains largely unexplored. Here, a total of 21 known hGH naturally-occurring missence mutations that have been clinically observed to be involved in IGHD disorder are collected and confirmed by original literature; they effects on the conformation, energetics and dynamics of hGH–hGHbp recognition and interaction are dissected at molecular level by using atomistic dynamics simulations, binding energy calculations and fluorescence spectroscopy assays. A systematic profile of hGH–hGHbp binding response to these clinical missence mutations is created, based on which it is revealed that (i) most mutations have appreciably unfavorable effect on the binding, which potentially destabilize the complex interaction, while only very few are predicted as moderate stabilizers for the complex system, and (ii) these disease-related mutations can locate either at complex interface or in hGH protein interior far away from the interface; both can influence the complex binding through either direct interaction or indirect allostericity. Two mutations, E100K (non-interface) and G146R (interface), are identified to address potent destabilization effect on hGH–hGHbp complex system; they can reduce the complex binding affinity by 8-fold (Kd changes from 0.76 to 5.9 nM) and 46-fold (Kd changes from 0.76 to 34.7 nM), respectively.

Auxological characteristics of pediatric patients with permanent or transient isolated growth hormone deficiency. Response to treatment and final height

IntroductionTreatment with recombinant human growth hormone (rhGH) has been shown to improve adult height in pediatric patients with GH deficiency (GHD). However, reassessment of patients after they reach their final height shows some of them have permanent GH deficiency (PGHD), while others had a transient deficiency (TGHD). The study objective was to assess, in a cohort of pediatric patients with GHD, potential differences in response to treatment with rhGH depending on whether deficiency is permanent or transient. Materials and methodsA retrospective study of 89 patients with GHD, who were monitored from diagnosis to adult height. Clinical, auxological, radiographic and laboratory variables were collected at diagnosis, after the first year of treatment, and when they had reached their adult height. ResultsPGHD was found in 28% of patients. Initial height was −2.46±0.86 SD and −2.24±0.68 SD in subjects with PGHD and TGHD respectively. Peak GH level at diagnosis was 4.26±2.78 and 6.20±2.01ng/ml (p<0.01) in the PGHD and TGHD groups respectively. After the first year of treatment, increase in growth velocity was greater in the PGHD group: 4.33±3.53 SD vs. 2.95±2.54 SD in the PGHD group (p=0.043). Final height was −0.81±0.87 SD in the PGHD and −0.95±0.83 SD in the TGHD group (p=0.47). ConclusionsPatients with PGHD had a better short- and long-term response to rhGH. They also showed lower GH levels in stimulation tests at diagnosis, as previously reported.

Formant Frequencies, Cephalometric Measures, and Pharyngeal Airway Width in Adults With Congenital, Isolated, and Untreated Growth Hormone Deficiency

Adult subjects with isolated growth hormone deficiency (IGHD) due to a mutation in the growth hormone releasing hormone receptor gene exhibit higher values formant frequencies. In normal subjects, a significant negative association between the formant frequencies and the reduction of linear craniofacial measurements, especially of maxilla and mandible, has been reported. This suggests smaller pharyngeal width, despite low prevalence of obstructive sleep apnea syndrome. Here we evaluate their pharyngeal airway width, its correlation with vowel formant frequencies, and the correlation between them and the craniofacial measures. A two-step protocol was performed. In the first case-control experiment, aimed to assess the pharyngeal width, we compared nine adult IGHD and 36 normal statured controls. Both upper and lower pharyngeal widths were measured. The second step (assessment of pharyngeal width) was performed only in the IGHD group. Upper and lower pharyngeal widths were similar in IGHD and controls. In IGHD subjects, the lower pharyngeal width exhibited a negative correlation with F1 [a] and a positive correlation with mandibular length. There were negative correlations between F1 and F2 with linear and positive correlations with the angular measures. Pharyngeal airway width is not reduced in adults with congenital, untreated lifetime IGHD, contributing to the low prevalence of obstructive sleep apnea syndrome. The formant frequencies relate more with cephalometric measurements than with the pharyngeal airway width. These findings exemplify the consequences of lifetime IGHD on osseous and nonosseous growth.

Differences of efficiency of treatment of isolated growth hormone deficiency and panhypopituitarism in children in real clinical practice

Differences of efficiency of treatment of isolated growth hormone deficiency and panhypopituitarism in children in real clinical practice

SUN-258 Prediction of Height Two Years after Start Treatment in Children with Growth Hormone Deficiency

Background: Various prediction models for the growth response to recombinant human growth hormone (rhGH) have been published, but none of these have been able to incorporate data on adherence to rhGH treatment. Previous studies have shown that suboptimal adherence negatively affects the growth response in the first two years of rhGH treatment. The availability of the easypod electronic drug-delivery device which continuously assesses adherence, enables to develop a prediction model taking adherence into account. Aim: To develop a model for prediction of height standard deviation score (HSDS) two years after start treatment, using information available at the start of GH treatment and adherence in the first two years. Patients and Methods: We included prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod device. Inclusion criteria were GHD, naïve to rhGH treatment, age <10y in girls and <12y in boys, height and adherence available in the first and second year, target height, birth weight, gestational age, and information on GH dose. Linear regression analyses were performed to construct a prediction model for HSDS 2y after start treatment, with age at start, HSDS at start, target height (TH) SDS, birth weight SDS, GH dose, gestational age (<37 weeks vs ≥37 weeks), sex, and adherence in the first and second year as potential predictors. Stepwise backward regression analyses were performed to simplify the model without a statistically significant loss of fit with a model fit criterion of p<0.1 for each predictor. Results: In total, 132 patients complied with the inclusion criteria. Mean (SD) HSDS was -2.4 (0.9) and age at start 6.5 (2.0) yrs. The prediction model was: HSDS at 2y after start treatment = 0.4699 - 0.0627 x Age at start + 0.7904 x HSDS at start + 0.1216 x TH SDS + 0.0418 x birth weight SDS + 0.1659 x sex (male) + 0.0050 x adherence in the second year. P-values were <.001 for HSDS at start and adherence in the second year, .002 for Age at start, and .07 for TH SDS, birth weight SDS and sex. This model explained 76% of the total variance. For example, if a girl starts with GH treatment at 6.5y with a HSDS of -2.4, TH SDS of 0, birth weight SDS of 0 and 100% adherence in the second year, her predicted HSDS 2y after start treatment is -1.3 SD. If she misses 2 injections/week in the second year, the predicted HSDS 2y after start treatment is -1.5 SD. Conclusion: We have developed a prediction model for height two years after start treatment for children with GHD. This model can be used to study the impact of information available at the start of GH treatment and adherence in the second year. More research is needed to explore the effect of individual patterns of adherence on growth in real word settings.

SUN-245 Heterozygous GH1 p.R209H Variant within a Large Pedigree May Mimic a Growth Hormone Insensitivity Pattern

Isolated growth hormone deficiency (IGHD) is most frequently caused by mutations in the GH1 gene. Pathogenic mutations in the GHRHR and GHSR have also been reported to cause IGHD. Individuals with IGHD type II present with variable clinical phenotype. Autosomal dominant GH1 p.R209H variant impairs GH secretion despite normal GH synthesis. The aim of this work is to expand the clinical and biochemical phenotype of heterozygous GH1 p.R209H missense mutation (previously known as p.R183H) in a large Argentinean pedigree. We report a non-consanguineous 4 generation pedigree. Two affected members showed classical IGHD phenotype: short stature (height -4.13 and -2.6 SD), low GH peak after arginine/clonidine provocative tests (3.6 and 2.6 ng/ml, cut-off value 4.7 ng/ml, GH IS 98/574, Immulite), non-detectable IGF-1, and low IGFBP-3 (-2.83 and -2.28 SD). Brain MRI showed anterior pituitary gland of 3.3 mm and 2.5 mm, respectively. The use of a customized panel for congenital hypopituitarism using single molecule molecular inversion probes sequencing (smMIPS) revealed a c.626G>A transition in GH1 gene, predicted to result in p.R209H mutation. The variant was subsequently confirmed by Sanger sequencing. Parents affected with the same variant presented either short (-1.91 SDS) or normal stature (-0.72 SDS). The patients’ response to rhGH treatment was adequate (Δ heights were 2.49 and 1.37 SDS in 2.4 and 1.0 year of treatment, respectively). Additionally, 4/9 siblings within this pedigree had short stature (mean height -2.48 ± 0.62 SD) with mild or no clinical phenotype of GHD, normal GH response to provocative pharmacologic tests (maximum GH peaks 5.46 to 10.9 ng/ml), associated to low serum IGF-1 (mean -3.27 ± 0.89 SD) and IGFBP3 (mean -2.61 ± 0.42 SD), resembling a pattern of growth hormone insensitivity (GHI). IGF-1 generation tests (GH dose 33 µg/kg.day) showed a mean increment in IGF-1 of 3.25 times over basal, confirming adequate GH sensitivity. Despite the absence of complete GHD phenotype, data from the extended pedigree suggested GH1 as the initial candidate gene, identifying the same pathogenic GH1 variant in these four siblings. Brain MRI showed normal height of the anterior pituitary gland (range 3.9 to 4.6 mm). Their affected father had normal stature (-1.69 SDS) with low serum IGF-1 (64 ng/mL). We have shown that members of a large pedigree affected with the p.R209H GH1 variant showed either a classical clinical and biochemical pattern of GHD or an initial biochemical pattern resembling GHI. This variability could lead in certain cases to an elusive diagnosis of GHD when the classical phenotype is absent. Therefore, these results highlight the need to explore GH1 gene in children with short stature associated to low IGF-1 and IGFBP-3 serum levels even when GH response to pharmacological tests is normal.

OR06-6 Whole-Exome Sequencing of Patients with Pituitary Stalk Interruption Syndrome (PSIS) Reveals Probably Pathogenic Variants in Novel Candidate Genes.

Background: Pituitary Stalk Interruption Syndrome (PSIS) is characterized by the presence of a thin or absent pituitary stalk, usually associated with an ectopic posterior pituitary, hypoplasia of the anterior pituitary and pituitary hormone deficiencies. The identification of pathogenic variants in novel genes has clinical implications for the management of the patients and genetic counseling. Objective: to identify pathogenic variants in patients with PSIS using whole-exome sequencing (WES) (trio approach). Method: We performed whole exome sequencing in eleven patients (trio approach) with PSIS using Agilent Sure Select and Illumina NextSeq technology. The patients had been screened for genes previously associated to hypopituitarism by Sanger or Target gene panel. We searched for pathogenic variants considering de novo, homozygous, compound heterozygous and X- linked inheritance. Results: We identified 116 rare allelic variants (excluding synonymous) located in exons or splice sites: 47 de novo, 20 homozygous, 48 compound heterozygous and 1 X-linked. All variants were expressed in pituitary and/or hypothalamus. Of these, 11 variants were highlighted because the genes had correlation to malformations of central nervous system, midline defects or hormonal deficiencies: LCMT1, PCDHB14, ATXN1, ATXN7, KRT18, SYNE1, WDR27, CC2D2A, HAUS5, IFT140 and ELF4. Among them, five were de novo: two were found in genes associated to cleft palate (LCMT1 and KRT18), two in genes previously associated to neurological phenotype (ATXN7 and ATXN1), one in a gene related to organization of neural cadherin-like cell adhesion (PCDHB14).ELF4 was X-linked and was previously associated with isolated growth hormone deficiency. Conclusion: The WES identified 11 potentially pathogenic variants in new candidate genes for PSIS.

MON-472 Potentially Pathogenic Variants Identified in Patients with Hypopituitarism by Molecular Inversion Probe Sequencing (MIPS), a New Molecular Approach for Low Cost Gene Panel Sequencing

Congenital hypopituitarism occurs in 1/3,000 - 1/10,000 live births and is highly variable phenotypically. The condition is life-long and life-threatening if untreated. Diagnosis remains a challenge, particularly in the neonatal period. There is a need for better diagnosis that would lead to improved prognosis and treatment. We recently implemented a novel and cost-effective approach based on Molecular Inversion Probe Sequencing (MIPS) to identify novel variants and candidate genes in sporadic trios and familial cases of combined pituitary deficiency (CPHD) in the absence or presence of any midline defects or optic nerve hypoplasia, and isolated growth hormone deficiency (IGHD). We captured 693 coding exons of 30 known genes and 37 candidate genes from studies in mice. We captured genomic DNA from 181 pediatric patients with CPHD or IGHD and 115 relatives and conducted next generation sequencing. We obtained a 600X average coverage per sample over targeted regions. We scored rare variants as pathogenic, likely pathogenic, or variants with uncertain significance that are predicted to be damaging using at least 3 independent software programs. We identified such variants in known genes (GH1, GLI2, LHX3, LHX4, PNPLA6, and HESX1) and in new candidate genes that require additional evidence demonstrating causality (BMP2, ACVRL1 and WDR11). GLI2 heterozygous loss of function mutations have been reported in over 50 patients with CPHD and variable associated features. We identified a GLI2 p.Leu761Phe variant in a patient with a complex phenotype, including GH and antidiuretic hormone (ADH) deficiencies, hypoplasia of the anterior lobe, arachnoid cyst, right cerebellar hemisphere hypoplasia, myopia and astigmatism, neonatal insipidus diabetes, speech neurodevelopmental delay and mild left foot paresis. We performed functional assays in cell culture and preliminary results suggested that GLI2 p.Leu761Phe has a gain of function effect on transcription. We hypothesize that this mutation affects the acetylation of the nearby p.Lys757 by modifying the recognition site of p300 acetylase. Acetylation of GLI2 at this lysine is a critical regulated step, controlling the activation status of the Hedgehog pathway, which is a major regulator of embryonic development. Further work is needed to demonstrate this effect. In summary, using the first comprehensive screening panel for known genes and candidates for congenital hypopituitarism, we identified variants that are likely disease-causing in about 30% of the cases. Identifying pathogenic variants will make it feasible to predict clinical outcomes from genetic data, which is necessary for patient diagnosis and prognosis, and for assessing the risk of future affected individuals.

MON-443 Periostin Concentrations in Childhood-Onset Craniopharyngioma Patients

Objective: The extracellular matrix protein periostin is highly expressed in adamantinomatous craniopharyngioma-associated fibroblasts. Periostin has been further identified as a novel marker for Non-Alcoholic Fatty Liver Disease (NAFLD). Half of childhood-onset craniopharyngioma patients (CP) with hypothalamic syndrome develop NAFLD. We hypothesized that periostin concentration is elevated in biological fluids of CP and associated with pathological hepatic parameters, indicating increased risk for NAFLD. Design: Cross-sectional study on patients with sellar masses (SMP) recruited in the German Craniopharyngioma Registry. Patients: 35 SMP (32 CP, 2 xanthogranuloma, one pilocytic astrocytoma), 3 short-statured patients with isolated growth hormone deficiency (GHD), 5 short-statured patients with normal findings in GH stimulating tests and decreased insulin-like growth factor (IGF)-1 (IGF-1D) and 7 healthy controls. Measurements: Periostin concentrations were measured by Elisa in serum (32 CP, 2 xanthograuloma, 3 GHD, 5 IGF-1D and 7 healthy controls), urine (27 CP, 3 GHD, 5 IGF-1D, 7 healthy controls) and saliva (18 CP, 3 GHD, 3 IGF-1D, 7 healthy controls). Results: Periostin serum, urine and saliva concentrations in CP were similar to concentrations of the other groups. Hypothalamic involvement/hypothalamic lesions, degree of obesity (BMI SDS) as well as hepatic enzymes were not associated with elevated periostin concentrations. Due to low patient numbers with pathological hepatic parameters, missing imaging data on the degree of steatosis hepatis and the lack of histological proof of NAFLD no definitive conclusions can be drawn from measured periostin concentrations in serum. Interestingly, the subgroup of patients with decreased IGF-1 levels showed elevated concentrations of serum periostin when compared with other groups. Conclusions: Periostin concentrations in biological fluids of CP are not associated with known risk factors for NAFLD such as hepatic and metabolic parameters, obesity and hypothalamic lesions. Accordingly, periostin does not seem to be a suitable marker for NAFLD in childhood-onset CP. The association between decreased IGF-1 and increased periostin concentrations should be part of further investigation.

Efficacy and safety of replacement treatment in isolated growth hormone deficiency

IntroductionGrowth in patients with isolated growth hormone (GH) deficiency is heterogeneous despite treatment due to the low specificity of diagnostic tests, making it necessary to define efficacy variables. AimsTo evaluate efficacy of hormone replacement therapy in children with isolated GH deficiency. MethodsObservational-ambispective study of patients treated in our department in the last 14 years for isolated GH deficiency. This was defined as a GH level less than 7.4mg/dL in response to 2 stimulation tests in patients with height<2SD and a decreased growth rate. ResultsThe study included a total of 97 patients, of whom 69% were boys. The large majority (89.58%) achieved final height. None of them had side effects. The median dose of GH used was 0.028mg/kg/day (0.03–0.025). There was a gain of 1.17 SD in final height. Around three-quarters (71.13%) of the patients were reassessed in adulthood, of whom 39.4% maintained the deficiency, and 79.31% achieved target range height. Target height, estimated height, and the total pubertal gain were positively correlated with final height, while the bone age/chronological age ratio and the initial insulin-like growth factor-1 showed a negative correlation. ConclusionsA majority of patients reached target size, although only a few of them maintained the deficiency in adulthood. Target size, estimated adult height, and pubertal variables are directly related to adult height, while bone age/chronological age and insulin-like growth factor-1 were inversely related, and these can be used as efficacy variables. No adverse effects were observed in the sample with the doses used for the treatment.

Limited Utility of Biochemical Screening for Pituitary Deficiencies and Adverse Effects in Idiopathic GH Deficiency.

ContextIn children with isolated growth hormone (GH) deficiency (GHD), routine biochemical screening for multiple pituitary hormone deficiencies (MPHD) and adverse effects related to growth hormone (GH) treatment are frequently performed. More evidence is needed to support this practice.ObjectivesTo evaluate the rate of development of MPHD among children initially diagnosed with isolated GHD and to assess the utility of screening tests to identify complications of GH therapy.DesignRetrospective analysis of subjects treated with GH since 2005. For the first objective, only subjects diagnosed with GHD were included. Subjects were excluded if GHD was associated with an acquired disorder or condition known to be associated with pituitary abnormalities. For the second objective, other GH-treated diagnoses were included.PatientsA total of 328 subjects (171 with GHD, 154 with idiopathic short stature, and three with SHOX deficiency).ResultsIn subjects with isolated GHD, MPHD was diagnosed in seven (4.2%) after a mean of 35.4 months (range, 9.4 to 68.0). Sex, age at diagnosis, duration of GH, and peak stimulated GH levels were not associated with developing MPHD. Among subjects with an MRI abnormality, 13.9% developed MPHD (OR, 6.3; 95% CI, 1.2 to 33.7). In the entire cohort, three subjects (0.9%) developed dysglycemia, and no subject had persistently abnormal liver or renal function tests.ConclusionsThere is a limited role for routine biochemical screening for MPHD in children with idiopathic isolated GHD or for adverse effects in otherwise healthy children. Routine biochemical screening for MPHD should be limited to those with an abnormal MRI.

Prevalence of diabetes among children treated with growth hormone in Israel.

To determine the long-term risk of diabetes in a cohort of children treated with recombinant human growth hormone in Israel, using data from the Israeli National Diabetes Register. Between 1988 and 2009, 2513 children were approved for growth hormone treatment. They were assigned to one of two groups. The first group included children treated for isolated growth hormone deficiency and who were small for gestational age and the second included those treated for multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome or Prader-Willi syndrome. The cohort was cross-linked with the Israeli National Diabetes Register for 2014 (mean follow-up duration 12.1±5.3 years), and prevalent cases of diabetes were identified. Standardized prevalence ratios for diabetes were calculated for people aged 10-29 years. In 2014, a total of 23 individuals were identified with diabetes (four with pre-existing diabetes, seven developed diabetes before age 17 years and 12 developed it at a later age). In the isolated growth hormone deficiency and small-for-gestational-age group there was no difference in the prevalence of diabetes compared with the general population (standardized prevalence ratio 2.05, 95% CI 0.94-3.89). In the group that included people with multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome and Prader-Willi syndrome there was a significantly higher diabetes prevalence (standardized prevalence ratio 11.94, 95% CI 6.53-20.00) compared with the general population. No difference in diabetes prevalence was found in the isolated growth hormone deficiency and small-for-gestational-age group, compared with the general population. Children treated with growth hormone with pre-existing risk factors had an increased prevalence of diabetes. It is advisable to monitor blood glucose levels closely during and after growth hormone treatment, especially in such children.