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The Journal of Clinical Endocrinology... Jul 2023
Randomized Controlled Trial
Response to Letter to the Editor From Chatelain et al: "Weekly Somapacitan Is Effective and Well Tolerated in Children With GH Deficiency: The Randomized Phase 3 REAL4 Trial".
Topics: Humans; Child; Human Growth Hormone; Dwarfism, Pituitary
PubMed: 36869702
DOI: 10.1210/clinem/dgad095 -
Journal of Clinical Research in... Nov 2023IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a...
IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to pediatric endocrinology for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his insulin-like growth factor 1 level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during long-term follow-up.
Topics: Adolescent; Humans; Male; Dwarfism, Pituitary; Hypothyroidism; Immunoglobulins; Insulin-Like Growth Factor I; Membrane Proteins; Prolactin; Testosterone; Thyrotropin; Transition to Adult Care
PubMed: 35466665
DOI: 10.4274/jcrpe.galenos.2022.2021-12-3 -
The Journal of Clinical Endocrinology... Apr 2024The pretreatment blood transcriptome predicts growth response to daily growth hormone (GH) therapy with high accuracy. (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
The pretreatment blood transcriptome predicts growth response to daily growth hormone (GH) therapy with high accuracy.
OBJECTIVE
Investigate response prediction using pretreatment transcriptome in children with GH deficiency (GHD) treated with once-weekly somapacitan, a novel long-acting GH.
METHODS
REAL4 is a randomized, multinational, open-label, active-controlled parallel group phase 3 trial, comprising a 52-week main phase and an ongoing 3-year safety extension (NCT03811535). A total of 128/200 treatment-naïve prepubertal children with GHD consented to baseline blood transcriptome profiling. They were randomized 2:1 to subcutaneous somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day). Differential RNA-seq analysis and machine learning were used to predict therapy response.
RESULTS
121/128 samples passed quality control. Children treated with somapacitan (n = 76) or daily GH (n = 45) were categorized based on fastest and slowest growing quartiles at week 52. Prediction of height velocity (HV; cm/year) was excellent for both treatments (out of bag [OOB] area under curve [AUC]: 0.98-0.99; validation AUC: 0.83-0.84), as was prediction of secondary markers of growth response: HV standard deviation score (SDS) (0.99-1.0; 0.75-0.78), change from baseline height SDS (ΔHSDS) (0.98-1.0; 0.61-0.75), and change from baseline insulin-like growth factor-I SDS (ΔIGF-I SDS) (0.96-1.0; 0.85-0.88). Genes previously identified as predictive of GH therapy response were consistently better at predicting the fastest growers in both treatments in this study (OOB AUC: 0.93-0.97) than the slowest (0.67-0.85).
CONCLUSION
Pretreatment transcriptome predicts first-year growth response in somapacitan-treated children with GHD. A common set of genes can predict the treatment response to both once-weekly somapacitan and conventional daily GH. This approach could potentially be developed into a clinically applicable pretreatment test to improve clinical management.
Topics: Child; Humans; Body Height; Dwarfism, Pituitary; Growth Hormone; Histidine; Human Growth Hormone; Insulin-Like Growth Factor I; Mannitol; Phenol; Transcriptome
PubMed: 38066644
DOI: 10.1210/clinem/dgad717 -
Journal of Clinical Research in... May 2024Growth disorders resulting in extreme short stature (ESS) are often a result of deficiency in growth hormone (GH) released from the pituitary gland or a defective GH...
Growth disorders resulting in extreme short stature (ESS) are often a result of deficiency in growth hormone (GH) released from the pituitary gland or a defective GH releasing receptor. Genetic defects in the and genes account for around 11.1-20% of ESS cases, resulting in a rare condition called isolated GH deficiency (IGHD). We describe the characterization of a genetic defect discovered in a 3-year-old male patient with ESS, developmental failure and undetectable serum levels of GH. There was a family history of short stature, with both parents being short. Whole genome sequencing of the patient DNA revealed a large, novel 6 kb homozygous deletion spanning the entire gene in the patient. While the deletion was homozygous in the proband, it was present in the heterozygous state in the parents. Thus, we report a novel homozygous deletion including the gene leading to IGHD-type 1A associated with ESS.
Topics: Humans; Male; Child, Preschool; Human Growth Hormone; Homozygote; Dwarfism, Pituitary; India; Sequence Deletion; Growth Disorders
PubMed: 36728277
DOI: 10.4274/jcrpe.galenos.2022.2022-5-9