Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

Context Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). Objective The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. Design REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). Setting This study took place at 29 sites in 11 countries. Patients Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. Interventions Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. Main Outcome Measures The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. Results At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week—daily GH): 1.7 [95% CI –0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was −1.62 (0.86), −1.09 (0.78), and 0.31 (1.06), respectively, vs −0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. Conclusions In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

rhIGF-1 at standard dosages resulted in similar PK characteristics in patients with PAPP-A2 deficiency, heterozygous relatives, and healthy controls. The youngest affected patient experienced a modest growth response to therapy with rhIGF-1, as well as beneficial effects on glucose metabolism and bone mass.

Context Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions. Objective The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency. Design and Setting Open-label, single-arm, prospective study at Cincinnati Children’s Hospital Medical Center. Patients Ten treatment-naïve patients were recruited. Inclusion criteria were: a confirmed heterozygous mutation in ACAN, age ≥ 2 years, pre-pubertal, bone age (BA) ≥ chronological age (CA), and normal IGF-I concentration. Intervention Treatment with rhGH (50 mcg/kg/day) over one year. Main Outcome Measure(s) Main outcomes measured were height velocity (HV) and change in (Δ) height SD (HtSDS). Results Ten patients (six females) were enrolled with median CA of 5.6 yrs (range 2.4 to 9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 yrs (range 2.5 to 10.0), with median BA/CA of 1.2 (range 0.9 to 1.5). Median pre-treatment HV was 5.2 cm/y (range 3.8 to 7.1), increased to 8.3 cm/y (range 7.3 to 11.2) after one year of therapy (p=0.004). Median ΔHtSDS after one year was +0.62 (range +0.35 to +1.39) (p=0.002). Skeletal maturation did not advance inappropriately (median Δ BA/CA -0.1, p=0.09). No adverse events related to rhGH were observed. Conclusion Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.

Patients with rare homozygous mutations in signal transducer and activator of transcription 5B (STAT5B) develop immunodeficiency resulting in chronic eczema, chronic infections, autoimmunity, and chronic lung disease. STAT5B deficient patients are typically diagnosed in the teenage years, limiting our understanding of the development of associated phenotypic immune abnormalities. We report the first detailed chronological account of post-natal immune dysfunction associated with STAT5B deficiency in humans. Annual immunophenotyping of three siblings Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record (EHR) algorithm in identifying patients at high risk for TS. Six percent of those identified had missed diagnoses of TS.Turner syndrome results from a complete or partial loss of the X chromosome and affects 25-50 per 100,000 females (1). TS is relatively common in females with unexplained short stature, but the heterogenous phenotype may result in a delayed diagnosis if classic features (e.g. lymphedema and webbed neck) are not present at birth. Only 20-40% of affected individuals are diagnosed in the newborn period with the remaining cases caught during late childhood with abnormal growth or in adolescence with lack of pubertal development (2-4). Savendhahl et al evaluated the age of diagnosis in 81 girls with TS, of which about half were diagnosed in infancy. If not diagnosed in infancy, the mean age of diagnosis was 8.8 ± 5 years (delay in diagnosis averaged 7.7 ± 5.4 years) at a mean height of −2.9 standard deviations (SD) (5). Studies have shown that combined auxological measures (an absolute height SD < −2 and a distance to target height of > 2 SD) provide the best predictive value for pathological short stature, and in patients >3 years old the distance to target height is the most important criterion (4, 6, 7). Careful growth monitoring with attention to such measures is paramount to a timely diagnosis of TS, especially in cases of mosaicism where short stature may be the only obvious sign. Furthermore, with early detection and initiation

<b><i>Introduction:</i></b> Short stature is one of the most common reasons for referral to a pediatric endocrinologist and can result from many etiologies. However, many patients with short stature do not receive a definitive diagnosis. <b><i>Objective:</i></b> To ascertain whether integrating targeted bioinformatics searches of electronic health records (EHRs) combined with genomic studies could identify patients with previously undiagnosed rare genetic etiologies of short stature. We focused on a specific rare phenotypic subgroup: patients with short stature and elevated IGF-I levels. <b><i>Methods:</i></b> We performed a cross-sectional cohort study at three large academic pediatric healthcare networks. Eligible subjects included children with heights below –2 SD, IGF-I levels &#x3e;90th percentile, and no known etiology for short stature. We performed a search of the EHRs to identify eligible patients. Patients were then recruited for phenotyping followed by exome sequencing and in vitro assays of IGF1R function. <b><i>Results:</i></b> A total of 234 patients were identified by the bioinformatics algorithm with 39 deemed eligible after manual review (17%). Of those, 9 were successfully recruited. A genetic etiology was identified in 3 of the 9 patients including 2 novel variants in <i>IGF1R</i> and a de novo variant in <i>CHD2</i>. In vitro studies supported the pathogenicity of the <i>IGF1R</i> variants. <b><i>Conclusions:</i></b> This study provides proof of principle that patients with rare phenotypic subgroups can be identified based on discrete data elements in the EHRs. Although limitations exist to fully automating this approach, these searches may help find patients with previously unidentified rare genetic disorders.

Aggrecan is a proteoglycan within the physeal and articular cartilage. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early‐onset osteoarthritis and degenerative disc disease. We aimed to further characterize this phenotypic spectrum with an emphasis on musculoskeletal health. Twenty‐two individuals from nine families were enrolled. Histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes, and imaging studies were performed. All patients had dominantly inherited short stature, with the exception of a de novo mutation. Short stature was worse in adults versus children (median height −3.05 SD vs. −2.25 SD). ACAN mutations were not always associated with bone age advancement (median advancement +1.1 years, range 0 to +2 years). Children had subtle disproportionality and clinically silent joint disease—25% with osteochondritis dissecans (OD). Adults had a high prevalence of joint symptomatology–decline in knee function, disability from spinal complaints, and lower physical activity on outcome measures. Osteoarthritis (OA) and OD was detected in 90% of adults, and orthopedic surgeries were reported in 60%. Aggrecan deficiency leads to short stature with progressive decline in height SD, mild skeletal dysplasia, and increasing prevalence of joint pathology over time. Optimal musculoskeletal health and quality of life can be attained with timely identification of pathology and intervention.