Search

Context Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. Objective To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates. Methods Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment. Results A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. Conclusion A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels. [ABSTRACT FROM AUTHOR]

Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia. [ABSTRACT FROM AUTHOR]

Context Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. Objective This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. Participants Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. Evidence Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. Conclusion Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks. [ABSTRACT FROM AUTHOR]

Severe 25-hydroxyvitamin D (25(OH)D) deficiency can result in life-threatening presentations due to hypocalcemia leading to seizures and cardiac arrhythmias. vitamin D deficiency is a common cause of hypocalcemia and rickets in children; however, there are no recent studies on the burden of inpatient admissions in the United States. Our study aims to describe the clinical characteristics and risk factors of inpatient admissions due to severe hypocalcemia and 25(OH)D deficiency at a freestanding academic children's hospital. A descriptive retrospective chart review was completed on all inpatient admissions from 2016 to 2021 for children 0–18 years of age with corrected calcium <8 mg/dL and 25(OH)D <10 ng/mL during admission. Thirty-eight patients met the inclusion criteria (74 % Black/African American). Neurological signs described in 49 %, bone abnormalities in 17 % and EKG abnormalities in 42 % of the patients. The mean calcium serum level was 6.0 mmol/L (range 5.0–7.9 mmol/L), the mean iCa 0.77 mmol/L (range 0.54–0.99 mmol/L). The mean level of 25(OH)D was 5.5 ng/mL (range 2.1–9.7 ng/mL). The median length of stay was 4.5 (range 1–59 days). In this retrospective observational study, risk factors identified: (1) Black/African American race (2) age less than two years (3) lack of supplementation of vitamin D and (4) dietary restrictions. Inpatient admissions are preventable through the implementation of education at the community and healthcare levels. [ABSTRACT FROM AUTHOR]

The article presents case study of a male infant of gestational age 34 and two-seventh weeks who was diagnosed with severe pancytopenia. Topics include information on complications during the pregnancy by asymptomatic bacteriuria with Escherichia coli, bacterial vaginosis, and the development of intrauterine growth restriction; development of bruising and petechiae over the body of the infant; and observation of poikilocytosis with teardrop-shaped erythrocytes through peripheral smear.

Introduction: Vosoritide is a C-type natriuretic peptide (CNP) analog that binds its receptor on chondrocytes, promoting growth by inhibiting the ERK1/2-MAPK pathway. We previously reported the results of a phase II study in children with hypochondroplasia. Vosoritide led to an average increase in annualized height velocity (AHV) of 1.81 cm/year and gain of 0.36 in height standard deviation (SD) over 12 months. We present here the pharmacokinetic/pharmacodynamic (PK/PD) data from this study and examine the correlations between these parameters and growth outcomes., Methods: We conducted a phase II trial of daily subcutaneous vosoritide (15 μg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 females, mean age 5.9 ± 2.3 years, mean height -3.29 + 0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PD markers including serum collagen X biomarker (CXM) and urine cyclic guanosine monophosphate (cGMP) production were measured at day 1, month 6, and month 12 visits. Pearson correlations and regression analyses were performed between PK and PD parameters and growth outcomes., Results: Vosoritide PK parameters were similar to those previously reported in patients with achondroplasia. CXM levels increased from a baseline mean of 22.5 ± 6.5 to 41.6 ± 15.9 ng/mL after 12 months of treatment (p < 0.0001). Urine cGMP increased within 1 h and peaked at 2 h after injection. The mean AUC for cGMP production was not significantly different at each study visit. The maximum change in cGMP AUC correlated with PK AUC (r = 0.46, p = 0.0001). However, drug exposure, as measured by average PK AUC, did not correlate with any growth outcome. CXM levels correlated with the prior 6-month interval height velocity (partial correlation coefficient = 0.40, p = 0.0048). However, change in CXM did not correlate with change in height velocity or change in height SD during treatment., Conclusions: Vosoritide treatment showed improvement in AHV and height SD in children with hypochondroplasia. PK analysis indicates that drug exposure was correlated to global CNP activity as measured by urine cGMP but did not correlate with growth outcomes. More studies are needed to identify specific patient characteristics that can predict response to therapy and clinical outcomes., (© 2024 S. Karger AG, Basel.)

Summary: Iodine nutrition is a growing issue within the USA due to newer trends of non-iodized salts. There are no recent reviews looking at the current state of iodine deficiency-induced hypothyroidism in children in the USA. We performed a retrospective chart review at our tertiary pediatric endocrine clinic; four met the diagnostic criteria for iodine deficiency defined by a low urine iodine level. We further characterized severity of disease, risk factors, goiter, thyroid labs and antibodies. All cases had significant goiter and were diagnosed within the last 2 years. One case had iodine deficiency due to no iodized salt intake along with concurrent diagnosis of developmental delay and multiple food allergies, while others involved the use of non-iodized salts. Two cases had iodine deficiency along with autoimmunity. It is critical to obtain a dietary history for all patients who present with goiter and/or hypothyroidism. There may be a need to consider reevaluating current preventative measures for iodine deficiency, especially for certain vulnerable populations such as children who do not consume iodized salt., Learning Points: In recent decades, iodine nutrition has become a growing concern due to changing dietary patterns and food manufacturing practices. A dietary history is crucial to obtain in children presenting with hypothyroidism and goiter, especially in children with restrictive diets due to behavioral concerns, developmental delays, or multiple food allergies. Of the 12 different types of salts commercially available, only table salt contains iodine in an appropriate amount; thus, individuals using specialty salts can develop mild to moderate iodine deficiency-related thyroid disease.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)