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IntroductionPoorly controlled type 1 diabetes (T1D) has been associated with impaired bone health, but the mechanisms remain unclear. We aimed to investigate whether changes in glycemic control and glucose variability are associated with skeletal health and to evaluate the roles of insulin-like growth factor I (IGF-I) and advanced glycation end-products (AGEs) in bone mineral accrual.Research design and methodsThis longitudinal study included adolescents with poorly controlled T1D (HbA1c >9%/75 mmol/mol), who underwent dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months. Glycemic control was assessed using glycohemoglobin (HbA1c), continuous glucose monitoring (CGM) parameters, and glycemic load. Serum IGF-I and AGEs, specifically methyl-glyoxal-hydro-imidazolone (MG-HI), were measured. Correlation analyses and linear regression models were used to evaluate the associations between glycemic markers, IGF-I, AGEs and bone parameters.ResultsAltogether, 37 adolescents (48.6 % female) with T1D, with mean HbA1c 9.9% (85 mmol/mol), were followed up from mean age of 14.3 for 12 months. DXA-derived bone mineral density (BMD) z-scores at lumbar spine, proximal femur, and total body less head were approximately 0.5 SDS lower than reference values (p=0.005–0.04). The only significant change in BMD z-scores during the 12-month follow-up was an increase in proximal femur in girls. In the whole group, an increase in IGF-1 was associated with BMD accrual, while changes in HbA1c, time in range, or MG-HI were not. No vertebral fractures were detected.ConclusionsDespite lower BMD in adolescents with poorly controlled T1D, neither changes in glycemic control nor MG-HI levels correlated significantly with bone health measures, while increase of IGF-1 was associated with BMD accrual. Future studies should explore alternative AGEs and use advanced bone imaging techniques to better understand skeletal fragility in T1D.

Background Cartilage-hair hypoplasia (CHH), an autosomal recessive skeletal dysplasia due to RMRP mutations, is characterized by short stature, immunodeficiency, anemia, and increased malignancies. Growth failure has its onset prenatally. Birth and neonatal care in pregnancies with fetal skeletal dysplasia have been studied in some other skeletal dysplasias but there have been no previous studies on these aspects in CHH. In this retrospective cohort study, we reviewed patient records for 35 Finnish children with CHH born in 2000–2023 to evaluate the course and management of pregnancies and deliveries and the prenatal and neonatal findings. Results Abnormal growth was observed in prenatal ultrasound in 26/30 (87%) children. Shortness was reported especially in the humeri and femora, but the ultrasound findings also included other abnormalities such as a small rib cage. Abnormal ultrasonographic findings mostly visualized during the second trimester. A prenatal genetic diagnosis was made in 6/34 (18%) cases. The median age at time of postnatal genetic diagnosis was 1 month. The Finnish founder mutation was observed in 94% of all cases. Most children (27/33; 82%) were born full-term but 6 children (18%) were born preterm (at 30 + 4–36+4 weeks). Less than half (11/24; 46%) were born by vaginal delivery and the others by elective (5/24; 21%), urgent (4/24; 17%), or emergency Csection (4/24; 17%). Breech position and other malpresentations were more common (30%) than in the general population (3–4%) and accounted for 10/18 (56%) of the Csection indications. The average 1 min Apgar score was 7.4. The median birth length for full-term neonates was 44.5 cm (40.0–50.0 cm) for boys ( n  = 10) and 44.0 cm (37.0- 48.0 cm) for girls ( n  = 16). The median birth length Z-score, adjusted for gestational age, for all was −3.9 (−7.5- −1.0) and below −2.0 in 84%. In 7/19 (37%) cases respiratory support was needed postnatally. Conclusion In conclusion, in most CHH pregnancies, growth failure was detected prenatally, the pregnancies were carried to full-term but less than half were born by normal vaginal delivery. At birth 16% had normal length. Respiratory challenges accounted for the majority of the neonatal complications.

Background Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. Methods In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5–33.1), 67 survivors (mean age 28.4, range 16.2–43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. Results Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p  < 0.001). Lumbar disc protrusions at L4-5 ( p  = 0.02) and extrusions at L3-4 ( p  = 0.04), L4-5 ( p  = 0.004), and L5-S1 ( p  = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration ( p  < 0.01). Blood pressure correlated with IVD degeneration ( P  < 0.05). Conclusions Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient’s clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.

Cartilage-hair hypoplasia is a syndromic immunodeficiency with short stature, chondrodysplasia, and variable degree of immune dysfunction. Patients with cartilage-hair hypoplasia are prone to recurrent respiratory tract infections, and the prevalence of bronchiectasis ranges from 29 to 52%. Pulmonary complications contribute significantly to the mortality; therefore, regular lung imaging is essential. However, the optimal schedule for repeated lung imaging remains unestablished. We determined the rate and correlates of progression of structural lung changes in a prospectively followed cohort of 16 patients with cartilage-hair hypoplasia. We analyzed clinical, laboratory, and pulmonary functional testing data and performed lung magnetic resonance imaging at a median interval of 6.8 years since previous imaging. Imaging findings remained identical or improved due to disappearance of inflammatory changes in all evaluated patients. Patients with subtle signs of bronchiectasis on imaging tended to have low immunoglobulin M levels, as well as suffered from pneumonia during the follow-up. In conclusion, our results suggest slow if any development of bronchiectasis in selected subjects with cartilage-hair hypoplasia.

Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation-induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.

Context:The short-term benefits of bisphosphonates (BPs) are evident in the treatment of children with osteogenesis imperfecta (OI), but some concerns related to long-term effects remain.Objective:To elucidate the effect of BPs on characteristics of femoral fractures in children with OI.Design and Setting:Retrospective cohort study at a university hospital.Patients and Main Outcome Measure:The study included 93 patients with OI. We recorded fracture histories and analyzed all femoral fractures for location and fracture type using radiographs obtained at fracture diagnosis. Effects of BPs were evaluated by comparing fracture characteristics in three groups: patients (1) naive to BPs, (2) receiving ongoing BP treatment, and (3) whose treatment was discontinued.Results:In total, 127 femoral fractures occurred in 24 patients. Of the fractures, 63 (50%) occurred in patients naive to BPs, 44 (35%) during BP treatment, and 20 (16%) after treatment discontinuation. Mid or distal shaft fractures were most common (41%), followed by subtrochanteric (33%) and distal (20%) fractures. Almost all fractures were transverse (65%) or oblique (28%). The pattern of femoral fractures was similar in all three BP treatment groups (P = 0.78 for location; P = 0.35 for fracture type) and was not related to cumulative BP dose. Instead, OI type correlated with fracture characteristics, and distal location and transverse configuration were more common in the more severe types III and IV compared with type I OI.Conclusion:Characteristics of femoral fractures in children with OI are affected by OI type but not by BP exposure.This retrospective study assessing effects of bisphosphonates on femoral fractures in children with OI showed that fracture characteristics are affected by OI type but not by bisphosphonate exposure.

Previous studies have indicated that children with inflammatory bowel disease (IBD) may not achieve optimal bone mass. We evaluated the skeletal characteristics in children and adolescents with IBD. This cross-sectional cohort study comprised 80 IBD patients (median age 14.9 years, range 5–20) with a median disease duration of 3.4 years; 51 had ulcerative colitis, 26 Crohn disease, and 3 unspecified colitis. Eighty age- and gender-matched healthy subjects served as controls. Areal bone mineral density (aBMD), body composition, and vertebral fractures (VFs) were assessed by DXA. Bone age (BA) was determined for IBD patients. Findings were correlated with disease- and treatment-related parameters and biochemistry. IBD patients had lower BA-adjusted lumbar spine and whole-body aBMD ( p  < 0.001 for both) and whole-body BMC adjusted for height ( p  = 0.02) than controls. Lean mass and fat mass Z scores did not differ between the groups, but IBD patients had lower whole-body BMC relative to muscle mass ( p  = 0.006). Despite vitamin D supplementation in 48 %, vitamin D deficiency was common. In IBD cumulative weight-adjusted prednisolone dose >150 mg/kg for the preceding 3 years increased the risk for low whole-body aBMD (OR = 5.5, 95 % CI 1.3–23.3, p  = 0.02). VFs were found in 11 % of patients and in 3 % of controls ( p  = 0.02). IBD in childhood was associated with low aBMD and reduced bone mass accrual relative to muscle mass; the risk for subclinical VFs may be increased. These observations warrant careful follow-up and active preventive measures.

In this randomized placebo-controlled study we examined the influence of aromatase inhibition on bone turnover, cortical bone growth, and vertebral body morphology in peripubertal boys. Thirty peripubertal boys with idiopathic short stature were treated with the aromatase inhibitor letrozole or placebo for 2 years. During treatment and posttreatment follow-up, dual-energy X-ray absorptiometry (DXA)-assessed bone mineral density, metacarpal index (MCI), and markers of bone turnover were examined. Vertebral morphology was examined by DXA after cessation of treatment. In letrozole-treated boys, the concentrations of the bone resorption marker urine aminoterminal telopeptide of type I collagen initially increased and thereafter slowly declined while the concentrations of the bone formation markers serum aminoterminal propeptide of type I collagen and serum alkaline phosphatase remained unchanged or slightly increased, respectively. In placebo-treated boys, all markers of bone turnover increased significantly during treatment. Among those who progressed into puberty, metacarpal index (MCI) increased more in the letrozole-treated than in the placebo-treated boys during treatment (25 vs. 9%, p = 0.007). The change in MCI correlated with the testosterone-to-estradiol ratio (r = 0.59, p = 0.02). Vertebral deformities were detected in 6 out of 13 boys receiving letrozole and in 4 out of 11 receiving placebo (p = 0.70). Aromatase inhibition suppresses bone turnover, possibly through an androgen-mediated effect. In pubertal boys, treatment stimulates cortical bone growth by increasing the testosterone-to-estradiol ratio.

Background: Intravenous disodium pamidronate has become an established treatment in osteogenesis imperfecta (OI). Another bisphosphonate, zoledronic acid, has been indicated for the treatment of adult osteoporosis. We studied its efficacy and safety in children with mild OI. Methods: Patients were treated for 1.0–3.2 years with 0.05 mg/kg zoledronic acid intravenously every 6 months as part of their clinical care. They were carefully followed for clinical and biochemical parameters, side effects, bone mineral densities (BMD) and compression fractures. Results: The study included 17 patients (age 1.5–16.8 years) with type I OI. They had sustained altogether 73 fractures; 9 had compression fractures. During the treatment, 6 patients suffered in total 10 new long-bone fractures. The median lumbar spine areal BMD z-score increased from –2.0 to –0.7 during 2 years of treatment. The infusions were associated with a transient decrease in serum calcium and phosphate and a significant increase in serum PTH. Two patients developed symptomatic hypocalcemia. Bone turnover markers decreased during the treatment. Conclusions: Intravenous zoledronic acid is an effective mode of treatment in children with OI. The treatment response is comparable to pamidronate but the infusion protocol is more convenient. Further studies are needed to establish optimal dosing and long-term safety.