PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants.

Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis. INTRODUCTION: The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features. METHODS: Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3. RESULTS: In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects. CONCLUSIONS: Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.

Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.

The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.

Body composition and adipokines in patients with juvenile idiopathic arthritis and systemic glucocorticoids.

OBJECTIVES: The aim of this cross-sectional study was to explore body composition, and the relationship of serum adipokines with bone mass and disease activity, in a cohort of JIA patients with at least three months' exposure to systemic glucocorticoids (GC). METHODS: Fifty patients with JIA (34 girls, median age 12.4 years and disease duration 6.3 years) and 88 controls matched for gender and age participated in this study. Bone mineral content (BMC) and areal bone mineral density (BMD) of the lumbar spine and whole body, as well as body composition were assessed with dual-energy x-ray absorptiometry. Fasting serum leptin and adiponectin were measured. RESULTS: Fat and lean mass were similar between patients and controls, but patients had slightly decreased BMD Z-scores. Serum leptin and adiponectin concentrations were similar. Disease activity was low, and no correlation with adipokines was observed. Patients with bone age-corrected lumbar spine BMD Z-score ≤-1.0 ("low BMD") did not show alterations in body composition, GC exposure or current disease activity, but had decreased BMC-to-lean mass ratio (p<0.001) and tendency for increased serum leptin (p=0.064). However, no association of leptin with BMD in multivariate analysis existed in patients or controls. An inverse association between adiponectin and whole body BMD was observed in both groups. CONCLUSIONS: Normal body composition was observed in a JIA cohort with low-dose GC exposure. Patients with "low BMD" tended to have increased serum leptin, but leptin did not associate with BMD. In this cohort with low disease activity, no correlation between adipokines and disease activity was present.

Bone Characteristics and Their Determinants in Adolescents and Young Adults with Early-Onset Severe Obesity.

Childhood obesity is associated with compromised bone health. We studied bone characteristics and their determinants in obese young adults. The study included 68 subjects with early-onset severe obesity and 73 normal-weight controls. Data on physical activity (PA), diet and smoking were collected. Bone characteristics were measured using peripheral QCT. The obese and control subjects were similar in age (mean 19.6 ± 2.6 years) and height but BMIs differed (39.7 and 22.6 kg/m(2)). A clustering of unhealthy lifestyles was marked: Obese subjects reported less supervised PA in childhood, adolescence and currently (p < 0.03) and were more likely to smoke (p = 0.005), and had a lower healthy eating index (HEI) (p = 0.007) but similar alcohol consumption compared with controls. In obese women, all crude bone characteristics were higher than in controls; in men, the differences were smaller. Associations of lifestyle factors with bone characteristics were tested using partial correlations. Independently of BMI, supervised PA in adolescence and alcohol consumption were related positively to bone characteristics in both groups. HEI associated positively with bone characteristics only in controls, while smoking was a positive determinant of bone characteristics only in obese subjects. The multivariate model showed that the contribution of lifestyle factors to bone characteristics was minimal compared with BMI. Early-onset obesity is accompanied by poor dietary quality, sedentary lifestyle, and more frequent smoking, but the overall contribution of these lifestyle factors to bone strength is limited. Bone strength is more likely to be compromised in men and in unloaded bone sites in subjects with early-onset severe obesity. The impact of obesity-related endocrine changes on bone characteristics need to be evaluated in future studies.

Hypercalciuria and kidney function in children with haemophilia.

Adults with haemophilia have a higher incidence of chronic kidney disease than general male population. We recently showed that children with haemophilia have higher urinary calcium excretion and lower whole body bone mineral density than controls in spite of prophylaxis with the deficient coagulation factor concentrate, serum vitamin D concentrations comparable to those of healthy children and physically active lifestyle. Persistent hypercalciuria may result in nephrocalcinosis and impact renal function. This study sought to assess persistence of urinary calcium excretion and kidney function in children with haemophilia. We investigated retrospectively urinary calcium excretion in 30 children with haemophilia (mean age 12.5 years) from consecutive urine samples over a 2-year period. Renal evaluation included blood and urine specimen, blood pressure, and renal ultrasound. High number of children with haemophilia had intermittent hypercalciuria. Hypercalciuria was not associated with age, severity of haemophilia or previous hypercalciuria. Kidney function and renal ultrasound were normal with the exception of suspected kidney stone in one patient with haemophilia and transient hypercalciuria. Vitamin D concentrations improved after the families had received information and recommendations concerning vitamin D substitution. Our findings indicate that haemophilia per se predisposes to hypercalciuria which may in turn affect bone mineral content and kidney function. Whether childhood-onset intermittent hypercalciuria contributes to hypertension and renal complications in adulthood remains to be elucidated in future studies.

Impaired bone health in adolescents after liver transplantation.

Long-term complications related to immunosuppressive medication are an important problem after liver transplantation (OLT). This study was carried out to evaluate the bone health and risk factors for osteoporosis and fractures in 40 pediatric liver transplant recipients. The results of 208 longitudinal bone mineral density (BMD) measurements were analyzed retrospectively. In addition, a dual-energy X-ray absorptiometry was performed to assess the bone mineral content more precisely and to detect subclinical vertebral fractures (VF). The median age of the patients was 14 years and mean postoperative follow-up 7.0 years. The results showed that over half (58%) had lumbar spine (LS) Z-score

Scoliosis after solid organ transplantation in children and adolescents.

The occurrence of scoliosis in children after solid organ transplantation is not known. A total of 196 children, which is 93% of patients surviving kidney, liver and heart transplantation in our country, participated in a cross-sectional survey. All children were screened for rib hump, and those with clinically significant hump (over 6 degrees ) underwent radiographs of the spine. The occurrence of scoliosis was compared to data obtained from a previously published comparison group. Forty-three (21.9%) of the patients had scoliosis greater than 10 degrees , and 21 (10.7%) of them had curves greater than 20 degrees . The RR (95% CI) for scoliosis needing treatment (over 20 degrees ) was 17.0 (6.75-42.7) in the patients as compared with control population. The occurrence of scoliosis was 17.9% of the kidney, 13.6% of the liver and 51.7% of the heart transplant patients (p < 0.001). In a logistic regression model, heart transplantation (OR (95% CI) 7.27 (2.62-20.2)) and growth hormone treatment (3.98 (1.77-8.94)) were most significant risk factors for scoliosis. The risk of scoliosis is increased in patients with solid organ transplantation. Pediatricians treating these patients should be aware of this increased risk to diagnose early curves and to refer these patients to an orthopedic surgeon.