Helena Valta

Incidence and Predictors of Fractures in Children After Solid Organ Transplantation: A 5‐Year Prospective, Population‐Based Study

In this population‐based prospective follow‐up study, children undergoing solid organ transplantation had a highly elevated risk for fractures: The incidence of all fractures was 6‐fold higher (92 versus 14 fractures/1000 persons/year; p < 0.001) and vertebral fractures was 160‐fold higher (57 versus 0.35 fractures/1000 persons/year; p < 0.001) in the study group compared with the control population. Thus, screening of vertebral fractures at regular intervals is recommended, and preventive strategies should be studied.

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 ≤−1.0 and one‐fifth (18%) had asymptomatic VF. LS Z‐score tended to increase from the first year after OLT, but during puberty the bone mass gain was suboptimal and Z‐scores decreased in some subjects. Patients with VF were older at the time of OLT (p = 0.002) and their LS Z‐score was lower (p = 0.001). Children transplanted before 10 years of age had less VF (p = 0.004) and higher LS Z‐score (p = 0.005) than older patients. In conclusion, adolescent liver recipients are prone to osteoporosis and prevention should be targeted especially to this age group.

Bone Health in Children and Adolescents After Renal Transplantation

The basis for lifelong bone health is established in childhood and adolescence. Whereas pediatric renal transplant (RTx) patients are at risk for impaired bone mass gain and fractures, scarce data on this subject are available. We performed a cross‐sectional and longitudinal study of bone health in a national cohort of 106 pediatric RTx patients (median age, 12.6 yr; median follow‐up, 5.1 yr after RTx). The patients underwent clinical evaluation, DXA for BMD, and spinal imaging for vertebral fractures. In longitudinal analysis, the median lumbar spine BMD Z‐score was lowest (median, −1.0) at 1 yr postoperatively but increased to a peak value of −0.2 at 5 yr. In boys, the lumbar spine BMD Z‐score increased also during puberty but decreased in girls. In cross‐sectional analysis, the lumbar spine, hip, and whole body BMD Z‐scores were < −2 SD in 4%, 6%, and 6% of the patients, respectively. Sixteen percent had sustained peripheral fractures, and 8% had vertebral fractures. Female sex and age >15 yr (OR, 56.26; 95% CI, 5.17–611.82; p = 0.0007) as well as high plasma PTH levels (OR, 4.03; 95% CI, 1.37–11.85; p = 0.009) were significant predictors for low BMD. Three‐year cumulative glucocorticoid dose, outside the immediate post‐RTx years, was not associated with BMD parameters. The observed BMD results were satisfactory. However, the high (8%) prevalence of vertebral fractures warrants careful evaluation of bone health in these patients.

Prevalence of Vertebral Compression Fractures and Associated Factors in Children and Adolescents with Severe Juvenile Idiopathic Arthritis

Objective. Vertebral fractures occur in patients with juvenile idiopathic arthritis (JIA), but data on their frequency and causes are scarce. Our cross-sectional study evaluated prevalence of compression fractures and associated factors in a high-risk pediatric population with severe JIA. Methods. Children and adolescents with a history of treatment-resistant polyarticular-course JIA for ≥ 5 years or systemic arthritis for ≥ 3 years were recruited. Clinical examination, dietary recall, laboratory measurements, bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry, and spinal radiography were performed. Results. Our study included 50 patients (41 girls), of whom 6 (12%) had systemic arthritis, with a median age of 14.8 years (range 7.0–18.7 yrs) and median disease duration of 10.2 years (range 3.9–16.8 years). Ninety-four percent had used systemic glucocorticoids (GC); the median total duration of GC treatment was 7.1 years (range 0–15.5 yrs). The median weight-adjusted cumulative GC dose for the preceding 3 years was 72 mg/kg (range 0–911 mg/kg). The median bone age-corrected lumbar spine and whole-body areal BMD Z-scores were −0.8 and −1.0, respectively. Twenty-two percent had vertebral fractures, mostly thoracic. Compression fractures were associated with high disease activity, high body mass index (BMI), and high recent cumulative GC dose, but not with disease duration or BMD. Thirty percent had sustained at least 1 peripheral low energy fracture. Twenty-six percent were deemed to have significantly compromised bone health. Conclusion. Severe JIA is associated with a significant risk of vertebral compression fractures. Associated factors include high disease activity, high BMI, and high recent GC exposure. Further studies are needed to establish optimal prevention and treatment guidelines.

Low Copy Number of the AMY1 Locus Is Associated with Early-Onset Female Obesity in Finland.

Background The salivary α-amylase locus (AMY1) is located in a highly polymorphic multi allelic copy number variable chromosomal region. A recent report identified an association between AMY1 copy numbers and BMI in common obesity. The present study investigated the relationship between AMY1 copy number, BMI and serum amylase in childhood-onset obesity. Patients Sixty-one subjects with a history of childhood-onset obesity (mean age 19.1 years, 54% males) and 71 matched controls (19.8 yrs, 45% males) were included. All anthropometric measures were greater in the obese; their mean BMI was 40 kg/m2 (range 25-62 kg/m2) compared with 23 kg/m2 in the controls (15-32 kg/m2). Results Mean AMY1 copy numbers did not differ between the obese and control subjects, but gender differences were observed; obese men showed the highest and obese women the lowest number of AMY1 copies (p=0.045). Further, only in affected females, AMY1 copy number correlated significantly with whole body fat percent (r=-0.512, p=0.013) and BMI (r=-0.416, p=0.025). Finally, a clear linear association between AMY1 copy number and serum salivary amylase was observed in all subgroups but again differences existed between obese males and females. Conclusions In conclusion, our findings suggest that AMY1 copy number differences play a role in childhood-onset obesity but the effect differs between males and females. Further studies in larger cohorts are needed to confirm these observations.

Different mutations in PDE4D associated with developmental disorders with mirror phenotypes

Background Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene. Methods We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation. To evaluate the functional consequences of the PDE4D changes, we used overexpression of mutated human PDE4D message and morpholino-based suppression of pde4d in zebrafish. Results We identified three novel and two previously described PDE4D point mutations in the acrodysostosis patients and two deletions and one duplication involving PDE4D in three patients suffering from an intellectual disability syndrome with low body mass index, long fingers, toes and arms, prominent nose and small chin. When comparing symptoms in patients with missense mutations and gene dose imbalances involving PDE4D, a mirror phenotype was observed. By comparing overexpression of human mutated transcripts with pde4d knockdown in zebrafish embryos, we could successfully assay the pathogenicity of the mutations. Conclusions Our findings indicate that haploinsufficiency of PDE4D results in a novel intellectual disability syndrome, the 5q12.1-haploinsufficiency syndrome, with several opposing features compared with acrodysostosis that is caused by dominant negative mutations. In addition, our results expand the spectrum of PDE4D mutations underlying acrodysostosis and indicate that, in contrast to previous reports, patients with PDE4D mutations may have significant hormone resistance with consequent endocrine abnormalities.

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°) 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°, and 21 (10.7%) of them had curves greater than 20°. The RR (95% CI) for scoliosis needing treatment (over 20°) 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.

Pubertal development is normal in adolescents after renal transplantation in childhood.

Background. This study was conducted to evaluate the pubertal development in adolescents after renal transplantation (RTx) in childhood. Methods. We performed a retrospective review of medical records of 109 RTx recipients (72 males) transplanted at the median age of 4.5 years (range: 0.9–15.8 years). Data on the clinical signs of puberty, growth, bone age, medication, and graft function of 98 patients were analyzed. Furthermore, serum levels of reproductive hormones in 87 patients were assessed to evaluate the progression and outcome of pubertal development. Results. The age at the onset of puberty averaged 12.7 years (range: 9.4–16.2 years) in 55 males and 10.7 years (range: 8.9–12.7 years) in 29 females. The mean age at menarche was 12.5 years (range: 10.5–14.5 years). Twenty-two percent of the boys and none of the girls had a moderately delayed onset of puberty. Children who underwent RTx before the age of 5 years reached puberty earlier than those transplanted at later age (boys 12.3±1.2 vs. 13.4±1.5 years, P<0.01; girls 10.3±0.9 vs. 11.0±1.0 years, P>0.05). The mean length of puberty was 3.9 and 4.7 years for boys and girls, respectively. The bone age was delayed in practically all, and final height was reached at the mean age of 18.1 and 16.0 years in boys and girls, respectively. Pubertal maturation resulted in acceptable final height and reproductive hormone status in great majority of the patients. Conclusion. Pubertal development was normal in all female and most male adolescents after RTx in childhood.

Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation

CONTEXT The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. CASE DESCRIPTION Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. CONCLUSIONS Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.

Skeletal Characteristics of WNT1 Osteoporosis in Children and Young Adults.

WNT proteins comprise a 19‐member glycoprotein family that act in several developmental and regenerative processes. In bone, WNT proteins regulate osteoblast differentiation and maintain bone health by activating the canonical WNT/β‐catenin pathway. We reported a heterozygous missense mutation c.652T>G (p.C218G) in WNT1 exon 4 as the cause for severe early‐onset, autosomal dominant osteoporosis. The initial study concerned a large Finnish family with 10 affected adults. Here we report clinical findings of the WNT1 osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1. Clinical assessments showed no apparent dysmorphia or features similar to typical osteogenesis imperfecta (OI). Biochemistry revealed no changes in parameters of calcium metabolism and bone turnover markers. Fracture frequencies varied, but all subjects had sustained at least one fracture and 4 had a pathological fracture history. Plain radiographs showed osteopenic appearance, loss in vertebral height, and thin diaphyses of the long bones. Bone densitometry showed the BMD to be below normal median in all subjects and the bone mass deficit seemed to be more severe in older participants. Bone histomorphometry revealed a low turnover osteoporosis in 2 subjects at ages 14 and 16 years. These findings are congruent with earlier findings in adult patients and indicate that WNT1 osteoporosis causes significant skeletal changes already in early childhood and impairs bone mass gain during pubertal years. Genetic testing of children or close relatives of affected individuals is recommended for appropriate preventive measures.