Disorders of phosphate homeostasis in children, part 1: primer on mineral ion homeostasis and the roles of phosphate in skeletal biology.

Phosphate has extensive physiological roles including energy metabolism, genetic function, signal transduction and membrane integrity. Regarding the skeleton, not only do phosphate and calcium form the mineral component of the skeleton, but phosphate is also essential in regulating function of skeletal cells. Although our understanding of phosphate homeostasis has lagged behind and remains less than that for calcium, considerable advances have been made since the recognition of fibroblast growth factor-23 (FGF23) as a bone-derived phosphaturic hormone that is a major regulator of phosphate homeostasis. In this two-part review of disorders of phosphate homeostasis in children, part 1 covers the basics of mineral ion homeostasis and the roles of phosphate in skeletal biology. Part 1 includes phosphate-related disorders of mineralization for which overall circulating mineral ion homeostasis remains normal. Part 2 covers hypophosphatemic and hyperphosphatemic disorders, emphasizing, but not limited to, those related to increased and decreased FGF23 signaling, respectively.

Disorders of phosphate homeostasis in children, part 2: hypophosphatemic and hyperphosphatemic disorders.

Phosphorus, predominantly in the form of inorganic phosphate PO4-3, has many essential physiological functions. In the skeleton, phosphate and calcium form the mineral component and phosphate is also essential in regulating function of skeletal cells. Considerable advances have been made in our understanding of phosphate homeostasis since the recognition of fibroblast growth factor-23 (FGF23) as a bone-derived phosphaturic hormone. This second part of a two-part review of disorders of phosphate homeostasis in children covers hypophosphatemic and hyperphosphatemic disorders that are of interest to the pediatric radiologist, emphasizing, but not limited to, those related to abnormalities of FGF23 signaling.

Changes in total body fat and body mass index among children with juvenile dermatomyositis treated with high-dose glucocorticoids.

OBJECTIVE: High-dose glucocorticoids (GC) remain the primary therapy to induce remission in Juvenile Dermatomyositis (JDM). Studies of the natural history of GC associated weight gain in children are very limited, especially in the JDM population. This study aims to measure BMI changes in a cohort of JDM subjects over 60 months and to examine the changes in body composition by DXA. METHODS: We included all subjects with JDM who had 5 years of follow-up data and multiple DXA studies. BMI and total body fat (TBF) percentiles were calculated based on the CDC published percentile charts. To study the natural history of weight gain and TBF, we assessed the data at four-time points (T0 = baseline, T1 > 1.5 years, T2 = 1.51-3.49 years, T3 = 3.5-5 years). RESULTS: 68 subjects (78% female, 70% white) were included in this retrospective study. Paired T-test showed a significant increase in the mean BMI percentile by 17.5 points (P = 0.004) after the initiation of medical treatment, followed by a gradual decrease over the study period. However, the TBF percentile did not change over the study period. TBF in the last visit (T3) had a strong correlation with the T1 BMI, and T1 TBF percentile (correlation coefficients 0.63, 0.56 P < 0.001, 0.002 respectively). Also, there was a positive correlation (correlation coefficients 0.39, P = 0.002) between the TBF percentile and muscle DAS but not the skin DAS. CONCLUSIONS: Although the BMI percentile decreased throughout the study, the TBF percentile remained high until the end of the study (60 months). This finding raises the concern that some of the reduction in the BMI percentile could reflect a drop in the lean body mass from muscle wasting rather than actual fat loss.

MRI characterization of brown adipose tissue under thermal challenges in normal weight, overweight, and obese young men.

PURPOSE: To implement quantitative Dixon magnetic resonance imaging (MRI) methods for brown adipose tissue (BAT) characterization at inactive and cold-activated states in normal weight, overweight, and obese subjects. The hypotheses are that MRI characteristics of BAT would differentiate between nonobese and obese subjects, and activation of BAT in response to thermal challenges that are detected by MRI would be correlated with BAT activity measured by positron emission tomography / computed tomography (PET/CT). MATERIALS AND METHODS: Fifteen male subjects (20.7 ± 1.5 years old) including six normal weight, five overweight, and four obese subjects participated in the study. A multiecho Dixon MRI sequence was performed on a 1.5T scanner. MRI was acquired under thermoneutral, nonshivering thermogenesis, and subsequent warm-up conditions. Fat fraction (FF), R2*, and the number of double bonds (ndb) were measured by solving an optimization problem that fits in- and out-of-phase MR signal intensities to the fat-water interference models. Imaging acquisition and postprocessing were performed by two MRI physicists. In each subject, Dixon MRI measurements of FF, R2*, and ndb were calculated for each voxel within all BAT regions of interest (ROIs) under each thermal condition. Mean FF, R2*, and ndb were compared between nonobese (ie, normal-weight/overweight) and obese subjects using the two-sample t-test. Receiver operating characteristic (ROC) analyses were performed to differentiate nonobese vs. obese subjects. BAT MRI measurement changes in response to thermal condition changes were compared with hypermetabolic BAT volume/activity measured by PET/CT using the Pearson's correlation. In addition, BAT MRI measurements were compared with body adiposity using the Pearson's correlation. P < 0.05 was considered statistically significant. RESULTS: Obese subjects showed higher FF and lower R2* than nonobese subjects under all three thermal conditions (P < 0.01). ROC analyses demonstrated that FF and R2* were excellent predictors for the differentiation of nonobese from obese subjects (100% specificity and 100% sensitivity). FF changes under thermal challenges were correlated with hypermetabolic BAT volume (r = -0.55, P = 0.04 during activation, and r = 0.72, P = 0.003 during deactivation), and with BAT activity (r = 0.69, P = 0.006 during deactivation), as measured by PET/CT. FF and R2* under all three thermal conditions were highly correlated with body adiposity (P ≤ 0.002). CONCLUSION: MRI characteristics of BAT differentiated between nonobese and obese subjects in both inactivated and activated states. BAT activation detected by Dixon MRI in response to thermal challenges were correlated with glucose uptake of metabolically active BAT. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:936-947.

The etiology and significance of fractures in infants and young children: a critical multidisciplinary review.

This paper addresses significant misconceptions regarding the etiology of fractures in infants and young children in cases of suspected child abuse. This consensus statement, supported by the Child Abuse Committee and endorsed by the Board of Directors of the Society for Pediatric Radiology, synthesizes the relevant scientific data distinguishing clinical, radiologic and laboratory findings of metabolic disease from findings in abusive injury. This paper discusses medically established epidemiology and etiologies of childhood fractures in infants and young children. The authors also review the body of evidence on the role of vitamin D in bone health and the relationship between vitamin D and fractures. Finally, the authors discuss how courts should properly assess, use, and limit medical evidence and medical opinion testimony in criminal and civil child abuse cases to accomplish optimal care and protection of the children in these cases.

MRI characterization of brown adipose tissue in obese and normal-weight children.

BACKGROUND: Brown adipose tissue (BAT) is identified in mammals as an adaptive thermogenic organ for modulation of energy expenditure and heat generation. Human BAT may be primarily composed of brown-in-white (BRITE) adipocytes and stimulation of BRITE may serve as a potential target for obesity interventions. Current imaging studies of BAT detection and characterization have been mainly limited to PET/CT. MRI is an emerging application for BAT characterization in healthy children. OBJECTIVE: To exploit Dixon and diffusion-weighted MRI methods to characterize cervical-supraclavicular BAT/BRITE properties in normal-weight and obese children while accounting for pubertal status. MATERIALS AND METHODS: Twenty-eight healthy children (9-15 years old) with a normal or obese body mass index participated. MRI exams were performed to characterize supraclavicular adipose tissues by measuring tissue fat percentage, T2*, tissue water mobility, and microvasculature properties. We used multivariate linear regression models to compare tissue properties between normal-weight and obese groups while accounting for pubertal status. RESULTS: MRI measurements of BAT/BRITE tissues in obese children showed higher fat percentage (P < 0.0001), higher T2* (P < 0.0001), and lower diffusion coefficient (P = 0.015) compared with normal-weight children. Pubertal status was a significant covariate for the T2* measurement, with higher T2* (P = 0.0087) in pubertal children compared to prepubertal children. Perfusion measurements varied by pubertal status. Compared to normal-weight children, obese prepubertal children had lower perfusion fraction (P = 0.003) and pseudo-perfusion coefficient (P = 0.048); however, obese pubertal children had higher perfusion fraction (P = 0.02) and pseudo-perfusion coefficient (P = 0.028). CONCLUSION: This study utilized chemical-shift Dixon MRI and diffusion-weighted MRI methods to characterize supraclavicular BAT/BRITE tissue properties. The multi-parametric evaluation revealed evidence of morphological differences in brown adipose tissues between obese and normal-weight children.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome.

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) -metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities.

The Use of 123I in Diagnostic Radioactive Iodine Scans in Children with Differentiated Thyroid Carcinoma.

BACKGROUND: Adult studies have shown that iodine-123 ((123)I) is as effective as (131)I in detecting metastatic disease in patients with differentiated thyroid carcinoma. However, the type and administered activity of radioiodine used for diagnostic imaging of metastatic thyroid cancer has not been well studied in children. Here we describe our institution's experience with using (123)I in diagnostic radioiodine scans in children with differentiated thyroid carcinoma. METHODS: Every patient with differentiated thyroid carcinoma who completed diagnostic scanning followed by radioiodine therapy at our institution over the past 8 years was included in this retrospective chart review. Patient age, sex, presentation of thyroid disease, past medical history, thyrotropin, thyroglobulin, and antithyroglobulin antibodies were recorded. A single nuclear medicine radiologist evaluated all scans. RESULTS: Thirty-three subjects completed 37 pairs of scans at a mean age of 13.4 years (range 6-17 years). The majority of subjects were female (81%) and had papillary thyroid cancer (91%). For diagnostic scanning, 5 received 2 mCi of (131)I, 21 received 2 mCi of (123)I, and 11 received 3 mCi of (123)I. There was no statistically significant difference in rate of discordant scan pairs when comparing (131)I and (123)I (20% and 23% respectively, p=0.9). The detection of metastatic pulmonary disease on diagnostic scanning was not improved by increasing the dose of (123)I from 2 mCi to 3 mCi (10% rate of missed lung detection with 2 mCi (123)I vs. 20% with 3 mCi (123)I). CONCLUSIONS: (123)I is effective for use in diagnostic radioactive iodine scans in children with differentiated thyroid cancer. The primary advantages of using (123)I include decreased radiation exposure and avoidance of stunning. However, in children there is a possibility of missed detection of metastatic pulmonary disease.

Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by enhanced renal phosphate absorption, hyperphosphatemia, and tumor-like extraosseous calcifications due to inactivating mutations in FGF23 or associated proteins. Surgical excision is needed when low phosphate diet and phosphate binders are ineffective. Sporadic reports have supported acetazolamide use. We report on a 7-year-old African American boy who presented with severe HFTC requiring numerous surgical excisions. Tumors continued to appear and others reoccurred despite phosphate restriction and sevelamer carbonate. At the age of 9.5 years, acetazolamide (40 mg/kg/day) was added and resulted in mild metabolic acidosis (bicarbonate 25.3 mEq/L vs. 21.4 mEq/L, P < 0.001; serum pH 7.38 vs. 7.31, P = 0.013, pre- and post-acetazolamide, respectively) but no change in tubular reabsorption of phosphate (TRP) (96.9% vs. 95.9%, P = 0.34) or serum phosphate (6.6 mg/dl vs. 6.9 mg/dl, P = 0.52 pre- and post-acetazolamide, respectively). Following the initiation of acetazolamide therapy, the patient experienced significant improvement in disease course as indicated by resolution of localized bone pain, cessation of tumor formation, and no tumor recurrence. Despite mild metabolic acidosis, our patient had improved linear growth and did not develop any other side effects related to therapy. Intact FGF23 remained abnormally low throughout disease course, while C-terminal FGF23 increased with acetazolamide. We conclude that acetazolamide can control severe HFTC by inducing mild metabolic acidosis despite no change in serum phosphate or TRP. This effect may be exerted though improved calcium-phosphate complex solubility and increased FGF23 locally.

Rickets: Part I.

Rickets is characterized by impaired mineralization and ossification of the growth plates of growing children caused by a variety of disorders, the most frequent of which is nutritional deficiency of vitamin D. Despite ample knowledge of its etiology and the availability of cost-effective methods of preventing it, vitamin D deficiency rickets remains a significant problem in developing and developed countries. This two-part review covers the history, etiology, pathophysiology and clinical and radiographical findings of vitamin D deficiency rickets. Other less frequent causes of rickets and some of the disorders entering into the differential diagnoses of rickets are also considered. Controversial issues surrounding vitamin D deficiency include determination of what constitutes vitamin D sufficiency and the potential relationship between low levels of vitamin D metabolites in many individuals and unexplained fractures in infants.

Rickets: Part II.

This is the continuation of a two-part review of rickets. This part emphasizes the specific pathophysiology, clinical features, pathoanatomy and radiographic findings of vitamin D deficiency rickets. Other forms of rickets, differential diagnostic considerations and the potential relationship between low levels of vitamin D metabolites and unexplained fractures in infants are also discussed.

Pediatric renal lymphangiectasia: importance of recognition and accurate renal imaging.

Renal lymphangiectasia is a rare diagnosis. It is also referred to as renal lymphangioma, renal lymphangiomatosis, peripelvic lymphangiectasia, renal peripelvic multicystic lymphangiectasia, and hygroma renale. The presentation varies, and the diagnosis depends on accurate radiologic interpretation. We present the radiologic images of a pediatric patient who was diagnosed with renal lymphangiectasia after being evaluated for suspected nonaccidental trauma to emphasize the importance of identifying this entity by the characteristic radiologic findings.

Positron emission tomography/computed tomography (PET/CT) in children.

Although PET imaging has been available for more than two decades, its use has greatly increased lately due to the advent of PET/CT, readily available sources of commercially supplied FDG, and mobile scanners. These features have enabled PET scanning to expand beyond select major university medical centers, with on-site cyclotron facilities to smaller institutions including free- standing children's hospitals. In these settings, imaging is generally limited to FDG, which suffices for most applications, with the majority of studies performed for tumor imaging. FDGI is being used for evaluation of many tumors in children, with its use in lymphoma being the most established. In lymphoma, it has proven quite useful in determining whether active tumor is present in residual masses following treatment, which may otherwise contain only residual fibrous tissue. For brain tumors, FDGI has some relation to tumor grade, although its more important role is distinguishing recurrent or residual tumor from the effects of treatment, particularly radiation necrosis. For neurological evaluation, interictal FDGI is helpful in localizing potential seizure foci for subsequent subdural EEG monitoring. Because of the relatively long uptake time of FDG, true ictal studies cannot be performed with FDG, and these remain within the domain of SPECT imaging of tracers such as Tc-99m HMPAO. Examinations utilizing radiopharmaceuticals other than FDG are significantly more limited in their availability and are limited to PET centers with on-site cyclotrons. However, these additional agents open the door to many additional studies, including more specific tumor-imaging agents of certain tumors such as neuroblastoma. Another neurotransmitter, F-18-fluoro-L-dopa, is of benefit outside of the central nervous system for evaluating infantile hyperinsulism. The use of PET/CT in children is increasing quickly, particularly FDGI imaging of tumors. It is expected that over the next few years, its role will become increasingly better defined.

RANKL:osteoprotegerin ratio and bone mineral density in children with untreated juvenile dermatomyositis.

OBJECTIVE: To determine bone mineral density (BMD) in patients at the time of diagnosis of juvenile dermatomyositis (DM), to compare the RANKL:osteoprotegerin (OPG) ratio in patients with juvenile DM with that in healthy control subjects, and to evaluate whether BMD is associated with the RANKL:OPG ratio and the duration of untreated disease. METHODS: Thirty-seven children with juvenile DM were enrolled. Dual x-ray absorptiometry (DXA) was performed before treatment, and Z scores for the lumbar spine (L1-L4) were determined. The duration of untreated disease was defined as the period of time from the onset of rash or weakness to the time at which DXA was performed. Serum specimens obtained at the time of DXA were analyzed for concentrations of RANKL and OPG, using enzyme-linked immunosorbent assay. The RANKL:OPG ratio was also determined in 44 age-matched healthy control subjects. RESULTS: At the time of diagnosis of juvenile DM, patients had a significantly increased RANKL:OPG ratio compared with that in healthy children (mean +/- SD 2.19 +/- 3.03 and 0.13 +/- 0.17, respectively; P < 0.0001). In patients with a lumbar spine BMD Z score of -1.5 or lower, the RANKL:OPG ratio was significantly higher than that in patients with a lumbar spine BMD Z score higher than -1.5 (P = 0.038). Lumbar spine BMD Z scores (mean +/- SD -0.13 +/- 1.19 [range -2.10 to 2.85]) were inversely associated with the duration of untreated disease (R = -0.50, P = 0.003). CONCLUSION: Children with juvenile DM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to a lack of normal bone mineral accretion and a subsequent reduction in the lumbar spine BMD Z score. Patients with a longer duration of untreated juvenile DM have reduced lumbar spine BMD Z scores. These data suggest that early diagnosis could reduce the likelihood of reduced lumbar spine BMD in these patients by prompting intervention strategies at an early stage.

Newborn society of fetal urology grade 3 hydronephrosis is equivalent to preserved percentage differential function.

PURPOSE: In newborn hydronephrosis (HN), the level of differential function (%df) measured by diuretic renography (DR) is used to judge the need for pyeloplasty. As DR testing is complex, we sought to determine if grading the level of HN (Society of Fetal Urology grade, SFU Gr) by a simple ultrasound correlates with percentage differential function (%df) and thereby obviates the need to perform DR. MATERIALS AND METHODS: Between 1990 and 2003 our institution prospectively enrolled all cases of fetal HN who showed unilateral newborn SFU Gr HN > or =3. The cases underwent standardized testing. DR was done using the method of Well-Tempered Renography which was then followed by ultrasound (US). The US studies were performed while the hydration induced by DR was in effect. The level of %df was categorized as preserved (> or =40%) or reduced (<40%). Cases were excluded if there was an additional urological abnormality (e.g. ureterocele). RESULTS: There were 71 cases that met our study criteria. The SFU Gr HN was 3 (n=33) or 4 (n=38). Kidneys with SFU Gr 3 HN showed preserved %df (33/33,100%) (mean=50.1+/-3.6) significantly more often than kidneys with SFU Gr 4 HN (27/38, 71%) (mean=42.2+/-13.9) (RR=1.41, 95% CI (1.15-1.72), p<0.001). CONCLUSION: In newborns with a history of fetal HN, the postnatal finding of SFU Gr 3 HN uniformly correlates with preserved %df. Standardized hydration prior to US study is done to assure consistency in measurement of the SFU Gr HN. Determining the duration of the relationship between SFU Gr 3 HN and preserved %df will require prospective, longitudinal studies.

Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma.

PURPOSE: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB). PATIENTS AND METHODS: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated. RESULTS: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% +/- 11% v 80% +/- 18%, respectively; P =.13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% +/- 10% v 83% +/- 15%, respectively; P =.06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of >/= 3 compared to those with scores of less than 3 (0% v 58% +/- 11%; P =.002). There was no correlation between bone scan scores and outcome following induction therapy. CONCLUSION: MIBG scores >/= 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.

Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study.

PURPOSE: To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS: From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS: Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively. CONCLUSION: The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.