Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25-dihydroxy-vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1-fibroblast growth factor receptor 1 (FN1-FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1-FGFR1 proteins, the effectiveness of infigratinib, a FGFR1-3 tyrosine kinase inhibitor, was studied in an open-label, single-center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)-DOTATATE and 18Fluoride (18F)-Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment-related, dose-limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher-than-expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment-related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life-limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PTH 1-34 Replacement Therapy Has Minimal Effect on Quality of Life in Patients With Hypoparathyroidism.

In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and "brain fog." Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.3 years, with individualized fine-dosing titration. Prior to initiation of PTH 1-34, conventional therapy was optimized. The 36-Item Short Form (SF-36) Health Survey, Fatigue Symptom Inventory (FSI), and 6-minute walk test (6MWT) were assessed at PTH start (baseline), every 6 months on PTH, and after PTH discontinuation. The SF-36 assesses physical function (PF), physical role limitations (RP), bodily pain (BP), general health (GH), vitality (VT), emotional role limitations (RE), social function (SF), and mental health (MH). Compared to population norms, patients at baseline had lower scores in RP, GH, VT, and MH (p < 0.05), consistent with impaired QOL. With PTH therapy, only GH at 6 months and VT at 12 months improved (p < 0.05). At the last treatment time point, RP, VT, and SF improved compared to baseline (p < 0.05). However, follow-up scores were unchanged from baseline or last PTH treatment, except for SF, which had decreased at follow-up compared to on-PTH (p < 0.05). On the FSI, there were no changes in fatigue frequency; perceived interference was improved at 12 and 18 months and composite severity was improved only at 60 months (p < 0.05). The 6MWT measures did not change. In conclusion, hypoparathyroidism is associated with decreased QOL. Despite the bias in open-label studies to predict improvements in QOL, PTH therapy had limited and non-sustained effects on QOL, inconclusive changes in fatigue experience, and no change in the 6MWT. Although PTH 1-34 can adequately manage the hypocalcemia in hypoparathyroidism, its effects on QOL appear to be minimal. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

A randomized controlled trial of exercise in spinal and bulbar muscular atrophy.

OBJECTIVE: To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA). METHODS: Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up and go, sit-to-stand test, health-related quality of life, creatine kinase, and insulin-like growth factor-1. RESULTS: Functional exercise was well tolerated but did not lead to significant group differences in the primary outcome measure or any of the secondary measures. The functional exercise did not produce significantly more adverse events than stretching, and was not perceived to be difficult. To determine whether a subset of the subjects may have benefited, we divided them into high and low functioning based on baseline AMAT scores and performed a post hoc subgroup analysis. Low-functioning individuals receiving the intervention increased AMAT functional subscale scores compared to the control group. INTERPRETATION: Although these trial results indicate that functional exercise had no significant effect on total AMAT scores or on mobility, strength, balance, and quality of life, post hoc findings indicate that low-functioning men with SBMA may respond better to functional exercises, and this warrants further investigation with appropriate exercise intensity.

Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.

Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes.

Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism.

CONTEXT: Vitamin D therapy for hypoparathyroidism does not restore PTH-dependent renal calcium reabsorption, which can lead to renal damage. An alternative approach, PTH 1-34 administered twice daily, provides acceptable long-term treatment but is associated with nonphysiological serum calcium fluctuation. OBJECTIVE: Our objective was to compare continuous PTH 1-34 delivery, by insulin pump, with twice-daily delivery. RESEARCH DESIGN AND METHODS: In a 6-month, open-label, randomized, crossover trial, PTH 1-34 was delivered by pump or twice-daily sc injection. After each 3-month study period, serum and 24-h urine mineral levels and bone turnover markers were measured daily for 3 d, and 24-h biochemical profiles were determined for serum minerals and 1,25-dihydroxyvitamin D(3) and for urine minerals and cAMP. STUDY PARTICIPANTS AND SETTING: Eight patients with postsurgical hypoparathyroidism (mean ± sd age 46 ± 5.6 yr) participated at a tertiary care referral center. RESULTS: Pump vs. twice-daily delivery of PTH 1-34 produced less fluctuation in serum calcium, a more than 50% reduction in urine calcium (P = 0.002), and a 65% reduction in the PTH dose to maintain eucalcemia (P < 0.001). Pump delivery also produced higher serum magnesium level (P = 0.02), normal urine magnesium, and reduced need for magnesium supplements. Finally, pump delivery normalized bone turnover markers and significantly lowered urinary cross-linked N-telopeptide of type 1 collagen and pyridinium crosslinks compared with twice-daily injections (P < 0.05). CONCLUSION: Pump delivery of PTH 1-34 provides the closest approach to date to physiological replacement therapy for hypoparathyroidism.

Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies.

OBJECTIVE: To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM). METHODS: Patients with PM/DM (73 children and 45 adults) were assessed at baseline and reevaluated 6-9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0-10 scale with 144 subsets of 6 and 96 subsets of 8 muscle groups tested unilaterally. Expert consensus was used to rank the best abbreviated MMT subsets for face validity and ease of assessment. RESULTS: The Total, Proximal, and best MMT subsets had excellent internal reliability (Total MMT r(s) = 0.91-0.98), and consistency (Cronbach's alpha = 0.78-0.97). Inter- and intrarater reliability were acceptable (Kendall's W 0.68-0.76, r(s) = 0.84-0.95). MMT subset scores correlated highly with Total and Proximal MMT scores and with the Childhood Myositis Assessment Scale, and correlated moderately with physician global activity, functional disability, magnetic resonance imaging, and axial and distal MMT scores, and, in adults, with creatine kinase level. The standardized response mean for Total MMT was 0.56 in juveniles and 0.75 in adults. Consensus was reached to use a subset of 8 muscles (neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps, and ankle dorsiflexors) that performed as well as the Total and Proximal MMT, and had good face validity and ease of assessment. CONCLUSION: These findings aid in standardizing the use of MMT for assessing strength as an outcome measure for myositis.

Sensory motor and functional skills of dizygotic twins: one with Smith-Magenis syndrome and a twin control.

Smith-Magenis syndrome (SMS), the result of an interstitial deletion within chromosome 17p11.2, is a disorder that may include minor dysmorphic features, brachydactyly, short stature, hypotonia, speech delays, cognitive deficits, signs of peripheral neuropathy, scoliosis, and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behaviors. Physical and occupational therapists provide services for children who have the syndrome, whose genetic disorder is frequently not identified or diagnosed before 1 year of age. A comprehensive physical and occupational therapy evaluation was completed in nonidentical twins with one having SMS, using the Sensory Profile; Brief Assessment of Motor Function (BAMF); Peabody Developmental Motor Scales, Second Edition (PDMS-2); and Pediatric Evaluation of Disability Inventory (PEDI). This provides a framework for conducting assessments to enhance early detection and interdisciplinary management with this specialized population.

Neurodevelopment of children under 3 years of age with Smith-Magenis syndrome.

Systematic data regarding early neurodevelopmental functioning in Smith-Magenis syndrome are limited. Eleven children with Smith-Magenis syndrome less than 3 years of age (mean, 19 months; range, 5-34 months) received prospective multidisciplinary assessments using standardized measures. The total sample scored in the moderately to severely delayed range in cognitive functioning, expressive language, and motor skills and exhibited generalized hypotonia, oral-motor abnormalities, and middle ear dysfunction. Socialization skills were average, and significantly higher than daily living, communication, and motor abilities, which were below average. Mean behavior ratings were in the nonautistic range. According to exploratory analyses, the toddler subgroup scored significantly lower than the infant subgroup in cognition, expressive language, and adaptive behavior, suggesting that the toddlers were more delayed than the infants relative to their respective peers. Infants aged approximately 1 year or younger exhibited cognitive, language, and motor skills that ranged from average to delayed, but with age-appropriate social skills and minimal maladaptive behaviors. At ages 2 to 3 years, the toddlers consistently exhibited cognitive, expressive language, adaptive behavior, and motor delays and mildly to moderately autistic behaviors. Combining age groups in studies may mask developmental and behavioral differences. Increased knowledge of these early neurodevelopmental characteristics should facilitate diagnosis and appropriate intervention.

Intra-rater and inter-rater reliability of the 10-point Manual Muscle Test (MMT) of strength in children with juvenile idiopathic inflammatory myopathies (JIIM).

OBJECTIVE: Children with juvenile idiopathic inflammatory myopathies (JIIM) present with muscle inflammation and decreased strength that may affect their functional abilities. The purpose of this study was to determine the intra-rater and inter-rater reliability of the 0 to 10-point manual muscle testing method for children with JIIM. METHODS: For the intra-rater and inter-rater reliability studies, 10 and 9 children with JIIM participated, respectively. For intra-rater reliability, one pediatric therapist completed two assessments in one day with a one-hour break. For inter-rater reliability, four therapists assessed the same child within a single morning. RESULTS: Spearman correlations for intra-rater reliability ranged from 0.70 to 1.00. Kendall's W coefficient for inter-rater reliability of groups of muscles (total, proximal, distal, and peripheral) ranged from 0.51 to 0.76. CONCLUSIONS: The total, proximal, and peripheral Manual Muscle Test (MMT) score, using the 0-10 point scale, has acceptable reliability in JIIM patients.

Motor Skill Development of Children with HIV Infection Measured with the Peabody Developmental Motor Scales.

PURPOSE: Improved health care for pregnant women who are HIV+has minimized complications during delivery and resulted in a measurable cohort of children entering the health care system who are HIV+ with potential for motor disorders. This study was designed to determine how gross and fine motor skills were affected by HIV infection in children aged five years and younger using the Peabody Developmental Motor Scales, and to follow a subsample of these children for one and a half years to determine if their relative skill performances changed over time. METHODS: A sample of 143 children who were HIV+ was evaluated using the Peabody Developmental Motor Scales for their gross and fine motor skills. Their performance scores were compared with the Peabody normative values for age-matched healthy children. A subset of 22 children were reevaluated at six-month intervals (six months; one year;one year six months) to determine if their gross and fine motor skills would change. Raw scores and Peabody Developmental Motor Quotients (DMQ, normalized to the reference population) were calculated. RESULTS: The children who were HIV+ as a group performed below the 50th percentile of the normal reference population. During the one year six month study period, the children who were HIV+improved in raw scores but did not improve in relative (DMQ) scores. The exceptions were the fine motor skill subcategories of "grasping" and "hand use," for which the children who were HIV+performed comparably with the reference population. CONCLUSIONS: Clinicians working with children who are HIV+ should emphasize intervention strategies generally designed to develop all gross motor skills and the specific fine motor skills of "eye-hand coordination" and "manual dexterity."