Spontaneous reshaping of vertebral fractures in an adolescent with osteogenesis imperfecta.

Background: Vertebral compression fractures (VFs) are a common and severe finding in patients with osteoporosis. In children, VFs have the unique potential to reshape and regain their original configuration. Spontaneous vertebral body reshaping (i.e., medication-unassisted) has been reported in secondary osteoporosis. Here we describe a previously unreported spontaneous vertebral reshaping in an adolescent with osteogenesis imperfecta (OI) with multiple vertebral fractures. Case report: A 17-year-old female was diagnosed with OI type I at 5 years of age caused by a novel frameshift variant in COL1A1 (NM_000088.4: c.540delC; p.Met181TrpfsTer84). Due to parental reservations about medication, she had never received bisphosphonate or any other bone active therapy. A lateral spine X-ray demonstrated transparent bones and no VF. However, previous spine X-rays taken at age of 6 years at an external institution showed VFs in T5-7 (Genant semiquantitative method grade I-II). The two lateral spine x-rays, taken 11 years apart, demonstrate that substantial spontaneous vertebral reshaping occurred without bone active therapy during puberty. Discussion: Vertebral reshaping is explained by the stabilization of bone mineral density (BMD) and the remaining growth capacity the children. We hypothesize that spontaneous reshaping may occur in milder forms of OI, and that puberty may be a key mediator of the phenomenon. In all children with OI and vertebral fractures, we nevertheless recommend bisphosphonate therapy since it improves bone mass, BMD, vertebral shape, physical activity and reduces fracture rates.

The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis.

Objective: Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. Methods: PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Results: Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Conclusion: Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Influence of maternal socioeconomic deprivation and living environment on newborn bloodspot 25-hydroxyvitamin D levels.

Objectives: Vitamin D deficiency in neonates can have life-threatening consequences, hence the knowledge of risk factors is essential. This study aimed to explore the effect of maternal socioeconomic status (SES) on newborn 25-hydroxyvitamin D (25OHD) concentrations. Design: Over two 1-week periods (winter and summer of 2019), 3000 newborn heel prick dried blood spots (DBS) and additional data of newborns, from a regional newborn screening laboratory (52° N) in the West Midlands, UK, were gathered. Post code was replaced with lower layer super output area (LSOA). Index of Multiple Deprivation (IMD) quintiles for the corresponding LSOA was used to assess SES [quintile one (Q1): most deprived 20%, quintile five (Q5): least deprived 20%]. Each of the seven domains of deprivation were examined (income, employment, education, health, barriers to housing and services, crime and living environment). 25OHD was measured on 6mm sub-punch from DBS using quantitative liquid chromatography tandem mass spectrometry and equivalent plasma values were derived. Results: In total 2999 (1500 summer-born, 1499 winter-born) newborn DBS (1580 males) were analysed. Summer-born newborns had significantly higher 25OHD (IQR) concentrations [49.2 (34.3; 64.8) nmol/l] than winter-born newborns [29.1 (19.8; 40.6) nmol/l, p<0.001].25OHD levels varied significantly between the different IMD quintiles in the whole (p<0.001) and summer-born cohort (p<0.001), but not in the winter-born cohort (p=0.26), whereby Q1 had the lowest 25OHD concentrations. Among the domains of deprivation, living environment had a significant influence on 25OHD levels (ß=0.07, p=0.002). In this subdomain, 25OHD levels varied significantly between quintiles in the whole (p<0.001) and summer-born cohort (mean 25OHD Q1 46.45 nmol/l, Q5 54.54 nmol/l; p<0.001) but not in the winter-born cohort (mean 25OHD Q1 31.57 nmol/l, Q5 31.72 nmol/l; p=0.16). In a regression model, living environment was still significant (p=0.018), albeit less than season of birth and ethnicity. Conclusion: Among the seven domains of deprivation, maternal living environment had the greatest effect on newborn 25OHD levels. Whilst improved living environment positively influenced vitamin D status in the summer-born babies, winter-born had low 25OHD levels irrespective of the environment. Strategies such as enhanced supplementation and food fortification with vitamin D should be considered to overcome the non-modifiable main risk factors for vitamin D deficiency.

A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inherited genetic disorder characterized by frequent bone fractures and reduced bone mass. Most cases of OI are caused by dominantly inherited heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2. Here we describe a five-year-old boy with typical clinical, radiological and bone ultrastructural features of OI type I. Establishing the molecular genetic cause of his condition proved difficult since clinical exome and whole exome analysis was repeatedly reported negative. Finally, manual analysis of exome data revealed a silent COL1A2 variant c.3597 T > A (NM_000089.4), which we demonstrate activates a cryptic splice site. The newly generated splice acceptor in exon 50 is much more accessible than the wild-type splice-site between the junction of exon 49 and 50, and results in an in-frame deletion of 24 amino acids of the C-terminal propeptide. In vitro collagen expression studies confirmed cellular accumulation and decreased COL1A2 secretion to 45%. This is the first report of a cryptic splice site within the coding region of COL1A2. which results in abnormal splicing causing OI. The experience from this case demonstrates that routine diagnostic approaches may miss cryptic splicing mutations in causative genes due to the lack of universally applicable algorithms for splice-site prediction. In exome-negative cases, in-depth analysis of common causative genes should be conducted and trio-exome analysis is recommended.

Recombinant human parathyroid hormone (1-84) replacement therapy in a child with hypoparathyroidism.

First line conventional therapy of hypoparathyroidism comprises oral calcium and active vitamin D analogues. This approach may fail to correct hypocalcemia and hyperphosphatemia caused by the absence of parathyroid hormone and carries the risk of long-term complications including ectopic calcifications and renal damage. Full-length recombinant human parathyroid hormone (rhPTH[1-84]) is approved for the treatment of hypoparathyroidism in adults refractory to conventional therapy. To date, there is no data in children. Here, we report the successful use of rhPTH(1-84) in a 5-year old girl with hypoparathyroidism and concomitant chronic diarrhea manifesting as part of the autoimmune polyglandular syndrome type 1. Prior to starting rhPTH(1-84), the patient had been on conventional and later on rhPTH(1-34) continuous pump therapy. Conventional therapy failed to meet serum and urinary calcium target levels, whilst the pump therapy wasn't well tolerated and posed handling difficulties. Dose optimization for rhPTH(1-84) was informed by serum ionized calcium, spot urinary calcium-to-creatinine ratio and 24-hour urinary calcium excretion. Twice-daily subcutaneous injections of rhPTH(1-84) with a total dose of 3.35 µg/kg/d was well-tolerated, raised serum ionized calcium to target range (1.05-1.15 mmol/L) and normalized serum phosphate levels. Urinary calcium excretion was slightly above the recommended limit of 4 mg/kg/24 h, but improved compared to conventional therapy, with no evidence of nephrocalcinosis. Twice-daily administration stabilized serum calcium and phosphate levels compared to once-daily injections. rhPTH(1-84) treatment was well tolerated and the girl did not manifest any acute clinical complications of hypoparathyroidism throughout the entire observation period. Our experience with this case indicates that rhPTH(1-84) may be a physiological hormone replacement for managing hypoparathyroidism in children.