Juvenile Paget disease (JPD) is a very rare disease, mainly caused by biallelic inactivating mutations in the TNFRSF11B gene that encodes osteoprotegerin. Owing to its rarity, the treatment of JPD is largely empirical. Accelerated bone turnover as assessed by biochemical markers, such as alkaline phosphatase (ALP), can be suppressed by bisphosphonate treatment, but it relapses if bisphosphonate treatment is discontinued. In this report, we describe our experience with long-term denosumab treatment in two adults with JPD, homozygous for the “Balkan” mutation (966_969delTGACinsCTT) in TNFRSF11B. Subject 1 started denosumab in age 35 and subject 2 in age 34. Both continue treatment until today, for 13.5 and 12 years, respectively. ALP was steadily normalized in both. Bone pain decreased and mobility improved. Hearing did not further deteriorate and no new fracture occurred. Vision remained unchanged in subject 2, but subject 1 experienced sudden vision loss of the right eye at age 46, which was successfully managed with intravitreal treatment with anti-vascular endothelial growth factor medications. In conclusion, long-term denosumab administration in adults with JPD, who had been previously treated with bisphosphonates, was safe and effective in terms of the skeletal disease, but it may not prevent the emergence of retinopathy.

In a 2015 study of SQSTM1 mutation carriers who had initial negative bone scintigraphy, we found that the rate of development of Paget's disease of bone (PDB) over 5 yr was low. We report here an additional 8-yr follow-up of this cohort, exploring the hypothesis that the rate of development of PDB would increase as the cohort aged. In the current study, 21 of 24 subjects from 2015 who had a negative bone scintiscan at baseline and at first follow-up, had a repeat scintiscan and measurement of total serum alkaline phosphatase activity. Two subjects with P392L mutations were identified as having PDB (monostotic in one case, 2 bones involved in the other), giving an incidence during this follow-up period of 1 per 87 patient years or 11.9 per 1000 patient years. This was contrary to our hypothesis, as the rate of development had decreased as the cohort aged. When we compared by survival analysis the age at presentation with symptomatic PDB in the older generation, we found that the age of onset was later and disease severity in the affected relatives was markedly less than in their clinically affected parents (p < .001). Our results are in keeping with other recently published studies and the general secular trend in PDB and support the idea that an important environmental-genetic interaction is involved with the development of PDB and that exposure to the putative environmental factor has substantially reduced.

Idiopathic juvenile osteoporosis (IJO) is a rare condition presenting with vertebral and metaphyseal fractures that affects otherwise healthy prepubertal children. Bone mineral density (BMD) measurements are very low. The primary problem appears to be deficient bone formation, with a failure to accrue bone normally during growth. The onset in childhood suggests IJO is a genetic disorder, and a number of reports indicate that some children carry heterozygous pathogenic variants in genes known to be associated with defective osteoblast function and low bone mass, most commonly LRP5 or PLS3. However, a positive family history is unusual in IJO, suggesting the genetic background can be complex. We describe a young man with classical IJO who was investigated with a bone fragility gene panel and whole genome sequencing. The proband was found to carry four variants in three different genes potentially affecting osteoblast function. From his mother he had inherited mutations in ALPL (p.Asn417Ser) and LRP5 (p.Arg1036Gln), and from his father mutations in LRP5 (p.Asp1551Alsfs*13) and activating transcription factor 4 (ATF4) (p.Leu306Ile). His sister had also inherited the LRP5 (p.Asp1551Alsfs*13) from her father, but not the ATF4 mutation. Their spinal BMD z-scores differed substantially (sister -1.6, father -3.2) pointing to the potential importance of the ATF4 mutation. Activating transcription factor 4 acts downstream from RUNX2 and osterix and plays an important role in osteoblast differentiation and function. This case, together with others recently published, supports the view that IJO can result from clustering of mutations in genes related to osteoblast development and function. Novel genes in these pathways may be involved. Our case also emphasizes the value of detailed study of other family members. After a bone biopsy had excluded a mineralization defect due to hypophosphatasia, the proband was treated with zoledronate infusions with good clinical effect. Idiopathic juvenile osteoporosis (IJO) is a rare but disabling condition presenting with vertebral and metaphyseal fractures that affects otherwise healthy prepubertal children. Bone mineral density measurements are very low. The primary problem appears to be deficient bone formation, with a failure to accrue bone normally during growth. The onset in childhood suggests IJO is a genetic disorder, but a positive family history is unusual, suggesting that its genetic basis can be complex. We describe a young man with classical IJO who was investigated with a bone fragility gene panel and whole genome sequencing. He was found to have inherited four variants in three different genes potentially affecting osteoblast function: from his mother an ALPL mutation and an LRP5 mutation, and from his father a different LRP5 mutation and a mutation in AFT4, which codes for a transcription factor important in osteoblast differentiation. Together with some recently published cases, the findings in this family indicate that IJO may have a polygenic etiology. Graphical Abstract

The cause of Paget’s disease of bone (PDB) is unknown. It emerged as a distinct entity in Britain in the late nineteenth century when it was prevalent, and florid presentation not uncommon. Epidemiological surveys in the 1970s showed that Britain had a substantially higher prevalence of PDB than any other country. Studies in the late twentieth and early twenty-first centuries have documented an unexplained change in presentation, with a greatly reduced prevalence and less severe disease than formerly. The emergence of PDB in Britain coincided with rapid industrialization which, in turn, was driven by the use of coal for energy. In the home, bituminous coal was customarily burnt on an open hearth for heating. Using data on coal production, population size, and estimates of domestic use, the estimated exposure to domestic coal burning rose threefold in Britain during the nineteenth century and began to fall after 1900. This pattern fits well with the decline in PDB documented from death certification and prevalence surveys. Colonists moving from Britain to North America, Australia and New Zealand established coal mines and also used coal for domestic heating. PDB was found in these settler populations, but was largely absent from people indigenous to these lands. In all parts of the world PDB prevalence has fallen as the burning of coal in open hearths for domestic heating has reduced. The nature of the putative factor in coal that could initiate PDB is unknown, but possible candidates include both organic and inorganic constituents of bituminous coal.

Journal of Bone and Mineral ResearchVolume 38, Issue 3 p. 451-451 Letter to the Editor Calcium Supplements in the Treatment of Hypoparathyroidism Tim Cundy, Corresponding Author Tim Cundy t.cundy@auckland.ac.nz orcid.org/0000-0003-4890-9400 Faculty of Medical & Health Sciences, University of Auckland, Auckland, Aotearoa New Zealand Address correspondence to: Tim Cundy, MD, Faculty of Medical & Health Sciences, University of Auckland, Auckland, Aotearoa New Zealand. Email: t.cundy@auckland.ac.nzSearch for more papers by this author Tim Cundy, Corresponding Author Tim Cundy t.cundy@auckland.ac.nz orcid.org/0000-0003-4890-9400 Faculty of Medical & Health Sciences, University of Auckland, Auckland, Aotearoa New Zealand Address correspondence to: Tim Cundy, MD, Faculty of Medical & Health Sciences, University of Auckland, Auckland, Aotearoa New Zealand. Email: t.cundy@auckland.ac.nzSearch for more papers by this author First published: 11 September 2022 https://doi.org/10.1002/jbmr.4692 This Letter to the Editor comments on the original article by Naciu AM, et al. https://doi.org/10.1002/jbmr.4564 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume38, Issue3March 2023Pages 451-451 RelatedInformation

Background and Aims:Diabetic gastroenteropathy is associated with poor glycemic control and morbidity in people with type 1 diabetes (T1D). There is a lack of noninvasive techniques to assess and monitor gastric abnormalities. We aimed to define phenotypes of gastric myoelectrical abnormalities in people with longstanding T1D with and without symptoms using a novel noninvasive body surface gastric mapping (BSGM) device. Methods:BSGM was performed on people with T1D of >10 years duration and matched controls, employing Gastric Alimetry (Alimetry, New Zealand), comprising of a high-resolution 64-channel array, validated symptom-logging App, and wearable reader. Results:Thirty-two people with T1D were recruited (15 with a high symptom burden), and 32 controls. Those with symptoms showed more unstable gastric myoelectrical activity (Gastric Alimetry Rhythm Index 0.39 vs 0.51, P = .017; and lower average spatial covariance 0.48 vs 0.51, P = .009) compared with controls. Symptomatic patients also had a higher prevalence of peripheral neuropathy (67% vs 6%, P = .001), anxiety/depression diagnoses (27% vs 0%, P = .001), and higher mean hemoglobin A1C levels (76 vs 56 mmol/mol, P < .001). BSGM defined distinct phenotypes in T1D participants including those with markedly unstable gastric rhythms (4/32, 12.5%) and abnormally high gastric frequencies (9/32, 28%). Deviation in gastric frequency was positively correlated with symptoms of bloating, upper gut pain, nausea and vomiting, and fullness (R > 0.35, P < .05). Conclusion:Gastric symptoms in people with longstanding T1D correlate with myoelectrical abnormalities on BSGM evaluation, in addition to glycemic control, psychological comorbidities, and peripheral neuropathy. BSGM using Gastric Alimetry identified a range of myoelectrical phenotypes, presenting targets for diagnosis, monitoring, and therapy.

Osteoblast Wnt/β-catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low-density lipoprotein receptor-related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β-propeller of LRP5 or LRP6, thereby disassociating these cognate co-receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle-aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z-scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Both obesity and type 2 diabetes are associated with an increased risk of skin and soft tissue (SSTI), urinary tract, and lower respiratory tract infections but it is not clear whether the incidence of such infections is reduced after bariatric surgery. In people accepted onto our publicly funded bariatric program, we recorded unplanned admissions to public hospitals over a median follow-up of 4.5 years in those successfully undergoing surgery and in those who withdrew from the program. Rates of admission for the composite outcome (SSTI, urinary tract, or lower respiratory infection) were compared. Of 774 people accepted onto the program, 49% underwent surgery. Infections accounted for 27% of unplanned admissions in those not completing surgery and 13% of those who underwent surgery (p < 0.001). The rate of admission was 60% lower in people who underwent surgery than those who did not: 4.3 vs 12.2 per 100 patient-years (P < 0.002), a difference maintained across 8 years’ follow-up. The impact of surgery was independent of enrolment age, BMI, or diabetes and smoking status. Of the three types of infection in the composite outcome, SSTI were the most prevalent and showed the greatest reduction (p < 0.0001). The median day stay for infection was 0.5 day less in those who underwent surgery (p < 0.01). Hospitalization for these three infectious diseases in people undergoing bariatric surgery was lower than that in people enrolled in the bariatric program but not completing surgery. The effect was greatest for SSTI, and sustained to at least 8 years.

AIM: Lower socio-economic status (SES) is linked to greater morbidity in people with young-onset type 2 (T2D) and type 1 diabetes (T1D). We assessed healthcare utilisation from this population and the impact of SES. METHODS: Retrospective analysis of 1,350 people with T2D and 731 with T1D diagnosed between 15-30 years of age referred to secondary diabetes services in Auckland, New Zealand. Primary care visits, referral to/attendance at diabetes clinics, and hospital admissions were recorded; their relationship to a validated national index of deprivation (NZDep) was assessed. RESULTS: The proportion with primary care attendance was similar in both groups with no significant variation with NZDep. For T2D, NZDep was a predictor of delayed referral (>= 1-year post-diagnosis) to diabetes services, following adjustment for age and HbA(1c) in the year of diagnosis (OR 1.15 for every decile increase in NZDep, 95% CI 1.07-1.24, p=0.0003). The median number of appointments offered over a 2-year period was greater for T1D (2.0 (IQR 0, 7) vs (0 (IQR 0, 2), p<0.001); non-attendance increased with NZDep for T2D (p=0.016). The proportion with hospital admissions was similar in both groups and increased with NZDep (T1D p<0.001, T2D p=0.015). CONCLUSION: SES impacts several measures of healthcare utilisation. Current healthcare models are inadequately servicing people with young-onset T2D.

Introduction Young people with type 2 diabetes (T2D) develop complications earlier than those with type 1 diabetes (T1D) of comparable duration, but it is unclear why. This apparent difference in phenotype could relate to relative inequality. Research design and methods Cross-sectional study of young people referred to secondary diabetes services in Auckland, Aotearoa-New Zealand (NZ): 731 with T1D and 1350 with T2D currently aged <40 years, and diagnosed between 15 and 30 years. Outcome measures were risk factors for complications (glycemic control, urine albumin/creatinine ratio (ACR), cardiovascular disease (CVD) risk) in relation to a validated national index of deprivation (New Zealand Deprivation Index (NZDep)). Results Young people with T2D were an average 3 years older than those with T1D but had a similar duration of diabetes. 71% of those with T2D were of Māori or Pasifika descent, compared with 24% with T1D (p<0.001). T1D cases were distributed evenly across NZDep categories. 78% of T2D cases were living in the lowest four NZDep categories (p<0.001). In both diabetes types, body mass index (BMI) increased progressively across the NZDep spectrum (p<0.002), as did mean glycated hemoglobin (HbA1c) (p<0.001), the prevalence of macroalbuminuria (p≤0.01), and CVD risk (p<0.001). Adjusting for BMI, diabetes type, and duration and age, multiple logistic regression revealed deprivation was the strongest risk factor for poorly controlled diabetes (defined as HbA1c >64 mmol/mol, >8%); OR 1.17, 95% CI 1.13 to 1.22, p<0.0001. Ordinal logistic regression showed each decile increase in NZDep increased the odds of a higher ACR by 11% (OR 1.11, 95% CI 1.06 to 1.16, p<0.001) following adjustment for BMI, blood pressure, diabetes type and duration, HbA1c, and smoking status. Multiple linear regression indicated a 4% increase in CVD risk for every decile increase in NZDep, regardless of diabetes type. Conclusions The apparent more aggressive phenotype of young-onset T2D is at least in part explicable by relative deprivation.

Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.

INTRODUCTION: Macroalbuminuria in people with type 2 diabetes is common among Pasifika peoples and is associated with end-stage kidney disease and major cardiovascular disease. AIM: In a primary care practice catering for Pasifika people, to determine the time after first recognition of macroalbuminuria to the occurrence of major cardiovascular and renal events, and to examine the relationship with retinopathy status. METHODS: In a retrospective observational cohort study, we documented the occurrence of major cardiovascular events and amputations, end-stage kidney disease and death in 115 people with type 2 diabetes reviewed by a specialist diabetes physician at the Langimalie Tongan Health practice between 2005 and 2018. The follow up was 1-19 (median 9.5) years from the first recognition of macroalbuminuria (albumin:creatinine ratio of >30 g/mol). Survival was described by using Kaplan-Meier analysis. RESULTS: Macroalbuminuria was detected a mean of 9 years after the diagnosis of diabetes, at a mean age of 52 (standard deviation 12) years. Within 6 years of macroalbuminuria detection, 4% of people had died, 15% had reached end-stage kidney disease, 15% had cardiovascular events or amputations and 30% had the composite outcome of any of these. Within 12 years, the respective proportions were: 24%, 29%, 20% and 48%. The composite outcome was less frequent (P < 0.002) in patients without retinopathy at the time macroalbuminuria was recognised. Compared to patients with retinopathy, this group were younger (P = 0.025), more obese (P < 0.0001), had better baseline renal function (P = 0.018) and a shorter interval between the diagnosis of diabetes and recognition of macroalbuminuria (P < 0.0001). DISCUSSION: In this Pasifika population, macroalbuminuria was a marker for serious adverse cardiovascular and renal disease, and mortality, but in the 29% of patients without retinopathy at the time of recognition of macroalbuminuria, the natural history was more benign. The management of such comorbid patients is a substantial challenge for primary health-care services.

Brittle cornea syndrome is a rare recessively inherited disorder (a sub-type of Ehlers-Danlos syndrome) with a clinical presentation dominated by corneal fragility and deafness. There have been suggestions that it may also have a bone fragility phenotype, but there has been little detailed description. We describe two siblings with brittle cornea syndrome due to compound heterozygous mutations in ZNF469 who had sustained ten or more fractures, the majority before the age of 15. When investigated as adults they had osteopenia, with lower z-scores than their parents who each carried one mutation. A bone biopsy from one sibling showed reduced cortical porosity. Both parents, who were heterozygous mutation carriers, had also suffered fractures but had normal bone density. This data supports the view that brittle cornea syndrome may have a bone fragility phenotype.

In people with chronically severe hyperglycemia, a paradoxical deterioration of microvascular complications may occur if glycemic control is improved very rapidly. This “early worsening” is well documented for retinopathy (1) and painful neuropathy (2), but not nephropathy. We describe three men and one woman (ages 38–61 years) who presented with marked hyperglycemia. Type 2 diabetes had not previously been recognized in three cases, but the presence of retinopathy and signs of neuropathy indicated diabetes of at least 5 years’ duration. In the fourth case, diabetes had been diagnosed 6 years earlier, but the subject had declined treatment. In case 1, diabetes was recognized coincident with Hodgkin lymphoma, which was successfully treated with nonnephrotoxic chemotherapy. In case 2, diabetes was recognized at presentation with sepsis and acute kidney injury that rapidly improved with volume repletion and antibiotic treatment. None were smokers, had cardiovascular disease, or had a family history of renal disease. At presentation mean values were as follows: BMI 25.0 kg/m2, A1C 118 mmol/mol (12.9%), and estimated glomerular filtration rate (eGFR) 70 mL/min/1.73 m2. One subject was treated with insulin from diagnosis; one took insulin for 3 months, then transferred to oral hypoglycemic agents; and two were treated only with …

ObjectiveHypophosphatemic rickets with hypercalciuria (HHRH) is a rare, recessively-inherited form of rickets caused by homozygous or compound heterozygous mutations in the SLC34A3 gene that encodes the renal tubular phosphate transporter protein NaPi2c. The bone phenotype varies from severe rickets to no disease. Accurate diagnosis is important as the treatment differs from other forms of rickets.MethodsThe patient was a 12-year-old boy from the Indian subcontinent with florid hypophosphatemic rickets. A targeted gene panel to search for mutations in genes associated with inherited forms of rickets was performed. We also completed a literature search of published cases of HHRH.ResultsThe targeted gene panel demonstrated a novel homozygous SLC34A3 mutation: c.1339 G>A (p.Ala447Thr). His parents were heterozygous for the mutation. In our literature review we found that people with homozygous SLC34A3 mutations were more likely to have rickets than those with compound heterozygous mutations (85% versus 45%, p<0.002) and that serum phosphate z scores were lower in those with rickets than those without (-3.3 with a standard deviation of 1.5 versus -2.1 with a standard deviation of 1.5, p<0.005).ConclusionThe bone phenotype of HHRH is related to the nature of the mutation and serum phosphate levels. Targeted gene panels can aid in the accurate diagnosis of inherited forms of rickets, and facilitate correct treatment.

To The Editor We commend Hughes and colleagues1 for their study entitled “Observations on the Natural History of Camurati–Engelmann Disease”, published in the Journal of Bone and Mineral Research. In this study, 10 members of a family carrying a common TGFB1 gene mutation had their symptoms evaluated and both skeletal radiographs and scintigraphies performed. Here, we propose a potential role for whole-body magnetic resonance imaging (WB-MRI) in evaluations of Camurati–Engelmann disease. A 7-year-old female child presented with chronic fatigue, muscle weakness, and hypotonia, especially in the shoulder and pelvic girdle. Her blood count and serum levels of calcium, potassium, sodium, phosphate, and creatine kinase were normal. A 3-Tesla WB-MRI was performed, without sedation, to address a suspicion of inflammatory myopathy. Symmetrical edema was observed in the bone marrow of the diaphyses and metadiaphyseal regions of the femur, tibia, radius, ulna, and humerus. This edema was associated with cortical concentric thickening and irregularities, with bilateral diaphyseal enlargement. Periosteal soft tissue edema was also noted in these regions. No edema was observed in the epiphyseal regions (Fig. 1). The scan took around 35 min. A genetic analysis revealed a heterozygous mutation present in the patient's TGFB1 gene. None of the child's family members presented similar symptoms. Over the past few years, WB-MRI has gained greater attention with a rapidly growing number of indications. WB-MRI allows lesions to be detected and comprehensive evaluations of treatment response to be conducted in many oncologic and nononcologic disorders. In addition, WB-MRI has a clinically viable duration and excellent soft tissue contrast, especially when performed with 3-Tesla scanners.2 WB-MRI can cover either the body from head to toe or it can be more limited (eg, from “eyes to thighs”), depending on the basis of the examination. Overall, WB-MRI provides exquisite anatomical resolution with excellent tissue contrast and high sensitivity to bone and soft tissue alterations.2, 3 Initially, WB-MRI was used to assess the entire skeleton in oncology applications. Subsequently, WB-MRI has emerged as a technique for detecting and quantifying bone metastasis, multiple myeloma, and lymphoma. For these indications, WB-MRI has been found to outperform bone scintigraphy and radiographs for lesion detection.3 Thus, it has become the modality of choice for disease staging and treatment monitoring. In addition to oncologic applications, WB-MRI is progressively being applied to the detection and characterization of benign multisystemic and multifocal diseases that affect bones, joints, tendons, entheses, or neurovascular structures.3 For example, the main benign diseases that are assessed by WB-MRI include seronegative spondyloarthropathies, synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, systemic sclerosis, and idiopathic inflammatory myopathies. In pediatric patients, WB-MRI has the advantage of providing a comprehensive evaluation of the body without exposure to ionizing radiation. WB-MRI also reduces the number of examinations performed under sedation. Currently, WB-MRI is prescribed in pediatric cases of chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis, and juvenile dermatomyositis, as well as for pediatric patients with fevers of unknown origin.4 In Camurati–Engelmann disease, MRI can show exuberant diffuse cortical thickening in long bones diaphysis in addition to increases in diaphysis diameter. In fluid-sensitive sequences, such as T2-weighted imaging with fat saturation and short tau inversion recovery (STIR), intramedullary hyperintense signals are observed. Contrast enhancement after i.v. gadolinium injection is also observed due to edema and inflammatory activity, secondary to increased bone turnover. Furthermore, MRI can detect muscle atrophy. MRI is also as effective as CT for demonstrating hyperostotic bone and compressive effects on cranial nerves.5 To the best of our knowledge, the use of WB-MRI in cases of Camurati–Engelmann disease has not been evaluated. However, previous reports have described the use of WB-MRI in other skeletal dysplasias such as Trevor disease. WB-MRI can identify unsuspected lesions outside the limited field of view of the usual MRI scan or conventional radiography, and can identify characteristic distribution patterns of lesions. This ability to detect additional unknown lesions represents a clear therapeutic impact of WB-MRI.6 The clinical applicability of WB-MRI has contributed to greater recognition and use of this technique as a state-of-the-art evaluation method for various diseases. However, further investigation is needed to develop the technique for more clinical purposes and to reduce its cost, in addition to evaluate the advantages of WB-MRI over standard radiographic studies for early lesion detection, for evaluation of lesions distribution, and for treatment evaluation in bone dysplasias such as Camurati–Engelmann disease. The authors have no conflicts of interest to declare. Authors' roles: DGC: Substantial contributions to the conception and design of the work; drafting the work and revising it critically for important intellectual content; CC: Acquisition of data for the work; revising the work critically for important intellectual content; APQCA: Analysis of data for the work; revising the work critically for important intellectual content; SM: Acquisition of data for the work; revising the work critically for important intellectual content; FMC: Interpretation of data for the work; revising the work critically for important intellectual content. All authors had final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The mitochondrial DNA mutation mt.3243A>G is most commonly associated with maternally inherited diabetes and deafness (MIM 52,000), but it has protean phenotypes including renal disease due to focal segmental glomerulosclerosis. We describe monozygotic twins who both harboured this mutation and developed ESRD. Although otherwise genetically identical, the twins differed in their peripheral blood leucocyte levels of circulating mt.3243A>G heteroplasmy: 20 versus 10%, when assessed at 42 years of age. The twin with the higher heteroplasmy load developed end-stage kidney disease 15 years earlier than her sister. A review of the published literature supports a relationship between heteroplasmy level and the age at the development of the end stage of renal failure in patients with mt.3243A>G-related kidney disease.

Juvenile Paget's disease (JPD) is a rare recessively-inherited bone dysplasia. The great majority of cases described to date have had homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin. We describe a boy who presented with recurrent clavicular fractures following minor trauma (8 fractures from age 2 to 11). He was of normal height and despite mild lateral bowing of the thighs and anterior bowing of the shins he remained physically active. Abnormal modelling was noted in ribs and humeri on clavicular radiographs, and a skeletal survey at the age of 7 showed generalised diaphyseal expansion of the long bones with thickening of the periosteal and endosteal surfaces of the cortices. On biochemical evaluation, serum alkaline phosphatase was noted to be persistently elevated. The diagnosis of JPD was confirmed by the finding of compound heterozygous mutations in TNFRSF11B: a maternally-inherited A>G missense mutation at position 1 of the first amino acid codon (previously reported) and a paternally-inherited splice acceptor site mutation in intron 3 at a highly conserved position (not previously reported). Bioinformatics analysis suggested both mutations were disease-causing. Compound heterozygote mutations in TNFRSF11B causing JPD have been previously reported only once - in a boy who also had a relatively mild skeletal phenotype. The milder features may lead to delay in diagnosis and diagnostic confusion with other entities, but the extraskeletal features of JPD may nonetheless develop.