Real-world non-interventional post-authorization safety study of long-term use of burosumab in children and adolescents with X-linked hypophosphatemia: first interim analysis.

Background: X-linked hypophosphatemia (XLH) is a rare, progressive disorder characterized by excess fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D synthesis. Burosumab is a recombinant human monoclonal antibody that inhibits FGF23, restoring patient serum phosphate levels. Safety data on long-term burosumab treatment are currently limited. Objectives: This post-authorization safety study (PASS) aims to monitor long-term safety outcomes in children and adolescents (1-17 years) treated with burosumab for XLH. This first interim analysis reports the initial PASS safety outcomes. Design: A 10-year retrospective and prospective cohort study. Methods: This PASS utilizes International XLH Registry (NCT03193476) data, which includes standard diagnostic and monitoring practice data at participating European centers. Results: At data cut-off (13 May 2021), 647 participants were included in the International XLH Registry; 367 were receiving burosumab, of which 67 provided consent to be included in the PASS. Mean (SD) follow-up time was 2.2 (1.0) years. Mean (SD) age was 7.3 (4.3) years (range 1.0-17.5 years). Mean duration of burosumab exposure was 29.7 (25.0) months. Overall, 25/67 participants (37.3%) experienced ⩾1 adverse event (AE) during follow-up; 83 AEs were reported. There were no deaths, no AEs leading to treatment withdrawal, nor serious AEs related to treatment. The most frequently reported AEs were classified as 'musculoskeletal and connective tissue disorders', with 'pain in extremity' most frequently reported, followed by 'infections and infestations', with 'tooth abscess' the most frequently reported. Conclusion: In this first interim analysis of the PASS, covering the initial 2 years of data collection, the safety profile of burosumab is consistent with previously reported safety data. The PASS will provide long-term safety data over its 10-year duration for healthcare providers and participants with XLH that contribute to improvements in the knowledge of burosumab safety. Trial registration: European Union electronic Register of Post-Authorisation Studies: EUPAS32190.

The Diagnostic Odyssey in Children and Adolescents With X-linked Hypophosphatemia: Population-Based, Case-Control Study.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic disorder causing renal phosphate wasting, which predicates musculoskeletal manifestations such as rickets. Diagnosis is often delayed. OBJECTIVE: To explore the recording of clinical features, and the diagnostic odyssey of children and adolescents with XLH in primary care electronic healthcare records (EHRs) in the United Kingdom. METHODS: Using the Optimum Patient Care Research Database, individuals aged 20 years or younger after January 1, 2000, at date of recorded XLH diagnosis were identified using Systematized Nomenclature of Medicine Clinical Terms (SNOMED)/Read codes and age-matched to 100 controls. Recording of XLH-related clinical features was summarized then compared between cases and controls using chi-squared or Fisher's exact test. RESULTS: In total, 261 XLH cases were identified; 99 met the inclusion criteria. Of these, 84/99 had at least 1 XLH-related clinical feature recorded in their primary care EHR. Clinical codes for rickets, genu varum, and low phosphate were recorded prior to XLH diagnosis in under 20% of cases (median of 1, 1, and 3 years prior, respectively). Rickets, genu varum, low phosphate, nephrocalcinosis, and growth delay were significantly more likely to be recorded in cases. CONCLUSION: This characterization of the EHR phenotypes of children and adolescents with XLH may inform future case-finding approaches to expedite diagnosis in primary care.

A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE.

By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.

The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. RESULTS: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. CONCLUSION: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.

OBJECTIVES: To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). STUDY DESIGN: A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. RESULTS: Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. CONCLUSION: Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

A Multidisciplinary and a Comprehensive Approach to Reducing Fragility Fractures in Preterm Infants.

With advances in neonatal care, bone fractures prior to discharge from the hospital in preterm infants receiving contemporary neonatal care, are rare. Nevertheless, such fractures do occur in very low birth weight and extremely low birth weight infants who go on to develop metabolic bone disease of prematurity (MBDP), with or without secondary hyperparathyroidism. MBDP is a multifactorial disorder arising from the disruption of bone mass accrual due to premature birth, postnatal immobilisation, and loss of placental oestrogen resulting in bone loss, inadequate provision of bone minerals from enteral and parenteral nutrition, and medications that leach out bone minerals from the skeleton. All of these factors lead to skeletal demineralisation and a decrease in bone strength and an increased risk of fractures of the long bones and ribs. Secondary hyperparathyroidism resulting from phosphate supplements, or enteral/parenteral feeds with a calcium-to-phosphate ratio of < 1.3:1.0 leads to subperiosteal bone resorption, cortical thinning, and further skeletal weakening. Such fractures may occur from routine handling and procedures such as cannulation. Most fractures are asymptomatic and often come to light incidentally on radiographs performed for other indications. In 2015, we instituted a comprehensive and multidisciplinary Neonatal Bone Health Programme (NBHP), the purpose of which was to reduce fragility fractures in high-risk neonates, by optimising enteral and parenteral nutrition, including maintaining calcium-to-phosphate ratio ≥1.3:1, milligram to milligram, biochemical monitoring of MBDP, safe-handling of at-risk neonates, without compromising passive physiotherapy and skin-to-skin contact with parents. The at-risk infants in the programme had radiographs of the torso and limbs at 4 weeks and after 8 weeks from enrolment into the program or before discharge. Following the introduction of the NBHP, the bone fracture incidence reduced from 12.5% to zero over an 18-month period.

An Unusual Case of Transient Cardiac Calcification Identified on Antenatal Echocardiography: A Generalized Arterial Calcification of Infancy (GACI) Like Presentation.

Generalised arterial calcification of infancy (GACI) is an ultra-rare life-threatening genetic disorder. Arterial calcification is identified during foetal ultrasound scan (USS) as increased cardiac and/or vascular echogenicity. Inorganic pyrophosphate (PPi) is the main inhibitor of arterial calcification. Pathogenic variants in ENPP1, ABCC6 and NT5E causing low PPi lead to ectopic calcifications. Rheumatoid arthritis (RA) is an acquired condition that can also lead to arterial calcification in adults. We present an extremely rare case of a transient GACI-like condition identified during foetal echocardiogram of an infant born to a mother diagnosed with RA, which spontaneously resolved postnatally. This case highlights that foetal ultrasound scans of pregnant women with RA should be carefully evaluated for cardiovascular calcifications.

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description.

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year. Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab. Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports. Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab. Registry identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

The skeletal muscle phenotype of children with Neurofibromatosis Type 1 - A clinical perspective.

Neurofibromatosis type 1 (NF1) can affect multiple systems in the body. An under recognised phenotype is one of muscle weakness. Clinical studies using dynamometry and jumping mechanography have demonstrated that children with NF1 are more likely to have reduced muscle force and power. Many children with NF1 are unable to undertake physical activities to the same level as their peers, and report leg pains on physical activity and aching hands on writing. Children and adolescents with NF1 reporting symptoms of muscle weakness should have a focused assessment to exclude alternative causes of muscle weakness. Assessments of muscle strength and fine motor skills by physiotherapists and occupational therapists can provide objective evidence of muscle function and deficits, allowing supporting systems in education and at home to be implemented. In the absence of an evidence base for management of NF1-related muscle weakness, we recommend muscle-strengthening exercises and generic strategies for pain and fatigue management. Currently, trials are underway involving whole-body vibration therapy and carnitine supplementation as potential future management options.

An Infant with Asymptomatic Vitamin D Intoxication: A Prolonged and Sustainable Recovery.

Vitamin D intoxication (VDI) usually develops due to inappropriate use of vitamin D in high doses by the families of infants with complaints suggestive of vitamin D deficiency such as delayed teething, knock knees, or delayed walking. We present here an experience of treating an infant with asymptomatic VDI that had a prolonged course of recovery and a sustainable level of vitamin D over a follow-up period of 2.5 years. In our patient, vitamin D started to drop steadily after a month of stopping vitamin D supplements but not to a normal level. It reached an acceptable level only after six months. This case emphasizes the importance of educating parents about the empirical use of vitamin D over the counter, assessing the baseline level of serum vitamin D level prior to initiation of treatment and highlights the value of verifying additional dietary sources of vitamin D or oral supplements in patient's history.

Successful use of cinacalcet monotherapy in the management of siblings with homozygous calcium-sensing receptor mutation.

OBJECTIVES: Neonatal severe hyperparathyroidism (NSHPT) due to pathogenic mutations in the calcium-sensing receptor (CASR) is a serious medical condition that can lead to symptomatic hypercalcaemia and has detrimental effects on a child's growth and development. What is new: This report adds to evidence that homozygous CASR mutations can be managed with cinacalcet monotherapy as an alternative to parathyroidectomy. And, early use of cinacalcet in NSHPT can result in improvements in symptoms, growth and developmental milestones. CASE PRESENTATION: We present two siblings with NSHPT due to homozygous mutation in the CASR gene with moderate hypercalcaemia. Both were treated with cinacalcet monotherapy and showed significant improvement in growth parameters including head circumference, developmental milestones and hypercalcaemic symptoms, once their calcium and parathyroid hormone levels normalised. CONCLUSIONS: This report highlights the role of cinacalcet in managing elevated serum calcium levels in a select group of infants with NSHPT due to homozygous CASR mutations, resulting in improvement in hypercalcaemic symptoms, growth and neurodevelopmental outcomes.

Burosumab for X-linked hypophosphatemia in children and adolescents: Opinion based on early experience in seven European countries.

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood.

Development of tibia & fibula bone deficits in children with neurofibromatosis type I - A longitudinal case-control comparison.

Neurofibromatosis type 1 (NF1) is associated with lower bone mass and increased risk of fracture. Children with NF1 display faltering growth from mid-childhood. However, to date tibia bone development in children with NF1 across childhood and the role of body size have not been explored. Therefore, we recruited 24 children with NF1 (12 girls, mean age 8.2 ± 1.1y) and 104 children without NF1 (52 girls, mean age 11 ± 1.7y). Tibia and fibula bone characteristics were assessed at 4% and 38% distal-proximal tibia length in all children at baseline using peripheral quantitative computed tomography (pQCT). Longitudinal scans were obtained in 21 children with NF1 (12 girls) over 3.4 ± 0.3y and 71 children without NF1 (34 girls) over 1.1 ± 0.1y, such that at follow-up mean age of both groups (NF1 10.9 ± 1.3y, controls 11.4 ± 1.4y) were similar. Effects of group (NF1/control) on bone outcomes as well as group-by-age interactions, indicating differences in rate of change in bone outcome bone outcomes were assessed via linear mixed effects models with adjustment for sex, age, pubertal status and in additional models with adjustment for height and weight Z-scores. Group (NF1/control)-by-age interactions indicated a slower rate of tibia and fibula bone mass accrual in children with NF1 at all measured sites. These associations were attenuated by 25-50% by adjustment for height and weight Z-scores. At the 4% site, deficits in bone mass at older ages were related to slower trabecular BMD accrual. At the 38% site, group-by-age interactions suggested that bone mass deficits resulted from poorer accrual of cortical CSA and to a lesser extent cortical BMD. Lower limb bone mass deficits evident in children with NF1 appear to be progressive and emerge in mid-childhood. In part, they are related to development of a similar pattern of deficits in longitudinal growth and body weight in NF1. Interventions promoting muscle development or physical activity may be partially effective in attenuating bone mass accrual deficits in this population.

Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a rare disorder caused by somatic mosaicism for the gain of function RAS mutations . Affected patients have segmental epidermal nevi, dysplastic cortical bony lesions, and fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic rickets. Herein, we describe a case of an Emirati girl with CSHS, whose hypophosphatemic rickets and osteomalcic pseudofractures and dysplastic bony lesions failed to recover due to poor adherence to treatment with oral phosphate supplements and alfacalcidol (conventional treatment). Treatment with burosumab, a fully human immunoglobulin G1 monoclonal antibody against FGF23 for 12 months, led to normalization of serum inorganic phosphate and alkaline phosphatase levels, radiographic healing of rickets, partial healing of pseudofractures, improvement in 6-minute walk test, and the physical scale of the Pediatric Quality of Life Inventory. We conclude that burosumab is effective in treatment of CSHS, however results of the ongoing phase 2 trial in adults (NCT02304367) are awaited.

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of 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.

Normal Mid-Gestation Fetal Ultrasonography Cannot Reliably Exclude Severe Perinatal Hypophosphatasia.

INTRODUCTION: Hypophosphatasia is a systemic bone disease characterized by inhibition of bone mineralization due to mutations in the ALPL gene that results in a deficiency of tissue nonspecific alkaline phosphatase. The perinatal form is the most severe. In the past, this form was lethal, although human recombinant enzyme replacement therapy has now been developed and licensed, which improves survival. Perinatal hypophosphatasia is usually suggested on antenatal ultrasonography with undermineralization of the long bones, skull, and thoracic cavity. In the UK, antenatal ultrasonography for fetal anomalies is conducted at mid-gestation (i.e., 18-21 weeks gestational age), and if normal, no further routine scans are performed. Usually, this would identify abnormalities in bone mineralization suggestive of perinatal hypophosphatasia. CASES: We describe 2 cases of perinatal hypophosphatasia where mid-gestation ultrasonography was normal. In the first case, where a previous pregnancy had been terminated for perinatal hypophosphatasia, third trimester ultrasonography revealed skeletal features of hypophosphatasia. In the second case, the diagnosis of perinatal hypophosphatasia was made only immediately after birth. CONCLUSION: We conclude that serial antenatal ultrasonography or antenatal genetic testing should be considered in all pregnancies with a positive family history of hypophosphatasia, as mid-gestation ultrasonography cannot reliably exclude perinatal hypophosphatasia. This is especially important given that effective enzyme replacement therapy is now available.

Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf Cooperation Council countries.

INTRODUCTION: X-linked hypophosphatemia (XLH) is a rare inherited cause of hypophosphatemic rickets and osteomalacia. It is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX). This results in increased plasma fibroblast growth factor-23 (FGF23), which leads to loss of renal sodium-phosphate co-transporter expression leading to chronic renal phosphate excretion. It also leads to low serum 1,25-dihydroxyvitamin D (1,25(OH)2D), resulting in impaired intestinal phosphate absorption. Chronic hypophosphatemia in XLH leads to impaired endochondral mineralization of the growth plates of long bones with bony deformities. XLH in children and adolescents also causes impaired growth, myopathy, bone pain, and dental abscesses. XLH is the most frequent inherited cause of phosphopenic rickets/osteomalacia. Hypophosphatemia is also found in calcipenic rickets/osteomalacia as a result of secondary hyperparathyroidism. Thus, chronic hypophosphatemia is a common etiologic factor in all types of rickets. RESULTS: There is considerable overlap between symptoms and signs of phosphopenic and calcipenic rickets/osteomalacia. Wrong diagnosis leads to inappropriate treatment of rickets/osteomalacia. Nutritional rickets and osteomalacia are common in the Gulf Cooperation Council countries which include Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman. Due to high levels of consanguinity in the region, genetic causes of phosphopenic and calcipenic rickets/osteomalacia are also common. CONCLUSION: This guideline was developed to provide an approach to the diagnosis of XLH, especially where there is no family history of the disease, and that other related conditions are not mistaken for XLH. We also guide the medical management of XLH with conventional treatment and with burosumab, a recombinant human IgG1 monoclonal antibody to FGF23.

Vitamin D for Growth and Rickets in Stunted Children: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Vitamin D is essential for healthy development of bones, but little is known about the effects of supplementation in young stunted children. Our objective was to assess the effect of vitamin D supplementation on risk of rickets and linear growth among Afghan children. METHODS: In this double-blind, placebo-controlled trial, 3046 children ages 1 to 11 months from inner-city Kabul were randomly assigned to receive oral vitamin D3 (100 000 IU) or placebo every 3 months for 18 months. Rickets Severity Score was calculated by using wrist and knee radiographs for 631 randomly selected infants at 18 months, and rickets was defined as a score >1.5. Weight and length were measured at baseline and 18 months by using standard techniques, and z scores were calculated. RESULTS: Mean (95% confidence interval [CI]) serum 25-hydroxyvitamin D (seasonally corrected) and dietary calcium intake were insufficient at 37 (35-39) nmol/L and 372 (327-418) mg/day, respectively. Prevalence of rickets was 5.5% (placebo) and 5.3% (vitamin D): odds ratio 0.96 (95% CI: 0.48 to 1.92); P = .9. The mean difference in height-for-age z score was 0.05 (95% CI: -0.05 to 0.15), P = .3, although the effect of vitamin D was greater for those consuming >300 mg/day of dietary calcium (0.14 [95% CI: 0 to 0.29]; P = .05). There were no between-group differences in weight-for-age or weight-for-height z scores. CONCLUSIONS: Except in those with higher calcium intake, vitamin D supplementation had no effect on rickets or growth.

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

PURPOSE: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. METHODS: We performed deep phenotyping of 20 GACI survivors. RESULTS: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. CONCLUSION: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Characterization of tracheobronchomalacia in infants with hypophosphatasia.

BACKGROUND: Perinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Effective management of such complications is of key clinical importance. In some infants with HPP, severe tracheobronchomalacia (TBM) contributes to respiratory difficulties. The objective of this study is to characterize the clinical features, investigations and management in these patients. METHODS: We report a case series of five infants with perinatal HPP, with confirmed TBM, who were treated with asfotase alfa and observed for 3-7 years. Additionally, we reviewed respiratory function data in a subgroup of patients with perinatal and infantile HPP included in the clinical trials of asfotase alfa, who required high-pressure respiratory support (positive end-expiratory pressure [PEEP] ≥6 cm H2O and/or peak inspiratory pressure ≥18 cm H2O) during the studies. RESULTS: The case series showed that TBM contributed significantly to respiratory morbidity, and prolonged respiratory support with high PEEP was required. However, TBM improved over time, allowing weaning of all patients from ventilator use. The review of clinical trial data included 20 patients and found a high degree of heterogeneity in PEEP requirements across the cohort; median PEEP was 8 cm H2O at any time and some patients presented with high PEEP (≥8 cm H2O) over periods of more than 6 months. CONCLUSION: In infants with HPP presenting with persistent respiratory complications, it is important to screen for TBM and initiate appropriate respiratory support and treatment with asfotase alfa at an early stage. TRIAL REGISTRATION: ClinicalTrials.gov numbers: NCT00744042 , registered 27 August 2008; NCT01205152 , registered 17 September 2010; NCT01176266 , registered 29 July 2010.