Oral health-related quality of life in X-linked hypophosphataemia and osteogenesis imperfecta.

X-linked hypophosphataemia (XLH) and osteogenesis imperfecta (OI) are rare congenital disorders characterised by skeletal dysplasia. The two disorders may include dental anomalies potentially affecting individual well-being. The aims of study were (a) to assess the oral health-related quality of life (OHRQoL) in Danish adults with XLH or OI, and (b) to compare the results of the groups. A cross-sectional study including 35 adults with XLH, 56 adults with OI type I and 17 adults with OI types III-IV was conducted. The OHRQoL was assessed by the 49-item version of the questionnaire Oral Health Impact Profile (OHIP). Summed domain scores (seven) were compared between XLH and OI groups. Prevalence of severe impact on OHRQoL (scores 3-4) was compared between groups. The median scores in XLH group exceeded the medians in OI (P < .05) in the domains functional limitation (XLH:6.5; OI:4.0), pain (XLH:9.5; OI:5.0), psychological discomfort (XLH:5.5; OI:2.0), psychological disability (XLH:2.0; OI:0.0), handicap (XLH:2.0; OI:0.0) and total OHIP (XLH:35.0; OI:14.0). Differences in domains physical disability (XLH: 4.0; OI: 1.0) and social disability (XLH: 0.0; OI: 0.0) were not significant. Prevalence of severe impact on OHRQoL in the XLH group significantly exceeded the level in OI group in the domains functional limitation (XLH: 59%; OI: 35%), psychological discomfort (XLH: 38%; OI: 20%) and physical disability (XLH: 32%; OI: 13%). In conclusion, adults with XLH experience a higher negative impact on their OHRQoL than adults with OI. Only to a minor degree, individuals with OI types III-IV experience a higher impact on OHRQoL than individuals with OI type I.

Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect.

There is growing evidence that TP63 is associated with isolated as well as syndromic premature ovarian insufficiency (POI). We report two adolescent sisters diagnosed with undetectable ovaries, uterine hypoplasia, and mammary gland hypoplasia. A novel paternally inherited nonsense variant in TP63 [NM_003722.4 c.1927C > T,p.(Arg643*)] in exon 14 was identified by exome sequencing. One of the syndromes linked to TP63 is limb mammary syndrome (LMS), an autosomal dominant inherited disorder characterized by ectrodactyly, hypoplasia of mammary-gland and nipple, lacrimal duct stenosis, nail dysplasia, dental anomalies, cleft palate and/or cleft lip and absence of skin and hair defects. The TP63 variant segregated with symptoms of LMS in the family, however, no affected individual had limb defects. The phenotype reported here represents a novel syndromic phenotype associated with TP63. Reported cases with TP63 associated POI are reviewed.

Elevated Bone Remodeling Markers of CTX and P1NP in Addition to Sclerostin in Patients with X-linked Hypophosphatemia: A Cross-Sectional Controlled Study.

Aspects of bone remodeling have only been scarcely studied in X-linked hypophosphatemia (XLH). In this cross-sectional controlled study, we assessed biochemical indices of bone remodeling and sclerostin in 27 adult patients (median age 47 [range 24-79] years, 19 women, 8 men) with XLH matched with 81 healthy control subjects (1:3) with respect to age-, sex-, and menopausal status. Markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen, CTX) and formation (N-terminal propeptide of type 1 procollagen, P1NP) were higher in XLH patients compared to controls (median [IQR] 810 [500-1340] vs 485 [265-715] ng/l and 90 [57-136] vs 49 [39-65] ug/l, respectively, both p < 0.001) as well as sclerostin (0.81 [0.60-1.18] vs 0.54 [0.45-0.69] ng/ml, p < 0.001). Similar differences were found when comparing currently treated (with phosphate and alfacalcidol) (n = 11) and untreated (n = 16) XLH patients with their respective controls. We found no significant associations with treatment status and indices of bone remodeling or sclerostin although sclerostin tended to be increased in untreated versus treated (p = 0.06). In contrast to previous histomorphometric studies suggesting a low remodeling activity in XLH, these biochemical indices suggest high osteoblast and osteoclast activity. Further studies are needed to ascertain if the higher sclerostin level in XLH is related to osteocyte dysfunction or represents a secondary phenomenon.

Impact of Conventional Medical Therapy on Bone Mineral Density and Bone Turnover in Adult Patients with X-Linked Hypophosphatemia: A 6-Year Prospective Cohort Study.

X-linked hypophosphatemia (XLH) is a rare, inheritable disorder manifesting as rickets in children and osteomalacia in adults. While conventional medical treatment with oral phosphate and alfacalcidol is recommended in childhood, it is undecided whether adults should continue therapy. The aim of this 6-year prospective study was to determine the impact of conventional medical treatment on areal bone mineral density (aBMD), bone turnover markers (BTMs) and measures of calcium homeostasis in 27 adult patients with XLH, 11 of whom received medical treatment. Lumbar spine and total hip aBMD, as assessed by DXA, and biochemical measures of calcium, phosphate, PTH, 1,25 dihydroxyvitamin D2+3 (1,25(OH)2D), fibroblast growth factor 23 (FGF23), P1NP and CTX were measured at baseline and at follow-up. The renal tubular reabsorption of PO4 (TmPO4/GFR) was calculated at both time points. Multilevel mixed-effects linear regression models were used for analyses. During the study period, spine and hip aBMD did not change significantly between treated and non-treated XLH patients. There was a trend towards a decrease in calcium, phosphate and TmPO4/GFR in the treatment group (p = 0.057, p = 0.080 and p = 0.063, respectively), whereas PTH, FGF23, 1,25(OH)2D and P1NP did not change significantly in either groups. However, CTX increased significantly in the treated compared to non-treated group (p = 0.044). Continuing conventional medical therapy in adulthood, although associated with increased bone resorption, does not promote or prevent loss of bone mass as evidenced from the stable aBMD of the hip and spine in XLH patients.

Craniofacial and dental characteristics of patients with vitamin-D-dependent rickets type 1A compared to controls and patients with X-linked hypophosphatemia.

ᅟOBJECTIVES: Vitamin-D-dependent rickets type 1A (VDDR1A) is a rare inherited disease caused by defective activation of vitamin D. The aim of the study was to describe the craniofacial characteristics and the dental phenotype of patients with genetically confirmed VDDR1A. The VDDR1A findings were compared to findings in patients with X-linked hypophosphatemia (XLH) and healthy controls. MATERIAL AND METHODS: Ten patients with VDDR1A were identified. The reference group for the comparison of cephalometric findings was 49 adults without chronic disease. The reference group for the comparison of dental findings was 30 adults with XLH. Clinical examination, clinical photos, and radiographs were obtained. Cephalometric analysis was performed. Photos and radiographs were visually evaluated. RESULTS: The depth of the posterior cranial fossa (d-p and d-s-iop) in VDDR1A adults was reduced compared to the reference group (p < 0.05). Five (83%) of six adults with VDDR1A and one (4%) of 25 adults with XLH had enamel hypoplasia on several incisors and/or canines (p < 0.001). Three (75%) of four adults with VDDR1A and none of 16 adults with XLH had several first molars with enamel hypoplasia (p = 0.004). Five of 7 (71%) adults with VDDR1A and 24 of 30 (80%) adults with XLH had endodontically affected teeth. CONCLUSIONS: The dental aberration of VDDR1A is more in line with the dental aberration of nutritional rickets than with the dental aberrations in XLH, suggesting the combination of low availability of both calcium and phosphate to be critical in periods of enamel formation. CLINICAL RELEVANCE: Knowledge on craniofacial and dental aberration in patients with rare diseases, e.g., inherited rickets, is of importance to the dental practitioner, especially during diagnostics and treatment in special care units.

Prevalence of maternal chronic diseases during pregnancy - a nationwide population based study from 1989 to 2013.

INTRODUCTION: There is substantial evidence of a negative impact of maternal chronic disease during pregnancy on reproductive outcomes. Knowledge of the prevalence of chronic diseases during pregnancy is limited, but essential for a focused preventive effort regarding optimal disease control during pregnancy. We aimed to analyze the prevalence of chronic diseases during pregnancy. MATERIAL AND METHODS: This register-based cohort study included all women giving birth in Denmark between 1989 and 2013 based on data from Danish health registers. Maternal chronic diseases included 23 disease categories of both physical and mental health conditions recorded within a period of 10 years before childbirth. RESULTS: We included 1 362 200 childbirths during the study period. The overall prevalence of maternal chronic disease increased from 3.71% in 1989 to 15.76% in 2013. The most frequently registered chronic diseases were chronic lung diseases/asthma (1.73%), thyroid disorders (1.50%) and anxiety and personality disorders (1.33%). Taking increasing maternal age at birth into account, the relative risk for women to have a chronic disease from 2009 to 2013 was 4.14 (95% CI 4.05-4.22), compared with mothers giving birth from 1989 to 1993. CONCLUSIONS: We found an increasing prevalence of maternal chronic disease during pregnancy and more than a four-fold increased risk of maternal chronic disease during pregnancy for childbirths in the period 2009 through 2013, compared with 1989 through 1993. The main limitation of our study is related to a potentially greater awareness and hence more careful registration of maternal chronic disease over time and thereby an increased tendency to register diseases.

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review.

Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are major complications to preterm birth. Hypovitaminosis D is prevalent in pregnancy. We systematically reviewed the evidence of the impact of vitamin D on lung development, surfactant synthesis, RDS, and BPD searching PubMed, Embase, and Cochrane databases with the terms vitamin D AND (surfactant OR lung maturation OR lung development OR respiratory distress syndrome OR fetal lung OR prematurity OR bronchopulmonary dysplasia). Three human studies, ten animal studies, two laboratory studies, and one combined animal and laboratory study were included. Human evidence was sparse, allowing no conclusions. BPD was not associated with vitamin D receptor polymorphism in a fully adjusted analysis. Animal and laboratory studies showed substantial positive effects of vitamin D on the alveolar type II cell, fibroblast proliferation, surfactant synthesis, and alveolarization. These data support the hypothesis of hypovitaminosis D as a frequent, modifiable risk factor of RDS and BPD, which should be tested in randomized controlled trials on pregnant women, those with threatening preterm delivery, or in the preterm neonates. Future experimental and human studies should aim to identify optimal time windows, vitamin D doses, and cut-off levels for 25-hydroxyvitamin D in interventions against RDS, BPD, and later adverse respiratory outcomes.

Administering different levels of parenteral phosphate and amino acids did not influence growth in extremely preterm infants.

AIM: When a new high amino acid parenteral nutrition (PN) solution was introduced to our hospital, a design error led to decreased phosphate levels. This prompted us to examine the effect of three different PN solutions on plasma phosphate, plasma calcium and weight increases on extremely preterm infants. METHOD: This was a retrospective study of 186 infants with a gestational age of <28 weeks during their first month of life. They were divided into three groups based on the PN they received during hospitalisation. Group one received high levels of phosphate and low levels of amino acids. Group two received low levels of phosphate and high levels of amino acids. Group three received high levels of both phosphate and amino acids. RESULTS: The lowest plasma phosphate values varied significantly between groups one (1.80 ± 0.46 mmol/L), two (1.05 ± 0.48 mmol/L) and three (1.40 ± 0.37 mmol/L) (p < 0.001), but no significant difference in weight increase was seen (p = 0.497). CONCLUSION: The phosphate content of the PN influenced plasma phosphate and plasma calcium levels, but increasing the levels of both phosphate and amino acids did not improve weight gain during the first month of life.

Upper spine morphology in hypophosphatemic rickets and healthy controls: a radiographic study.

BACKGROUND/OBJECTIVES: The aim of this study was to describe upper spine morphology in adult patients with hypophosphatemic rickets (HR) compared with controls to assess differences in spine morphology in terms of severity of skeletal impact and to study associations between spine morphology and craniofacial morphology. MATERIAL/METHODS: The study population comprised 36 HR patients and 49 controls. The atlas and axis dimensions were measured on cephalograms, and the differences between the groups were estimated by regression analysis. The upper spine morphology was visually assessed to estimate the prevalence of cervical vertebral anomalies. RESULTS: The dimensions of the atlas and the axis were larger in HR patients than in controls (P ≤ 0.001), and fusions (FUS) occurred more often in HR patients (39%) than in controls (6%; P ≤ 0.001). In HR patients, the length of the atlas correlated positively (P = 0.008) and the height of the dens correlated negatively (P = 0.043) with the severity of skeletal impact. The height of the posterior arch of the atlas and the length of the axis correlated negatively with the cranial base angle (P ≤ 0.017), and the vertical dimensions of the atlas correlated positively with the thickness of the occipital skull (P ≤ 0.015). The length of the atlas correlated positively with mandibular prognathism (P = 0.042). FUS correlated positively with the frontal and parietal thickness (P = 0.034 and P = 0.003, respectively). CONCLUSIONS: The dimension of the atlas and the axis and the prevalence of the FUS were increased in HR patients compared with controls. Upper spine dimensions were associated with craniofacial dimensions, primarily in relation to the posterior cranial fossa.

Management of RANKL-mediated Disorders With Denosumab in Children and Adolescents: A Global Expert Guidance Document.

CONTEXT: Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. OBJECTIVE: This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. PARTICIPANTS: Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. EVIDENCE: Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. CONCLUSION: Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.

Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.

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.

Giant cell tumour of bone in os sacrum of a prepubertal girl - Surgical and medical treatment with zoledronate and denosumab.

A giant cell tumour of bone presented in the os sacrum of a prepubertal girl. Surgery with reconstruction was performed, but total resection was impossible. Zoledronate failed to avoid tumour regrowth, and treatment was changed to denosumab, despite not being recommended for use in growing children. Denosumab treatment for 21 months reduced and stabilized tumour size, the girl became pain free with asymptomatic side effects as mild hypocalcemia, hypophosphatemia and sclerosis of newly formed bone.

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.

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets.

This study aimed to identify the underlying genetic mutation in patients with hypophosphatemic rickets (HR). Genomic DNA was analysed for mutations in PHEX, FGF23 and CLCN5 by polymerase chain reaction (PCR) followed by denaturing high-performance liquid chromatography (dHPLC). Bi-directional sequencing was performed in samples with deviating chromatographic profiles. DMP1 and SLC34A3 were sequenced, only. In addition, a multiplex ligation-dependent probe amplification (MLPA) analysis was performed to detect larger deletions/duplications in PHEX or FGF23. Familial cases accounted for 12 probands while 12 cases were sporadic. In 20 probands, mutations were detected in PHEX of which 12 were novel, and one novel frameshift mutation was found in DMP1. Three PHEX mutations were identified by the MLPA analysis only; that is, two large deletions and one duplication. No mutations were identified in FGF23, SLC34A3 or CLCN5. By the methods used, a disease causing mutation was identified in 83% of the familial and 92% of the sporadic cases, thereby in 88% of the tested probands. Genetic analysis performed in HR patients by PCR, dHPLC, sequencing and in addition by MLPA analysis revealed a high identification rate of gene mutations causing HR, including 12 novel PHEX and one novel DMP1 mutation.

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).

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Craniofacial morphology in patients with hypophosphatemic rickets: a cephalometric study focusing on differences between bone of cartilaginous and intramembranous origin.

Hypophosphatemic rickets (HR) are diseases characterized by deficient mineralization of bone due to abnormal renal wasting of phosphate. Deformation of bony structures of cartilaginous origin has been described as a major characteristic in patients with HR, but little is known about the impact on bony structures of intramembranous origin. The aim of the present study was to describe the osseous morphology of the craniofacial structures in patients with HR compared to healthy controls, and to investigate the impact of different bone origin on the osseous morphology. Fifty-three patients with HR (17 males, 36 females), aged 3-74 yrs, were included. Fifty HR patients had dominant X-linked disease, and in three patients no mutations were identified. A total of 79 healthy individuals (37 males, 42 females), aged 6-79 yrs, with normal occlusion served as controls. Significant cephalometric differences were found between HR patients and controls. In HR patients, the cranial base was flattened and the depth of the posterior cranial fossa was decreased. The anterior height of the cranium, the angle nasion-sella-frontale, and the thickness of theca were increased. The length of the nasal bone and the height of the maxilla were reduced. In contrast, the vertical as well as the sagittal relation between the jaws were unaffected in HR patients compared to controls. In conclusion, we found that the cranial structures of cartilaginous origin as well as the structures of intramembraneous origin were affected in patients with HR.

Phenotype presentation of hypophosphatemic rickets in adults.

Hypophosphatemic rickets (HR) is a group of rare disorders caused by excessive renal phosphate wasting. The purpose of this cross-sectional study of 38 HR patients was to characterize the phenotype of adult HR patients. Moreover, skeletal and endodontic severity scores were defined to assess possible gender differences in disease severity in patients with genetically verified X-linked HR. Compared to normal reference data, i.e., z = 0, HR patients had significantly lower final height, with a mean difference in z-score of -1.9 (95% CI -2.4 to -1.4, P < 0.001). Compared to paired z-scores of final height, z-scores of leg length were significantly lower and those of sitting height were significantly higher (P < 0.001), resulting in disproportion as indicated by the significantly elevated sitting height ratio, mean difference in z-score of 2.6 (95% CI 2.1-3.1, P < 0.001). Z-scores of head circumference (median 1.4, range -0.4 to 5.5, P < 0.001) and z-scores of bone mineral density (BMD) of the lumbar spine (median 1.9, range -1.5 to 8.6, P < 0.001) were significantly elevated compared to normal reference data. The relative risk (RR) of fracture was reduced (RR = 0.34, 95% CI 0.20-0.57, P < 0.001). The skeletal severity score tended to be higher in males compared to females (P = 0.07), and no gender difference in endodontic severity was found. In conclusion, adult HR patients were characterized by short stature and were disproportioned. They had elevated BMD of the lumbar spine and a reduced risk of fractures. We found a tendency for males to be more severely affected than females.

The international X-linked hypophosphataemia (XLH) registry (NCT03193476): rationale for and description of an international, observational study.

BACKGROUND: X-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20-25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys - mediated by downregulation of renal tubular phosphate transporters - and reduced phosphate absorption in the intestines - due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice. RESULTS: The XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment. CONCLUSION: The data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease.