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.

A study protocol for the randomized controlled trial SAFIR FAMILY TALK: a selective primary preventive intervention vs. service as usual for children of parents with mental illness.

BACKGROUND: Children of parents with mental illness have an increased risk of developing mental illness themselves throughout their lifespan. This is due to genetic factors but also environmental disadvantages during childhood associated with parental mental illness. Selective primary preventive interventions for the children are recommended to mitigate risk factors and strengthen protective factors, but large-scale, longitudinal studies are needed. This study aims to investigate the effect of the Family Talk Preventive Intervention in a cohort of children and their parents with mental illness. METHODS: The study is a randomized controlled trial with 286 planned families with at least one parent with any mental illness and at least one child aged 7 to 17 years. It will be carried out in the mental healthcare system in the Capital Region of Denmark. Families will be referred from hospitals and municipalities. The children and parents will be assessed at baseline and then randomized and allocated to either the Family Talk Preventive Intervention or service as usual. The intervention group will be assigned to Family Talk Preventive Intervention, a manualized programme consisting of ~ seven sessions for the family, including psychoeducation about parental mental illness and resilience in children, stimulating dialogue between family members and creating a common family narrative. The study period for both groups will be 12 months. Follow-up assessments will be conducted after 4 months and 12 months. The primary outcomes are the children's level of functioning, parental sense of competence and family functioning. DISCUSSION: Given the prevalence of transgenerational transmission of mental illness, a systematic approach to prevention is needed in the mental healthcare setting. This study provides valuable knowledge on the Family Talk Preventive Intervention with a large sample size, inclusion of any parental mental illness and examination of the primary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05615324. Registered on 26 October 2022. Retrospectively registered.

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.

Children Born by Women With Rheumatoid Arthritis and Increased Susceptibility for Chronic Diseases: A Nationwide Cohort Study.

OBJECTIVE: Fetal exposure to maternal rheumatoid arthritis (RA) might impact the long-term risk of disease in the offspring. We examined a possible association between maternal RA and 15 selected groups of chronic diseases in the offspring. METHODS: This nationwide cohort study was based on the Danish health registries and included data on all children born alive in Denmark between January 1, 1989 and December 31, 2013. The cohort comprised 2,106 children born by women with RA (exposed), and 1,378,539 children born by women without RA (unexposed). Cox proportional hazards regression models were used, taking a large range of confounders into consideration, and the hazard ratios (HRs) of child and adolescent diseases were calculated. RESULTS: In children exposed to maternal RA in utero, the HR of thyroid diseases was 2.19 (95% confidence interval [95% CI] 1.14-4.21), epilepsy 1.61 (95% CI 1.16-2.25), and RA 2.89 (95% CI 2.06-4.05). The HRs for anxiety and personality disorders and chronic lung disease including asthma were in the range of 1.15-1.16, but these were not statistically significant associations. CONCLUSION: Our results suggest that in utero exposure to maternal RA is associated with an increased risk of thyroid disease and epilepsy in childhood and adolescence, and in particular an increased risk of RA, compared to children born to mothers without RA. These important findings should encourage pediatricians and general practitioners to have an increased awareness of certain chronic diseases in children exposed to RA in utero.

The Association Between Maternal Chronic Inflammatory Bowel Disease and Long-term Health Outcomes in Children-A Nationwide Cohort Study.

BACKGROUND: Very little is known about the long-term impact of maternal inflammatory bowel disease (IBD) on the offspring's future health. We aimed to examine whether children born to mothers with IBD had an increased risk of long-term morbidities. METHODS: In this nationwide register-based cohort study, including all children born alive in Denmark between 1989 and 2013, we investigated the association between maternal IBD and 15 selected disease categories of physical and mental conditions in the offspring. We used multivariate regression models estimating the hazard ratio (HR) of long-term child morbidities. RESULTS: The cohort comprised 9238 children born to women with IBD (exposed), and 1,371,407 born to women without IBD (unexposed). Median follow-up time among the exposed was 9.7 years (interquartile range [IQR] 4.9-15.7) and 13.8 (interquartile range 7.4-19.9) among the unexposed. In children, who in utero had been exposed to maternal ulcerative colitis, the HR of IBD in the offspring was 4.63 (95% confidence interval, 3.49-6.16). For maternal Crohn's disease, the HR of IBD in the offspring was 7.70 (95% confidence interval, 5.66-10.47). For all other diseases in the offspring, we did not find a significantly increased risk associated with maternal IBD. CONCLUSIONS: Children born to mothers with IBD are more likely to be diagnosed with IBD themselves, compared with children born to women without IBD. Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring.

Vitamin D insufficiency is associated with increased risk of first-trimester miscarriage in the Odense Child Cohort.

BACKGROUND: Miscarriage is the most common negative outcome of pregnancy, and identification of modifiable risk factors is potentially of great importance for public health. Low vitamin D concentrations in pregnancy are widespread worldwide, and vitamin D deficiency is implicated in immune cell regulation at the feto-maternal interface and several diseases of pregnancy. OBJECTIVE: We investigated whether 25-hydroxyvitamin D serum concentration was a modifiable risk factor for early miscarriage. DESIGN: In a prospective cohort study of 1683 pregnant women donating serum before gestational week 22, we investigated the association between maternal serum concentrations of serum 25-hydroxyvitamin D [25(OH)D] and the risk of subsequent miscarriage (n = 58). RESULTS: The adjusted hazard of first-trimester miscarriage was lower with higher 25(OH)D concentrations (HR: 0.98; 95% CI: 0.96, 0.99). Concentrations of 25(OH)D <50 nmol/L were associated with a >2-fold increased adjusted HR for miscarriage (HR: 2.50; 95% CI: 1.10, 5.69). Concentrations of 25(OH)D were not associated with an increased risk of second-trimester miscarriage. CONCLUSIONS: We found an association between 25(OH)D and first-trimester miscarriages, suggesting vitamin D as a modifiable risk factor for miscarriage. To test this hypothesis, randomized controlled trials should investigate the possible effect of vitamin D supplementation to increase 25(OH)D concentrations in early pregnancy, or before conception, to decrease risk of miscarriage. This trial was registered at clinicaltrials.gov as NCT02434900.

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.

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.

Is there equity in use of healthcare services among immigrants, their descendents, and ethnic Danes?

BACKGROUND: Legislation in Denmark explicitly states the right to equal access to healthcare. Nevertheless, inequities may exist; accordingly evidence is needed. Our objective was to investigate whether differences in healthcare utilisation in immigrants, their descendents, and ethnic Danes could be explained by health status, socioeconomic factors, and integration. METHODS: We conducted a nationwide survey in 2007 with 4952 individuals aged 18-66 comprising ethnic Danes; immigrants from the former Yugoslavia, Iran, Iraq, Lebanon, Pakistan, Somalia, Turkey; and Turkish and Pakistani descendents. Data were linked to registries on healthcare utilisation. Using Poisson regression models, contacts to hospital, emergency room (ER), general practitioner (GP), specialist in private practice, and dentist were estimated. Analyses were adjusted for health symptoms, sociodemographic factors, and proxies of integration. RESULTS: In adjusted analyses, immigrants and their descendents had increased use of ER (multiplicative effect 1.19-5.02 dependent on immigrant and descendent group) and less frequent contact to dentist (multiplicative effect 0.04-0.80 dependent on the group). For hospitalisation, GP, and specialist doctor, physical health symptoms had positive but different explanatory effects within groups; however, most immigrant and descendent groups had increased use of services compared with that of ethnic Danes. Socioeconomic factors and integration had no systematic effect on the use in the different groups. CONCLUSIONS: The Danish healthcare system seems responsive to health across different population groups. We found no systematic pattern of inequity in use of free-of-charge healthcare services, but for dentists, who require co-payment, we found inequity among immigrants and descendents compared with ethnic Danes.

A registry-based follow-up study, comparing the incidence of cardiovascular disease in native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia: do social inequalities play a role?

BACKGROUND: This study compared the incidence of cardiovascular disease (CVD) and acute myocardial infarction (AMI) between native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia. Furthermore, we examined whether different indicators of socioeconomic status (SES), such as employment, income and housing conditions influenced potential differences. METHODS: In this registry-based follow-up study individuals were identified in a large database that included individuals from two major regions in Denmark, corresponding to about 60% of the Danish population. Incident cases of CVD and AMI included fatal and non-fatal events and were taken from registries. Using Cox regression models, we estimated incidence rates at 5-year follow-up. RESULTS: Immigrant men and women from Turkey and Pakistan had an increased incidence of CVD, compared with native Danish men. In the case of AMI, a similar pattern was observed; however, differences were more pronounced. Pakistanis and Turks with a shorter duration of residence had a lower incidence, compared with those of a longer residence. Generally, no notable differences were observed between former Yugoslavians and native Danes. In men, differences in CVD and AMI were reduced after adjustment for SES, in particular, among Turks regarding CVD. In women, effects were particularly reduced among Yugoslavians in the case of CVD and in Turks in the case of CVD and AMI after adjustment for SES. CONCLUSIONS: In conclusion, country of birth-related differences in the incidence of CVD and AMI were observed. At least some of the differences that we uncovered were results of a socioeconomic effect. Duration of residence also played a certain role. Future studies should collect and test different indicators of SES in studies of CVD among immigrants.

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.

Migrants' utilization of somatic healthcare services in Europe--a systematic review.

BACKGROUND: Utilization of services is an important aspect of migrants' access to healthcare. The aim was to review the European literature on utilization of somatic healthcare services related to screening, general practitioner, specialist, emergency room and hospital by adult first-generation migrants. Our study question was: 'Are there differences in migrants' utilization of somatic healthcare services compared to non-migrants?' METHODS: Publications were identified by a systematic search of PUBMED and EMBASE. Appropriateness of the studies was judged independently by two researchers based on the abstracts. Additional searches were conducted via the references of the selected articles. The final number of studies included was 21. RESULTS: The results suggested a diverging picture regarding utilization of somatic healthcare services by migrants compared to non-migrants in Europe. Overall, migrants tended to have lower attendance and referral rates to mammography and cervical cancer screening, more contacts per patient to general practitioner but less use of consultation by telephone, and same or higher level of use of specialist care as compared to non-migrants. Emergency room utilization showed both higher, equal and lower levels of utilization for migrants compared to non-migrants, whereas hospitalization rates were higher than or equal to non-migrants. CONCLUSION: Our review illustrates lack of appropriate epidemiological data and diversity in the categorization of migrants between studies, which makes valid cross-country comparisons most challenging. After adjusting for socio-economic factors and health status, the existing studies still show systematic variations in somatic healthcare utilization between migrants and non-migrants.

Mental health among children seeking asylum in Denmark--the effect of length of stay and number of relocations: a cross-sectional study.

BACKGROUND: The process of seeking asylum and the related organisational conditions in the host country may adversely affect the children's mental health. The objective of this study was to examine the mental health of children seeking asylum in relation to organisational factors of the asylum system including length of stay and number of relocations. METHODS: The population included all 260 parent-accompanied asylum-seeking children aged 4-16 years living in the asylum centres managed by the Danish Red Cross in October-December 2006. Mental health was evaluated using the Strengths and Difficulties Questionnaire. School teachers evaluated children aged 4-16; and the 11-16-year-olds completed the self-report version. To assess the association between organisational factors and mental health, binary logistic regression analyses were done using backwards elimination. We received responses for 246 children equivalent to 95% of the study population. RESULTS: Using teachers' reports, we found that children who had been asylum-seeking for more than one year in Denmark had an increased risk of having mental difficulties (odds ratio 5.5, 95% CI 1.8-16.3); four or more relocations in the asylum system were also associated with a higher risk (3.0, 1.4-6.7). When the self-report data were included, the associations were even stronger. CONCLUSION: Protracted stays at asylum centres and multiple relocations within the asylum system appear to have an adverse effect on asylum-seeking children's mental health. A limit to the duration of the children's stay in the asylum system should be ensured. Follow-up studies with inclusion of other conditions, such as parental mental health and the children's previous trauma, are needed to clarify the influence of the different factors and their interactions.