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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]