Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia

Elevated fibroblast growth factor 23(FGF23)in X-linked hypophosphatemia(XLH)results in rickets and phosphate wasting,manifesting by severe bone and dental abnormalities.Burosumab,a FGF23-neutralizing antibody,an alternative to conventional treatment(phosphorus and active vitamin D analogs),showed significant improvement in the long bone phenotype.Here,we examined whether FGF23 antibody(FGF23-mAb)also improved the dentoalveolar features associated with XLH.Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg−1 of FGF23-mAb for 2 months and compared to wild-type(WT)and vehicle(PBS)treated Hyp mice(n=3–7 mice).Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice,the higher concentration resulting in a rescue similar to WT levels.FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones.Histology revealed improved mineralization of the dentoalveolar tissues,with a decreased amount of osteoid,predentin and cementoid.Better periodontal ligament attachment was also observed,evidenced by restoration of the acellular cementum.These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features.Taken together,our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment,heralding its benefit in clinics for dental abnormalities.

Implicit Hypotheses Are Hidden Power Droppers in Family-Based Association Studies of Secondary Outcomes

Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform such studies. However, researchers are also often interested in the genetic contribution to a more specific manifestation of the phenotype (e.g. severe vs. non-severe form) known as a secondary outcome. Here, what we demonstrate is the limited power of the classical formulation of the FBAT statistic to detect the effect of genetic variants that influence a secondary outcome, in particular when these variants also impact on the onset of the disease, the primary outcome. We prove that this loss of power is driven by an implicit hypothesis, and we propose a derivation of the original FBAT statistic, free from this implicit hypothesis. Finally, we demonstrate analytically that our new statistic is robust and more powerful than FBAT for the detection of association between a genetic variant and a secondary outcome.

Genetics of congenital hypothyroidism: Modern concepts

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.