# Targeted Gene Sequencing, Bone Health, and Body Composition in Cornelia de Lange Syndrome
## 4 Discussion
Interpretations of our data should be performed with caution, because we did not perform lateral spine radiographs. Another important consideration is that three out of the nine used or had used proton pump inhibitors, and there has been emerging evidence showing a link between long-term proton pump inhibitor usage and bone health [41]. For all the reasons stated above, analyzing the calcium-PTH-vitamin D axis and ALP levels was imperative. It was surprising to find that only in the oldest participant the decline in vitamin D levels was accompanied by a decrease in the level of calcium, which could induce a rise in PTH level. Future studies are needed to clarify this point. Particularly, there is a need to carry out other body composition studies in older individuals with CdLS, because in the above-mentioned situation, bone resorption is expected to increase and could lead to osteoporosis. Regarding other treatments affecting bone, seizures are common in CdLS individuals, and the use of anticonvulsants may have an impact on bone health and vitamin D metabolism [3, 8, 42]. Only one individual (participant V) has epilepsy, currently under treatment with levetiracetam and oxcarbazepine. Despite that, her bone and vitamin D values seemed to not be affected. However, it is well known that epilepsy is a prevalent disorder in childhood and that classic antiepileptic drugs, such as phenobarbital and carbamazepine, are inducers of hepatic cytochrome P450 enzymes and can cause vitamin D deficiency [43, 44, 45, 46]. Nonetheless, there are few studies on the effects of newer antiepileptic drugs like levetiracetam. A recent Spanish study in a pediatric population suggested there was vitamin D deficiency associated with treatment with the latest generation of antiepileptic drugs [34]. These discrepancies highlight the importance of accounting for these factors in future body composition studies. This study had some limitations. It was a single-center study with a limited sample size. Moreover, comparisons between groups were not possible due to the lack of a control group; a normative dataset and Z-score values were used instead. In addition, it is important to acknowledge that CdLS is a rare disease. Importantly, as far as we know, this is the first study to document aBMD in some children and adolescents with CdLS. In conclusion, individuals with CdLS might have normal adiposity by FMI and low levels of lean mass by LMI measured with DXA. Bone health in this population seems to not be as much of a concern during childhood and adolescence. However, these individuals might be at risk for impaired bone health due to low lean mass in adulthood. Accordingly,more studies are needed to determine whether there is an increased risk of fracture or poor musculoskeletal outcomes associated with CdLS. Conceptualization, F.R., J.A.C., J.P. and G.B.-L.; DXA scans, A.M.-L. and J.A.C. ; molecular analyses, A.L.-P., M.A., B.P. and J.P.; clinical studies, A.A., L.T., A.A.-C., L.A.M., F.R. and G.B.-L.; biochemical analyses, E.L. and J.J.P.-L.; writing--original draft preparation, A.M.-L. and A.A.; writing--review, J.A.C., F.R., J.P. and G.B.-L.; writing--editing, A.M.-L., A.A., L.-P., B.P., L.T., A.A.-C., E.L., J.J.P.-L., M.A., L.A.M., F.R., J.P., J.A.C. and G.B.-L.; funding acquisition, [PERSON], [PERSON] and [PERSON]. All authors have read and agreed to the published version of the manuscript. [PERSON] and [PERSON] contributed equally to this work. This research was funded by the Universidad de Zaragoza, grant number JIUZ-2019-BIO-04; the Spanish Ministry of Health--Fondo de Investigacion Sanitaria (FIS) (Ref.# PI19/01860, to [PERSON] and [PERSON]), and the Diputacion General de Aragon--FEDER: European Social Fund (grupo de referencia B32_17R, to [PERSON]). The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Clinical Research of the Government of Aragon (CEICA; PI16/225). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.