Biobank for craniosynostosis and faciocraniosynostosis, rare pediatric congenital craniofacial disorders: a study protocol.

PURPOSE: Craniosynostosis (CRS) is a rare congenital cranial malformation in which 1 or more cranial or facial sutures are fused in utero or rapidly fused in early infancy. The cranial sutures separate the skull bone plates and enable rapid growth of the skull in the first 2 years of life, in which growth is largely dictated by growth of the brain. CRS is a rare disease that occurs in 1 in 2100 to 1 in 2500 births and may be either nonsyndromic (also referred to as isolated) or syndromic. In syndromic CRS, other birth defects are present next to the CRS. The distinction between nonsyndromic and syndromic manifestations is made on the basis of dysmorphologic evaluation and genetic evaluation. Owing to advances in genetic diagnostics, nonsyndromic patients are increasingly recognized as syndromic patients. CRS treatment is almost entirely surgical and is sometimes paired with postoperative helmet therapy for maintenance. Corrective procedures are complex, long, and associated with the risk of numerous complications, including heavy blood loss and its sequelae. Although surgery may restore a normal appearance, even in nonsyndromic patients, patients may experience persistent deficits in intellectual ability and cognitive function. The European Commission (EC) has prioritized rare diseases in recent horizon European research programs; indeed, collections or even individual samples may be extremely valuable for research. METHODS AND RESULTS: Here, we present a study protocol in which the combined expertise of clinicians and researchers will be exploited to generate a biobank dedicated to CRS. The generation of the CRS biobank presented in this study will include the collection of different types of biological materials as well as advanced radiological images available to the scientific community. CONCLUSION: The activation of a CRS biobank will provide an opportunity to improve translational research on CRS and to share its benefits with the scientific community and patients and their families.

Bone metabolism in patients with type 1 neurofibromatosis: key role of sun exposure and physical activity.

Bone metabolism has been rarely investigated in children affected by Neurofibromatosis type 1 (NF1). Aim of the present study was to assess bone mineral metabolism in children and adults NF1 patients, to determine the relevant factors potentially involved in the development of reduced bone mineral density (BMD), and provide possible therapeutic intervention in NF1 patients. 114 NF1 patients and sex and age matched controls were enrolled into the study. Clinical and biochemical factors reflecting bone metabolism were evaluated. Factors potentially affecting BMD were also investigated including: physical activity, sun exposure, vitamin D intake. Whenever the presence of vitamin D deficiency was recorded, cholecalciferol supplementation was started and z-score data obtained at Dual-Energy X-ray Absorptiometry (DXA) during supplementation were compared with previous ones. NF1 patients showed lower Z-scores at Dual-Energy X-ray Absorptiometry DXA than controls. Physical activity was significantly reduced in NF1 patients than in controls. Sun exposure was significantly lower in NF1 compared to control subjects. At linear regression analysis vitamin D was the most predictive factor of reduced z-score at DXA (p = 0.0001). Cholecalciferol supplementation significantly increased BMD z-score (p < 0.001). We speculated that a combination of different factors, including reduced sun exposure, possibly associated with reduced serum vitamin D levels, and poor physical activity, concur to the impaired bone status in NF1 patients. We also demonstrated that treatment with vitamin D can be effective in improving z-score value in NF1 patients, including children. In conclusion, the findings of the current study are expected to have important implications for the follow-up and prevention of osteopenia/osteoporosis in this common genetic disease.

Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1.

s: The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0-18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS.

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. RESULTS: Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. CONCLUSIONS: The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.