trabecular bone score tbs and bone metabolism in patients affected with type 1 neurofibromatosis nf1

In patients with neurofibromatosis type 1 (NF1), decreased bone mineral density (BMD) and low levels of 25-hydroxy vitamin D3 (25OHD) have been reported. Recently, the trabecular bone score (TBS) measurement has been proposed as index of bone microarchitecture and fracture risk. In 74 NF1 patients (48 females, 26 males, age 41 ± 12), we measured TBS and investigated clinical stage, lifestyle, vitamin D, serum bone turnover markers, vertebral and femoral BMD. A homogenous cohort of 61 healthy subjects was used as control group. TBS was lower in NF1 patients (1.266 ± 0.113 vs. 1.346 ± 0.105) without differences between sexes. No correlations with 25OHD, low exercise, low calcium intake, reduced sun exposure, and number of skin neurofibromas were observed. As expected, hypovitaminosis D was common (98.6%), as well as BMD reduction in hip and spine sites: In NF1 patients, bone texture evaluated by TBS was low in both sexes without any correlation with clinical or metabolic parameters, suggesting a direct role of the fibromin mutation

Prenatal manifestation and management of a mother and child affected by spondyloperipheral dysplasia with a C-propeptide mutation in COL2A1: case report

It is not unusual for patients with "rare" conditions, such as skeletal dysplasias, to remain undiagnosed until adulthood. In such cases, a pregnancy may unexpectedly reveal hidden problems and special needs. A 28 year old primigravida was referred to us at 17 weeks for counselling with an undiagnosed skeletal dysplasia with specific skeletal anomalies suggesting the collagen 2 disorder, spondyloperipheral dysplasia (SPD; MIM 156550)

Early neonatal Glutaric aciduria type I hidden by perinatal asphyxia: a case report

Abstract Background Perinatal asphyxia (PA) occurs in about 2 to 10 per 1000 live full-term births. Although neonatal epileptic seizures are observed in up to 60% of cases, PA may mimic or subtend other conditions. Hypoxia related brain injury is particularly relevant, as it may have permanent effects on neuropsychomotor development. Antepartum obstetric conditions, may, in turn, lead to hypoxic-ischemic damage to the fetus and the newborn, often underlying PA. Herein, a case of PA that hid and triggered signs and symptoms of Glutaric Aciduria type I (GA-I), is reported. Case presentation R.F. was born at term after prolonged labour, by induced vaginal delivery with the Kristeller manoeuvre. He presented with severe asphyxia and asystoly. Immediate cardiopulmonary resuscitation promptly restored cardiorespiratory parameters, allowing for early extubation 30 min after. During the following hours, severe axial muscle hypotonia with an increased tone of the limb extensor muscles became evident. The absence of crying and archaic reflexes persisted and there was an onset of generalized tonic or clonic seizure. First level metabolic and inflammatory markers were within the normal range. An inherited metabolic disease was then suspected, due to the persistent clinical signs of severe neurological damage without any detectable septic parameter. GA-I was assessed and specific treatment started without any clinical improvement, although ensuring adequate growth and metabolic control. Thereafter, the baby developed a severe encephalopathy with drug resistant epileptic seizures. The progression of the neurological damage and a CVC-related sepsis led him to exitus at 2 years. Conclusions To the best of our knowledge, this is the first case of early post-natal onset of GA-I reported in literature to date, in the absence of expanded newborn screening (NBS) programme. As expanded NBS programmes for inborn errors of metabolism have not yet been internationally adopted, we are of the opinion that such diseases may well be hidden by misleading signs and symptoms imputable to other more frequent harmful clinical conditions. Moreover, it would be advisable that neonatologists be trained to include GA-I in the differential diagnosis of neurological damage secondary to PA

The Contribution of Oxidative Stress to <i>NF1</i>-Altered Tumors

The neurofibromatosis-1 gene (NF1) was initially characterized because its germline mutation is responsible for an inherited syndromic disease predisposing tumor development, in particular neurofibromas but also various malignancies. Recently, large-scale tumor sequencing efforts have demonstrated NF1 as one of the most frequently mutated genes in human cancer, being mutated in approximately 5–10% of all tumors, especially in malignant peripheral nerve sheath tumors and different skin tumors. NF1 acts as a tumor suppressor gene that encodes neurofibromin, a large protein that controls neoplastic transformation through several molecular mechanisms. On the other hand, neurofibromin loss due to NF1 biallelic inactivation induces tumorigenic hyperactivation of Ras and mTOR signaling pathways. Moreover, neurofibromin controls actin cytoskeleton structure and the metaphase–anaphase transition. Consequently, neurofibromin deficiency favors cell mobility and proliferation as well as chromosomal instability and aneuploidy, respectively. Growing evidence supports the role of oxidative stress in NF1-related tumorigenesis. Neurofibromin loss induces oxidative stress both directly and through Ras and mTOR signaling activation. Notably, innovative therapeutic approaches explore drug combinations that further increase reactive oxygen species to boost the oxidative unbalance of NF1-altered cancer cells. In our paper, we review NF1-related tumors and their pathogenesis, highlighting the twofold contribution of oxidative stress, both tumorigenic and therapeutic

Congenital Myasthenic Syndrome Due to Choline Acetyltransferase Mutations in Infants

Congenital myasthenic syndromes are inherited disorders caused by various defects in neuromuscular transmission. Although the typical presentation is fatigable weakness with prominent cranial involvement, neonates can lack these hallmark manifestations, and in those with choline acetyltransferase gene mutations, basal electrophysiological testing can yield negative findings. The authors report the case of a male infant presenting at birth with oculomotor and bulbofacial weakness, hypotonia, clubfoot, and severe respiratory insufficiency. Electromyography showed myogenic signs, and basal repetitive nerve stimulation yielded negative findings. Since age 6 months, the infant had progressively improved, acquiring autonomous respiration. Prolonged subtetanic repetitive nerve stimulation disclosed a marked decremental response compatible with suspected congenital myasthenic syndrome with episodic apnea. Genetic testing identified 2 novel choline acetyltransferase mutations (R470X, F580C). Keeping a high clinical suspicion of this rare condition and undertaking early comprehensive electrophysiological assessments including prolonged repetitive nerve stimulation (10 Hz for 5 minutes) can expedite the diagnosis

Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients

Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up