Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (O... more Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3–26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14–26) versus 10 (3–17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual,...
Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. In... more Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), ...
Tuberous sclerosis complex (TSC) is an autosomal dominant condition clinically presenting with he... more Tuberous sclerosis complex (TSC) is an autosomal dominant condition clinically presenting with heterogenous clinical features. Multiple neuroradiological manifestations have been associated with TSC, such as tubers, radial migration lines, subependymal nodules, subependymal giant cell astrocytomas, and cyst-like lesions of the white matter (CLLWMs). The latter have been described as non-enhancing well-defined cysts whose pathogenesis is still unknown. We describe 2 TSC patients with CLLWM showing contrast enhancement after Gadolinium injection, a previously unreported entity.
Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, c... more Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of...
Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by... more Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p.Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p.Pro260Leu variant, suggesting a possible role of the p.Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.
Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikil... more Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.
Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss‐of‐... more Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss‐of‐function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain‐of‐function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway... more Context Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce. Objectives The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment. Design Multicenter retrospective study. Settings and patients Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers. Main outcome measures We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification. Results Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency ...
Object. In this study the authors evaluate the safety, efficacy, and indications for endoscopic t... more Object. In this study the authors evaluate the safety, efficacy, and indications for endoscopic third ventriculostomy (ETV) in patients with a history of subarachnoid hemorrhage or intraventricular hemorrhage (IVH) and/or cerebrospinal fluid (CSF) infection. Methods. The charts of 101 patients from seven international medical centers were retrospectively reviewed; 46 patients had a history of hemorrhage, 42 had a history of CSF infection, and 13 had a history of both disorders. All patients experienced third ventricular hydrocephalus before endoscopy. The success rate for treatment in these three groups was 60.9, 64.3, and 23.1%, respectively. The follow-up period in successfully treated patients ranged from 0.6 to 10 years. Relatively minor complications were observed in 15 patients (14.9%), and there were no deaths. A higher rate of treatment failure was associated with three factors: classification in the combined infection/hemorrhage group, premature birth in the posthemorrhage ...
Additional file 1. Audiological, Cognitive functioning, MRI data evaluation. S. Fig.1. Relative a... more Additional file 1. Audiological, Cognitive functioning, MRI data evaluation. S. Fig.1. Relative auditory cortex perfusion values among patients with auditory evaluation. e-Table. Pearson's correlations between cognitive scores derived by the WAIS and right and left auditory/visual cerebral area perfusion ratio in healthy controls and patients.
Background Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID... more Background Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson’s disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype. Case presentation Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features...
Simple Summary Central nervous system involvement (CNS) is a common finding in Neurofibromatosis ... more Simple Summary Central nervous system involvement (CNS) is a common finding in Neurofibromatosis type 1 (NF1). Beside tumor-related manifestations, NF1 is also characterized by a wide spectrum of CNS alterations with variable impacts on functioning and life quality. Here, we propose an overview of non-oncological neuroradiological findings in NF1, with an insight on pathophysiological and embryological clues for a better understanding of the development of these specific alterations. Abstract Neurofibromatosis type 1 (NF1), the most frequent phakomatosis and one of the most common inherited tumor predisposition syndromes, is characterized by several manifestations that pervasively involve central and peripheral nervous system structures. The disorder is due to mutations in the NF1 gene, which encodes for the ubiquitous tumor suppressor protein neurofibromin; neurofibromin is highly expressed in neural crest derived tissues, where it plays a crucial role in regulating cell proliferat...
Oculogyric crisis (OGC) represent an unusual type of dystonic movement disorder, usually reported... more Oculogyric crisis (OGC) represent an unusual type of dystonic movement disorder, usually reported as an adverse event of antipsychotic drugs, with acute or tardive onset, likely due to a functional disruption of dopaminergic neurotransmission. It is seldom reported in children with aripiprazole, an atypical antipsychotic commonly used in youths. In this manuscript, we report on a case series of three pediatric patients and provide a brief narrative review of the literature, in order to increase the awareness of clinicians and to foster future research in this area.
Epileptic disorders : international epilepsy journal with videotape, 2019
To further characterise CDKL5-related disorder, previously classified as an early-onset seizure v... more To further characterise CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of "honeymoon periods", as well as EEG features. The "honeymoon period", defined as a seizure-free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the "honeymoon period", the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared be...
Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (O... more Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3–26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14–26) versus 10 (3–17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual,...
Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. In... more Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), ...
Tuberous sclerosis complex (TSC) is an autosomal dominant condition clinically presenting with he... more Tuberous sclerosis complex (TSC) is an autosomal dominant condition clinically presenting with heterogenous clinical features. Multiple neuroradiological manifestations have been associated with TSC, such as tubers, radial migration lines, subependymal nodules, subependymal giant cell astrocytomas, and cyst-like lesions of the white matter (CLLWMs). The latter have been described as non-enhancing well-defined cysts whose pathogenesis is still unknown. We describe 2 TSC patients with CLLWM showing contrast enhancement after Gadolinium injection, a previously unreported entity.
Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, c... more Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of...
Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by... more Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p.Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p.Pro260Leu variant, suggesting a possible role of the p.Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.
Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikil... more Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.
Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss‐of‐... more Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss‐of‐function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain‐of‐function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway... more Context Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce. Objectives The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment. Design Multicenter retrospective study. Settings and patients Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers. Main outcome measures We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification. Results Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency ...
Object. In this study the authors evaluate the safety, efficacy, and indications for endoscopic t... more Object. In this study the authors evaluate the safety, efficacy, and indications for endoscopic third ventriculostomy (ETV) in patients with a history of subarachnoid hemorrhage or intraventricular hemorrhage (IVH) and/or cerebrospinal fluid (CSF) infection. Methods. The charts of 101 patients from seven international medical centers were retrospectively reviewed; 46 patients had a history of hemorrhage, 42 had a history of CSF infection, and 13 had a history of both disorders. All patients experienced third ventricular hydrocephalus before endoscopy. The success rate for treatment in these three groups was 60.9, 64.3, and 23.1%, respectively. The follow-up period in successfully treated patients ranged from 0.6 to 10 years. Relatively minor complications were observed in 15 patients (14.9%), and there were no deaths. A higher rate of treatment failure was associated with three factors: classification in the combined infection/hemorrhage group, premature birth in the posthemorrhage ...
Additional file 1. Audiological, Cognitive functioning, MRI data evaluation. S. Fig.1. Relative a... more Additional file 1. Audiological, Cognitive functioning, MRI data evaluation. S. Fig.1. Relative auditory cortex perfusion values among patients with auditory evaluation. e-Table. Pearson's correlations between cognitive scores derived by the WAIS and right and left auditory/visual cerebral area perfusion ratio in healthy controls and patients.
Background Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID... more Background Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson’s disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype. Case presentation Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features...
Simple Summary Central nervous system involvement (CNS) is a common finding in Neurofibromatosis ... more Simple Summary Central nervous system involvement (CNS) is a common finding in Neurofibromatosis type 1 (NF1). Beside tumor-related manifestations, NF1 is also characterized by a wide spectrum of CNS alterations with variable impacts on functioning and life quality. Here, we propose an overview of non-oncological neuroradiological findings in NF1, with an insight on pathophysiological and embryological clues for a better understanding of the development of these specific alterations. Abstract Neurofibromatosis type 1 (NF1), the most frequent phakomatosis and one of the most common inherited tumor predisposition syndromes, is characterized by several manifestations that pervasively involve central and peripheral nervous system structures. The disorder is due to mutations in the NF1 gene, which encodes for the ubiquitous tumor suppressor protein neurofibromin; neurofibromin is highly expressed in neural crest derived tissues, where it plays a crucial role in regulating cell proliferat...
Oculogyric crisis (OGC) represent an unusual type of dystonic movement disorder, usually reported... more Oculogyric crisis (OGC) represent an unusual type of dystonic movement disorder, usually reported as an adverse event of antipsychotic drugs, with acute or tardive onset, likely due to a functional disruption of dopaminergic neurotransmission. It is seldom reported in children with aripiprazole, an atypical antipsychotic commonly used in youths. In this manuscript, we report on a case series of three pediatric patients and provide a brief narrative review of the literature, in order to increase the awareness of clinicians and to foster future research in this area.
Epileptic disorders : international epilepsy journal with videotape, 2019
To further characterise CDKL5-related disorder, previously classified as an early-onset seizure v... more To further characterise CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of "honeymoon periods", as well as EEG features. The "honeymoon period", defined as a seizure-free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the "honeymoon period", the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared be...
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Papers by Claudia Santoro