Social deficits in mouse models of Neurofibromatosis type 1 and Legius syndrome

AbstractNeurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

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Erratum: Corrigendum: Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Nature Medicine ◽

10.1038/nm0415-414c ◽

2015 ◽

Vol 21 (4) ◽

pp. 414-414 ◽

Cited By ~ 2

Author(s):

Jean de la Croix Ndong ◽

Alexander J Makowski ◽

Sasidhar Uppuganti ◽

Guillaume Vignaux ◽

Koichiro Ono ◽

...

Keyword(s):

Mouse Models ◽

Neurofibromatosis Type 1 ◽

Bone Growth ◽

Neurofibromatosis Type

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Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

10.1101/2020.10.12.336586 ◽

2020 ◽

Author(s):

Rachel M. Rahn ◽

Claire T. Weichselbaum ◽

David H. Gutmann ◽

Joseph D. Dougherty ◽

Susan E. Maloney

Keyword(s):

Mouse Models ◽

Williams Syndrome ◽

Neurofibromatosis Type 1 ◽

Neurodevelopmental Disorders ◽

Early Adulthood ◽

Neurofibromatosis Type ◽

Model Organisms ◽

Mouse Development ◽

Gait Abnormalities

AbstractMotor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms, and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. We therefore characterized gait using the DigiGait assay in two different NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a patient-derived heterozygous germline NF1 mutation. We collected longitudinal data across five developmental time points (postnatal days 21-30) and one early adulthood time point. Compared to wild type littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across Nf1+/R681X mouse development persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in CD mice largely resolved by adulthood. These findings suggest that gait subcomponents affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models, and a platform to examining circuits or longitudinal therapeutics.Lay SummaryGait changes have been reported in Williams Syndrome and Neurofibromatosis Type 1, but how these changes develop over time has not been explored. We therefore studied gait in mouse models of these two disorders across time. We found multiple shared differences in gait as compared to healthy controls at the younger ages in both models. However, those differences were resolved in the Williams Syndrome model by adulthood, yet persisted in the Neurofibromatosis Type 1 model.

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Legius Syndrome in a 13 Month Old Boy: A Case Report

Journal of Pediatrics & Neonatal Biology ◽

10.33140/jpnb.02.01.10 ◽

2017 ◽

Vol 2 (1) ◽

Keyword(s):

Learning Disabilities ◽

Case Report ◽

Developmental Delay ◽

Neurofibromatosis Type 1 ◽

Autosomal Dominant ◽

Clinical Manifestations ◽

Neurofibromatosis Type ◽

Café Au Lait Spots ◽

Legius Syndrome

Legius syndrome is autosomal dominant and caused by mutations in the SPRED1 gene. Clinical manifestations include multiple cafe-au-lait spots, axillary/ inguinal freckling and a degree of macrocephaly, without the non-pigmentary signs of neurofibromatosis type 1 (NF1). Learning disabilities, developmental delay and ADHD are also known.

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Café-au-lait macules and intertriginous freckling in piebaldism: Clinical overlap with neurofibromatosis type 1 and Legius syndrome

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.35297 ◽

2012 ◽

Vol 158A (5) ◽

pp. 1195-1199 ◽

Cited By ~ 13

Author(s):

Cathy A. Stevens ◽

Pei-Wen Chiang ◽

Ludwine M. Messiaen

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Legius Syndrome

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Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders

Genes ◽

10.3390/genes10080580 ◽

2019 ◽

Vol 10 (8) ◽

pp. 580 ◽

Cited By ~ 8

Author(s):

Teresa Giugliano ◽

Claudia Santoro ◽

Annalaura Torella ◽

Francesca Del Vecchio Blanco ◽

Anna Grandone ◽

...

Keyword(s):

Molecular Diagnosis ◽

Neurofibromatosis Type 1 ◽

Target Genes ◽

Positive Impact ◽

Neurofibromatosis Type ◽

Legius Syndrome ◽

Almost All ◽

Dependent Probe

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 (n = 150), only pigmentary features (café au lait macules with or without freckling; (n = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders (n = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The NF1 and SPRED1 genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype–phenotype associations that may have a positive impact on patient follow-up.

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Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Nature Medicine ◽

10.1038/nm.3583 ◽

2014 ◽

Vol 20 (8) ◽

pp. 904-910 ◽

Cited By ~ 31

Author(s):

Jean de la Croix Ndong ◽

Alexander J Makowski ◽

Sasidhar Uppuganti ◽

Guillaume Vignaux ◽

Koichiro Ono ◽

...

Keyword(s):

Mouse Models ◽

Neurofibromatosis Type 1 ◽

Bone Growth ◽

Neurofibromatosis Type

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Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105664 ◽

2018 ◽

Vol 56 (2) ◽

pp. 53-62 ◽

Cited By ~ 12

Author(s):

Manon Suerink ◽

Tim Ripperger ◽

Ludwine Messiaen ◽

Fred H Menko ◽

Franck Bourdeaut ◽

...

Keyword(s):

Differential Diagnosis ◽

Mismatch Repair ◽

Neurofibromatosis Type 1 ◽

Healthy Child ◽

Neurofibromatosis Type ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Legius Syndrome ◽

Constitutional Mismatch Repair Deficiency

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

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Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Genetics in Medicine ◽

10.1038/s41436-021-01170-5 ◽

2021 ◽

Author(s):

Eric Legius ◽

Ludwine Messiaen ◽

Pierre Wolkenstein ◽

Patrice Pancza ◽

Robert A. Avery ◽

...

Keyword(s):

Diagnostic Criteria ◽

Neurofibromatosis Type 1 ◽

Young Patients ◽

Neurofibromatosis Type ◽

Consensus Recommendation ◽

International Consensus ◽

Legius Syndrome ◽

Multistep Process ◽

Patient Advocacy Groups

Abstract Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

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