neurofibromatosis-Noonan Syndrome Research Articles

Neurofibromatosis-Noonan syndrome and growth deficiency in an Iranian girl due to a pathogenic variant in NF1 gene

BackgroundMutations in NF1 gene could cause allelic disorders with clinical spectrum of Neurofibromatosis type 1 to Noonan syndrome. Here, a 7-year-old Iranian girl is described with Neurofibromatosis-Noonan syndrome due to a pathogenic variant in NF1 gene.MethodsClinical evaluations were performed along with genetic testing using whole exome sequencing (WES). The variant analysis including pathogenicity prediction was also done using bioinformatics tools.ResultsThe chief compliant of the patient was short stature and lack of proper weight gain. Other symptoms were developmental delay, learning disability, inadequate speech skill, broad forehead, hypertelorism, and epicanthal folds, low set ears and webbed neck. A small deletion, c.4375-4377delGAA, was found in NF1 gene using WES. This variant was classified as pathogenic according to ACMG.ConclusionsNF1 variants may show variable phenotypes among the patients; identifying such variants is helpful in therapeutic management of the disease. WES is considered as an appropriate test to diagnose Neurofibromatosis-Noonan syndrome.

P240: WES identifies a pathogenic variant in NF1 gene in an Iranian girl with neurofibromatosis-Noonan syndrome and growth deficiency

P240: WES identifies a pathogenic variant in NF1 gene in an Iranian girl with neurofibromatosis-Noonan syndrome and growth deficiency

Abstract #1321514: Neurofibromatosis-Noonan’s Syndrome With Associated Lymphangioma in a Young Girl

Neurofibromatosis-Noonan syndrome (NFNS) is a RASopathy characterized by the combination of features of neurofibromatosis type-1 (NF1) and Noonan syndrome (NS). They have significant phenotypic overlap, molecular genetic testing is often necessary for diagnosis.

Recurrent labial xanthoma infection in a patient with Neurofibromatosis-Noonan syndrome: case report and literature review

Introduction: Noonan Syndrome is a clinically and genetically heterogeneous syndrome, characterized by marked phenotypic variability. All the clinical manifestations of this syndrome are still not fully known. Observation: We present the case of a 58-year-old woman with a diagnosis of Neurofibromatosis-Noonan syndrome with SOS2 mutation, observed by her general practitioner for a recurrent left upper lip abscess despite drainage and antibiotic therapy. The anatomo-pathological result of the sample was in favor of an infected xanthoma. Discussion: The most common oral manifestation of Noonan syndrome includes malocclusion, dental anomalies and radiologic jaw lesions. Xanthomas of the lip have never been reported in this syndrome. Conclusion: Oral xanthomas could be one of the many oral clinical manifestations of Noonan Syndrome. However, more research is needed to understand clinical consequences of mutations in identified genes.

EP292 - Potential management strategies for neurofibromatosis-Noonan syndrome: a case series

eP292 - Potential management strategies for neurofibromatosis-Noonan syndrome: a case series

Chinese patient with neurofibromatosis-Noonan syndrome caused by novel heterozygous NF1 exons 1\u201358 deletion: a case report

BackgroundNeurofibromatosis-Noonan syndrome (NFNS) is a rare autosomal dominant hereditary disease. We present a case of NFNS due to the heterozygous deletion of exons 1–58 of the NF1 gene on chromosome 17 in a 15-month-old boy.Case presentationA 15-month-old boy was admitted for motor and language developmental delay, numerous café-au-lait spots, hypertelorism, left blepharoptosis, pectus excavatum, cryptorchidism, secondary atrial septal defect, and UBOs (undefined bright objects) revealed by cranial MRI T2FLAIR in basal ganglia and cerebellum. Using whole exome sequencing, we identified a de novo heterozygous deletion including exons 1–58 of the NF1 gene.ConclusionAlthough genetic tests are useful tools for diagnosis of NFNS, NF1, or NS, comprehensive analysis of genetic factors and phenotypes is indispensable in the clinical practice. To the best of our knowledge, this case presents the first Chinese NFNS case due to NF1 defects, and the NF1 exons 1–58 deletion-related phenotype is unlike any other reported case.

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1.

BackgroundRASopathies are a group of disorders caused by disruptions to the RAS‒MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis‐Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management.MethodsA derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café‐au‐lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14‐gene RASopathy‐associated panel.ResultsIn the derivation cohort, six (21%) patients had disease‐causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease‐causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with disease‐causing variants, 5/17 only had an NSD diagnosis.ConclusionsAdding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results.

Inherited Disorders of the Ras-MAPK Pathway

RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaciocutaneous syndrome, and Costello syndrome); (2) Neurofibromatosis type 1 and the related disorders Neurofibromatosis-Noonan syndrome and Legius syndrome; (3) Mosaic RASopathies including a rapidly growing group of mainly (neuro)cutaneous disorders with “oncogenic” mutations in a somatic mosaic state; (4) RAS-MAPK pathway dysregulation without a NS-like phenotype including non-syndromic intellectual disability due to SYNGAP1mutations and capillary malformation-arteriovenous malformation/Parkes-Weber syndrome; (5) RAS-MAPK pathway defects without overactivation such as metachondromatosis. Germline mutations leading to Ras-MAPK dysregulation typically lead to a characteristic pattern of craniofacial anomalies, heart defects, shorts stature, and variable neurodevelopmental deficits as seen in NS and other RASopathies of category 1. Confirmed genes leading to RASopathies from this category include BRAF,CBL, HRAS, KRAS, MAP2K1, MAP2K1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, LZTR1, and PPP1CB. Newer genes include SOS2, MRAS, RRAS, and RASA2. For some individual RASopathy disease entities, specific genotype associations exist, for others, this correlation is not tight. The cancer risk in many patients with RASopathies is only moderately increased, however, for a subgroup of patients the cancer risk is very high. These include patients with Costello syndrome (HRAS) who develop rhabdomyosarcoma, neuroblastoma and bladder cancer, patients with NF1 who develop juvenile myelomonocytic leukemia (JMML), neurofibroma/-fibrosarcoma, and brain tumors, and patients and with CBL syndrome who develop JMML. New clinical studies explore the use of RAS-MAPK Pathway inhibitors in this unique population. Various animal and in vitro models have been described, which (partially) recapitulate the human RASopathy phenotype and phenotypic rescue by manipulating RAS-MAPK signal flow has been demonstrated. DisclosuresNo relevant conflicts of interest to declare.

NF1 Gene Mutations are the Major Molecular Event in Neurofibromatosis-Noonan Syndrome

NF1 Gene Mutations are the Major Molecular Event in Neurofibromatosis-Noonan Syndrome

Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors.

Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.

Neurofibromatosis-Noonan Syndrome Due to a Newly Occurred Microdeletion 17q11.2

Neurofibromatosis-Noonan Syndrome Due to a Newly Occurred Microdeletion 17q11.2

Novel association of neurofibromatosis type 1‐causing mutations in families with neurofibromatosis‐noonan syndrome

Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

Multiple café au lait spots in familial patients with MAP2K2 mutation

Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated.

A new nonsense mutation in the NF1 gene with neurofibromatosis–Noonan syndrome phenotype

Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.

Lethal presentation of neurofibromatosis and Noonan syndrome

Neurofibromatosis type 1 and Noonan syndrome are both common genetic disorders with autosomal dominant inheritance. Similarities between neurofibromatosis type 1 and Noonan syndrome have been noted for over 20 years and patients who share symptoms of both conditions are often given the diagnosis of neurofibromatosis-Noonan syndrome (NFNS). The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades until the discovery that the syndromes are related through disturbances of the Ras pathway. We present an infant male with coarse facial features, severe supravalvar pulmonic stenosis, automated atrial tachycardia, hypertrophic cardiomyopathy, airway compression, severe neurological involvement, and multiple complications that lead to death during early infancy. The severity of clinical presentation and significant dysmorphic features suggested the possibility of a double genetic disorder in the Ras pathway instead of NFNS. Molecular analysis showed a missense mutation in exon 25 of the NF1 gene (4288A>G, p.N1430D) and a pathogenic mutation on exon 8 (922A>G, p.N308D) of the PTPN11 gene. Cardiovascular disease has been well described in patients with Noonan syndrome with PTPN11 mutations but the role of haploinsufficiency for neurofibromin in the heart development and function is not yet well understood. Our case suggests that a double genetic defect resulting in the hypersignaling of the Ras pathway may lead to complex cardiovascular abnormalities, cardiomyopathy, refractory arrhythmia, severe neurological phenotype, and early death.

Neurofibromatosis-Noonan syndrome: Case report and clinicopathogenic review of the Neurofibromatosis-Noonan syndrome and RAS-MAPK pathway

Neurofibromatosis-Noonan syndrome is an entity that combines both features of Noonan syndrome and Neurofibromatosis type 1. This phenotypic overlap can be explained by the involvement of the RAS-MAPK pathway (mitogen-activated protein kinase) in both disorders. We report the case of a 17-year-old boy with Neurofibromatosis 1 with Noonan-like features, who complained of the progressive appearance of blue-gray lesions on his back.

LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria

Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis-Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Independent NF1 and PTPN11 mutations in a family with neurofibromatosis‐Noonan syndrome

Neurofibromatosis-Noonan syndrome (NFNS), an entity which combines both features of Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), was etiologically unresolved until recent reports demonstrated NF1 mutations in the majority of patients with NFNS. The phenotypic overlap was explained by the involvement of the Ras pathway in both disorders, and, accordingly, clustering of the NF1 mutations in the GTPase-activating protein (GAP) domain of neurofibromin was observed in individuals with NFNS. We report on an 18-month-old girl with typical findings suggestive of NS in combination with multiple café-au-lait spots and bilateral optic gliomas suggestive of NF1. The patient was found to carry a de novo PTPN11 mutation p.T2I as well as the maternally inherited NF1 mutation c.4661+1G>C. Her otherwise healthy mother and brother, who also had the NF1 mutation, showed few café-au-lait spots as the only sign of neurofibromatosis. Since our patient's unique NF1 mutation results in skipping of exon 27a and thus involves the same region, Gap-related domain, that had been shown to be associated with NFNS, her phenotype could have been misleadingly attributed to the NF1 mutation only. Contrarily, absence of both cutaneous neurofibromas and NS features in her relatives with the same NF1 mutation, suggests that the index patient's typical NFNS phenotype is caused by an additive effect of mutations in both NF1 and PTPN11. In contrast to previous findings, we speculate that absence of cutaneous neurofibromas is not solely associated with the recurrent 3-bp in-frame deletion in exon 17.

A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene

Signs of neurofibromatosis type 1 (NF1) and Noonan syndrome (NS), two distinct autosomal dominant disorders, occur together in patients reported as Watson syndrome (WS), neurofibromatosis-Noonan syndrome (NFNS), partial LEOPARD syndrome, NS with features of NF1, and NF1 with Noonan-like features. The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades. Only recently, there is increasing evidence for WS and NFNS being allelic to NF1 in the majority of patients. In this study we describe seven novel patients from five unrelated families with variable phenotypes of the NF1-NS spectrum which were systematically analyzed for mutations in the disease-causing genes NF1 for NF1 and PTPN11 for NS. Heterozygous mutations or deletions of NF1 were identified in all patients, while no PTPN11 mutation was found. The NF1 mutation segregated with the phenotype in both familial cases. These results support the hypothesis that variable phenotypes of the NF1-NS spectrum represent variants of NF1 in the majority of cases. Constitutive deregulation of the Ras pathway either through activating mutations of PTPN11 or through haploinsufficiency of neurofibromin, which acts as a Ras-inactivating GTP-ase, is probably the common pathogenetic mechanism explaining the phenotypic overlap of NS and NF1.