Schwannomatosis (SWN) is a rare tumor predisposition syndrome caused by pathogenic variants in NF2, SMARCB1, or LZTR1. Mosaicism contributes to up to 30

Importance:Neurofibromatosis type 1 (NF1) is a multisystem, tumor predisposition syndrome in which vascular manifestations, including cutaneous lesions, remain poorly characterized. Cherry angiomas (CAs) have been sporadically reported in NF1, but their prevalence and biological basis are unknown. Objective:To assess the association between NF1 and CAs and define the histopathologic, cellular, and genetic mechanisms underlying NF1-associated CAs. Design, Setting, and Participants:This prospective, comparative, cross-sectional epidemiological study was conducted from October 2020 to March 2021 at a French national referral center for neurofibromatoses within the dermatology department at Henri-Mondor University Hospital, Créteil, France. It was followed by integrated histopathologic, genomic, and cell-specific molecular analyses. The epidemiological analysis included individuals 15 years or older with confirmed NF1 and controls without NF1. Pathophysiological analyses were conducted on CAs from individuals with NF1 and healthy volunteers following written consent. Data were analyzed in 2022. Main Outcomes and Measures:Outcomes included the prevalence of CAs; age-adjusted and sex-adjusted odds ratios; histopathologic features; detection of somatic NF1 second-hit variants; identification of co-occurring oncogenic variants; localization of NF1 loss within vascular cell populations; and evidence of rat sarcoma-mitogen-activated protein kinase pathway activation. Results:Of 259 participants (125 female individuals [48.3%]), 102 (39.4%) individuals had NF1 (median [range] age, 34 [18-70] years) and 157 (60.6%) were controls (median [range] age, 40 [15-91] years). CAs were more frequent in individuals with NF1 than controls (48% vs 18%; odds ratio, 4.26; 95% CI, 2.44-7.56) and occurred at a younger age. This association persisted after adjustment for age and sex and in propensity score-matched analyses. Somatic NF1 loss-of-function second hits were identified in 26 of 39 of NF1-associated CAs (67%) and none from controls, indicating biallelic NF1 inactivation. Comprehensive genomic profiling revealed frequent co-occurring activating variants, most commonly in GNAQ. Cell-specific sequencing showed that NF1 second hits arose predominantly in endothelial cells and telocytes, with higher variant allele frequencies in endothelial cells. Immunofluorescence demonstrated increased phosphoextracellular signal-regulated kinase signaling in these vascular cell populations. Conclusions and Relevance:The results of this cross-sectional study suggest that CAs represent a frequent and previously unrecognized vascular manifestation of NF1, which is supported by epidemiological enrichment and mechanistic evidence of biallelic NF1 inactivation in vascular cells. These findings potentially expand the spectrum of NF1-associated neoplasms and establish CAs as a model for NF1-related vasculopathy.

Congenital smooth muscle hamartomas (CSMH) are benign hamartomatous proliferations (of the smooth muscles of the arrector pili muscles). They are most often present at birth and associated with many clinical and pathological signs common to Becker's nevus (BN). Pathogenic mosaic variants in the beta actin gene (ACTB) have been described in both entities. We present two children with CSMH in whom an identical and previously unreported likely pathogenic variant of ACTB was identified. This supports the hypothesis that Becker's nevus and CSMH are part of the same nosological spectrum; therefore, the term CSMH is more appropriate.

Pigmentary mosaicism (PM) refers to various developmental patterns of skin pigmentation. It can present as a hypopigmented, hyperpigmented, or mixed form combining both types (cutis tricolor). In about one-third of cases, PM is associated with extracutaneous manifestations, most often neurological. The cause of PM is primarily genetic, including chromosomal mosaicism, mosaic intragenic pathogenic variants, as well as epigenetic mosaicism in females carrying a pathogenic variant on the X chromosome. This article summarizes recent literature in order to better identify the underlying causes and improve the management of these patients.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Among 847 patients, the median age was 23 years, 27.5

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Mosaic errors of immunity (MEI) encompass a group of immune disorders caused by somatic or gonosomal gene variants affecting hematopoiesis and immune function. Although the causal role of mosaicism in monogenic immune disorders has been recognized for over two decades, our understanding of their pathogenesis, genotype-phenotype correlation and clonal evolution remains poor. In this review, we synthesize shared and distinct molecular determinants from the currently recognized MEI and provide a mechanistic framework for future research. Exploring the implications of mosaic genetic variation in patients with unexplained immune disorders could uncover novel, actionable genetic disorders. Moreover, the study of these rare 'experiments of nature' may shed light on cell-specific immune pathways, non-malignant clonal dynamics, and mosaic disorders more broadly.

We present a neonatal case of skin blisters and erythema. While epidermolysis bullosa was initially suspected, immunofluorescence antigen mapping and genetic testing confirmed epidermolytic ichthyosis, with a heterozygous pathogenic variant in the KRT10 gene (c.467G>A, p.Arg156His). A multidisciplinary approach is essential for accurate diagnosis and treatment of neonatal blistering conditions.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition with a birth incidence of one in 2000 to one in 3000 [...]

A 6-year-old boy with multiple capillary malformations of the port-wine birthmark (PWB) type on the right leg since birth presented with a varicose vein and segmental overgrowth of the affected leg. Genetic testing on affected skin confirmed the presence of a somatic novel pathogenic HRAS 30 bp in-frame duplication/insertion in the switch II domain. This case illustrates the phenotypic overlap of different genotypes and shows that somatic HRAS pathogenic variants, especially in-frame duplications/insertions, must be added to the list of the underlying causes in capillary malformations.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

AIM:To find proof-of-principle evidence for short-term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1). METHOD:This was a double-blind, parallel-group, randomized, placebo-controlled clinical trial (the NF1-EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17  years 6 months. The short-term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention-deficit/hyperactivity problems, and executive functioning. RESULTS:We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete-case analysis showed no effect of lamotrigine on either performance IQ (-0.23, 95% CI -6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (-0.81, 95% CI -1.67 to 0.04). INTERPRETATION:Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion.

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Dear Editors, Neurofibromatosis type I (NF1) caused by pathogenic variants (PVs) in NF1, is a progressive condition characterized by multiple cafe-au-lait macules (CALMs), skinfold freckling, Lisch nodules, cutaneous, subcutaneous or plexiform neurofibromas, optic pathway glioma and distinctive osseous lesions, developing over time.1 According to the revised diagnostic criteria either at least two of the above mentioned clinical features or at least one clinical feature and the detection of a heterozygous NF1 PV are required in order to establish a diagnosis.2 Particularly in young children with multiple CALMs with/without skinfold freckling and no family history, the identification of an NF1 PV is frequently the only way to establish an early diagnosis and to distinguish NF1 from the clinically overlapping Legius syndrome, caused by SPRED1 PVs. The birth incidence of NF1 is 1/3,000, ∼50% being de novo cases.1 In a small subset of cases the PV arises postzygotically resulting in mosaic NF1 which is estimated to be 10–20 times rarer than constitutional NF1.3 In mosaics, severity and expression of the clinical phenotype depends on the affected tissues and the proportion of mutated cells. Early postzygotic PVs which involve tissues from different germ layers result in (mild) generalized NF1 and the PV is usually present also in the gametes (gono-somatic mosaicism).4 PVs occurring later in embryogenesis may result in purely somatic mosaicism presenting for example as neurofibromas and/or CALMs with a segmental distribution in NF1.3, 5 Because mosaicism frequently goes along with a milder phenotype,3, 5 some affected individuals may remain undiagnosed.6 This applies in particular to mosaicism for a PV which is restricted to gametes (gonadal or germline mosaicism) and, hence, does not lead to any clinical symptoms.4 Parental genetic mosaicism should always be taken into account when counselling parents of a child with “apparently” de novo NF1 as we illustrate with two families in which NF1 occurred in more than one child. Informed consent for publication was obtained for all individuals tested. Family 1: The index patient, a 2-year-old girl, presented with multiple CALMs and a facial plexiform neurofibroma. Genetic testing identified the NF1 PV NM_000267.3:c.1783_2001+205delins13, p.(Glu595Argfs*6). When her younger sister was clinically diagnosed with NF1 at the age of 2 years based on multiple CALMs, juvenile xanthogranulomas on the scalp and axillary freckling, the suspicion of mosaicism in one of the parents was raised. This was substantiated by identification of subtle bilateral inguinal freckling in the 37-year-old mother (Figure 1a, b). Using the sensitive method of locked nucleic acid analysis,7 we confirmed the presence of the NF1 PV in the daughter, at low percentages in blood (1.5%), left buccal swab (2.8%), urine (3.8%) and hair roots (2.9%) (Table 1) and, thus, gonado-somatic mosaicism in the mother. The mother developed at the age of 54 years an atypical neurofibroma in the left lower leg. Identification of the PV in this tumor also indicates Schwann cell involvement. Family 2: The female index patient presented with >15 CALMs at 7 months. NF1 was confirmed by identification of the recurrent NF1 PV NM_000267.3:c.910C>T, p.(Arg304Ter). Although NF1 clinical signs were absent in both parents, analysis of DNA from blood lymphocytes of both parents was requested. In neither of the two parents, Sanger sequencing revealed evidence for the presence of this NF1 PV. Due to the rare possibility of gonadal mosaicism, prenatal testing was offered to the parents on their inquiry in the next pregnancy, which unexpectedly detected the same NF1 PV in chorionic villi (Figure 2a). Gonadal mosaicism was retrospectively confirmed by Sanger sequencing detecting the PV in the sperm cells of the father (Figure 2b). The more sensitive digital droplet PCR revealed the mutated allele in 9% of sperm cells but not in blood, urine, buccal mucosa, and hair roots (Figure 2c, Table 1). Parents having a child with “apparently” de novo NF1 frequently raise worries of a recurrence risk in siblings. Case 1 illustrates the importance of a thorough dermatological and clinical examination of both parents followed by highly sensitive techniques to confirm low-level mosaicism in cases with suspected mosaicism in a parent. This strategy is superior to genetic testing of parental blood DNA for the PV with methods like Sanger sequencing, which due to limited sensitivity would not have detected the PV in the mosaic mother. Since freckling in the mother was restricted to one body part compatible with segmental NF1, case 1 as well as cases from the literature8 illustrate also the difficulties of predicting the transmission risk of the PV from the presentation of mosaicism in the patient. Only few cases of pure gonadal mosaicism have been reported in NF1.9-11 Nonetheless, as case 2 illustrates, parents should be made aware of this rare possibility to make an informed decision. Since the majority of point mutations are located on the paternal allele, analysis of sperm cells by Sanger sequencing, a method with limited sensitivity, may be informative as illustrated in case 2. Prenatal diagnosis should also be offered at the parents' request, as this is the only way to rule out the PV in subsequent pregnancies with certainty. We wish to thank the Austrian lay association NF Kinder (https://www.nfkinder.at/) for their continuous support of patients and their families with neurofibromatosis and of our work. None.

Background 15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited. Methods Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype. Results Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination. Conclusions Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.

The SPRED family proteins act as negative regulators of the Ras-ERK pathway: the N-terminal EVH1 domain interacts with the Ras-GAP domain (GRD) of the NF1 protein, while the C-terminal Sprouty-related (SPR) domain promotes membrane localization of SPRED, thereby recruiting NF-1 to Ras. Loss-of-function mutations in the hSPRED1 cause Legius syndrome in an autosomal dominant manner. In this study, we investigated the effects of missense mutations in the SPR domain identified in patients with Legius syndrome. Among the 18 mutations we examined, six (C368S, M369L, V408E, P415A, P415L, and P422R) have defects in the palmitoylation of the SPRED1 protein, losing plasma membrane localization and forming cytoplasmic granular aggregates. To evaluate the in vivo effects of SPR mutations, knock-in (KI) mice with P415A and P415V substitutions or M417Afs∗4, a C-terminal 28 amino acid deletion, were generated. All these KI mice exhibited cranial malformations, a characteristic feature of Legius syndrome. However, both P415A and P415V mutants formed granular aggregates, whereas M417Afs∗4 showed a diffuse cytoplasmic distribution, and Spred1P415A and Spred1P415V mice, but not Spred1M417Afs∗4 mice, developed cerebellar ataxia and Purkinje cell loss with age. These data suggest that in addition to loss of palmitoylation, the C-terminal region is required for the granular aggregate formation and Purkinje cell loss. The autophagy inducer spermidine rescued the ataxia phenotypes and Purkinje cell loss in Spred1P415A mice. These results suggest that some, but not all, SPR mutations that lose lipid modification induce abnormal cytoplasmic aggregation, which could be a target for autophagic clearance, and potentially cause neurodegenerative diseases.