Aim: To investigate clinical and molecular features of neurofibromatosis type 1 (NF1)-associated breast cancer (BC) in a large multicenter cohort. Methods: Clinical and histopathological data from 86 NF1 patients with BC (69 with molecular data) were collected, and 111 published cases were reviewed. NF1 variants were assessed in silico, and their distribution across neurofibromin domains was compared with the general NF1 population. Results: NF1 patients developed BC earlier than the general population (mean 49 years), with missense variant heterozygotes showing the earliest onset (43.9 vs. 49.5 years for truncating variants, p = 0.014). Tumors were frequently high-grade (49 %), HER2-enriched (31 %) or luminal B subtypes (31 %), with reduced luminal A (28 %) frequency. NF1+BC patients had more subcutaneous (p = 0.006) and plexiform neurofibromas (p < 0.00001). Compared with the general NF1 population, they lacked large deletions (0 % vs. 3 %, p = 0.0148), showed enrichment for N-HEAT missense variants (70 % vs. 42 %; p = 0.0078), and carried recurrent variants significantly enriched in NF1+BC. Structural modeling predicted deleterious effects for >70 % of variants, with proline/arginine substitutions accounting for 83 % of missense variants (vs. 44 % in the general NF1 population, p = 0.0012). Conclusions: NF1-associated BC is characterized by earlier onset, aggressive tumor features, and distinct mutational patterns.

Urbach-Wiethe syndrome, also known as lipoid proteinosis (LP), is a rare genodermatosis clinically characterized by mucocutaneous lesions, dysphonia with onset in early childhood, and, sometimes, neurological complications. Clinical signs, as well as the severity of the disease, are highly variable, while its course is usually slowly progressive. The typical primary sign is hoarse crying due to laryngeal infiltration at birth or during early childhood. Alterations of the skin and mucous membranes develop within the first two years of life. The skin lesions initially appear on the face and limbs and usually resolve by healing. Infiltration of the respiratory system can cause upper respiratory tract infections, hoarseness or aphonia, dysphagia, and even airway obstruction. Dystonia, epileptic seizures, and learning disorders may be observed in affected children. Treatment remains a major challenge as no standardized therapies exist, but oral acitretin appears to be effective in improving skin manifestations. We report two clinical cases of young women suffering from LP, presenting with dermatological, otorhinolaryngological, and neurological symptoms, currently referred to our Rare Cutaneous Syndrome Center at the Policlinico Umberto I in Rome (Italy).

Introduction: Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by progressive mineralization and fragmentation of elastic fibers, leading to multisystem involvement. Diagnosis relies on clinical features, histopathology, and, in selected cases, genetic testing, with cutaneous manifestations often representing the earliest signs. Objective: To validate dynamic optical coherence tomography (D-OCT) as a noninvasive diagnostic method for detecting PXE-related dermal abnormalities. Methods: In this case-control study, PXE patients evaluated at Umberto I Policlinic (Rome, Italy) between May 2023 and September 2024 underwent clinical and instrumental assessment. The left lateral cervical, retrocervical, left axillary, and periumbilical folds were analyzed using a standardized 0–3 clinical severity scale and D-OCT imaging. Control subjects were individuals undergoing routine mole checks. D-OCT quantified fiber density, attenuation, and vessel density at 300 µm and 500 µm depths. Statistical analysis included Spearman’s correlation and the Mann-Whitney U test, with p < 0.05 considered significant. Results: Twenty-three PXE patients and eleven controls were included. Cutaneous involvement was observed in 91.30% of patients, predominantly in retrocervical (86.95%) and lateral cervical (82.60%) areas. Clinical severity significantly correlated with D-OCT fiber density in the retrocervical region (ρ = 0.507). Compared with controls, PXE patients showed reduced fiber density and increased attenuation across most regions, except the axillae. At 500 µm depth, vessel density was markedly decreased in the axillary area, with approximately 2.5-fold fewer vessels in PXE skin. Conclusion: D-OCT effectively detects dermal alterations in PXE, including subclinical changes, providing a promising noninvasive alternative to skin biopsy.

BACKGROUND:Pseudoxanthoma elasticum (PXE) is a rare genetic autosomal recessive metabolic disease characterized by progressive mineralization and fragmentation of elastic fibers from soft connective tissues. The objective of our study was to analyze the epidemiological, genetic, cutaneous, and extracutaneous clinical data from the largest Italian monocentric cohort of PXE patients. METHODS:We included all patients diagnosed with PXE and referred to Neurocutaneous Rare Diseases at Umberto I Polyclinic Hospital (Rome, Italy) between January 1983 and February 2024. A retrospective analysis of their data was performed. RESULTS:We enrolled 86 patients (77.9% women), revealing compound heterozygosity in 19.8% of cases and homozygosity in 5.8%. Missense (34.9%), non-sense (5.8%), splice-site (5.8%), deletion (4.7%), and frameshift (2.3%) mutations were disclosed. Cutaneous alterations were noted in the neck (69.7%), axilla (33.7%), inguinal (17.5%), and cubital folds (11.7%). The most common ocular findings were angioid streaks (64.0%) and choroidal neovascularization (18.6%), with blindness reported in 5.8% of cases. Thicker intima-media was observed around the mid-fifties in the supra-aortic trunks (40.7%), lower limb arteries (32.6%), and renal arteries (4.7%). Regurgitation was more common in atrioventricular valves (48.8%) than in semilunar ones (10.5% and 9.3%). Dyslipidemia (19.8%), hypertension (18.8%), and fatty liver disease (12.8%) were prevalent, with calcifications found in the kidneys (25.6%), liver (15.1%), spleen (11.6%), and testicles (8.1% of males). Autoimmune diseases and depression were observed in 11.6% and 4.7% of cases, respectively. CONCLUSIONS:Enhanced understanding of PXE can improve patients' quality of life and facilitate the development of more effective therapeutic strategies.

PURPOSE:Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). METHODS:A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. RESULTS:Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling. CONCLUSION:Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.

Neurofibromatosis type 2 (NF2) is a genetically determined tumor-predisposing syndrome. Ocular manifestations include cataracts, epiretinal membranes, retinal hamartomas, optic disk gliomas, and optic nerve sheath meningiomas. Moreover, optic disk edema, optical atrophy, motility disorders, pupil and lid dysfunction, and neurotrophic keratitis can be observed as indirect signs. An observational study was conducted with the aim to collect clinical data and describe the most frequent NF2 ocular manifestations. Fourteen patients affected by NF2, according to the Manchester criteria, were enrolled. All patients underwent complete ophthalmologic and orthoptic evaluation and a spectral domain optical coherence tomography. Ocular manifestations were present in all patients. The slit lamp evaluation of the anterior segment highlighted cataracts in five patients, keratitis in two patients, corneal leukoma in two patients, and corneal pannus in one patient. Fundus oculi and OCT evaluation identified epiretinal membranes in four patients, vitreoretinal tufts in three patients, optic nerve edema in one patient, and retinal hamartoma in one patient. Moreover, the orthoptic evaluation identified different types of ocular motility disorders in seven patients. This is a descriptive study of a rare disease with poor previous literature. Clinical data are shown, emphasizing the role of NF2-specific ophthalmological and orthoptic findings to help establish an early diagnosis.

Background and Objectives: Different pathophysiological mechanisms, especially involving astrocytes, could contribute to Tuberous Sclerosis Complex (TSC). We assessed neurodegeneration and astrocytopathy plasma biomarkers in TSC adult patients to define TSC biomarker profile and investigate clinical-radiological correlations. Methods: TSC patients >= 15 years followed at Policlinico "Umberto I" of Rome were consecutively enrolled (July 2021-June 2022). The plasma levels of the following biomarkers were compared between patients and age/sex-matched healthy controls (HC): tTau, pTau181, Abeta(40), Abeta(42), Neurofilament Light Chain, Glial Fibrillary Acid Protein (GFAP). Results: Thirty-one patients (20 females/11 males; median age 30 years, IQR 24-47) and 38 HC were enrolled. Only GFAP was significantly higher in the whole TSC population than in HC [132.71 (86.14-231.06) vs 44.80 (32.87-66.76) pg/mL, p<0.001], regardless of genotype. GFAP correlated with the disease clinical (rho=0.498, p=0.005) and radiological severity (rho=0.417, p=0.001). It was significantly higher in patients with epileptic spasms [254.50 (137.54-432.96) vs 86.92 (47.09-112.76) pg/mL, p<0.0001], moderate-severe intellectual disability [200.80 (78.40-427.6) vs 105.08 (46.80-152.58) pg/mL, p=0.040] and autism spectrum disorder [306.26 (159.07-584.47) vs 109.34 (72.56-152.08) pg/mL, p=0.021]. Discussion: Our exploratory study documented a significant increase of GFAP plasma concentration in TSC adult patients, correlated with their neurological severity, supporting the central role of astrocytopathy in TSC pathophysiology.

Adalimumab is the only biologic agent approved for the treatment of moderate-to-severe hidradenitis suppurativa (HS) patients (i.e., with Hurley II or III), which is recommended in two different maintenance doses (i.e., 40 mg weekly or 80 mg every two weeks). We conducted a prospective multicentric study to measure outcomes related to the severity of disease and quality of life (QoL) of patients affected by moderate-to-severe HS, treated with adalimumab at a maintenance dosing of 40 mg or 80 mg. Assessments were performed at baseline (T0) and after 32 weeks of treatment (T32). We enrolled 85 moderate-to-severe HS Italian patients, 43 men (50.6%) and 42 women, aged between 16 and 62 years (median 31 years, interquartile range 24.4–43.8). Statistically significant improvements were observed for clinical status (with a mean reduction of 7.1 points for the International Hidradenitis Suppurativa Severity Score System (IHS4)), pain levels (3.1 mean decrease in VAS), and QoL (3.4 mean improvement in DLQI score). Patients with no comorbidities, and those with higher levels of perceived pain showed significantly greater improvement in QoL than their counterpart from T0 to T32. As for the proportion of patients who at follow-up reached the minimal clinical important difference (MCID) in QoL, significantly higher proportions of success were observed for age (patients in the 29–39 category), pain (patients with higher reported pain), and Hurley stage III. While both treatment regimen groups (i.e., 40 vs. 80 mg) improved significantly, no statistical differences were observed when comparing the two treatment dosages.

Neurofibromatosis Type 1 (NF1) is a rare neurocutaneous disorder transmitted in an autosomal dominant fashion, mainly affecting the nervous system, the eye and skin. Ocular diagnostic hallmarks of NF1 include iris Lisch nodules, optic gliomas, orbital and eyelid neurofibromas, eyelid café-au-lait spots. In recent years, a new ocular sign represented by choroidal abnormalities (CAs) has been characterized in NF1. The CAs, identified with near-infrared reflectance, have been reported with a frequency of up to 100% in NF1, and have recently been added to the actual diagnostic criteria for NF1. The present Letter to the journal is intended to provide an update on features and clinical significance of CAs in NF1. Moreover, the relation with other ocular manifestations recently described in NF1 including hyperpigmented spots and retinal microvascular abnormalities is discussed.

Abstract:Neurofibromatosis type 1 (NF1), is a rare genetic disorder that may involve almost every organ system in the body such as cutaneous, ophthalmologic and central and peripheral nervous system. Cutaneous findings are usually the first sign of the disease. In this study, we investigate the real prevalence of xanthogranulomas juvenile (JXG) and possible correlation with lymphoproliferative diseases. This is a retrospective study conducted on a population with NF1 followed by February 1983 to February 2022 at the "Sapienza" University of Rome, Italy. We investigate the real prevalence of juvenile xanthogranuloma in NF1 and possible correlation with lymphoproliferative diseases. JXG was present in 39 cases (3.1%). JXG is more frequent in NF1 than in the general population while the possible association with lymphoproliferative diseases in NF1 remains controversial.

AIM: To examine neuroretinal function by using the multifocal electroretinography (mfERG) test in patients with neurofibromatosis type 1 (NF1) without optic pathway gliomas (OPGs). METHODS: This study was conducted on 35 patients (35 eyes) with NF1 and 30 healthy subjects (30 eyes) for the control group. Each subject underwent a complete ophthalmological examination including spectral domain-optical coherence tomography (SD-OCT) and mfERG. The 1.5-Tesla magnetic resonance imaging (MRI) scan of the brain was performed in NF1 patients to assess the presence of OPGs. All participants were recruited having a best corrected visual acuity (BCVA) of no less than 20/20 in each eye. The amplitude and implicit time of the P1 wave (first-order Kernel component) were evaluated on mfERG. Data analysis was carried out in the two central degrees and in the four quadrants from two to 25 degrees of visual field. RESULTS: Statistically significant results were obtained for the P1 wave amplitudes in the 4 quadrants in NF1 patients compared to healthy controls, while the reduction was not significant in the 2 central degrees between the groups. A statistically significant difference was observed among the P1 wave amplitudes as recorded in the 4 quadrants within the NF1 group, with lower amplitudes detected in the nasal quadrants. No differences in the implicit times were recorded in the 2 central degrees and in the 4 quadrants as compared between NF1 patients and controls. CONCLUSION: Impaired neuroretinal function in NF1 patients is expressed in a decreased amplitude of the P1-wave between 2 and 25 central retinal degrees on mfERG. Altered intracellular signal transduction due to abnormal neurofibromin-mediated cyclic adenosine monophosphate (cAMP) generation, can be involved. The possible use of mfERG as subclinical retinal damage indicator has a potential utility in clinical practice for the follow-up of NF1 patients.

Objective:To investigate the risk and pattern of tumors in italian neurofibromatosis type 1 (NF1) patients.Materials and Methods:A retrospective single institution case review of 711 patients (seen between March 1992 and February 2018) with NF1 was conducted to identify individuals with diagnoses of both NF1 and neoplasm. NF1-associated tumors have been collected and analyzed.Results:We identified 221 tumors in 191 subjects with a percentage of 26.9%, diagnosed at a median age of 32.5 years (range, 0.6-70.1 years); 111 of these patients were females (58%) and all were fol-lowed up for a median of 5.3 years. The cumulative risks for tumor in patients with NF1 by the ages of 30 and 60 years were 10% and 42.5%, respectively. In our patients with tumor, overall survival at 70 years was significantly shorter than in those without it (50% vs 95%, P<0.0001). We found an unequivocally increased incidence for breast cancer in females (33 cases observed).Conclusions:Tumors that develop in patients with NF1 are heterogeneous, our data are consistent with other reports suggesting an increase in some cancers risk among these individuals, therefore systematic medical follow-up in people with NF1 is important.

OBJECTIVE:Neurofibromatosis 1 (NF1) is a chronic medical disease that often presents with psychiatric disorders. We investigated suicidal ideation in NF1 patients compared to healthy controls. We also evaluated whether hopelessness, depressive symptoms and perceived disability may mediate suicidal ideation in patients with NF1.METHODS:We enrolled 60 patients with NF1 and 50 healthy controls with no history of NF1. Patients underwent a full psychiatric evaluation. Psychiatric diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria. Patients and controls underwent a series of psychometric measures, namely the Columbia Suicide Severity Rating Scale, the Beck Hopelessness Scale, the Italian Perceived Disability Scale and the Beck Depression Inventory.RESULTS:Suicidal ideation was significantly higher in patients with NF1 (45%) than in controls (10%). Patients also presented more severe perceived disability and hopelessness and more frequent psychiatric disorders than controls. Multivariable logistic regression analysis showed that perceived disability was independently associated with the presence of suicidal ideation in patients with NF1.CONCLUSIONS:In conclusion, our results showed that suicidal ideation was present in almost half of patients with NF1, suggesting the importance of suicide assessment in these patients.Key pointsPatients with NF1 have an increased suicide ideation when compared to healthy controlsIncreased suicidal ideation correlates with perceived disability, but not with the presence of psychiatric disordersAssessment of suicidal ideation should be performed in patients with NF1.

Introduction: Gorlin-Goltz syndrome (GGS) also known as nevoid basal cell carcinoma syndrome (NBCCS) is a complex rare genetic disorder characterized by a wide range of clinical and radiological manifestations. Ophthalmological alterations have always been reported, but no study on the eventual pattern visual evoked potentials (pVEPs) abnormalities has yet been published. Purpose: The purpose of the study was to evaluate the functionality of the optic pathways in a group of NBCCS patients through pattern reversal VEPs, after a thorough exclusion of subjects with preexisting ocular and optic pathways pathologies. Methods: Nineteen NBCCS patients (31 eyes) and 20 healthy controls (40 eyes) have been recruited for this study. All subjects underwent an evaluation of the functionality of the optic pathways through pVEPs with small (120'), medium (60'), and large (15') check size stimulation. Results: NBCCS patients showed a statistically significant alteration in the transmission of the macular pathway function when compared to controls. PVEPs analysis confirmed a reduced amplitude and an increased latency of the P100 component, suggesting an involvement of the visual pathway even in the absence of ocular clinical manifestations. Conclusion: Visual pathways may have been affected both by a subclinical myelination deficit, determined directly by the genetic alteration, as well as by neurological abnormalities typical of this syndrome. Further studies are warranted.

Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

Abstract Madelung's disease is a rare syndrome characterized by the pre-sence of multiple masses of unencapsulated adipose tissue, symme-trically distributed throughout different regions. It predominantly affects middle-aged men of Mediterranean origin with a history of alcoholism. The pathogenesis is still unknown. Diagnosis is essentially established through clinical history and physical examination. We report two cases for their unusual presentation and to emphasize the importance of early diagnosis.