Juvenile xanthogranuloma in neurofibromatosis type 1. Prevalence and possible correlation with lymphoproliferative diseases: experience of a single center and review of the literature.

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.

Tumors in patients with neurofibromatosis type 1: a single- center retrospective study.

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.

Madelung's disease. Two case reports with pseudoathletic appearance.

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.

Ectropion Uveae in neurofibromatosis type 1: a new manifestation.

Abstract: Neurofibromatosis type 1 (NF1) is a rare genetic disorder with an autosomal dominant transmission and an estimated incidence of 1:2500-3500 live birth. Penetrance is virtually 100%, but the expression is highly variable and almost every organ can be affected. Diagnosis of NF1 is made with at least two of the following diagnostic criteria: six or more cafè-au-lait spots, two neurofibromas or one plexiform neurofibroma, axillary or groin freckling, optic glioma, two Lisch nodules, bone dysplasia and first-degree relative with NF1. Other ocular manifestations include orbital neurofibromas, cafè-au-lait spots on the eyelids, congenital dysplasia of the sphenoids wing and con-genital glaucoma and choroidal abnormalities. Congenital Ectropion Uveae (CEU) is a rare, non-progressive anomaly characterized by the presence of iris pigment epithelium on the anterior surface of the iris stroma, resulting from its proliferation. CEU probably depends on embryological disorders in neural cells and/or neuroectoderm of the optic cell. In this paper the authors describe three patients with CEU and NF1 found in 243 consecutive NF1 patients.

Mite bites, comet signs and possible mammary prosthesis rejection after returning to a vacation home: a diagnostic challenge.

Pyemotes ventricosus is a free-living mite feeding on larvae or nymphs of insects, including moths, beetles, wasps and bees, that are usually found in grain, straw and firewood. When present in great number or when its food is lacking, it could accidentally bite mammals, including humans, causing a highly pruritic self-limiting dermatitis, sometimes followed by a lymphangitis known as "comet sign".We present a singular case of mite lymphangitis that surrounds and delimitates breast prosthesis in a 30-year-old Caucasian woman. Other bite in the lower abdomen did not present comet sign. The patient got the infestation in her vacation home in the South of Italy, uninhabited for 10 months since COVID-19 confinement. We hypothesize that the previous surgery made the lymphatic vessels more prone to inflammation and we compare other insect bites that can occur vacationing in a long period uninhabited room.A delayed diagnosis of comet sign implies a retarded fumigation allowing new mite bites and, in this case, extends the patient's preoccupation about the prosthesis rejection.

Cutaneous manifestations in neurofibromatosis type 1.

OBJECTIVE: To better understand the real prevalence of cutaneous manifestations, in Neurofibromatosis type 1. MATERIALS AND METHODS: We reviewed all clinical charts of 1102 NF1 patients followed by February 1983 to February 2020 at the "Sapienza" University of Rome, Italy. NF1 patients are seen usually every year by a dermatologist. RESULT: Café-au-lait macules were shown in 1063 patients (96.5%), axillary and inguinal freckling in 991 (90%) and neurofibromas in 861 (78.1%). Other skin manifestations included: lipoma (6.2%), nevus anemicus (3.9%), psoriasis (3.4%), spilus nevus (3.2%), juvenile xanthogranuloma (3.2%), vitiligo (2.3%), Becker's nevus (1.9%), melanoma (0.7%) and poliosis (0.5%). CONCLUSION: Neurofibromatosis type 1 is a multisystem disorder primarily involving the skin and nervous system. The clinical manifestations are extremely variable even within a family. This study was performed to delineate the prevalence of cutaneous manifestations in NF1.

Ultrastructure study of skin fibroblasts in patients with Ehlers-Danlos Syndrome (EDS): preliminary results.

AIM OF THE STUDY: To investigate, in vivo and in vitro, the fibroblast-to-myofibroblast transition in patients with hypermobile Ehlers-Danlos Syndrome (EDS). To analyze the dermis of patients with classical form of EDS (cEDS) and with hEDS, to identify qualitative and/or quantitative differences in ECM component and ultrastructural changes in collagen. MATERIALS AND METHODS: Seven subjects, aged over 18, two with cEDS and five with hEDS underwent two skin biopsy. One sample was prepared for transmission electron microscopy (TEM), the other for immunofluorescence. The diameter of collagen fibers was measured with TEM. Fibrils were analyzed in four patients: the two with cEDS and two with hEDS. For each patient, the diameter of n=250 collagen fibrils was measured. αSMA was used as specific marker for myofibroblast to highlight their presence in vivo in the skin of patients with hEDS. RESULT: IF observation could not assess an increased expression of αSMA in hEDS patients, which showed no statistical difference compared to classic form patients. The major result from the analysis of TEM images is the clear difference in ECM composition between the two forms of EDS: ECM in hEDS is optically more dense and more prominently composed of elastic fibers. CONCLUSION: Our study provides the following important evidence: 1) the absence in vivo of dermal fibroblasts in patients with hEDS, demonstrated by αSMA negativity; 2) the presence of statistically significant changes in the diameter of collagen fibrils between the classic and the hypermobile forms.

Ocular surface involvement in patients with neurofibromatosis type 1 syndrome.

PURPOSE: The aim of this study is to evaluate ocular surface morphological and functional changes in patients with neurofibromatosis type 1 (NF1). METHODS: Twenty-eight patients with NF1 and 14 healthy subjects were included in this study. All participants underwent a medical history collection, a complete ophthalmological examination including slit lamp exam and assessment of best-corrected visual acuity (BCVA), corneal sensitivity, and lacrimal function (Schirmer test and fluorescein tear break-up time test). Corneal nerves' morphology and endothelial cells density were evaluated by in vivo corneal confocal microscopy (IVCM). Tear and conjunctiva epithelium samples were collected to evaluate nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) tear levels and conjunctival expression of their receptors TrkA and p75NTR. RESULTS: Patients with NF1 showed a significant decrease of FTBUT when compared with healthy subjects (p < 0.001). Corneal sensitivity was ≤ 50 mm in 46% of NF1 patients. IVCM showed a significant increase of corneal nerve branching and of corneal endothelial cells density. No significant difference was observed between the two groups on NGF and BDNF tear levels and conjunctival expression of their receptors. CONCLUSION: This study demonstrated the presence of ocular surface changes in NF-1 patients including decrease of tear stability and of corneal sensitivity. Patients with NF1 also showed changes of corneal endothelial cells' density.

A characteristic type of retinal microvascular abnormalities in a patient with Neurofibromatosis type 1.

This study aims to describe a typical retinal microvascular abnormality in patients with neurofibromatosis type 1 (NF-1). A 64-year-old man with diagnosis of NF-1 was evaluated by complete ophthalmological examination, including fluorescein angiography and spectral Domain OCT in Near-Infrared (NIR-OCT) modality. Slit lamp exam showed the presence of more than 10 Lisch nodules for each eye. Ophthalmic examinations and NIR-OCT scans showed the presence of retinal tortuous vessels ending in a 'puff of smoke' arrangement. The clinical significance as diagnostic and prognostic factor of this novel type of retinal microvascular abnormality in NF-1 should be further investigated.

Topical cetirizine and oral vitamin D: a valid treatment for hypotrichosis caused by ectodermal dysplasia.

BACKGROUND: Ectodermal dysplasia is a clinically and genetically heterogeneous group of inherited disorders characterized by abnormal development of two or more of the following ectodermal-derived structures: hair, teeth, nails and sweat glands. The hair is the most frequently affected structure. Hair shaft abnormalities are of great concern to these patients, but no effective treatments are available. METHODS: We describe three girls with congenital hypotrichosis (9, 5 and 6 years old) caused by ectodermal dysplasia treated with topical cetirizine solution (2 mL. once daily) and oral vitamin D supplementation (1000 IU daily). RESULTS: After 6 months of treatment, the density of hair on the scalp increased in all patients. The vellus hair was replaced by terminal hair. Hair regrowth was evaluated both from the clinical and trichoscopic point of view. CONCLUSION: We propose a combination of topical cetirizine and oral vitamin D as a rational treatment of choice in congenital hypotrichosis caused by ectodermal dysplasia.

Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections.

A new concept for treatment of infections is induction of our own antimicrobial peptides and the presented novel class of inducer, aroylated phenylenediamines (APDs), gives up to 20 to 30-fold induction of the human antimicrobial peptide LL-37, in vitro. In addition, oral administration of an APD in a rabbit model of Shigellosis resulted in recovery from the infection in a few days implying that APD's are promising candidates for treatment of infections.

Chiari type 1 malformation in Neurofibromatosis type 1: experience of a center and review of the literature.

OBJECTIVE: To evaluate the possible correlation and the true incidence between Neurofibromatosis type 1 and Arnold-Chiari malformation type I. MATERIALS AND METHODS: We reviewed all clinical charts, neurological consultations and MRI scans of 428 NF1 patients followed by 1994 to 2014 in our Department. NF1 patients in our clinic are seen usually every year by both the dermatologist and the neurologist. All patients also undergo a brain and spinal cord with the same 1.5 Tesla MRI scan. RESULTS: We found a diagnosis of Arnold Chiari malformation type I in 9 of the 428 NF1 cases (2%). CONCLUSION: This frequency is higher than that expected on the basis of a chance association. Therefore we underline the importance of serial MRI studies in patients with NF1 to assess the presence of cranio-cervical anomalies. Future studies should try to better understand what are the pathogenetic mechanisms underlying this close association.

Multiple painful papulo-nodular lesions: clinical pitfall.

A 43-year-old male presented with multiple (>10) painful, papulo-nodular lesions, associated with paresthesia, over the face, neck and trunk, appeared 15 years prior and increased with time. The patient's brother has cutaneous leiomyomas and testicle cancer, his mother underwent hysterectomy for symptomatic leiomyomas while his maternal grandfather died from aggressive renal cell carcinoma at age 57 years. The patient reported that he had removed a kidney cancer 5 years prior. Dermoscopy, histologic evaluation and genetical analysis were done and Hereditary leiomyomatosis and renal cell carcinoma was diagnosed.

Basal cell carcinomas in a young woman with Steinert's disease.

Steinert's disease or Myotonic dystrophy type I (DM1) is an autosomal dominant disease characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and electrocardiographic alterations.Several tumors have been associated with DM1 such as pilomatricoma, thymomas and insulinomas. Herein, we describe the unusual onset of multiple basal cell carcinomas in a young woman with DM1.

Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression.

BACKGROUND AND PURPOSE: Artemisinin is an antimalarial drug exerting pleiotropic effects, such as the inhibition of the transcription factor nuclear factor-kappa B and of the sarcoplasmic/endoplasmic reticulum Ca(++)-ATPase (SERCA) of P. falciparum. As the sesquiterpene lactone thapsigargin, a known inhibitor of mammalian SERCA, enhances the expression of P-glycoprotein (Pgp) by increasing the intracellular Ca(++) ([Ca(++)](i)) level, we investigated whether artemisinin and its structural homologue parthenolide could inhibit SERCA in human colon carcinoma HT29 cells and induce a resistance to doxorubicin. EXPERIMENTAL APPROACH: HT29 cells were incubated with artemisinin or parthenolide and assessed for SERCA activity, [Ca(++)](i) levels, Pgp expression, doxorubicin accumulation and toxicity, and translocation of the hypoxia-inducible factor, HIF-1alpha. KEY RESULTS: Artemisinin and parthenolide, like the specific SERCA inhibitors thapsigargin and cyclopiazonic acid, reduced the activity of SERCA. They also increased intracellular calcium concentration ([Ca(++)](i)) and Pgp expression and decreased doxorubicin accumulation and cytotoxicity. The intracellular Ca(++) chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, and the inhibitor of calmodulin-dependent kinase II (CaMKII) KN93 prevented these effects. CaMKII is known to promote the phosphorylation and the activation of HIF-1alpha, which may induce Pgp. In HT29 cells, artemisinin and parthenolide induced the phosphorylation of HIF-1alpha, which was inhibited by KN93. CONCLUSIONS AND IMPLICATIONS: Our results suggest that artemisinin and parthenolide may act as SERCA inhibitors and, like other SERCA inhibitors, induce resistance to doxorubicin in human colon cancer cells, via the CaMKII-dependent activation of HIF-1alpha and the induction of Pgp.

Immune tolerance induction in haemophilia A patients with high-responding inhibitors to factor VIII: experience at a single institution.

Inhibitor antibodies to transfused factor VIII pose significant challenges in the management of haemophilia A patients. The main concern is the inefficacy of replacement therapy in patients with high-titre antibodies, who have a shorter life-span and a greater morbidity compared to subjects without inhibitors. The ultimate goal in treating these patients is to eliminate the inhibitor antibody entirely, allowing the recommencement of specific replacement therapy. The results of an immune tolerance regimen based on pharmacokinetic parameters are reported here. In 12 high-responder haemophilia A patients immune tolerance induction (ITI) was attempted with daily administration of factor VIII concentrates of very high purity, either plasma-derived or produced by recombinant-DNA technology. Patients were given 100 IU kg(-1) day(-1) until the inhibitor was shown to be absent by at least two negative assays 1 month apart, with normal recovery of infused factor VIII and normal half-life (> 6 h), as assessed after a 3-day washout period. After the patient was judged to be inhibitor-free, immune tolerance treatment was continued with unmodified factor VIII doses for 2 months. Doses were thereafter gradually reduced and finally, regular prophylaxis by administration of 25 IU kg(-1) three times weekly was instituted. Immune tolerance was achieved in 10 of the 12 patients (including six of seven with long-standing inhibitors) within a median time of 8 months. Outcome of immune tolerance was not influenced by age at start of ITI nor by the interval between inhibitor development and ITI. The success rate and the inhibitor disappearance time of our immune tolerance regimen, utilizing high-purity factor VIII, agrees with those reported by other investigators.

Feasibility of peripheral blood stem cell rescue as intensification in elderly patients with acute myelocytic leukaemia: a pilot study from the Gimema Group. Gruppo Italiano Malattie Ematologiche Maligne Dell'Adulto.

Elderly patients with untreated acute myeloid leukaemia (AML, n = 47) tested the feasibility of out-patient consolidation therapy and post-consolidation treatment (for patients aged < 71 years) with autologous peripheral blood stem cell transplantation (APBSCT). Overall, 13 patients out of 24 (51%) who achieved complete remission (CR) were eligible for further treatment after consolidation. Five patients were primed with granulocyte colony stimulating factor (G-CSF); a suitable number of CD34+ cells were harvested in three patients and were actually autotransplanted. The toxicity of APBSCT was negligible. Psychosocial problems impaired treatment of some patients on an out-patient basis. Resistant disease, toxicity and logistic problems reduced the number of patients to whom this procedure could actually be applied.