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Cutaneous birth marks are heterogeneous group of congenital skin lesions with a high diagnostic value. A good clinician by looking at the skin, eye and face can diagnose conditions like Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex (TSC), Ataxia-telangiectasia, Von Hippel-Lindau disease, Sturge-Weber Syndrome (SWS) and others. The author reports in the present case series, six cases presenting with one or more of the following seven different types of facial neurocutaneous markers like Café-au-lait Macules (CALM), neurofibromas, facial angiofibromas, forehead plaque, hypomelanotic macules (ash-leaf) on the trunk and extremities, capillary malformation in the face (port-wine stain) and ocular telangiectasia. Using these cutaneous markers as red alerts, the authors did a focused clinical examination, ophthalmic and auditory evaluation, neuroimaging, renal and cardiac evaluation to come to a diagnosis. This helped us in detecting clinical syndromes like NF1, TSC, SWS and unveiled the hidden morbidities like hypertension, intracranial tumours, intracardiac rhabdomyoma, glaucoma and others ocular abnormalities. The present case series emphasises on the need for all Paediatrician and Ophthalmologist, to develop a clinical eye to identify neurocutaneous markers in children, who may arrive at their clinic with various problems for early diagnosis and treatment of various neurocutaneous syndrome and their co-morbidities. [ABSTRACT FROM AUTHOR]

Cutaneous birth marks are heterogeneous group of congenital skin lesions with a high diagnostic value. A good clinician by looking at the skin, eye and face can diagnose conditions like Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex (TSC), Ataxia-telangiectasia, Von Hippel-Lindau disease, Sturge-Weber Syndrome (SWS) and others. The author reports in the present case series, six cases presenting with one or more of the following seven different types of facial neurocutaneous markers like Café-au-lait Macules (CALM), neurofibromas, facial angiofibromas, forehead plaque, hypomelanotic macules (ash-leaf) on the trunk and extremities, capillary malformation in the face (port-wine stain) and ocular telangiectasia. Using these cutaneous markers as red alerts, the authors did a focused clinical examination, ophthalmic and auditory evaluation, neuroimaging, renal and cardiac evaluation to come to a diagnosis. This helped us in detecting clinical syndromes like NF1, TSC, SWS and unveiled the hidden morbidities like hypertension, intracranial tumours, intracardiac rhabdomyoma, glaucoma and others ocular abnormalities. The present case series emphasises on the need for all Paediatrician and Ophthalmologist, to develop a clinical eye to identify neurocutaneous markers in children, who may arrive at their clinic with various problems for early diagnosis and treatment of various neurocutaneous syndrome and their co-morbidities.

Malignant peripheral nerve-sheath tumors (MPNSTs) are rare malignancies that are often observed in patients with neurofibromatosis type 1 (NF1). However, the occurrence of MPNST associated with mosaic localized NF1 is extremely rare. Previous reports have revealed that MPNST was associated with mosaic localized NF1 in only three patients who were >40 years of age. The present report details a 16-year-old man who presented with pain and a 3 cm mass on the medial side of the right knee. Magnetic resonance imaging revealed a circumscribed soft tissue tumor located in the subcutaneous tissue. His previous doctor believed that it was benign and conducted a marginal resection. However, postoperative histology results demonstrated spindle cell sarcoma, following which the patient was referred to The Osaka International Cancer Institute. Localized café-au-lait spots were identified in the affected leg, which inferred that the patient had NF1-related MPNST. A wide resection was performed to completely resect the residual tumor; however, a definitive histological diagnosis was challenging due to the small residual tumor. Hence, the genomic mutations of NF1 in the regional café-au-lait spots were analyzed. The result revealed an NF1 microdeletion and a consistently limited expression of NF1 in the tumor sample. Finally, the patient was diagnosed with MPNST with mosaic localized NF1. Local recurrence and distant metastasis were not observed 1.5 years after surgery. In conclusion, the present report presented MPNST in an adolescent patient with mosaic localized NF1. The occurrence of MPNSTs correlated with mosaic localized NF1 is extremely rare. However, it is of high-grade malignancy and therefore, its clinical features should be considered by orthopedists and pathologists. [ABSTRACT FROM AUTHOR]

Type 1 Neurofibromatosis (NF1) is a rare autosomal dominant genetic disorder. There are seven clinical features of which two are necessary to diagnose it. Another important feature is plexiform neurofibroma which commonly presents as painful expansile lesion. Here we present a case of NF1 with huge swelling of left hemiface and chin following trauma over pre-existing swelling and presented as life threatening emergency and managed surgically. [ABSTRACT FROM AUTHOR]

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals. [ABSTRACT FROM AUTHOR]

A 40-year-old woman presented with an itchy erythematosquamous change of a café-au-lait spot in her face. The onset of this change occurred just after her relocation. The café-au-lait spot had been irradiated by laser approximately 20 years ago. Clinically, there was a coin-sized erythema with a slight scale on the pigmented lesion in the left lateral orbital region. Histopathologically, the lesion demonstrated both spongiotic dermatitis and interface dermatitis together with lymphohistiocytic cell infiltration, in addition to moderate acanthosis and elongation of rete ridges with slight basal hyperpigmentation. From these clinical and histopathological findings, the lesion was diagnosed as eczematous dermatitis occurring on the café-au-lait spot after laser radiation. Another interesting histopathological finding was that some parts of a lobule of the sebaceous gland were occupied exclusively by degenerative atrophic sebocytes. From the viewpoint of pathogenesis, the eczematous dermatitis of this patient could have been an accompanying feature of a neurogenic inflammation occurring on the café-au-lait spot after laser radiation, and the atrophic change of a part of the sebaceous lobule might have been induced by a morphogenetic alteration of certain germinative cells of the sebaceous lobule due to laser radiation.

Neurofibromatosis is a relatively common autosomal dominant hereditary neuro-cutaneous disease caused by mutation in tumor-suppressor genes. It results in the development of multiple hamartomas, benign and malignant tumors. The disease is currently classified into 3 individual subunits with different clinical presentations based on mutations of different genes - neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. The most common type is NF1. The symptoms are age-dependent, the severity of clinical picture is variable. Cutaneous symptoms are present namely in NF1, they are less common in other types. They include multiple café-au-lait spots and axillary and inguinal freckling. Neurofibromas, plexiform neurofibromas and optic gliomas are present in NF1, Lisch nodules in the iris are pathognomonic. Vestibular schwannomas are typical for NF2, and multiple schwannomas in peripheral nerves are present in schwannomatosis. The prognosis differs and is based on the clinical picture and complications. Diagnostic criteria play a key role in differentiating various types of neurofibromatosis and dermatological examination plays a key role. Patients should be concentrated in specialized centers. The treatment of neurofibromatosis is symptomatic. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 is fully penetrant by the age of 8 years, and 3 criteria of diagnosis are dermatological: café-au-lait spots (CLS), intertriginous freckling and neurofibromas (NF). Objectives: The aim of our study was to determine the evolving pattern of cutaneous manifestations during adulthood. Methods: Phenotypic data of patients seen in our center between March 2003 and December 2009 were studied. Patients were classified in 10-year groups. Following clinical characteristics, the number of CLS and the number of cutaneous and subcutaneous NF were compared according to age. Results: 728 subjects, 404 females and 324 males (mean age of 32.4 years, range 6-80 years) were studied. Four hundred eighty-nine patients were over 20 years old (67%). The number of CLS (small or large) was significantly decreased with age while the number of cutaneous and subcutaneous NF was strongly increased (p < 0.001). Conclusions: The decrease in CLS with age has not been previously reported while an increase in the number of NF is well described during puberty and pregnancy and with age. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Solitary café-au-lait spots are quite common in the general population but multiple café-au-lait macules (CALM) are often indicative of an underlying genetic disorder. The frequency of having more than five CALM is rare in normal individuals and is therefore considered as a cut-off for the diagnosis of neurofibromatosis type 1 (NF1). The etiopathogenesis of these macules is still very obscure. In this study we compared epidermal melanocyte and dermal mast cell numbers between four groups: control normal and control CALM skin, and NF1 normal and NF1 CALM skin and elaborated a possible role for stem cell factor (SCF) in CALM formation. The groups were analyzed by immunohistochemistry for numerical analysis of the melanocyte and mast cell population and by ELISA, western blot analysis and real-time quantitative PCR for further determination of the role of SCF. We found a significant increase in melanocyte density in NF1 CALM skin compared with the isolated CALM in control individuals. However, both groups displayed a similar increase in mast cell density. In addition, we found increased levels of soluble SCF in NF1 CALM and in NF1 normal fibroblast supernatant. We conclude that SCF is an important cytokine in NF1 skin, but that additional (growth) factors and/or genetic mechanisms are needed to induce NF1-specific CALM hyperpigmentation. [ABSTRACT FROM AUTHOR]

Background: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment., Methods: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017., Results: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families)., Conclusions: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: McCune-Albright syndrome is a rare sporadic disease defined by the triad of café-au-lait spots, fibrous dysplasia of bone and endocrine disorder. Diagnosis is classically confirmed by the presence of bone lesions or precocious puberty. We report a case of McCune-Albright syndrome diagnosed solely on the basis of the cutaneous signs., Patients and Methods: A four-year-old girl was seen in our clinic due to the presence of congenital café-au-lait spots on her back. These macules were irregular, with jagged borders, and were disposed in a broad band on the left shoulder and in the lumbar region, in a Blaschko-linear pattern. McCune-Albright syndrome was immediately suspected, despite the absence of other signs of the disease. Genetic assessment carried out a year and a half later confirmed the diagnosis, with arginine substitution at position 201 of Gs alpha protein. The child was still asymptomatic. Regular radiographic and endocrine assessments remained normal for three years until the sudden appearance at the age of seven years of precocious puberty and radiographic evidence of fibrous dysplasia of the right hand., Discussion: Café-au-lait spots are very common in the general population. An underlying genetic disorder should only be sought when such spots are multiple. However, in the case of McCune-Albright syndrome, it is the irregular borders and the Blaschko-linear arrangement of the spots in broad irregular bands that are pathognomonic, reflecting as they do the genetic mosaicism characteristic of this disease., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)