Melanoma on congenital melanocytic nevi.

Among nevus-associated melanomas, which overall account for 20%-30% of all melanomas, those arising specifically in congenital melanocytic nevi are infrequent, but can be disproportionately frequent in childhood and adolescence. Congenital melanocytic nevi (CMNi) are common benign melanocytic tumors that are present at birth or become apparent in early childhood. They are classified based on the projected adult size. Small and medium-sized CMNi are frequent, whereas large/giant CMNi (over 20 cm in diameter) are rare, but can be associated with high morbidity due to marked aesthetic impairment and the risk of neurocutaneous syndrome or melanoma development. In this setting, melanomas can appear in early childhood and are very aggressive, while the risk of small-medium CMNi of developing melanoma is low and similar to non-congenital melanocytic nevi. Histologically, most melanomas on CMNi initiate their growth at the epidermal-dermal junction, but in large/giant CMNi they can develop entirely in the dermis, in deeper tissues, or in extracutaneous sites (especially in the central nervous system). Most CMNi harbour an NRAS mutation, but other genes are rarely involved, and gene translocations have recently been described. However, no prognostic implications have been associated with the CMN genotype. Melanomas developed on CMNi harbour additional molecular alterations to which the aggressive clinical course of these tumors has been attributed. This review covers the distinctive clinical and pathological aspects of melanomas on CMNi, and includes the epidemiology, etiopathogenesis, clinical and dermoscopic presentation, histological and molecular characteristics, as well as tumour behaviour.

Superimposed Mosaicism in the Form of Extremely Extended Segmental Plexiform Neurofibroma Caused by a Novel Pathogenic Variant in the NF1 Gene.

Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the NF1 gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the NF1 gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl's plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.

Síndrome de Klippel-Trenaunay en gestante, a propósito de un caso / Klippel-Trenaunay syndrome in pregnant woman, about a case

Introducción: El síndrome de Klippel-Trenaunay es un trastorno neurocutáneo que se asocia a complicaciones trombóticas y hemorrágicas graves durante la gestación. Principales síntomas y/o hallazgos clínicos: Presentamos el caso de una primigesta afecta del síndrome de Klippel-Trenaunay a la que se realizó un seguimiento estrecho del embarazo de forma conjunta con el Servicio de Medicina Física y Rehabilitación. Ingresó a la 39+2 semanas por rotura de membranas que finalizó mediante parto vaginal eutócico, con aplicación de anestesia epidural sin complicaciones. Diagnósticos principales: Desde que el síndrome de Klippel-Trenaunay fue descrito por primera vez en 1900, se han informado menos de cien embarazos de pacientes afectas de esta patología en todo el mundo. A pesar del incremento del riesgo obstétrico y la posibilidad de exacerbación de las manifestaciones propias del síndrome durante la gestación, son posibles unos buenos resultados obstétricos con un asesoramiento adecuado y un seguimiento estrecho de la gestación. Intervenciones terapéuticas y resultados: Es fundamental realizar una valoración individualizada del riesgo-beneficio de la tromboprofilaxis dadas las potenciales complicaciones hemorrágicas y trombóticas que pueden sufrir estas pacientes. Conclusión: Es necesario un asesoramiento preconcepcional cuidadoso así como una atención intraparto y posparto sistemática para reducir la morbimortalidad en estas pacientes. (AU)

Introduction: Klippel-Trenaunay syndrome is a neurocutaneous disorder that is associated with severe thrombotic and hemorrhagic complications during pregnancy. Main symptoms and/or clinical findigns: We present the case of a primigravida affected by Klippel-Tre-naunay syndrome in whom a follow-up of the pregnancy was carried out jointly with the Physical Medicine and Rehabilitation Service. She was admitted at 39+2 weeks due to rupture of the membra-nes which ended with eutocic vaginal delivery, with the application of epidural anesthesia without complications.Main diagnoses: Since the Klippel-Trenaunay syndrome was first described in 1900, less than one hundred pregnancies of patients affected by this pathology have been reported worldwide. Despite the increased obstetric risk and the possibility of exacerbation of the syndrome’s own manifestations during pregnancy, good obstetric outcomes are possible with appropriate counseling and close moni-toring of pregnancy.Therapeutic interventions and results:It is essential to carry out and individualized assessment of the risk-benefit of thromboprophylaxis given the potential bleeding and thrombotic complications that these patients may suffer.Conclusion: Careful preconception counseling as well as systematic intrapartum and postpartum care are necessary to reduce mortality and morbidity in these patients. (AU)

Sturge-Weber Syndrome: A Rare Case Report.

Sturge-Weber syndrome (SWS) is a rare sporadic neurocutaneous syndrome characterized by angiomas involving the face, eyes, and brain (leptomeninges). Classical port-wine stains are seen in the ophthalmic and maxillary division of the trigeminal nerve. The most common presenting feature is seizures, the onset of which ranges from birth to late adulthood. Diagnosis is mainly done by brain radio imaging (CT scan and MRI with gadolinium contrast) where characteristic features of calcification and leptomeningeal enhancement are seen. We report a newly diagnosed case of SWS in a 31-year-old female patient who presented to our hospital with a complaint of generalized tonic-clonic (GTCS) type of convulsion two days prior to the admission with purple discoloration of the skin on the right side of the face, trunk, and right upper limb since birth. During the evaluation of past medical history, the patient was found to have a known case of epilepsy since the age of three months and on was on irregular treatment. To find out the cause of the seizure and skin lesions, further investigations were done which were suggestive of SWS in MRI and CT scanning of the brain. The patient was counseled about the syndrome and discharged on anti-convulsion treatment with advice for dye laser photocoagulation for port-wine stain.  SWS is a rare sporadic genetic disease and diagnosis is primarily done by evaluating history, the presence of port-wine stain, and characteristic features on brain radio imaging. As no definitive treatment is available yet, patients are being treated by medical and surgical interventions for symptoms as well as for associated complications.

Cutaneous and ocular manifestations in Indian children with neurocutaneous syndromes: A cross-sectional study.

The phenotypical profile of cutaneous and ocular manifestations in neurocutaneous syndromes is inconstant. We made a cross-sectional study over 18 months of children with neurocutaneous syndromes aged between 1-15 years. A varied presentation was found. Attention to both the typical but also the rare atypical presentations enhances an early identification of the disorder and therefore opportune management.

GNA11-mutated Sturge-Weber syndrome has distinct neurological and dermatological features.

BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. METHODS: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. RESULTS: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. CONCLUSIONS: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.

Cutis verticis gyrata: Three cases illustrating three different etiologies.

Cutis Vertcis gyrata is an uncommon neurocutaneous syndrome characterized by excessive growth of the skin of the scalp or the face, forming folds of similar aspect to cerebral cortex gyri. Three categories have been individualized: the primary form, essential or non-essential, and the secondary form.

Adults with tuberous sclerosis complex: A distinct patient population.

OBJECTIVES: There are few data on adults living with tuberous sclerosis complex (TSC), with most studies focusing on pediatric populations. The objective of our study was to examine a large national cohort of adults with TSC, and to describe the clinical characteristics of these adults and the nature of the multidisciplinary care that they receive. METHODS: Six Canadian medical centers collaborated in this study. Data were collected using a standardized form, and descriptive statistics were used for the analyses. RESULTS: Our study included 181 adults with definite TSC (mean age = 33.6 years [SD = 13.7]). More than 40% (n = 75) had family members affected by TSC. Forty-six percent (n = 83) of individuals had intellectual disability. Nearly 30% (n = 52) of individuals reported living alone or with a partner/spouse. Seventy-six percent (n = 138) of people had epilepsy, 43% (n = 59) of whom had drug-resistant epilepsy, and 21% (n = 29) had undergone epilepsy surgery. Neuropsychiatric disease (n = 128) and renal angiomyolipomas (n = 130) were both present in approximately 70% of people. Renal imaging was performed in 75.7% (n = 137) of participants within the past 3 years. Renal and pulmonary function tests, as well as electrocardiograms, were recently performed in a minority of individuals. SIGNIFICANCE: Our cohort of adults with TSC showed that an important proportion have a milder phenotype, and are more frequently familial, as compared to children with TSC (and differing from prior reports in adult cohorts). Drug-resistant epilepsy, neuropsychiatric comorbidities, and renal angiomyolipoma are challenging factors in adults with TSC. Our participating medical centers generally followed recommended screening strategies, but there remain important gaps in care. Multidisciplinary and structured TSC care centers offering service to adults may help to improve the health of this important patient population.

Neurosurgical Considerations of Neurocutaneous Syndromes.

The phakomatoses are a group of genetic and acquired disorders characterized by neurologic, cutaneous, and often ocular manifestations, thus commonly referred to as neurocutaneous syndromes. In several of these conditions the underlying genetic pathophysiology has been elucidated, which will continue to play an important role in advancing therapeutic techniques. This article focuses on several examples of such neurocutaneous syndromes, with special attention to the relevant neurosurgical considerations of these patients.

Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2.

PURPOSE: To examine long-term alterations of the dorsal root ganglia (DRG) and the peripheral nerve in patients with neurofibromatosis type 2 (NF2) by in vivo high-resolution magnetic resonance neurography (MRN) and their correlation to histology. METHODS: In this prospective study the lumbosacral DRG, the right sciatic, tibial, and peroneal nerves were examined in 6 patients diagnosed with NF2 and associated polyneuropathy (PNP) by a standardized MRN protocol at 3 T. Volumes of DRG L3-S2 as well as peripheral nerve lesions were assessed and compared to follow-up examinations after 14-100 months. In one patient, imaging findings were further correlated to histology. RESULTS: Follow-up MRN examination showed a non-significant increase of volume for the DRG L3: +0.41% (p = 0.10), L4: +22.41% (p = 0.23), L5: +3.38% (p = 0.09), S1: +10.63% (p = 0.05) and S2: +1.17% (p = 0.57). Likewise, peripheral nerve lesions were not significantly increased regarding size (2.18 mm2 vs. 2.15 mm2, p = 0.89) and number (9.00 vs. 9.33, p = 0.36). Histological analyses identified schwannomas as the major correlate of both DRG hyperplasia and peripheral nerve lesions. For peripheral nerve microlesions additionally clusters of onion-bulb formations were identified. CONCLUSION: Peripheral nervous system alterations seem to be constant or show only a minor increase in adult NF2. Thus, symptoms of PNP may not primarily attributed to the initial schwannoma growth but to secondary long-term processes, with symptoms only occurring if a certain threshold is exceeded. Histology identified grouped areas of Schwann cell proliferations as the correlate of DRG hyperplasia, while for peripheral nerve lesions different patterns could be found.

Linear Nevus Sebaceous Syndrome in a Child With Infantile Spasms and Focal Cortical Dysplasia.

Linear nevus sebaceous syndrome (LNSS) is a rare neurocutaneous syndrome with important neurological involvement including brain malformation, focal seizures, and developmental delay. We discuss a case with a unique presentation with localization-related infantile spasms and review the clinical and radiological features of this case. To our knowledge, there are no previously reported cases of LNSS with infantile spasms and cortical dysplasia. Therefore, the presented case will make an important contribution to the available knowledge.

Speckled brain lesions in Incontinentia Pigmenti patients with acquired brain syndromes.

Incontinentia Pigmenti (IP) is a neurocutaneous syndrome, with malformations of cortical development and neurodevelopmental delay in some patients. Neonates with IP may develop acute encephalopathy with multifocal ischemic brain lesions with a speckled pattern on diffusion-weighted magnetic resonance imaging (MRI). We observed a similar MRI pattern in 4 female patients with IP who presented with childhood acute encephalopathy syndromes. These patients, aged 9 days to 13 years old, had acute neonatal encephalitis, Influenza A virus related acute necrotizing encephalopathy (ANE) of childhood, Influenza B virus related acute encephalopathy with biphasic seizures and late restricted diffusion (AESD) and acute disseminated encephalitis (ADEM) with transverse myelitis (TM). These lesions could possibly reflect the white matter changes in IP patients with encephalopathy.

Systemic and CNS manifestations of inherited cerebrovascular malformations.

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.

Neurofibromatosis Type 1 in Children: A Single-Center Experience.

OBJECTIVE: Neurofibromatosis (NF) is the most common autosomal dominantly inherited neurocutaneous syndrome. The characteristic features of NF type 1 (NF-1) are café au lait spots, axillary and inguinal freckling, peripheral neurofibromas, optic pathway glioma, and Lisch nodules. The present study aimed to analyze the clinical features of children with NF-1. MATERIALS AND METHODS: In this study, the children with NF-1 diagnosed and followed-up in our center between 2000 and 2020 were retrospectively evaluated. Demographic and clinical features of patients were defined. RESULTS: The study group consisted of 52 patients. Of those, 25 were boys and 27 were girls. The children's median age at diagnosis was 5.9 years (1-15.8). Café au lait (CAL) spots and axillary/inguinal freckling were observed in 50 and 24 patients, respectively. Neurofibroma was present in 22 cases. Ten of the cohort had optic gliomas, and 39 of them had cranial hamartomas. Orthopedic complications such as scoliosis, tibial pseudoarthrosis, and osteoporosis were observed in 13 patients. Eleven children had neurocognitive disorders. CONCLUSIONS: Early diagnosis is important in neurofibromatosis to prevent the complications of the disease. Also, neurological development and secondary malignancy follow-up should be done carefully in this group of patients.

Sturge-Weber Syndrome and Glaucoma.

Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome characterized by capillary venous malformations in the skin, eye, and brain with the occurrence of angiomas of the face, choroid, and leptomeninges. The characteristics signs include facial port-wine birth mark, glaucoma, choroidal hemangioma with brain malformations, and cognitive abnormalities. In this article, we have documented the case report of a 24-year-old male with SWS presenting with glaucoma.

Cutis verticis gyrata: Two cases associated with drug-resistant epilepsy.

Cutis verticis gyrata (CVG) is a neurocutaneous syndrome characterized by the formation of folds in the scalp that resembles the cerebral cortex. We present two cases of CVG and intellectual disability with drug-resistant epilepsy. Recognizing CVG is necessary to provide interdisciplinary support for the treatment of comorbidities associated with this entity.

Intracranial calcifications in childhood: Part 1.

This article is the first of a two-part series on intracranial calcification in childhood. Intracranial calcification can be either physiological or pathological. Physiological intracranial calcification is not an expected neuroimaging finding in the neonatal or infantile period but occurs, as children grow older, in the pineal gland, habenula, choroid plexus and occasionally the dura mater. Pathological intracranial calcification can be broadly divided into infectious, congenital, endocrine/metabolic, vascular and neoplastic. The main goals in Part 1 are to discuss the chief differences between physiological and pathological intracranial calcification, to discuss the histological characteristics of intracranial calcification and how intracranial calcification can be detected across neuroimaging modalities, to emphasize the importance of age at presentation and intracranial calcification location, and to propose a comprehensive neuroimaging approach toward the differential diagnosis of the causes of intracranial calcification. Finally, in Part 1 the authors discuss the most common causes of infectious intracranial calcification, especially in the neonatal period, and congenital causes of intracranial calcification. Various neuroimaging modalities have distinct utilities and sensitivities in the depiction of intracranial calcification. Age at presentation, intracranial calcification location, and associated neuroimaging findings are useful information to help narrow the differential diagnosis of intracranial calcification. Intracranial calcification can occur in isolation or in association with other neuroimaging features. Intracranial calcification in congenital infections has been associated with clastic changes, hydrocephalus, chorioretinitis, white matter abnormalities, skull changes and malformations of cortical development. Infections are common causes of intracranial calcification, especially neonatal TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus and herpes) infections.

Morning glory disc anomaly associated with large facial infantile hemangioma as the presenting signs of PHACE syndrome / Anomalia de Morning Glory associada à extenso hemangioma infantil como apresentação da Síndrome PHACE

ABSTRACT Infantile hemangioma, the most common benign tumor in infancy, is usually an isolated condition occurring in many different locations in the body. However, large infantile hemangioma may be associated with other systemic malformations, including central nervous system, cerebrovascular, cardiac, and ophthalmology abnormalities, a condition termed PHACE syndrome. In this paper, we describe a case of PHACE syndrome that was presented with the unique association of a large facial infantile hemangioma and morning glory anomaly.

RESUMO O hemangioma infantil é a causa mais comum de tumor benigno na infância e usualmente é uma condição isolada podendo ocorrer em diferentes regiões do corpo. No entanto, hemangiomas infantil extensos podem ser associados com outras malformações sistêmicas incluindo anomalias no sistema nervoso central, cerebrovasculares, cardíacas e oftalmológicas, uma condição denominada síndrome PHACE. Neste trabalho, descrevemos o caso de um paciente com síndrome PHACE que se apresentou com um extenso hemangioma facial e anomalia de "morning glory".

Epileptic Spasms in an Infant with Incontinentia Pigmenti: Report of a Rare Case with Brief Review of the Literature.

Incontinentia pigmenti (IP) or Bloch-Sulzberger's disease is a rare neurocutaneous syndrome with dermatological, neurologic, and systemic manifestations including retinal, dental and hair abnormalities. It follows X-linked dominant inheritance and predominantly affects female children. The characteristic evolution of skin lesions in four stages is a hallmark diagnostic feature of the disease. The pigmented lesions of IP are usually distributed in linear streaks, macular whorls, reticulated patches, and flecks along the Blaschko lines. Neurologic morbidities are found in a considerable proportion of affected children, and the spectrum includes seizures, neuromotor impairment, microcephaly, developmental delay, and intellectual disability. Seizures are reported in 10% to 25% of children with IP in various previous clinical studies. The majority of these children had seizures in the neonatal period or early infancy, and focal-clonic seizure is the commonest observed semiology. However, there are only a few case reports of infants with IP with epileptic spasms. In this report, the clinical course of a 6-month-old girl with IP and epileptic spasms has been described, who responded favorably to treatment with adrenocorticotropic hormone injection. Clinicians managing children with IP should be aware of their predisposition to develop epileptic spasms and consider neuroimaging, electroencephalogram, and other investigations accordingly.