Ocular manifestations of facial port-wine stain, nevus of Ota, and phakomatosis pigmentovascularis in Asian patients.

BACKGROUND: Heightened intraocular pressure resulting in glaucoma and impaired vision is treatable if detected early. It is therefore necessary to identify populations at risk for glaucoma for regular screening visits. OBJECTIVE: To investigate the prevalence of glaucoma in patients with facial port-wine stains (PWSs), nevus of Ota, and phakomatosis pigmentovascularis (PPV) and to establish the association between facial vascular birthmarks and ocular complications. METHODS: This study is a retrospective chart review of 166 patients with facial PWS, PPV, and nevus of Ota over a 10-year period. RESULTS: Of the 166 cases, 76 patients were diagnosed with PWS, 83 with nevus of Ota, and 7 with PPV. The mean age of patients was 12.8 years, ranging from newborn to 63 years old. Fifteen patients were diagnosed with glaucoma. Of 15 patients, 11 presented with PWS, and 4 presented with both PWS and PPV. Of 83 patients with nevus of Ota, only 2 (2.4%) presented with increased ocular pressure. LIMITATIONS: The relatively short follow-up period is a limiting factor in this study. CONCLUSIONS: Early and periodic ophthalmic examinations in patients with PWS, PPV, and nevus of Ota are essential to minimizing the risk of developing glaucoma in these groups of patients.

Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study.

BACKGROUND: PHACE syndrome is a rare inborn condition characterized by large facial hemangiomas and variable malformations of the arterial system, heart, central nervous system, and eyes. According to Orphanet estimates, the prevalence is <1.0 per million. Data from Europe are limited to small case series, and there are no population-based data available. OBJECTIVES: We conducted the present study to provide population-based estimates of the disease prevalence of PHACE syndrome in children in Germany, Switzerland, and Austria. We compared these first systematic data on PHACE syndrome from Europe to published data from the PHACE Syndrome International Clinical Registry and Genetic Repository (USA). Clinical features in our cohort with PHACE syndrome were assessed in detail, including the need for early supportive measures. METHODS: We used a population-based approach by means of a previously well-established network of child neurologists from Germany, Switzerland, and Austria ("ESNEK") to identify potential patients. The patients' guardians and child neurologists were asked to fill in questionnaires developed in collaboration with the International PHACE Registry. RESULTS: We identified 19 patients with PHACE syndrome. Estimated prevalence rates were 6.5 per million in Switzerland, 0.59 per million in Germany, and 0.65 per million in Austria. A subset of 10 patients from Germany and Switzerland participated in our study, providing detailed clinical assessment (median age: 2.5 years; 9 females, 1 male). Cerebrovascular involvement was frequent (80%). Facial hemangioma extent correlated significantly with the number of organs involved (p = 0.011). In 9 out of 10 patients, facial hemangiomas were treated successfully with oral propranolol. Baseline demographic data as well as the rate of cerebrovascular and cardiovascular anomalies were in line with those from the US International PHACE Registry and other published PHACE cohorts. CONCLUSIONS: Our study provides population-based estimates for PHACE syndrome in 3 German-speaking countries. The data from Switzerland indicate that PHACE syndrome may be more prevalent than demonstrated by previous reports. Underreporting of PHACE syndrome in Germany and Austria likely accounts for the differences in prevalence rates. The clinical observation of a potential association between the size of facial hemangioma and extent of organ involvement warrants further investigation.

Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.

PURPOSE: Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by giant melanocytic cutaneous nevi and melanosis within the central nervous system (CNS), often sparing leptomeninges and concentrated in the brain parenchyma. Epilepsy and neurodevelopmental abnormalities are the only complications reported in children with isolated parenchymal melanosis. A minority of patients experience drug-resistant epilepsy, and up to now, no predictors of epilepsy prognosis have been identified. METHODS: In this systematic review, according to preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, we aggregated clinical cases of patients with isolated parenchymal melanosis affected by epilepsy, in order to recognize predictors of clinical outcome and to clarify indications of available therapeutic approaches. RESULTS: Sixteen articles (19 patients) were included in the final analysis from initial database research; 4 articles (4 patients) were selected from reference lists and 1 from conference abstracts (1 patient). In our series, distribution of parenchymal melanosis was the best predictor of epilepsy outcome: frequencies of seizure-free patients were different between cases of isolated/bilateral amygdale melanosis and those of multiple localizations (p = 0.037). Failure of antiepileptic drugs (AEDs) and/or surgical epilepsy therapy were associated with poor cognitive outcome (p = 0.03). CONCLUSION: Antiepileptic drugs were effective in the majority of patients with epilepsy with parenchymal melanosis. In case of multifocal distribution, more than one-third of patients presented a drug-resistant epilepsy. Epilepsy surgery is the best choice in patients with isolated amygdala localization. We propose the recognition of a multifactorial nature of cognitive impairment in neuromelanosis, emphasizing the role of drug-resistant epilepsy.

Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository.

The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.

Variations in herpes zoster manifestation.

Herpes zoster (HZ) is a neurocutaneous disorder due to endogenous reactivation of the varicella-zoster virus (VZV). The typical clinical manifestation is an acute segmental eruption of herpetiform umbilicated vesicles associated with malaise, pain, dysaesthesia, allodynia and probably fever. This review focuses on other possible clinical manifestations of the disease to sensitize physicians not to overlook HZ since only an early antiviral treatment can reduce the risk of post-zosteric neuralgia.

Practical application of the new classification scheme for congenital melanocytic nevi.

A new consensus-based classification of congenital melanocytic nevi (CMN) has recently been proposed. It includes categories for projected adult size (PAS) and location, satellite nevi counts, and morphologic characteristics (color heterogeneity, rugosity, nodularity, and hypertrichosis). The objective of the current study was to test the applicability of the new categorization scheme and to correlate classification outcome with the patient's history of melanoma and neurocutaneous melanocytosis (NCM). Children and adults with CMN attending a patient conference in Dallas, Texas, in 2012 were invited to participate in the study. Anamnestical data were collected using a standardized questionnaire. Two dermatologists performed clinical examinations. Of 45 patients enrolled, 33 had a giant CMN (G1 [>40 cm PAS], n = 13; G2 [>60 cm PAS], n = 20), 12 had an NCM (5 symptomatic, 7 asymptomatic), and 1 had a history of melanoma. CMN size was positively correlated with NCM (p < 0.05). The classification system allowed an easy and detailed phenotypic characterization of each individual CMN. CMN size and morphology were difficult to assess in patients after surgical removal, and the number of satellite nevi at birth or during infancy was not always known. Our report provides practical aids for the application of the newly proposed CMN classification. Prospective evaluation of accurately classified patients in CMN registries will reveal the predictive value of the scheme. The small study sample limits meaningful conclusions regarding the correlation between CMN parameters and the risk of NCM and melanoma.

Risk of dysphagia and speech and language delay in PHACE syndrome.

PHACE (posterior fossa, hemangioma, arterial lesions, cardiac, and eye) syndrome consists of infantile hemangiomas of the head and neck along with a spectrum of noncutaneous anomalies. Neurodevelopmental abnormalities have also been noted. Here we describe the association between PHACE syndrome and abnormalities in oropharyngeal development and coordination manifesting as dysphagia or speech and language delay. A retrospective chart review was conducted of 34 patients with PHACE syndrome. Data were collected from prior clinical notes and radiographic studies and the results of a comprehensive questionnaire that those who attended the July 2012 PHACE Syndrome Family Conference completed. Seventeen of 34 patients with PHACE syndrome and signs or symptoms of dysphagia or speech or language problems were included for analysis. Nine had dysphagia, seven had a history of cardiac surgery, four had a posterior fossa malformation, and seven had lip or oropharynx hemangiomas. Speech or language delay was noted in 16; posterior fossa abnormalities and lip or oropharynx hemangiomas were the most commonly seen associated finding in this group. There was considerable overlap between subset populations with dysphagia, speech delay, and language delay. A subset of individuals with PHACE syndrome experience dysphagia, speech delay, or language delay. This risk seems to be greater in certain subsets of patients, including those with posterior fossa malformations or lip or oropharynx hemangiomas and those with a history of cardiac surgery. Although this descriptive study was not comprehensive enough to examine prevalence, the high incidence of dysphagia and speech and language delay seen in our cohort warrants future prospective studies to further investigate the association.

Incidence of neurocutaneous melanosis in Japanese pediatric patients with congenital melanocytic nevi.

Neurocutaneous melanosis (NCM) is a rare, non-hereditary neurocutaneous disorder characterized by excessive melanocytic proliferation in the skin and central nervous system. As no major studies have covered the incidence of NCM among Japanese patients with congenital melanocytic nevi (CMN), we prospectively investigated the incidence of NCM among Japanese patients who underwent initial treatment for CMN. The relationship of CMN and NCM was also investigated. Japanese pediatric patients with CMN under 1 year of age were included between January 2020 and November 2022, and all patients underwent brain MRI to check for NCM in this study. NCM lesions were most frequently seen in the amygdala, followed by the cerebellum, brainstem, and cerebral hemispheres. NCM was diagnosed on brain MRI in 31.6% of the 38 patients with CMN and in 25.0% of patients with no prior examination or treatment. Distribution and size of CMN, number of satellite nevi, rugosity and nodules were strongly associated with the existence of NCM, and these findings may guide a future registry study with a large cohort of CMN patients.

Operative Surveillance of Airway Hemangiomas in PHACE Syndrome.

OBJECTIVE: PHACE is a rare syndrome that can present with airway hemangiomas. Management for these patients is variable and the utilization of operative endoscopic airway evaluation has not been described. The objectives of this study were to identify the incidence of airway symptoms in patients being evaluated for PHACE syndrome and determine the utility of operative endoscopy. METHODS: An IRB-approved retrospective cohort study was conducted on consecutive pediatric patients with head and neck infantile hemangioma (IH) evaluated in a multi-disciplinary vascular anomalies center between 2013 and 2019. Patients were included if they were being worked up for PHACE syndrome and had an otolaryngology evaluation. Demographics, clinical, and surgical variables were collected. RESULTS: There were 317 patients with head and neck IH. Thirty-six patients met inclusion criteria. The majority of patients were female (31/36; 86.1%) and less than half of the patients (15/36; 41.7%) were eventually diagnosed with PHACE syndrome. Median age at presentation was 2 months (range 0-82 months). A total of 28/36 (77.8%) of patients were managed with propranolol. The majority of the patients presented without aerodigestive symptoms; however, 16/36 (44.4%) of patients presented with symptoms such as stridor, hoarseness, and dysphagia. A total of 20/36 (55.6%) of patients underwent operative endoscopy. A total of 8/20 (40.0%) of patients who underwent operative endoscopy had operative intervention. Of the entire cohort, only 2/15 (13.3%) patients diagnosed with PHACE were found to have a subglottic hemangioma. Both patients presented with stridor. CONCLUSION: Operative endoscopy remains useful in the workup of PHACE syndrome to identify subglottic hemangiomas, however there may be relatively low yield in asymptomatic patients. In office flexible laryngoscopy may be a less invasive means to examine the subglottic region. A multi-center prospective study would be necessary to evaluate incidence of subglottic hemangiomas in asymptomatic patients evaluated for PHACE.

Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis.

Congenital melanocytic nevi (CMN) are present at birth or arise during the first few weeks of life. They are quite common, may have a heritable component, and can present with marked differences in size, shape, color, and location. Histologic and dermatoscopic findings may help suggest the diagnosis, but they are not entirely specific. CMN are categorized based on size, and larger lesions can have a significant psychosocial impact and other complications. They are associated with a variety of dermatologic lesions, ranging from benign to malignant. The risk of malignant transformation varies, with larger CMN carrying a significantly higher risk of malignant melanoma (MM), although with an absolute risk that is lower than is commonly believed. They may also be associated with neuromelanosis, which may be of greater concern than cutaneous MM. The information presented herein aims to help dermatologists determine when it is prudent to obtain a biopsy specimen or excise these lesions, to obtain radiographic imaging, and to involve other specialists (eg, psychiatrists and neurologists) in the patient's care.

Sleep Problems in Children With Neurocutaneous Syndromes: A Cross-Sectional Study.

Introduction: The prevalence and patterns of sleep disturbances in neurocutaneous syndromes are variable and understudied. Methods: Cross-sectional study for 18 months at a tertiary care pediatric hospital, involving 100 children with neurocutaneous syndromes aged between 4 and 10 years using the Children's Sleep Habits Questionnaire-Abbreviated. Results: In 100 children with neurocutaneous syndromes, 47 (47%) had significant sleep problems. In subgroup analysis, 7 of 17 children with neurofibromatosis 1, 24 of 63 children with tuberous sclerosis complex, 10 of 12 children with Sturge-Weber syndrome, 2 of 3 children with linear nevus sebaceous syndrome, and each of the children with hypomelanosis of Ito, McCune-Albright syndrome, megalencephaly-capillary malformation syndrome, and unclassified neurocutaneous syndrome had significant sleep problems. Conclusion: The prevalence of sleep problems in our study population was not more than that observed in the general pediatric population. Prospective multicentric studies are needed to comprehend sleep problems in children with neurocutaneous syndromes.

[Some etiopathogenetic and diagnostic considerations in neuroendocrine tumors, with particular attention to those in urology]. / Alcune considerazioni etiopatogenetiche e diagnostiche sui tumori neuroendocrini, con particolare attenzione a quelli in ambito urologico.

Some aetiopathogenetic and diagnostic considerations about the neuro-endocrine tumours, with particular attention to those pertinent of urology.Some neuroendocrine tumours (NET) occur in hereditary-familial neoplastic syndromes such as MEN (multiple endocrine neoplasias) or neuroectodermic dysplasias (neurofibromatosis-NF1, von Hippel Lindau disease, pheochromocytoma-chemodectoma familial syndrome, etc.) while others arise as solitary-isolated tumours such as those of gastrointestinal tract, pancreas, lung, skin, genitourinary system. The diagnostics of NET implies plasmatic assay of common neuroendocrine markers and specific peptide hormones, and more properly, their immuno-histochemical characterisation, together with molecular-genetic studies. Several gene alterations (MEN1, RET, NF1, VDL, SDH-B and -D) are associated with pheochromocytoma, showing that almost 25% of subjects with apparent-sporadic pheochromocytoma at the sheer clinical examination, are actually syndromic-familial pheochromocytoma patients at the genetic testing. The functional imaging provides intriguing data regarding not only the diagnostics but also the assessment of tumour response to the therapy. This paper aims to review the literature on morphological, functional as well as biological features of NET and to briefly summarize the recent advances in their diagnosis, with particular attention to those pertinent the urology.

Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 1-epidemiology, phenotype and outcomes.

BACKGROUND: The aetiology of congenital melanocytic naevi (CMNs) is unknown. OBJECTIVES: To identify potential aetiological factors in families of children with CMNs, and to relate these to long-term outcome measures. METHODS: Three hundred and forty-nine CMN families completed questionnaires about pregnancy and parental factors, and yearly questionnaires on the health of their child and details of the CMN. Seventy-nine control families completed one set of questionnaires, excluding CMN details. RESULTS: The mean prospective follow-up of 301 CMN families was 9.2 years, median 8.9 years, total 2679 years. Forty per cent of patients had CMNs > 20 cm projected adult size (PAS) or multiple CMNs. Twenty per cent of patients had abnormal neurodevelopment and although this was positively associated with PAS it was seen across all size categories. The rate of malignant melanoma was 1.4%. This was strongly associated with PAS with all five cases in patients with CMNs > 60 cm PAS/multiple CMNs (rate in that group 14%). Twenty-five per cent of CMN patients had a positive family history of a CMN in a second-degree relative (FHCMN). This group had a significantly different gender ratio, suggesting a different underlying mutation. Maternal FHCMN was negatively associated with PAS and satellites at birth, and maternal freckling was negatively associated with PAS. Other factors found to be significantly increased in CMN families compared with controls were maternal smoking and ill health during pregnancy. Maternal smoking was positively associated with PAS. CONCLUSIONS: This study relies on data from families after they have had a child with a CMN, and therefore may be subject to recall bias. Despite this, it contributes significantly to the knowledge of epidemiology of CMNs, and provides some important clues to the genetic basis of the condition.

Demographical Profile and Spectrum of Multiple Malignancies in Children and Adults with Neurocutaneous Disorders.

BACKGROUND/AIM: Neurocutaneous disorders, also referred as phacomatoses, are congenital disorders manifesting at different ages with central nervous system and cutaneous abnormalities. Analysis of the demographic and clinical profile of patients with phacomatoses in the context of the incidence and spectrum of malignancy. MATERIALS AND METHODS: This is a retrospective analysis of 20 years of data in a single-center study in Poland. RESULTS: Phacomatoses were diagnosed in 45.6% (913/2,003) of referred patients, including 61.4% children. The distribution of phacomatoses included: neurofibromatosis type 1 (NF1) in 92.4%, tuberous sclerosis complex (TSC) 3.9%, neurofibromatosis type 2 (NF2) 2.0%, Klippel-Trenaunay syndrome 0.5%, Von Hippel-Lindau syndrome 0.5%, and other sporadic diseases 0.7%. Non-phacomatosis patients were diagnosed mainly for cafe-au-lait-macules (42.8%). The frequency of malignancy was 9.4% (86/913), including 9.1% in patients with NF1; 27.8% in NF2; and 8.3% in TSC. Multiple malignancies were diagnosed in 0.7% and 7% of all phacomatosis and malignancy-diagnosed patients, respectively. CONCLUSION: The risk of malignancy in patients with phacomatoses was 21.3-fold higher than in the general population. The risk of secondary malignancy was 7%.

Vascular malformations. Part II: associated syndromes.

UNLABELLED: Cutaneous vascular malformations are rare disorders representing errors in vascular development. These lesions occur much less commonly but are often confused with the common infantile hemangioma. It is important to properly diagnose vascular malformations because of their distinct differences in morbidity, prognosis and treatment. Vascular malformations may be associated with underlying disease or systemic anomalies. Several of these syndromes are well defined and can often be distinguished on the basis of the flow characteristics of the associated vascular malformation. LEARNING OBJECTIVE: At the completion of this learning activity, participants should be able to better recognize underlying diseases or systemic anomalies that may be associated with vascular malformations. Participants should also better understand the various syndromes and conditions discussed and become more familiar with their management.

Parenchymal neurocutaneous melanosis in association with intraventricular dermoid and Dandy-Walker variant: a case report.

Neurocutaneous melanosis (NCM) is a rare congenital disease that is characterized by the presence of large or multiple congenital melanocytic nevi and melanotic lesions of the central nervous system. We report here on the CT and MR imaging findings of an unusual case of NCM that was associated with intraventricular dermoid and Dandy-Walker malformation.

Prevalence and Clinical Characteristics of Headaches in PHACE Syndrome.

PHACE (posterior fossa brain malformation, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) syndrome is a neurocutaneous disorder often involving the cerebral vasculature. PHACE patients appear to have early-onset and severe headaches more commonly than children without PHACE. The objective of this study was to characterize the clinical features and prevalence of headache by conducting a cross-sectional survey of families in 2 large PHACE registries. Sixty-six percent of eligible families completed the survey in which 62.7% of respondents reported headaches. Average age of headache onset was 48.8 months. Females were more likely to have headaches (68.6% vs 30.8%, P = .014). Families reported associated migrainous features including nausea (62.5%), vomiting (37.5%), photophobia (75%), and phonophobia (75%). Headaches occurred at least weekly in 29.4%, lasted ≥1 hour in 85.4%, and led to ≥1 hospital admission in 15.7%. Three respondents with headaches had at least 1 ischemic stroke. We demonstrated that headaches are common among PHACE patients, develop at an early age, and have migrainous features.

Office-Based Subglottic Evaluation in Children With Risk of Subglottic Hemangioma.

PURPOSE: Children with V3 cutaneous infantile hemangiomas (IH) and PHACE syndrome have a high incidence for airway hemangioma, 29% and 52%, respectively. Therefore, a clinical evaluation for these high-risk children is essential. We report our experience with in-office lower airway evaluation (OLAE) in these high-risk children. RESULTS: Since 2003, 5 children with IH of the V3 cutaneous distribution and 3 children with PHACE syndrome underwent OLAE. Average age of presentation was 2.75 months. Two children had stridor at initial evaluation, and 1 child had subglottic hemangioma. This child was evaluated serially with OLAE to monitor disease progression and treatment response. A total of 10 upper tracheoscopies were performed on the 8 patients without respiratory complications. CONCLUSION: An airway evaluation is essential to evaluate and manage this high-risk population. Typically, operative endoscopy requires general anesthesia. However, in these high-risk children, we have performed OLAE without sedation to evaluate the trachea. High-speed recording and playback is essential in this method. Our series demonstrates that awake OLAE is possible and may be a safe technique to evaluate and monitor disease progression in these high-risk patients. These patients avoided general anesthesia and delay in diagnosis and did not incur any complications during or after OLAE.

Phacomatosis pigmentovascularis revisited and reclassified.

OBJECTIVE: To provide a new comprehensible and practicable classification by use of descriptive terms to distinguish the various types of phacomatosis pigmentovascularis (PPV), which has previously been classified by numbers and letters that are difficult to memorize. STUDY SELECTION: Published case reports on PPV were reassessed. DATA EXTRACTION AND DATA SYNTHESIS: A critical review revealed that only 3 well-established types of PPV so far exist. To eliminate the cumbersome traditional classification by numbering and lettering, the following new terms are proposed: phacomatosis cesioflammea (blue spots [caesius = bluish gray] and nevus flammeus); phacomatosis spilorosea (nevus spilus coexisting with a pale-pink telangiectatic nevus), and phacomatosis cesiomarmorata (blue spots and cutis marmorata telangiectatica congenita). Phacomatosis cesioflammea is identical with the traditional types IIa and IIb; phacomatosis spilorosea corresponds to types IIIa and IIIb; and phacomatosis cesiomarmorata is a descriptive term for type V. A categorical distinction of cases with and without extracutaneous anomalies seems inappropriate. The traditional type I does not exist, and the extremely rare traditional type IV is now included in the group of unclassifiable forms. CONCLUSION: The proposed new classification of PPV by using 3 descriptive terms may be easier to memorize compared with the time-honored grouping of in part not even existing subtypes by numbers and letters.