Utilisation of advanced MRI techniques to understand neurovascular complications of PHACE syndrome: a case of arterial stenosis and dissection.

PHACE syndrome is a rare disorder with posterior fossa brain malformations, segmental infantile haemangiomas, arterial anomalies, cardiac defects and eye anomalies. Cerebral and cervical arterial abnormalities occur commonly in these patients, predisposing subjects with PHACE syndrome to neurovascular complications including migraine-like headaches, moyamoya vasculopathy, arterial dissection and arterial ischaemia stroke. We leveraged institutional MRI protocols developed for adult neurovascular disease to better elucidate the pathogenesis of the arterial alternations observed in PHACE. Using high-resolution vessel wall and 4D flow MRI, we demonstrated enhancement, focal dissection and altered blood flow in a 7-year-old girl with PHACE syndrome. This is the first-time vessel wall imaging has been used to detail the known arterial changes in PHACE, and these findings may indicate that progressive vascular narrowing and vessel wall changes/inflammation are a factor in chronic headaches and other arterial complications seen in subjects with PHACE syndrome.

Evaluating the Safety of Oral Propranolol Therapy in Patients With PHACE Syndrome.

Importance: Oral propranolol is widely considered to be first-line therapy for complicated infantile hemangioma, but its use in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome has been debated owing to concerns that the cardiovascular effects of the drug may increase the risk for arterial ischemic stroke. Objective: To assess the incidence of adverse events among patients with PHACE syndrome receiving oral propranolol for infantile hemangioma. Design, Setting, and Participants: This multicenter retrospective cohort study assessed the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed. Exposures: Patients received oral propranolol, 0.3 mg/kg/dose or more. Main Outcomes and Measures: The main outcome was the rate and severity of adverse events occurring throughout the course of treatment with oral propranolol, as documented in the medical records. Adverse events were graded from 1 to 5 using a scale derived from the Common Terminology Criteria for Adverse Events and were considered to be serious if they were grade 3 or higher. Results: A total of 76 patients (59 girls and 17 boys; median age at propranolol initiation, 56 days [range, 0-396 days]) met the inclusion criteria. There were no reports of serious adverse events (ie, stroke, transient ischemic attack, or cardiovascular events) during treatment with oral propranolol. A total of 46 nonserious adverse events were reported among 29 patients (38.2%); the most commonly reported nonserious adverse events were sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. In a comparison with 726 infants who received oral propranolol for hemangioma but did not meet criteria for PHACE syndrome, there was no significant difference in the rate of serious adverse events experienced during treatment (0 of 76 patients with PHACE syndrome and 3 of 726 patients without PHACE syndrome [0.4%]). Conclusions and Relevance: This study found that oral propranolol was used to treat infantile hemangioma in 76 patients with PHACE syndrome and that no serious adverse events were experienced. These data provide support for the safety of oral propranolol in this patient population.

Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome.

Synaptosomal-associated protein 29 (SNAP29) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.

Development of a multidisciplinary clinic of neurofibromatosis type 1 and other neurocutaneous disorders in Greece. A 3-year experience.

Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care. Subjects and Methods: Retrospective analysis of a cohort of 157 patients during a 3-year period, seen at a newly developed neurocutaneous clinic in a pediatric tertiary care hospital in Athens (Greece); and systematic chart review of the patients diagnosed with neurofibromatosis type 1 during this time period. Results: The most frequent neurocutaneous syndromes were neurofibromatosis type 1 (NF1) in 89 patients and tuberous sclerosis complex in 17. In 20.38% of patients a neurocutaneous syndrome was not confirmed. Approximately 2/3 of the NF1 patients underwent genetic analysis, and for 76.67% of them, a pathogenic mutation on the NF1 gene was revealed. Eighty-one patients manifested with generalized NF1 and eight with mosaic NF1. Dermatological manifestations included café-au-lait macules in all patients, followed by axillary and/or inguinal freckling (n = 57), external plexiform neurofibromas (n = 17), and cutaneous and subcutaneous neurofibromas (n = 11). Approximately half of patients had learning disabilities and attention deficit hyperactivity disorder, followed by mental retardation (n = 9), autistic spectrum disorders (n = 4), headaches (n = 3) and seizures (n = 2). Neuroimaging showed characteristic areas of hyperintensity on T2-weighted images in 74.07% of patients and optic pathway glioma in 19.75%. Two patients developed malignant peripheral sheath nerve tumor. Conclusions: Neurocutaneous syndromes are clinically heterogeneous and the surveillance of potential clinical complications is challenging. The availability of genetic diagnosis and novel imaging methods in this group of disorders is likely to further expand their clinical spectrum. Guidelines for assessment and management will need to be modified based on new available data.

A genetic model of CEDNIK syndrome in zebrafish highlights the role of the SNARE protein Snap29 in neuromotor and epidermal development.

Homozygous mutations in SNAP29, encoding a SNARE protein mainly involved in membrane fusion, cause CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis and Keratoderma), a rare congenital neurocutaneous syndrome associated with short life expectancy, whose pathogenesis is unclear. Here, we report the analysis of the first genetic model of CEDNIK in zebrafish. Strikingly, homozygous snap29 mutant larvae display CEDNIK-like features, such as microcephaly and skin defects. Consistent with Snap29 role in membrane fusion during autophagy, we observe accumulation of the autophagy markers p62 and LC3, and formation of aberrant multilamellar organelles and mitochondria. Importantly, we find high levels of apoptotic cell death during early development that might play a yet uncharacterized role in CEDNIK pathogenesis. Mutant larvae also display mouth opening problems, feeding impairment and swimming difficulties. These alterations correlate with defective trigeminal nerve formation and excess axonal branching. Since the paralog Snap25 is known to promote axonal branching, Snap29 might act in opposition with, or modulate Snap25 activity during neurodevelopment. Our vertebrate genetic model of CEDNIK extends the description in vivo of the multisystem defects due to loss of Snap29 and could provide the base to test compounds that might ameliorate traits of the disease.

Pathophysiology and management of glaucoma associated with phakomatoses.

The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases.

Hearing loss in PHACE syndrome: clinical and radiologic findings.

PURPOSE: To characterize the types of hearing loss, auditory-related imaging findings, and hemangioma characteristics in patients with Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and abnormalities of the Eye (PHACE) syndrome. METHODS: Retrospective medical records, audiologic data, and imaging review of all patients presenting to a tertiary care children's hospital with a proven diagnosis of PHACE syndrome from 2005 to 2016. RESULTS: Twelve patients were identified with hearing and imaging data. 5/12 had hearing loss, 1 had unilateral severe sensorineural loss with minor conductive component, 1 had unilateral moderate sensorineural loss with minor conductive component, 1 had mild bilateral conductive loss, 1 had bilateral hearing loss (left severe mixed and right severe sensorineural), and 1 had moderate bilateral conductive loss. All patients passed their newborn hearing screening. Of the 5 patients with hearing loss, 3 had IAC hemangiomas (1 bilateral), 3 had enlarged IACs with prominent posterior petrous bones (1 bilateral), 2 had dysgenesis of the cerebellar vermis and hemispheres, there was 1 patient each with a deformed pinna and middle ear and mastoid effusions, and 1 patient had no abnormal auditory-related imaging findings. Patients with hearing loss were more likely to have more areas of cutaneous hemangioma involvement (mean 6.4 vs 3.1, p = .05). Laterality of hearing impairment correlated with the side of cutaneous hemangioma in all patients with hearing loss. Treatment with systemic propranolol did not improve hearing. CONCLUSIONS: Patients with PHACE are at risk for hearing loss and may demonstrate radiologic abnormalities within the ear structures, although the type of hearing loss, imaging findings, and their respective correlation vary. While our results are limited by our small sample size, comprehensive audiology evaluations (as opposed to newborn screening testing only) should be considered for PHACE patients who have extensive cutaneous hemangioma or auditory-related imaging abnormalities, such as internal auditory canal hemangiomas.

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis related to or comparable with mechanisms seen in inflammatory pathways? Part II: angiogenesis- and inflammation-related molecular pathways, tumor-associated macrophages, and possible therapeutic implications: a comprehensive review.

Phacomatoses are a special group of familial hamartomatous syndromes with unique neurocutaneous manifestations as well as characteristic tumors. Neurofibromatosis type 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. A vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with these syndromes, related to NF2 and TSC, respectively. These tumors can present with an obstructive hydrocephalus due to their location adjacent to or in the ventricles. Remarkably, both tumors are also known to have a unique association with elevated protein concentrations in the cerebrospinal fluid (CSF), sometimes in association with a non-obstructive (communicating) hydrocephalus. Of the two, SGCT has been shown to be associated with a predisposition to CSF clotting, causing a debilitating recurrent shunt obstruction. However, the exact relationship between high protein levels and clotting of CSF remains unclear, nor do we understand the precise mechanism of CSF clotting observed in SGCT. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiological processes for that in the context of tumorigenesis are angiogenesis and inflammation. Both these processes are correlated to the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin pathway which is tumorigenesis related in many neoplasms and nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation pathways on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I described the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating hydrocephalus. Part II hereafter describes the different cellular and molecular pathways involved in angiogenesis and inflammation observed in both tumors and explores the existing metabolic overlap between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both tumors, inflammatory processes seem significantly more prominent in SGCT. Both SGCT and VS are characterized by different subgroups of tumor-associated macrophages (TAMs): the pro-inflammatory M1 type is predominating in SGCTs, while the pro-angiogenetic M2 type is predominating in VSs. We suggest that a lack of NF2 protein in VS and a lack of TSC1/TSC2 proteins in SGCT significantly influence this fundamental difference between the two tumor types by changing the dominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, the pro-inflammatory state of SGCT may also explain the associated tendency for CSF clotting. The underlying cellular and molecular differences observed can potentially serve as an access point for direct therapeutic interventions for tumors that are specific to certain phacomatoses or others that also carry such genetic changes.

Alu-mediated deletion of PIGL in a Patient with CHIME syndrome.

CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease-causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL.

Ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis.

This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.

PERIOPERATIVE CARE OF AN INFANT WITH GOMEZ-LOPEZ-HERNANDEZ SYNDROME.

Gomez-Lopez-Hernandez syndrome, also known as cerebello-trigeminal dermal dysplasia, is a rare neurocutaneous syndrome classically characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parietal alopecia. Associated clinical features include a characteristic facial appearance (mid-face hypoplasia, hypertelorism, and low-set, posteriorly rotated ears), brachycephaly, strabismus, ataxia, developmental delay, short stature, and corneal opacities. Given the associated congenital anomalies, anesthetic care may be required for various surgical interventions. We report a 7-month-old with Gomez-Lopez-Hernandez syndrome scheduled for laparoscopic gastrostomy with tube placement and frenulotomy under general anesthesia. The potential perioperative implications of such patients are reviewed and options for anesthetic care discussed.

A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features.

Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported. We report on a 4.5-year-old girl with primary microcephaly, who had in addition moderate to severe developmental delay, behavioral and stereotypic abnormalities and a cutaneous pattern of paired hypo- and hyperpigmented lesions variously distributed over the body, particularly on the trunk. Failure to thrive and mild facial dysmorphic features were also present. To our knowledge, this complex malformation (neurocutaneous) phenotype has not been previously reported.

5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease.

We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder.

Common Neurocutaneous Syndromes.

Neurocutaneous syndromes are a diverse group of neurologic disorders with concurrent skin manifestations. Most neurocutaneous syndromes have a genetic basis and are believed to arise from a defect in the differentiation of the primitive ectoderm. In this regard, the skin can be a window into the central nervous system and can aid in the diagnosis of neurologic disease in children. The cutaneous signs may be subtle, which places great importance on the physical examination skills of clinicians providing primary care to children. Early recognition can help with proper diagnosis, formulating a treatment plan, anticipating potential complications, making appropriate referrals, and offering genetic counseling to families.

Neurocutaneous melanosis.

Neurocutaneous melanosis is a rare neurocutaneous syndrome that is associated with a high rate of mortality early in life. Individuals with large cutaneous melanocytic nevi (LCMN) are at risk, especially when the nevi are posterior, midline and accompanied by satellite nevi. Disrupted production and migration of melanocytic precursors from neural crest likely are responsible. Although the cutaneous lesions are at risk for melanoma, the most likely source of morbidity and mortality comes from "benign" melanocytic proliferation in the brain or central nervous system melanoma. Seizures and hydrocephalus are the common neurologic manifestations and typically arise in the first years of life. Brain magnetic resonance imaging in infants before myelination has matured is most sensitive for detecting abnormal melanosis in the brain, which preferentially involves the leptomeninges, cerebellum and anterior temporal lobes. Treatment is symptomatic and death occurs in many within 3 years of onset of neurologic symptoms. This prognosis may limit the extent to which extensive procedures or interventions are undertaken.

Encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is an unusual condition marked by characteristic dermatologic and neurologic findings presenting in a mosaic fashion. These are now being found to be due to specific genetic mutations. Traditionally, the diagnostic features include ocular dermoids, scalp changes, and spinal lipomas. While there are other similar diagnostic considerations, ECCL, is sufficiently distinct clinically to allow differentiation. Such information is of use when considering pathogenesis and in counseling. Consideration of possible associated clinical findings is key for correct clinical assessment and management. The condition highlights the need for a collaborative approach to diagnosis and management. Dermatology, ophthalmology, genetics, neurology, and neurosurgery can be engaged in the care of such patients.