Neurocutaneous Syndrome Research Articles

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.

Tuberous sclerosis: a case report

Tuberous sclerosis is a neurocutaneous syndrome with an autosomal dominant inheritance. The clinical triad of papular facial nevus seizures and mental retardation is found in less then half of the patients. Thus the radiological hallmarks of this neurocutaneous syndrome are universally accepted as sufficient for diagnosis.1

Sturge-Weber Syndrome: A Diagnosis Not to be Ignored

Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome characterized by angiomas involving the face, choroid, and leptomeninges. The early diagnosis and the prompt treatment may reduce the incidence of neurologic sequelae, and may prevent irreversible blindness. We report a case of a 32-year-old man with SWS.

Renal Stones and Tuberous Sclerosis: A Rare Co-Existence

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome first described by Bourneville in 1880. It is a rare genetic disorder characterized by a triad of seizures, mental retardation and cutaneous lesions due to mutations in two genes, TSC1 and TSC2. We report a case of 46-years old male with generalised weakness and seizures. Patient was investigated and diagnosed after examination and investigation with tuberous sclerosis involving central nervous system i.e. sub-ependymal nodules and cortical tubers, skin manifestation adenoma sebaceum and ash leaf spots, lungs with cysts i.e. lymhangioleiomyomatosis, kidneys with angiomyolipomas and cysts . Patient also had right partial staghorn stone which was challenge for management. The patient was managed with right extended pyelolithotomy and discharged only to be re-admitted with vesical calculus after 18 months. This case report emphasizes the rare co-existence of renal stone formation with tuberous sclerosis.

The Rare Neurocutaneous Disorders: Update on Clinical, Molecular, and Neuroimaging Features.

Phakomatoses, also known as neurocutaneous disorders, comprise a vast number of entities that predominantly affect structures originated from the ectoderm such as the central nervous system and the skin, but also the mesoderm, particularly the vascular system. Extensive literature exists about the most common phakomatoses, namely neurofibromatosis, tuberous sclerosis, von Hippel-Lindau and Sturge-Weber syndrome. However, recent developments in the understanding of the molecular underpinnings of less common phakomatoses have sparked interest in these disorders. In this article, we review the clinical features, current pathogenesis, and modern neuroimaging findings of melanophakomatoses, vascular phakomatoses, and other rare neurocutaneous syndromes that may also include tissue overgrowth or neoplastic predisposition.

Tuberous Sclerosis Complex: A Case Report

Tuberous sclerosis complex is an uncommon neurocutaneous syndrome characterized by development of benign tumors affecting multiple body systems including skin, brain, retina and viscera. The management of these patients is multidisciplinary, involving specialists from different fields. Since it can present with a wide range of manifestations, the quality of life and prognosis depends on the particular abnormalities seen in a patient. Here, we report a case of an 11 year old boy with typical clinical and radiological features of tuberous sclerosis. Key Words: adenoma sebaceum, subependymal giant cell astrocytoma, nonrenal hamartoma.

Clinical and genetic heterogeneity in Melkersson-Rosenthal Syndrome

Melkersson Rosenthal syndromes (MRS) is a rare autosomal dominantly inherited neurocutaneous syndrome characterised by a triad of facial (seventh cranial) nerve palsy, recurrent orofacial swelling and fissuring of the tongue. A recent report implicated a heterozygous missense variant in SLC27A1 (FATP1) as the cause of this condition in members of an affected Chinese family. We undertook Sanger sequencing of this gene in 14 affected unrelated individuals affected by MRS. We did not detect any putative pathogenic variants. Our data indicates that there is both clinical and genetic heterogeneity in this condition and that the causative gene remains to be identified for the majority of cases.

Central nervous system manifestations of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal-dominant genetic syndrome marked by development of hamartomatous lesions arising from dysfunction of the mammalian target of rapamycin (mTOR) pathway. Although TSC remains a heterogeneous clinical entity, the recent inclusion of genetic diagnostic criteria reflects advancement in our understanding of its underlying etiopathogenesis. Abnormal cellular growth, differentiation, and migration result in multisystem sequelae, with neurologic manifestations of TSC representing the primary cause of morbidity and mortality for the majority of individuals. Modern imaging techniques aid in the diagnosis of TSC and guide treatment strategies by revealing central nervous system findings. Cortical tubers are the namesake lesion of the disorder and occur in up to 90% of cases, often exerting significant epileptogenic potential. Subependymal nodules are found in 80% of patients as calcified tumors lining the ependyma of the lateral ventricles. In some cases, these nodules are thought to progress to subependymal giant cell astrocytomas and may present with obstructive hydrocephalus. Retinal astrocytic hamartomas are also common, present in 50% of patients. Surgery remains the treatment of choice for large or symptomatic lesions, though clinical trials have highlighted a potential role for mTOR pathway antagonism. A multidisciplinary approach is necessary for achieving optimal patient outcomes.

Current concepts on epilepsy management in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

Neurodegeneration in an adolescent with Sjogren-Larsson syndrome: a decade-long follow-up case report

BackgroundSjogren-Larsson syndrome is a hereditary neurocutaneous syndrome that is non-progressive in nature. Although neuroregression has been reported in seizure-prone preschool children requiring anti-epileptic treatment, teenage-onset dystonia precipitating neurodegeneration without any immediate causal events has yet to be reported.Case presentationWe describe a young woman with spastic diplegia and intellectual disability who began to show progressive neurological deterioration from 12 years of age, with the onset of dystonia and tremor. She was initially diagnosed with spastic cerebral palsy and periventricular leukomalacia based on brain magnetic resonance imaging. Follow-up brain imaging from 13 years of age did not reveal apparent changes, though abnormal electroencephalographic findings occurred in parallel with her decline in motor function. By 19 years of age, she had developed dysphagia and became completely dependent on others for most activities of daily living. Ultimately, whole-exome sequencing revealed a heterozygous compound mutation in the ALDH3A2 gene that corresponds to Sjogren-Larsson syndrome: an exon 9 deletion (1291-1292delAA) from the mother and an exon 5 splicing mutation (798 + 1delG) from the father. Neuroregression has been reported in preschool children after seizures requiring treatment, though our patient did not experience any immediate causal events. This report summarizes the clinical, radiologic, and electrophysiological findings observed over a decade concurrent with neurological deterioration after the onset of dystonia and tremor at the age of developmental ceiling in Sjogren-Larsson syndrome.ConclusionsIn addition to the influence of additive variants or other environmental factors, accumulation of metabolites due to defective fatty aldehyde dehydrogenase is a potential pathomechanism of neurodegeneration in this patient. Neurological deterioration may be a presentation that is unnoticed in Sjogren-Larsson syndrome due to the rarity of the disease. This report highlights a unique clinical feature of Sjogren-Larsson syndrome with progressive neurodegeneration associated with dystonia and tremor.

Hypomelanosis of Ito

AbstractHypomelanosis of Ito (HI) is a congenital neurocutaneous syndrome presenting in the first year of life. It was first described by Ito in 1952 as a purely cutaneous disease presenting with skin hypopigmentation. Several extracutaneous manifestations were later described, and it is now known that several organs can be involved (including brain, muscle, bone, heart, eye, kidney, and teeth) and that the prognosis is strictly related to the number of involved organs. The incidence and prevalence of this syndrome have been estimated to range between 1 in 7,540 births and 1 in 82,000; the disorder affects both the sexes, occurs in all races, and is characterized by depigmentation of the skin along the lines of Blaschko on the trunk and extremities in whorled and linear streaks and patterns. The pathogenesis is unknown, but it is likely to be multifactorial. Several models of inheritance have been proposed but not proved; genetic mosaicism is nowadays the most likely explanation for its inheritance. The differential diagnosis comprises other disorders with hypopigmentation following the lines of Blaschko and thus includes the atrophic/hypopigmented (fourth) stage manifestations of incontinentia pigmenti of the Bloch–Sulzberger type, tuberous sclerosis complex, vitiligo, and skin fungal infections. Consensus recommendations for the screening of associated extracutaneous conditions do not exist and management is symptomatic, but a regular evaluation of somatic growth, neurodevelopment, endocrine status, eyes, and teeth should be performed, and the screening of renal function is also advisable. HI still represents a challenging disorder for the child neurologist and a controversial issue in the medical literature. Awareness of this disorder could allow an early diagnosis and appropriate genetic counseling and screening.

Tuberous sclerosis syndrome: a typical case of a rare disease

The article is devoted to a rare hereditary disease from the group of phak omatoses with an autosomal dominant type of inheritance — Pringle — Burnevill disease. The questions of the prevalence of the disease, the variability of the clinical picture, the timeliness of the clinical diagnosis are considered. Particular attention is paid to skin manifestations and their differential diagnosis. A clinical case of this disease is described.

Three-dimensional Photogrammetric Analysis of Facial Soft-to-Hard Tissue Ratios After Bimaxillary Surgery in Facial Asymmetry Patients With and Without Sturge-Weber Syndrome.

Sturge-Weber syndrome (SWS) is a rare neurocutaneous syndrome characterized by facial port-wine stains. Most patients with facial asymmetry due to SWS have soft and/or hard tissue hypertrophy and require both soft tissue correction and bone surgery. In our experience, because SWS patients are more likely than non-SWS patients to be dissatisfied after bone surgery because of limited soft tissue change, we compared soft tissue changes after bimaxillary surgery between facial asymmetry patients with and without SWS.All patients-5 with SWS and 5 without SWS-underwent bimaxillary surgery by a single surgeon. Soft-to-hard ratios were determined using the preoperative and postoperative vertical lengths from the intersection point between the external orbital contour laterally and the oblique orbital line (LO) to the occlusion line (OL) and the LO to the mandible angle (AG) on cephalography and the distances between the lateral canthus (LC) and oral commissure (OC) and between the LC and soft tissue gonion (Go') on 3-dimensional scanned images.The average change in the [LC-OC] to [LO-OL] ratio was 23.03% ± 10.09% in SWS patients and 88.05% ± 10.44% in non-SWS patients (P = 0.008). The average change in the [LC-Go'] to [LO-AG] ratio was 35.54% ± 15.47% in SWS patients and 78.90% ± 47.56% in non-SWS patients (P = 0.032).Soft-to-hard tissue ratios after orthognathic surgery are significantly smaller in SWS patients than in non-SWS patients. This information is important for preoperative patient counseling, managing patient expectations, enhancing results, and planning the second-stage soft tissue surgery.

Identification of Mutation Regions on NF1 Responsible for High- and Low-Risk Development of Optic Pathway Glioma in Neurofibromatosis Type I.

Neurofibromatosis type I is a rare neurocutaneous syndrome resulting from loss-of-function mutations of NF1. The present study sought to determine a correlation between mutation regions on NF1 and the risk of developing optic pathway glioma (OPG) in patients with neurofibromatosis type I. A total of 215 patients with neurofibromatosis type I, from our clinic or previously reported literature, were included in the study after applying strict inclusion and exclusion criteria. Of these, 100 patients with OPG were classified into the OPG group and 115 patients without OPG (aged ≥ 10 years) were assigned to the Non-OPG group. Correlation between different mutation regions and risk of OPG was analyzed. The mutation clustering in the 5′ tertile of NF1 was not significantly different between OPG and Non-OPG groups (P = 0.131). Interestingly, patients with mutations in the cysteine/serine-rich domain of NF1 had a higher risk of developing OPG than patients with mutations in other regions [P = 0.019, adjusted odds ratio (OR) = 2.587, 95% confidence interval (CI) = 1.167–5.736], whereas those in the HEAT-like repeat region had a lower risk (P = 0.036, adjusted OR = 0.396, 95% CI = 0.166–0.942). This study confirms a new correlation between NF1 genotype and OPG phenotype in patients with neurofibromatosis type I, and provides novel insights into molecular functions of neurofibromin.

Neuroimaging Findings as a Predictor of Choice of Antiepileptic Drugs for Seizure Control in West Syndrome

Background: West syndrome (WS) is a severe form of encephalopathy that typically affects young infants ranges from 2-3.5/10,000 live births. Approximately 50% causes of Infantile Spasm are associated with prenatal factors that includes congenital CNS malformations, intrauterine insults, neurocutaneous syndromes such as Tuberous sclerosis complex, metabolic disorders or genetic syndromes and have poor prognosis. For early identification of underlying etiology a proper neuroimaging is essential that will also help to predict the outcome. For this reason my study aimed to correlate the presence of neuroradiologic abnormalities and its impact on seizure control in the children with West syndrome.Methodology: This retrospective cross sectional study was carried out in Institute of Pediatric Neurodisorder and Autism (IPNA) in BSMMU. All patients those who were diagnosed as a case of West syndrome in between age of 3 months to 3 years according to ILAE (International League against Epilepsy) during period of June 2013 to May 2015 were included in this study.Results: Thirty one (31) children with West Syndrome were studied, their mean age of presentation was 18±10.48 months, mean age of onset of seizure was 6.68±3.9 months, 67.7% of them were male. Patients with normal neuroradiologic findings had early remission of spasms and with anomalies, atrophy and calcification were associated with poor response to drug (p=0.03). ACTH was the most commonly used drug with good seizure remission where neuroimaging finding was normal and in cerebral atrophy as a consequence of perinatal asphyxia (p=0.06). Vigabatrin showed good seizure remission in WS due to Tuberous Sclerosis Complex.Conclusion: Seizure prognosis of West Syndrome differ greatly according to the type of brain lesion so in every suspected cases of West Syndrome early neuroimaging should have to be performed for choosing an appropriate antiepileptic drug.Bangladesh J Child Health 2018; VOL 42 (1) :9-14

Neurofibroma cervicodorsal en una niña con Neurofibromatosis Tipo 1

La neurofibromatosis es el sindrome neurocutaneo mas frecuente, una enfermedad hereditaria con afectacion multisistemica. Se distinguen tres formas clinicas de la enfermedad; la neurofibromatosis tipo 1 (NF-1) es la mas frecuente. A las lesiones cutaneas, presentes en la mayoria de los casos, se pueden asociar tumores en cualquier localizacion. Los neurofibromas son caracteristicos de la NF-1. El objetivo de esta comunicacion es describir una complicacion poco frecuente de la NF-1 que representa un desafio terapeutico debido a la topografia y frecuencia de recidivas. Se trata de una nina de 3 anos con NF-1 con sintomas de mielopatia multisegmentaria de instalacion progresiva de dos meses de evolucion. La imagenologia evidencio una tumoracion cervico-dorsal con compresion medular. La exeresis tumoral permitio confirmar neurofibroma intradural, extramedular. Los neurofibromas plexiformes se caracterizan por su comportamiento infiltrativo y diseminacion paraespinal extensa. La reseccion de estas lesiones genera habitualmente morbilidad asociada al compromiso de estructuras criticas extraespinales y dificulta su reseccion completa tal como ocurrio en el caso clinico presentado. Se destaca la importancia de realizar un correcto seguimiento clinico y eventualmente imagenologico de los pacientes con NF-1 para detectar y abordar oportunamente los tumores, su complicacion mas importante.

P.050 NICO-assisted neuroendoscopic management of enlarging subependymal giant cell astrocytoma in tuberous sclerosis complex: a case report

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome classically associated with mental disability, seizure disorder and adenoma sebaceum, among other anomalies. One of the major causes of mortality and morbidity in adults is the exclusive occurrence of subependymal giant cell astrocytoma (SEGA) which responds in at least 35% of cases to everolimus, mTOR inhibitor. However, drug treatment is associated with 33% rate of adverse events and requires long-term treatment Methods: In this report, we present a case of 49-year old female with TSC and a left enlarging SEGA that was approached endoscopically in order to minimize morbidity associated with open surgical approaches. Results: The use of NICO Myriad system is described in this case to achieve successful tumor debulking without post-operative neurologic morbidity. Conclusions: This report reveals the value of minimally invasive neuroendoscopic techniques in the management of challenging intraventricular tumors while avoiding injury to crucial deep venous structures.

Forehead reconstruction with a custom-made three-dimensional titanium implant in a Parry-Romberg syndrome patient.

Parry-Romberg syndrome is a rare neurocutaneous syndrome characterized by progressive shrinkage and degeneration of the tissues usually on only one side of the face. It is usually difficult to restore the facial contour due to skin tightness. In this case report, we report a forehead reconstruction with custom-made three-dimensional (3D) titanium implant of a Parry-Romberg syndrome patient who was treated with multiple fat grafts but had limited effect. A 36-year-old man presented with hemifacial atrophy. The disease progressed from 5 to 16 years old. The patient had alopecia on frontal scalp and received a surgery using tissue expander. The alopecia lesion was covered by expanded scalp flap done 22 years ago. Also, he was treated with fat grafts on depressed forehead 17 years ago. However, it did not work sufficiently, and there was noted depressed forehead. We planned to make 3D titanium implant to cover the depressed area (from the superior orbital rim to the vertex). During the operation, we confirmed that the custom-made 3D implant accurately fit for the depressed area without any dead spaces. Previously depressed forehead and glabella were elevated, and the forehead contour was improved cosmetically. A custom-made 3D titanium implant is widely used for skull reconstruction and bring good results. In our case, the depressed forehead of a Parry-Romberg syndrome patient was improved by a 3D titanium implant.

First five generations Chinese family of tuberous scleroses complex due to a new mutation of the TSC1 gene

Tuberous scleroses complex (TSC) is a rare neurocutaneous syndrome and has autosomal dominant inheritance. However, larger family with TSC is very rare. Here, we report the first five generations family with TSC from China, and localize the pathogenic gene. A boy with TSC and epilepsy underwent preoperative evaluation and epileptic surgery. His TSC family history was gotten, and the clinical data of a Chinese family with TSC were collected in 2016. Complete exons sequencing was performed in the proband and his parents, and whole exons sequence of TSC was performed in the other family members. The family showed autosomal dominant inheritance, and it was the largest reported family with TSC. In this pedigree, there were 14 patients in 5 generations, but only 1 case with epilepsy in them. All of examined patients had TSC 1 gene exon 15 c.1846delG p.A616Pfs*13 mutation. In conclusion, TSC patients with TSC 1 deletion presented mild neurological symptom and rendered larger family.

El síndrome de sturge-weber: reporte de un caso en el centro de diagnóstico y tratamiento de problemas de lenguaje y aprendizaje de la UNIFE, motivo de aprendizaje y crecimiento profesional

The Sturge-Weber syndrome is a neurocutaneous syndrome which severity is determined for the degree to which the brain is affected and the control of the epilepsy. It is a congenital vascular disease characterized for a capillary facial malformation (port-wine stain) associated with venous and capillaries malformations in the brain and in the eye. Also, alterations can be observed in other locations (oral cavity or airway) and neurological symptoms. Founded studies present that the SWS is of unknown etiology, although there is envisage the hypothesis that the capillary malformations are the result of somatic mutations in ectodermal fetal tissues. In the educational level, there is little information about rehabilitation of speech and language, which motivated educators and experts to research and use the ingenuity and creativity to help these children. There are several clinical manifestations of this syndrome, it is important know all of these to get a proper diagnosis, follow-up and treatment of them, thus improving the quality of life of these.