Cerebral Angiomatosis Research Articles

FINCA syndrome

FINCA (fibrosis, neuro-degeneration, cerebral angiomatosis) syndrome is a rare autosomal recessive early onset fatal disorder characterised by progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infection, chronic haemolytic anaemia and transient liver dysfunction. A 5 year old female baby born as a preterm 33 weeks (2nd twin of dichorionic diamniotic twin) to nonconsanguineous parents via intra-cytoplasmic sperm injection and surrogacy, delivered by emergency caesarean section (indication- pre-eclampsia in mother) with a birth weight of 1.8 kg. She had a stormy neonatal period and had anaemia requiring blood transfusion. Developmental delay was noted from early infancy which was not responding to developmental therapy, along with recurrent episodes of aspiration pneumonia. Her twin on the other hand had normal mile stones without any remarkable medical history. Examination and evaluation revealed features of chronic hemolysis. In view of constellation of developmental delay, recurrent infection, chronic hemolytic anaemia and cerebral atrophy beyond documented perinatal issues and dysmorphism, clinical exome sequencing was done which revealed missense variation in exon of NHLRC2 gene on chromosome 10 suggestive of FINCA syndrome. This case emphasized the need of genetic testing to resolve uncertainty in etiology and accurate prognostication.

Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement.

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease.

FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2-null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown. The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients. One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain. This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.

Інтерстиціальне захворювання легень та нейродегенеративні розлади при синдромі FINCA: нові знання змінюють старі судження

FINCA (Fibrosis, Neurodegeneration, Cerebral Angiomatosis) syndrome is a new genetic multiorgan disease caused by a mutation in NHLRC2 (NHL repeat-containing protein 2). Disease manifests at an early age by interstitial lung disease, neurodegenerative disorders, hemolytic anemia, gastrointestinal disorders, liver dysfunction and other multiorgan changes. The syndrome was first described in 2018 in three children who died before the age of two. Studies in recent years have significantly expanded the range of clinical symptoms of FINCA syndrome, and also showed great variability in the severity of the symptomes, especially respiratory lesions. Taking into account the neurological problems in all described patients, NHLRC2 should be included in the sequencing panels of neurological diseases (neurodegenerative, neurodevelopmental disorders, epilepsy). Recurrent respiratory infections and episodic diarrhea, as well as hypogammaglobulinemia in most patients require study of the role of NHLRC2 protein in the functioning of the immune system. No conflict of interests was declared by the authors.

FINCA syndrome-Defining neurobehavioral phenotype in survivors into late childhood.

We report for the first time a novel missense variant in NHLRC2. We extend the NHLRC2 gene associated neuropsychological and neuroimaging phenotype, and propose that the NHLRC2 gene should be considered in patients with symptoms of atypical Rett syndrome. We also summarise currently available literature on neuropsychological symptoms in children with FINCA who survived into late childhood.

Diffuse cerebral angiomatosis: a case report with fatal outcome

Diffuse cerebral angiomatosis is a rare disorder of the brain and only 5 cases have been reported to date. We report a 16-year-old female patient who presented to the emergency department with seizures. The patient had no hereditary syndromes, no epistaxis, no skin lesions and no telangiectasia. There was no livedo reticularis. The ophthalmologic examination was within normal limits. Magnetic resonance angiography (MRA) showed multiple diffuse tortuous vessels all around the brain tissue and ventricular system. Brain CT showed multiple calcifications. Digital subtraction angiography (DSA) demonstrated multiple arteriovenous shunts and diffuse arteriovenous malformations (AVM) without a typical nidus, draining into dilated cerebral veins. Multimodal ultrasound showed increased flow velocities in all cerebral arteries. We report the case of a patient with diffuse cerebral angiomatosis. This is the third study in which hemodynamic indices were evaluated through transcranial Doppler. Unlike all other case reports our patient had a bad outcome with important disability, dementia and drug resistant epilepsy that lead to the patient’s death.HighlightsDiffuse cerebral angiomatosis is a rare disorder of the brain and only 5 cases have been reported to date.Unlike all other case reports our patient had a bad outcome with disability, dementia and drug resistant epilepsy that lead to the patient’s death.

Biallelic mutations in human NHLRC2 enhance myofibroblast differentiation in FINCA disease.

The development of tissue fibrosis is complex and at the present time, not fully understood. Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA disease) have been described in patients with mutations in NHL repeat-containing protein 2 (NHLRC2). However, the molecular functions of NHLRC2 are uncharacterized. Herein, we identified putative interacting partners for NHLRC2 using proximity-labeling mass spectrometry. We also investigated the function of NHLRC2 using immortalized cells cultured from skin biopsies of FINCA patients and normal fibroblasts with NHLRC2 knock-down and NHLRC2 overexpressing gene modifications. Transmission electron microscopy analysis of immortalized cell cultures from three FINCA patients demonstrated multilamellar bodies and distinctly organized vimentin filaments. Additionally, two of three cultures derived from patient skin biopsies contained cells that exhibited features characteristic of myofibroblasts. Altogether, the data presented in this study show for the first time that NHLRC2 is involved in cellular organization through regulation of the cytoskeleton and vesicle transport. We conclude that compound heterozygous p.Asp148Tyr and p.Arg201GlyfsTer6 mutations in NHLRC2 lead to severe tissue fibrosis in humans by enhancing the differentiation of fibroblasts to myofibroblasts.

Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease.

NHLRC2 (NHL repeat-containing protein 2) is an essential protein. Mutations of NHLRC2, including Asp148Tyr, have been recently associated with a novel FINCA disease (fibrosis, neurodegeneration, cerebral angiomatosis), which is fatal in early childhood. To gain insight into the mechanisms of action of this essential protein, we determined the crystal structure of the Trx-like and NHL repeat β-propeller domains of human NHLRC2 to a resolution of 2.7 Å. The structure reveals two domains adjacent to each other that form a cleft containing a conserved CCINC motif. A SAXS structure of full-length NHLRC2 reveals that the non-conserved C-terminal domain does not pack against the N-terminal domains. Analysis of the surface properties of the protein identifies an extended negative electrostatic potential in the surface of the cleft formed by the two domains, which likely forms a binding site for a ligand or interaction partner(s). Bioinformatics analysis discovers homologs across a range of eukaryotic and prokaryotic species and conserved residues map mostly to the adjacent surfaces of the Trx-like and β-propeller domains that form the cleft, suggesting both that this forms the potential functional site of NHLRC2 and that the function is conserved across species. Asp148 is located in the Trx-like domain and is not conserved across species. The Asp148Tyr mutation destabilizes the structure of the protein by 2°C. The NHLRC2 structure, the first of any of its homologs, provides an important step towards more focused structure-function studies of this essential protein.

The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review

Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and angiographic finding of “cerebral angiomatosis”. A similar syndrome including livedo racemosa and cerebrovascular disease, often associated with anticardiolipin antibodies, has been described as Sneddon Syndrome (SS) highlighting the question whether these two conditions have to be considered different entities or indeed different features of a unique syndrome. Herein, we report the clinical, neuroradiological, histopathological findings and follow up of three cases diagnosed as Divry-van Bogaert Syndrome, including an updated review of literature of both DBS and SS cases. Our findings support the assumption that DBS and SS are different disease entities. DBS is characterized by the typical angiographic feature of angiomatosis, a hereditary trait and a juvenile onset of cognitive impairment and leukoaraiosis, whereas SS has less severe manifestations of cerebrovascular disease associated with livedo racemosa but without the characteristic cerebral angiography. The report of our cases and the literature review underline the necessity of a detailed work-up and the collection of larger series to better clarify the DBS and SS phenotype and course.

Sturge-Weber syndrome: decrease in intraocular pressure after transpupillary thermotherapy for diffuse choroidal haemangioma

To report intraocular pressure (IOP) reduction after selective and partial destruction of diffuse choroidal haemangioma (DCH) by transpupillary thermotherapy (TTT) using an 810 nm infrared diode laser in two patients with Sturge-Weber syndrome (SWS) having late-onset juvenile glaucoma (LOJG). An interventional small case series. Laser spots (diameter, 1 mm) were applied to the tumour surface located outside the posterior pole. Energy level (600-1700 mW) and exposure time (1-4 seconds) were increased stepwise until the tumour exhibited a greyish discoloration. The treatment was split into 2-4 sessions. Before TTT, both patients had uncontrolled LOJG with an IOP of 23 mmHg (Case 1) and 45 mmHg (Case 2) in spite of topical medications. In both cases, TTT led to normalization of IOP to 15 mmHg and 24 mmHg, respectively, and stopped the progression of LOJG during a follow-up period of 6 years (Case 1) and 1 year (Case 2). Visual loss or other complications were not observed. Our study highlights the close link that exists between LOJG and DCH in SWS. A single treatment modality such as TTT may both reduce IOP in LOJG and help to prevent exudative retinal detachment in DCH. We believe that TTT is a good therapeutic option for SWS patients who have both DCH and LOJG.

Spontaneous obliteration of MRI-silent cerebral angiomatosis revealed by CT angiography in a patient with Sturge–Weber syndrome

Type I Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome characterized by facial port wine stain and ipsilateral leptomeningeal angiomatosis. It is commonly complicated by glaucoma and neurological disturbances including seizures, hemiparesis, transient stroke-like deficits, and behavioral problems. Gadolinium-enhanced MRI is the study of choice for demonstrating the leptomeningeal angiomatosis, and is particularly useful for making the diagnosis. Cerebral hematoma and spontaneous obliteration of cerebral angiomatosis have never been reported in SWS. We describe a patient with type I SWS in which a hemorrhage in the left temporal lobe was caused by an underlying angiomatosis. No arteriovenous malformations were detected by brain CT or gadolinium-enhanced MRI, whereas a small angiomatous nidus draining into an ectasic venous collector near the hematoma was disclosed by brain CT angiography. Carotid angiography, performed 3 years after the hemorrhage, demonstrated the spontaneous obliteration of the angioma. This description expands the phenotypic spectrum of type I SWS in which the occurrence of cerebral hemorrhage and MRI-silent cerebral angiomatosis should be included, and emphasizes the need of performing a brain CT angiography in SWS patients whose routine neuroimaging studies fail to detect potentially harmful vessel malformation.

Sturge-Weber Syndrome Variant With Atypical Intracranial Findings

Sturge-Weber syndrome is characterized by a facial port-wine nevus, leptomeningeal angiomatosis, and glaucoma; it is commonly complicated by epilepsy and hemiparesis. We present a patient with a head and neck port-wine nevus, glaucoma, abnormalities of the intracranial deep veins, and untreated communicating hydrocephalus. The patient lacks any radiologic or clinical evidence of cerebral leptomeningeal angiomatosis. Considering that intracranial venous anomalies also are likely compatible with the embryologic explanation of Sturge-Weber syndrome, this child can serve as an unusual example of Sturge-Weber syndrome type II.

First cases of animal diseases published since 2000. 2. Cats1

Summary In this second article of a series of papers listing first case reports of animal diseases published since 2000, the following nine cases of cat diseases are discussed: - Congenital spongiform change in the brain stem nuclei. - Enterococcus hirae enteropathy. - Focal cerebral angiomatosis. - Glomus tumor. - Intraocular extramedullary plasmacytoma. - Lens epithelial neoplasias. - Phaeohyphomycosis due to Fonsecaea pedrosoi. - Pulmonary lymphomatoid granulomatosis. - Systemic amyloidosis in a Devon rex. After a short introduction, the bibliographical data, the abstract of the author(s) and some additional information derived from the article are given. The article will be regularly updated adding overlooked as well as new first reports.

Multimodal ultrasound assessment of cerebral hemodynamics in a patient with a diffuse cerebral angiomatosis

Recent newly developed ultrasound (US) techniques extend our ability to study the cerebral hemodynamics in patients with arteriovenous malformations (AVM) beyond the conventional cerebral blood flow velocity ( CBFV) analysis. We present US data of global cerebral blood flow ( CBF) and global cerebral circulation time ( CCT) in a patient with a unique bihemispherial diffuse cerebral angiomatosis and compare them with 10 age-matched controls. In addition, the estimation of an US-derived global cerebral blood volume ( CBV) is proposed. Duplex sonographic CBF analysis revealed 2620 mL/min in the patient and 754 ± 93 mL/min in controls. Doppler sonographic CCT was 2.9 s and 6.3 ± 1.5 s and CBV 126 mL and 79 ± 19 mL, respectively. US allows a simple, minimal invasive bedside analysis of several global hemodynamic parameters that might provide valuable additional information in patients with diffusely altered cerebral hemodynamics. (E-mail: Stephan.Schreiber@charite.de)

Cerebral venous drainage via the ophthalmic veins in the Sturge-Weber syndrome

We describe a 23-year-old girl with an extremely uncommon form of cerebral venous drainage and cerebellar leptomeningeal angiomatosis as a possible variant of the Sturge-Weber syndrome. Extensive congenital port-wine stains all over the body, hypoplastic left renal and subclavian and iliac veins, cardiomegaly and ptosis and hypoplasia of the left kidney had been recognised in early childhood. She rapidly developed signs of intracranial hypertension. CT and MRI showed a right medial temporal lesion. Angiography revealed cerebellar pial angiomatosis with enlarged medullary veins and no functioning sigmoid sinuses or jugular veins. Cerebral venous drainage was via enlarged ophthalmic veins. Although the intracranial venous abnormalities were characteristic of the Sturge-Weber syndrome anomalies beyond the encephalofacial territory suggested a more complex developmental abnormality.

EEG evaluation of children with Sturge-Weber syndrome and epilepsy

To define the contribution of the EEG evaluation in children with seizures and Sturge-Weber syndrome, we reviewed EEG data in 14 radiologically confirmed cases. Thirteen exhibited marked voltage attenuation that was localized to the region of the cerebral angiomatosis. Polymorphic slowing occurred ipsilateral to the lesion in six patients and was bilateral in six. By contrast, interictal spikes were evident in only two patients and did not always correlate with the angiomatosis. Seizures were captured in four patients and consistently revealed ictal discharges only at the periphery of the lesion. These findings indicate that abnormalities of EEG background rather than interictal spikes are consistently present early in the course of Sturge-Weber syndrome and correlate with the region of angiomatosis.

Bonnet-Dechaume-Blanc syndrome accompanied by mandibular angiomatosis and thrombocytopenia

Summary A case of retino-facial-mandibular angiomatosis with concomitant thrombocytopenia is presented. Cerebral angiomatosis was also assumed to be present. Bleeding and coagulation times were normal. Necrotisation and curettage of the tumour resulted in a rapid increase in the number of thrombocytes. It is obvious that the angioma alone is responsible for the increased intravascular coagulation and thrombocytopenia. A satisfactory therapeutic result is achieved by the relatively simple measures which eradicate the tumour. More attention should obviously be given to thrombocyte picture and the coagulation defect when the angioma shows signs of activation.

Cerebral angiomatosis: Report of a case in an infant, with a review of the literature

Summary The clinical history and autopsy findings are presented in a child with cerebral angiomatosis. The pertinent literature has been reviewed. General symptoms and signs of such lesions are paresis, epilepsy or convulsions, hemorrhage, less commonly chronic headache, mental deterioration, cranial bruits, visual field defects, diplopia due to sixth nerve paralysis, and symptoms secondary to increased intracranial pressure. Final diagnosis usually can be made by intracranial angiography. The treatment of choice is radical surgical excision or obliteration and should be carried out whenever feasible. The value of intracranial arterial ligation or incomplete removal of the anomaly may be questioned. Radiation is of no value.