Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy.

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi-allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD-EU register database and an in-house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi-allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.

Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome.

Two variants in the ubiquitously expressed NHLRC2 gene have been reported to cause a lethal fibrotic cerebropulmonary disease termed fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome in three Finnish children. Our objective was to determine the genetic basis of disease in a new patient with clinical features of FINCA syndrome using whole-exome sequencing (WES) and confirmation by Sanger sequencing. The patient has one known and one novel variant in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P, respectively). p.H143P is extremely rare and is not present in the gnomAD database of >140,000 allele sequences from healthy humans. Both variants affect the highly conserved N-terminal thioredoxin (Trx)-like domain of NHLRC2 and are predicted to be damaging. We conclude that a compound heterozygous combination of a known and a novel variant in NHLRC2 causes FINCA syndrome in a 2-year-old Ukrainian patient, underscoring the importance of NHLRC2 as a central regulator of fibrosis.

Diffuse bone and soft tissue angiomatosis with GNAQ mutation.

We describe a unique case of skeletal and extraskeletal angiomatosis complicated by Kasabach-Merritt syndrome. The patient was a 3-year-old boy, who presented with involvement of both femurs and left tibia, as well as with soft tissue lesions of the left thigh. At birth, multiple hemangiomas of the soft tissues of the frontal and parietal scalp had been identified, together with a space-occupying lesion of the lung. Histologically, the skeletal and soft tissue lesions consisted of a proliferation of thin-walled, dilated blood vessels, with an endothelial lining devoid of atypia and exhibiting immunoreactivity for CD31 and CD34, while podoplanin and GLUT1 were negative. Whole exome sequencing performed on samples from the lesion of the femur, the tibia and the skin of the thigh, showed a GNAQ (c.286A>T:p.T96S) variant in all specimens, that was confirmed with digital droplet PCR. This case expands the clinical and pathologic spectrum of vascular proliferations showing similar molecular biology, characterized by GNAQ, GNA11 or GNA14 mutations.

Extraocular muscle enlargement in retinoencephalofacial angiomatosis.

A 22-year-old female presented for evaluation of five years of progressive left exophthalmos and intermittent blurred vision. She had previously received laser treatment for peripheral retinal neovascularization and had undergone lip reconstruction for a left-sided congenital vascular facial malformation. Magnetic resonance imaging demonstrated diffuse enlargement of the left extraocular and temporalis muscles, with prominent vessels in the temporalis muscle and intraconal fat. Left fundoscopic examination revealed grossly enlarged, tortuous retinal vessels extending from the optic disc to the peripheral retina and an abnormal network of capillaries. On the basis of these findings, a diagnosis of retinoencephalofacial angiomatosis was established. Retinoencephalofacial angiomatosis is a rare, non-hereditary disorder associated with ipsilateral retinal, brain, and facial arteriovenous malformations. This is the first report, to the authors' knowledge, of retinoencephalofacial angiomatosis presenting with exophthalmos secondary to extraocular muscle enlargement.

Soft tissue angiomatosis: another PIK3CA-related disorder.

AIM: Angiomatosis of soft tissue (AST) is a rare, high-flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non-syndromic AST arises as a consequence of a somatic mutation. METHODS AND RESULTS: Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients' personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio -0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups. CONCLUSIONS: AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.

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.

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

Association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V polymorphisms with retinal angiomatous proliferation compared with typical age-related macular degeneration: a meta-analysis.

PURPOSE: To compare the published results of studies on the genotype association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V in cases diagnosed as retinal angiomatous proliferation (RAP) versus neovascular age-related macular degeneration (AMD) or healthy controls. METHODS: Heterogeneity of studies was evaluated using Cochran's Q test and I-square index. To modify the heterogeneity in the variables, we used random effects model. Meta-analysis was performed using STATA. RESULTS: Four studies were included with 1076 neovascular AMD patients, 222 RAP cases, and 2276 control subjects. Pooled overall odds ratios for RAP/AMD were 1.15 (95% CI 0.60-2.18) for GT versus GG, 3.52 (95% CI 1.25-9.91) for TT versus GG ARMS2, 0.98 (95% CI 0.22-4.29) for GA versus AA, 1.00 (95% CI 0.25-4.02) for GG versus AA CFHI62V, 0.57 (95% CI 0.35-0.93) for CT versus TT CFH Y402H, and 0.40 (95% CI 0.22-0.74) for CC versus TT CFH Y402H. Regression analysis showed that ARMS2 TT genotype has a statistically significant effect on RAP versus AMD compared to CFH genotypes (P < 0.001). CONCLUSION: This meta-analysis disclosed a stronger effect of ARMS2 genotypes in RAP cases compared with CFH Y402H and I62V genotypes.

The impact of advances in molecular genetic pathology on the classification, diagnosis and treatment of selected soft tissue tumors of the head and neck.

Recent advances in molecular pathology have had a significant impact on the diagnosis, classification, and treatment of soft tissue tumors. The practical application of these discoveries promises to assist greatly in the evaluation and treatment of soft tissue neoplasms in the head and neck region-an area characterized by exceedingly complex anatomy that often restricts the ample sampling of lesions and complete surgical resection. This reviews details some ways in which molecular techniques have strengthened conventional diagnostic and management approaches to low-grade fibromyxoid sarcoma, angiomatoid (malignant) fibrous histiocytoma, and dermatofibrosarcoma protuberans, all of which may involve the head and neck region.

Allelic loss on chromosomes 1p32, 9p21, 13q14, 16q22, 17p, and 22q12 in meningiomas associated with meningioangiomatosis and pure meningioangiomatosis.

Meningioangiomatosis (MA) is a rare lesion appearing sporadically or as a part of neurofibromatosis 2. The occurrences of meningiomas arising from MA (MA-M) have raised doubts about the traditional concept of a hamartomatous origin for MA. Cytogenetic or molecular studies on MA, with or without meningiomas, are limited because of the rarity of MA. The current study was to evaluate the loss of heterozygosity (LOH) in seven cases of MA-M and two cases of pure MA. LOH on six chromosomes (1p32, 9p21, 13q14, 16q22, 17p, and 22q12) were investigated using 13 sets of microsatellite markers, including D1S193, D1S463, D22S193, D22S929, D22S282, TP53, D17S796, D16S421, D16S512, D13S118, D13S153, D9S162, and D9S104. PCR was performed using each marker and polymorphic analysis was accomplished by silver staining. Immunohistochemical stain for Ki-67 was carried out and labeling index was measured by using a semiquantitative manual counting method. The meningioma portions of MA-Ms showed LOH for loci on chromosomes 22q12, 9p21, and 1p32 in 57.1% (4/7), 28.6% (2/7), and 28.6% (2/7) of cases, respectively. The MA portions of MA-M had a LOH for loci on 22q12 in 28.6% (2/7) of cases, whereas each pure MA harbored one LOH on either chromosome 22q12 or 9p21. The proliferation indices of MA-Ms were significantly higher in the meningioma than in the MA components. Our data suggest that both the meningioma and the MA undergo the same overlapping clonal process, with the MA-M while undergoing additional genetic alterations that confer a greater proliferative potential.

Familial multiple angiolipomatosis.

An 80-year-old man presented with a 50-year history of asymptomatic, subcutaneous masses on the arms, trunk, and legs. His father and maternal grandmother had had similar lesions. Histopathologic examination showed a benign angiolipoma; the same diagnosis has been made on several previous biopsy specimens. This patient's history and physical examination support the diagnosis of familial angiolipomatosis, which is a benign, autosomal-dominant condition that may be regarded as a subtype of familial multiple lipomatosis (FML) or as a distinct entity. Management of this condition may include liposuction or surgery to reduce the tumor burden.

VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality.

BACKGROUND: Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect. METHODS: This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS: Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHL germline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS: Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

Angiomatosis leptomeníngea occipital sin angioma facial. ¿Debe considerarse como variante del síndrome de Sturge-Weber? / Occipital leptomeningeal angiomatosis without facial angioma. Should it be considered to be a variant of the sturge-weber syndorme

Introducción. La asociación de angioma leptomeníngeo cerebral y nevus flameus facial en el territorio del la primera rama trigeminal ipsilateral al angioma se denomina síndrome de Sturge- Weber. Los casos con ausencia del angioma facial se incluyen habitualmente como una variedad del síndrome. Objetivo. Presentar cuatro casos con angioma leptomeníngeo occipital sin angioma facial y exponer las características que puedan diferenciarlo o incluirlo dentro del síndrome de SturgeWeber, así como establecer las diferencias con el síndrome de Gobbi (calcificaciones cerebrales occipitales, epilepsia y enfermedad celíaca). Casos clínicos. Se seleccionaron cuatro casos a los que se les realizó resonancia magnética craneal con administración de gadolinio intravenoso y en tres casos, estudio para descartar enfermedad celíaca. Las calcificaciones cerebrales, unilaterales en los cuatro casos, eran similares a las observadas en el síndrome de SturgeWeber. Todos los casos mostraban angioma leptomeníngeo a nivel de la calcificación cerebral evidenciado por la captación de contraste en la resonancia magnética. Tres casos presentaban epilepsia pero ninguno angioma facial, hemiparesia ni glaucoma. También se descartó enfermedad celíaca, tanto analíticamente como a través de biopsia intestinal. Conclusiones. Los casos descritos coinciden con el síndrome de SturgeWeber en la presencia común de angioma leptomeníngeo cerebral, hecho que los diferencia del síndrome de Gobbi que carece del angioma pial. Otra característica común con el síndrome de SturgeWeber es la presencia de epilepsia y déficit intelectual. En espera de estudios de genética molecular, nuestros casos pueden englobarse semánticamente como una variante del síndrome de SturgeWeber sin el característico angioma facial, aunque posiblemente correspondan a entidades genéticamente diferentes (AU)

Introduction. The association of cerebral leptomeningeal angioma and facial nevus flameus in the territory of the first branch of the trigeminal nerve ipsilateral to the angioma is known as the Sturge-Weber syndrome. The cases with absence of a facial angioma are usually considered to be variants of the syndrome. Objective. To present four cases with occipital leptomeningeal angioma without facial angioma and describe the characteristics which differentiate them from or permit their inclusion within the group of Sturge-Weber syndrome, and also to establish the differences between this and the Gobbi syndrome (occipital cerebral calcifications, epilepsy and coeliac disease. Clinical cases. We selected four cases in whom cranial magnetic resonance was done with intravenous gadolinium and three cases studied to rule out coeliac disease. The cerebral calcifications, unilateral in all four cases, were similar to those observed in the Sturge-Weber syndrome. All cases had leptomeningeal angiomas at the level of the cerebral calcification shown by the uptake of contrast material on magnetic resonance. Three patients had epilepsy but none had facial angiomas, hemiparesis or glaucoma. Coeliac disease was also ruled out, both on laboratory investigations and on intestinal biopsy. Conclusions. The cases described coincide with the Sturge-Weber syndrome in all having cerebral leptomeningeal angiomas. This differentiated them from the Gobbi syndrome which does not include meningeal angiomata. Another characteristic of the Sturge-Weber syndrome is the occurrence of epilepsy and mental deficiency. Whilst awaiting molecular genetic studies, our cases may be included semantically as a variant of the Sturge-Weber syndrome without the characteristic facial angioma, although they may possibly correspond to genetically different conditions (AU)

Meningioangiomatosis is associated with neurofibromatosis 2 but not with somatic alterations of the NF2 gene.

Meningioangiomatosis occurs sporadically and in patients with neurofibromatosis. The literature, however, is unclear concerning the type of neurofibromatosis associated with meningioangiomatosis. Because determining which form of neurofibromatosis predisposes to meningioangiomatosis would clarify the genetic alterations of this lesion, we reviewed all reported cases of meningioangiomatosis associated with neurofibromatosis in light of current diagnostic criteria for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2). All well-documented cases of meningioangiomatosis occurred in the setting of NF2, implying that germline alterations of the NF2 gene predispose to meningioangiomatosis. To determine whether sporadic (non-NF) cases of meningioangiomatosis arise from somatic alterations of the same gene, we screened the NF2 gene for mutations in 12 sporadic cases of meningioangiomatosis and in constitutional DNA from 6 of these 12 patients. No mutations were found in either the lesional or constitutional DNA, which suggests that sporadic meningioangiomatosis is not a forme fruste of NF2 and that somatic alterations of the NF2 gene do not play a major role in sporadic meningioangiomatosis. For some tumor suppressor genes, germline mutations may predispose to specific tumors, while similar sporadic lesions only rarely suffer somatic mutations in these genes. The present findings suggest a similar dichotomy for the NF2 gene in meningioangiomatosis.

Hereditary neurocutaneous angiomatosis. Report of four cases.

The authors report the coexistence of vascular nevi (hemangiomas and arteriovenous malformations (AVMs) of the skin) with AVMs and venous malformations of the brain in male siblings from two related but nonconsanguineous families of three generations. The proband, his siblings, parents, aunts, uncles, and cousins were examined, underwent magnetic resonance (MR) imaging and MR angiography, and when appropriate, cerebral angiography. A father had vascular nevi and a mother, his sister, had an azygos anterior cerebral artery. No other cutaneous or cerebrovascular malformations were present in the parents. Each of the two families had two boys and one girl, 9 to 18 years of age. All the children had vascular nevi and all of the boys had coexisting cerebrovascular malformations: AVMs in three, and a venous malformation in another. One boy had three cerebral AVMs. Two boys had a cerebral hemorrhage, and one also had focal motor seizures. The skin lesions were not those of the Sturge-Weber-Dimitri, Rendu-Osler-Weber, or Wybum-Mason syndromes. The association of cutaneous and cerebrovascular malformations was seen only in males in these families. but females have also been reported in the literature. The results obtained in these families and three other families reported from Western and Central Europe indicate that the association of cerebral and cutaneous vascular hamartomas constitutes a distinct, hereditary clinicopathological entity with autosomal dominant inheritance and variable penetrance. The clinical manifestations of this syndrome are visible, painful vascular nevi, epilepsy, cerebral hemorrhage, and focal neurological deficits. The preponderance of male patients with the full expression of the syndrome suggests a possible hormonal influence on the expression of the gene.

Clinical features and molecular genetics of Von Hippel-Lindau disease.

Although familial cancer syndromes are rare, a knowledge of these disorders is relevant to both clinicians and basic scientists. This is exemplified by Von Hippel-Lindau (VHL) disease which is caused by germline mutations in the VHL tumour suppressor gene. This multisystem disorder provides a complex clinical problem for ophthalmologists and other specialists. In addition, recent advances in the molecular genetics of this disorder are providing novel insights into the molecular mechanisms of tumourigenesis in VHL disease and in more common nonfamilial neoplasms such as clear cell renal carcinoma and central nervous system haemangioblastoma. In this review, we describe the clinical manifestations (with particular reference to the ocular complications) and the molecular genetics of VHL disease.