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

Rapp, Christina; Dijck, Ine Van; Laugwitz, Lucia; Boon, Mieke; Briassoulis, George; Ilia, Stavroula; Kammer, Birgit; Reu, Simone; Hornung, Stefanie; Buchert, Rebecca; Sofan, Linda; Froukh, Tawfiq; Witters, Peter; Rymen, Daisy; Haack, Tobias B.; Proesmans, Marijke; Griese, Matthias

doi:10.1111/cge.14016

Cited by 16 publications

(22 citation statements)

References 11 publications

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“…So far, only a few children without progressive pulmonary features were reported. In four of them, the recurrent variant was present in homozygous state and it was detected once in trans with the missense variant p.(Gly326Val) 7,8 . In our cohort, homozygosity for the recurrent p.(Asp148Tyr) variant was found in two children of two unrelated families (individual 3 and 9).…”

Section: Discussionmentioning

confidence: 99%

“…Brain magnetic resonance imaging (MRI) scans and histopathological examination revealed interstitial pulmonary brosis as well as brain atrophy and vacuolar white matter degeneration. While further studies on patients carrying biallelic NHLRC2 variants con rmed this severe FINCA phenotype 6 by now also milder cases with survival until the second decade of life have been reported 7,8 . In all 13 cases described so far, the recurrent missense variant c.442G > T, p.(Asp148Tyr) was present either in homozygous or compound heterozygous state.…”

Section: Introductionmentioning

confidence: 91%

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FINCA syndrome beyond pulmonary affection: biallelic NHLRC2 variants in eight families with intellectual disability and epilepsy

Boschann

Sczakiel

Zhao

et al. 2022

Preprint

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FINCA syndrome is an autosomal recessive inherited multisystemic disorder characterized by pulmonary fibrosis, neurodegeneration and cerebral angiomatosis. So far, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected at least on one allele. Common manifestations comprised pulmonary fibrosis, respiratory distress, developmental delay, muscular hypotonia, dystonia, seizures and brain atrophy, followed mostly by early demise due to progression of disease. Here, we present ten individuals from eight families with an overlapping but static phenotype with much longer survival, associated with seven novel NHLRC2 variants identified by exome analysis. All of the here described patients presented with severe global developmental delay. While seizures and EEG abnormalities were observed as frequent manifestations, eight individuals did not show any signs of pulmonary involvement or distinct MRI abnormalities. Notably, we also present the first seven cases in which the recurrent p.(Asp148Tyr) variant was not detected, neither in homozygous nor in compound heterozygous state. Interestingly, none of these cases presented with the classic FINCA phenotype. However, bioinformatic modeling and analyses could not establish a distinct genotype phenotype correlation. Taken together, our findings broaden the known phenotypic and molecular spectrum and propose that NHLRC2 related disease should also be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy without pulmonary findings.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

FINCA syndrome beyond pulmonary affection: biallelic NHLRC2 variants in eight families with intellectual disability and epilepsy

Boschann

Sczakiel

Zhao

et al. 2022

Preprint

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“…The genetic evolution reflected the expansion and the wider availability of new molecular techniques allowing the study of a panel of genes (next-generation sequencing (NGS) and whole-exome sequencing (WES)) instead of one by one (Sanger sequencing). This led to the discovery of new genetic entities in chILD, such as MARS mutations, other cytosolic aminoacyl-tRNA synthetase (ARS) mutations or OAS1 in pulmonary alveolar proteinosis [29][30][31][32][33], COPA and STING1 mutations for https://doi.org/10.1183/16000617.0188-2022 ILD related to autoinflammatory disorders [34][35][36], and many other even rarer diseases related to mutations in FLNA, TBX4, NHLRC2 or ZNFX1 [25,[37][38][39][40][41].…”

Section: Diagnostic Workup For Childmentioning

confidence: 99%

Diagnostic workup of childhood interstitial lung disease

Nathan

Griese²,

Michel³

et al. 2023

Eur Respir Rev

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Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of “undefined chILD” is stressed.

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“…Since our initial report, more FINCA patients have been diagnosed worldwide ( Brodsky et al, 2020 ; Rapp et al, 2021 ; Badura-Stronka et al, 2022 ). Interstitial lung disease and recurrent infections are pronounced in almost all patients during infancy and can lead to death before the age of 2–3 years.…”

Section: Introductionmentioning

confidence: 99%

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

Tallgren¹,

Kager²,

O’Grady³

et al. 2023

Front. Neurosci.

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PurposeFINCA 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.MethodsThe 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.ResultsOne 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.ConclusionThis 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.

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

Cited by 16 publications

References 11 publications

FINCA syndrome beyond pulmonary affection: biallelic NHLRC2 variants in eight families with intellectual disability and epilepsy

FINCA syndrome beyond pulmonary affection: biallelic NHLRC2 variants in eight families with intellectual disability and epilepsy

Diagnostic workup of childhood interstitial lung disease

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

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