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Classifications

Harrison's Part

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Inheritance

1

Autosomal Recessive HP:0000007

FINCA syndrome is inherited in an autosomal recessive manner due to compound heterozygous or homozygous pathogenic variants in NHLRC2. Complete loss of NHLRC2 is embryonic lethal in mice prior to the morula stage, and affected individuals carry at least one hypomorphic missense allele such as p.Asp148Tyr.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37188825 SUPPORT Human Clinical

"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..."

Confirms autosomal recessive inheritance of FINCA syndrome with biallelic NHLRC2 variants.

PMID:29423877 SUPPORT Model Organism

"Development of the Nhlrc2 null mouse strain stalled before the morula stage."

Demonstrates that complete loss of Nhlrc2 is pre-morula embryonic lethal in mice, explaining why human patients carry at least one hypomorphic missense allele.

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Mechanistic Hypotheses

1

ROS-Induced Caspase-8 Mediated Apoptosis in FINCA Neurodegeneration

ros_caspase8_apoptosis_hypothesis EMERGING

Evidence balance 1 support

In vitro studies in human HCT116 colon carcinoma cells showed that the thioredoxin-like domain of NHLRC2 binds pro-caspase-8, that ROS trigger caspase-8-mediated cleavage of NHLRC2 at Asp580, and that NHLRC2 loss sensitizes cells to ROS-induced apoptosis. While this mechanism has been proposed as a candidate driver of parenchymal and neuronal cell loss in FINCA syndrome, direct demonstration in patient neurons or FINCA animal brain tissue remains to be established.

Pathograph links

Increased Susceptibility to ROS-Induced Caspase-8 Mediated Apoptosis -> Vacuolar Neurodegeneration and Neuronal Depletion Proposed candidate mechanism whereby heightened sensitivity to oxidative stress-induced apoptosis may promote neuronal loss across the cerebral cortex, cerebellum, and spinal cord anterior horns.

Show evidence (1 reference)

PMID:29242562 SUPPORT In Vitro

"We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and..."

Establishes the in vitro interaction between NHLRC2 and pro-caspase-8 and increased susceptibility to ROS-induced apoptosis in HCT116 cells.

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Discussions and Knowledge Gaps

1

What molecular mechanism links biallelic NHLRC2 deficiency to the angiomatosis-like leptomeningeal and superficial cortical vascular proliferation seen on neuropathology in FINCA syndrome?

KNOWLEDGE GAP finca_cerebral_angiomatosis_mechanism_gap

Attached to

pathophysiology#Cerebral Angiomatosis

Although cerebral angiomatosis is one of the defining neuropathological features that gave FINCA syndrome its name (Uusimaa et al., 2018, PMID:29423877), the upstream molecular pathway connecting loss of NHLRC2 to excess small thin-walled leptomeningeal and superficial cortical blood vessels remains uncharacterized. Functional studies to date have focused on fibroblast-to-myofibroblast differentiation, macrophage phagocytosis, and neuronal vesicular trafficking and hnRNP C2 accumulation, leaving the vascular morphogenesis defect as an open mechanistic question.

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Pathophysiology

13

NHLRC2 Structural Destabilization and Protein Depletion

NHLRC2 comprises an N-terminal thioredoxin-like (Trx-like) domain, a six-bladed NHL repeat beta-propeller domain, and a C-terminal beta-stranded domain. Pathogenic missense variants such as p.Asp148Tyr in the Trx-like domain thermally destabilize the protein structure by 2 degrees Celsius and markedly reduce steady-state cellular NHLRC2 protein levels. Combined with null or hypomorphic second alleles, total cellular NHLRC2 falls below critical functional thresholds, with more severe depletion driving early multisystem and pulmonary disease.

fibroblast CL:0000057

NHLRC2 hgnc:24731

protein binding GO:0005515 ↓ DECREASED

Animal models

Nhlrc2-/- (homozygous null) Mus musculus Mus musculus perturbs Complete ablation of Nhlrc2 in mice causes pre-morula embryonic arrest, establishing the requirement for residual NHLRC2 activity.

Downstream

Cytoskeletal and Rho GTPase Signaling Dysregulation Loss of functional NHLRC2 disrupts its interactions with cytoskeleton and RhoA regulators (including p190RhoGAP) and vesicle transport machinery.

Neuronal Vesicular Trafficking Dysfunction Deficiency of functional NHLRC2 in neural progenitor cells and neurons perturbs intracellular vesicular transport.

Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation Deficiency of functional NHLRC2 in neural progenitor cells and hippocampal neurons causes accumulation of the RNA-binding protein isoform hnRNP C2 and perturbed RNA metabolism.

Increased Susceptibility to ROS-Induced Caspase-8 Mediated Apoptosis Loss of NHLRC2 sensitizes cells to reactive oxygen species-induced apoptotic cell death linked to caspase-8 interaction with the thioredoxin-like domain.

Show evidence (4 references)

PMID:30138417 SUPPORT In Vitro

"NHLRC2 contains three domains; an N-terminal thioredoxin-like (Trx-like) domain, followed by a six-bladed NHL repeat containing β-propeller domain and then a C-terminal β-stranded domain."

Defines the three-domain architecture of human NHLRC2.

PMID:30138417 SUPPORT In Vitro

"The Asp148Tyr mutation destabilizes the structure of the protein by 2°C."

Shows thermal destabilization of NHLRC2 by the recurrent p.Asp148Tyr variant.

PMID:30138417 SUPPORT In Vitro

"This in vitro data, taken together with the in vivo data that the D148Y mutation results in a large decrease of NHLRC2 levels in cells derived from patients"

Links structural destabilization to severe depletion of NHLRC2 protein in patient cells.

+ 1 more reference

Cytoskeletal and Rho GTPase Signaling Dysregulation

NHLRC2 regulates cellular organization via actin/vimentin cytoskeleton dynamics, Rho GTPase signaling (through association with p190RhoGAP to modulate RhoA activation), and vesicle-mediated transport. In patient fibroblasts and mutant cells, NHLRC2 deficiency causes abnormal multilamellar bodies, altered vimentin filament organization, and dysregulated Rho GTPase signaling pathways.

fibroblast CL:0000057 macrophage CL:0000235

cytoskeleton organization GO:0007010 ↕ DYSREGULATED vesicle-mediated transport GO:0016192 ↕ DYSREGULATED

Animal models

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote) Mus musculus Mus musculus recapitulates Transcriptomic and interactome comparisons in Nhlrc2^FINCA/- mice identify Rho GTPase signaling dysregulation.

Downstream

Enhanced Fibroblast-to-Myofibroblast Differentiation Altered cytoskeletal organization, vesicle transport, and vimentin/IL-1beta regulation drive excessive fibroblast-to-myofibroblast differentiation.

Macrophage Morphological Defect and Impaired Phagocytosis Disrupted cytoskeletal remodeling prevents filopodia formation and phagocytic cup assembly in macrophages while promoting hyperinflammatory responses.

Show evidence (3 references)

PMID:30239752 SUPPORT In Vitro

"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..."

Shows multilamellar bodies and abnormal vimentin cytoskeleton organization in FINCA patient fibroblasts.

PMID:40510178 SUPPORT Model Organism

"FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells,..."

Identifies Rho GTPase signaling as a conserved pathway disrupted by the FINCA p.Asp148Tyr variant across mouse and human cells.

PMID:37179546 SUPPORT BACKGROUND In Vitro

"In addition, NHLRC2 associates with p190RhoGAP and alters the activation levels of the cytoskeleton regulator RhoA (Haney et al., 2018)."

Connects NHLRC2 association with p190RhoGAP to RhoA cytoskeletal regulation.

Enhanced Fibroblast-to-Myofibroblast Differentiation

Compound heterozygous NHLRC2 mutations promote premature differentiation of fibroblasts into alpha-SMA-positive myofibroblasts and fail to restrain vimentin and IL-1beta expression, driving excessive extracellular matrix and collagen deposition across parenchymal organs.

fibroblast CL:0000057 myofibroblast cell CL:0000186

cell differentiation GO:0030154 ↑ INCREASED extracellular matrix organization GO:0030198 ↕ DYSREGULATED

Animal models

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote) Mus musculus Mus musculus fails to recapitulate Despite markedly decreased NHLRC2 protein levels, Nhlrc2^FINCA/- mice do not develop spontaneous pulmonary or multiorgan fibrosis.

Downstream

Pulmonary Interstitial Fibrosis Excessive myofibroblast differentiation and inflammatory signaling in lung parenchyma drive interstitial pulmonary fibrosis.

Hepatic Fibrosis Excessive myofibroblast activation and collagen deposition in the liver drive hepatic fibrosis alongside steatosis.

Show evidence (2 references)

PMID:30239752 SUPPORT In Vitro

"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..."

Demonstrates that biallelic NHLRC2 mutations cause tissue fibrosis by enhancing fibroblast-to-myofibroblast differentiation.

PMID:39328589 SUPPORT BACKGROUND In Vitro

"Overexpression of NHLRC2 has been shown to decrease the expression levels of vimentin and IL-1β, suggesting that NHLRC2 deficiency may be involved in the mechanism of fibrogenesis by regulating inflammatory pathways (8)."

Links NHLRC2 deficiency to fibrogenesis via failure to suppress vimentin and IL-1beta inflammatory signaling.

Pulmonary Interstitial Fibrosis

Progressive fibrotic remodeling of the pulmonary interstitium accompanied by granuloma-like lung lesions, ground-glass opacities, and pulmonary consolidations, leading to severe infantile interstitial lung disease and hypoxemic respiratory failure.

extracellular matrix organization GO:0030198 ↕ DYSREGULATED

lung UBERON:0002048

Downstream

Pulmonary fibrosis Interstitial collagen deposition directly manifests as clinical and histopathological pulmonary fibrosis.

Abnormal pulmonary interstitial morphology Interstitial fibrotic remodeling produces ground-glass opacities and consolidations on chest imaging.

Respiratory distress Impaired alveolar gas exchange from interstitial lung disease causes tachypnea, hypoxemia, and respiratory distress.

Failure to thrive Chronic hypoxemic respiratory insufficiency increases metabolic demand and impairs postnatal weight gain.

Show evidence (2 references)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents pulmonary interstitial fibrosis and granuloma-like lung lesions in FINCA patients.

PMID:39328589 SUPPORT Human Clinical

"About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."

Documents interstitial lung disease with ground-glass opacities and consolidations in FINCA patients.

Hepatic Fibrosis

Collagen accumulation in the liver parenchyma accompanied by hepatic steatosis, hepatomegaly, and transient liver dysfunction.

liver UBERON:0002107

Downstream

Hepatomegaly Hepatic lipid accumulation and fibrotic remodeling cause liver enlargement.

Hepatic steatosis Disturbed hepatocellular lipid and vesicular homeostasis manifests as hepatic steatosis.

Hepatic fibrosis Hepatic collagen accumulation directly manifests as hepatic fibrosis.

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents hepatomegaly, hepatic steatosis, and collagen accumulation in the liver of FINCA patients.

Neuronal Vesicular Trafficking Dysfunction

In developing neural progenitor cells and neurons, NHLRC2 deficiency disrupts intracellular vesicular trafficking networks and vacuolar homeostasis, creating a predisposition to progressive vacuolar neurodegeneration and myelin loss.

neuron CL:0000540

vesicle-mediated transport GO:0016192 ↕ DYSREGULATED

brain UBERON:0000955

Animal models

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote) Mus musculus Mus musculus recapitulates Proteomic and cellular studies of Nhlrc2^FINCA/- mice demonstrate dysregulated neuronal vesicular trafficking.

Downstream

Vacuolar Neurodegeneration and Neuronal Depletion Impaired neuronal vesicular transport leads to intraneuronal vacuolar degeneration and progressive neuronal loss.

White Matter Myelin Loss and Gliosis Disrupted vesicular trafficking of myelin components impairs myelin maintenance and promotes white matter degeneration.

Show evidence (1 reference)

PMID:33297935 SUPPORT Model Organism

"Collectively, the dysfunction in vesicular trafficking may create a predisposition to neurodegeneration in FINCA disease."

Identifies vesicular trafficking dysfunction as a driver of neurodegenerative vulnerability in FINCA disease.

Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation

In developing neural progenitor cells and adult hippocampal neurons, NHLRC2 dysfunction causes accumulation of the RNA-binding protein isoform hnRNP C2. Perturbed neuronal RNA metabolism and downregulated myelination-associated proteins predispose neurons and white matter to progressive degeneration.

neuron CL:0000540

RNA splicing GO:0008380 ↕ DYSREGULATED

brain UBERON:0000955 Ammon's horn UBERON:0001954

Animal models

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote) Mus musculus Mus musculus recapitulates Nhlrc2^FINCA/- mice exhibit increased hnRNP C2 isoform levels in developing neurons and adult hippocampus.

Downstream

Vacuolar Neurodegeneration and Neuronal Depletion Perturbed neuronal RNA metabolism driven by hnRNP C2 accumulation promotes progressive neuronal degeneration.

White Matter Myelin Loss and Gliosis Altered RNA metabolism and reduced myelination protein expression contribute to white matter myelin loss.

Show evidence (2 references)

PMID:33297935 SUPPORT Model Organism

"Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein."

Shows accumulation of hnRNP C2 in developing neurons and hippocampus in the FINCA mouse model.

PMID:33297935 SUPPORT Model Organism

"The increase in the hnRNP C2 protein in Nhlrc2FINCA/− embryonic NPCs and adult mouse hippocampus suggests a perturbation in overall RNA metabolism, which in turn may contribute to the neurodegeneration seen in FINCA disease."

Connects elevated hnRNP C2 and perturbed RNA metabolism to neurodegeneration in FINCA disease.

Increased Susceptibility to ROS-Induced Caspase-8 Mediated Apoptosis

In human HCT116 colon carcinoma cells, the N-terminal thioredoxin-like domain of NHLRC2 interacts with pro-caspase-8, and reactive oxygen species (ROS) trigger caspase-8-mediated cleavage of NHLRC2 at Asp580. Loss of NHLRC2 increases cellular sensitivity to ROS-induced apoptotic cell death, representing a candidate mechanism that may contribute to parenchymal and neuronal cell loss under oxidative stress.

ROS-Induced Caspase-8 Mediated Apoptosis in FINCA Neurodegeneration

apoptotic process GO:0006915 ↑ INCREASED

Downstream

Vacuolar Neurodegeneration and Neuronal Depletion Proposed candidate mechanism whereby heightened sensitivity to oxidative stress-induced apoptosis may promote neuronal loss across the cerebral cortex, cerebellum, and spinal cord anterior horns.

Show evidence (1 reference)

PMID:29242562 SUPPORT In Vitro

"We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and..."

Demonstrates that NHLRC2 interacts with pro-caspase-8 via its Trx-like domain and that NHLRC2 loss increases susceptibility to ROS-induced apoptosis in HCT116 cells.

Cerebral Angiomatosis

Neuropathology in FINCA syndrome reveals increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion.

brain UBERON:0000955

Downstream

Abnormal cerebral vascular morphology Angiomatosis-like leptomeningeal and cortical hypervascularization directly manifests as abnormal cerebral vascular morphology.

Show evidence (2 references)

PMID:29423877 SUPPORT Human Clinical

"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."

Establishes leptomeningeal, cortical, and superficial white matter angiomatosis as a hallmark neuropathological feature of FINCA syndrome.

PMID:33297935 SUPPORT BACKGROUND Human Clinical

"Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."

Summarizes cerebral angiomatosis among the core neuropathological findings in FINCA patients.

White Matter Myelin Loss and Gliosis

Progressive white matter degeneration in FINCA syndrome characterized by myelin loss, reactive gliosis, delayed myelination, and hypoplasia or atrophy of the corpus callosum.

brain UBERON:0000955

Downstream

Thin corpus callosum Loss of interhemispheric white matter tracts and impaired myelination cause corpus callosum hypoplasia and atrophy.

Spasticity Corticospinal tract white matter demyelination and gliosis produce pyramidal tract signs including spasticity and hyperreflexia.

Gait ataxia Cerebellar and spinocerebellar white matter tract degeneration contributes to wide-based unsteady gait.

Axial hypotonia Central white matter and motor pathway dysfunction contribute to infantile truncal hypotonia.

Show evidence (2 references)

PMID:29423877 SUPPORT Human Clinical

"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."

Demonstrates white matter myelin loss on neuropathology in FINCA patients.

PMID:33297935 SUPPORT BACKGROUND Human Clinical

"Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."

Summarizes white matter myelin loss with gliosis in FINCA patients.

Vacuolar Neurodegeneration and Neuronal Depletion

Progressive vacuolar degeneration and neuronal depletion across the cerebral cortex, cerebellum, and spinal cord anterior horns, resulting in progressive cerebral and cerebellar atrophy and severe neurodevelopmental impairment.

neuron CL:0000540

brain UBERON:0000955 cerebellum UBERON:0002037 spinal cord UBERON:0002240

Downstream

Cerebral atrophy Progressive cortical and subcortical neuronal loss manifests as cerebral and cerebellar atrophy on neuroimaging.

Microcephaly Impaired brain growth and progressive neurodegeneration result in postnatal microcephaly.

Global developmental delay Widespread cortical and cerebellar neuronal dysfunction causes severe global developmental delay.

Intellectual disability Cerebral cortical and hippocampal neuronal pathology leads to moderate to severe intellectual disability.

Developmental regression Ongoing vacuolar neurodegeneration drives loss of previously acquired speech and motor skills in childhood.

Seizure Cortical neuronal degeneration and gliosis create epileptogenic networks causing focal and generalized seizures.

Dystonia Subcortical and extrapyramidal neuronal involvement causes dystonia and hyperkinetic movement disorders.

Atypical behavior Frontotemporal and limbic neuronal dysfunction manifests as aggression outbursts, irritability, and attention deficit.

Gait ataxia Cerebellar and spinal cord neuronal depletion impairs motor coordination and gait.

Axial hypotonia Spinal cord anterior horn neuronal depletion and central motor dysfunction cause truncal hypotonia.

Show evidence (3 references)

PMID:29423877 SUPPORT Human Clinical

"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."

Establishes vacuolar degeneration and neuronal degeneration in FINCA syndrome.

PMID:33297935 SUPPORT BACKGROUND Human Clinical

"Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."

Summarizes brain atrophy, vacuolar neurodegeneration, and anterior horn neuronal depletion in FINCA patients.

PMID:37179546 SUPPORT Human Clinical

"Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."

Confirms progressive general cerebral and cerebellar atrophy in surviving adolescents.

Macrophage Morphological Defect and Impaired Phagocytosis

NHLRC2 interacts with FRYL, EIF2AK2, and KLHL13 during macrophage differentiation. Loss of NHLRC2 yields smaller macrophages lacking filopodia and membrane ruffling that fail to form phagocytic cups or engulf bacteria, accompanied by a hyperinflammatory phenotype and altered interferon-gamma innate immune responses. This predisposes individuals to recurrent respiratory and systemic infections.

macrophage CL:0000235

phagocytosis GO:0006909 ↓ DECREASED

Downstream

Recurrent respiratory infections Defective macrophage bacterial phagocytosis and dysregulated innate immune signaling predispose patients to recurrent respiratory tract infections.

Show evidence (2 references)

PMID:31594818 SUPPORT In Vitro

"Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL,..."

Demonstrates that NHLRC2 loss in human macrophages causes hyperinflammation and inability to phagocytose bacteria.

PMID:31594818 SUPPORT In Vitro

"Compared with WT macrophages, NHLRC2 mutant macrophages were smaller and lacked filopodia. In the presence of Salmonella, WT macrophages displayed increased membrane ruffling and engaged with Salmonella to form phagocytic cups, but the NHLRC2 mutant macrophage cell surface remained smooth and..."

Shows loss of filopodia, membrane ruffling, and phagocytic cup formation in NHLRC2-deficient macrophages.

Dyserythropoiesis and Multinucleated Erythroblast Formation

Bone marrow aspirates in affected infants show increased erythropoiesis and dyserythropoiesis with marked bi- and multinuclearity of erythroblasts resembling congenital dyserythropoietic anemia type II, accompanied by transfusion-dependent infantile macrocytic anemia.

erythroblast CL:0000765 erythrocyte CL:0000232

erythrocyte differentiation GO:0030218 ↕ DYSREGULATED

bone marrow UBERON:0002371

Downstream

Macrocytic anemia Ineffective erythropoiesis and disordered erythroid maturation produce infantile macrocytic anemia.

Multinucleated erythroblast Dyserythropoiesis directly manifests as bi- and multinucleated erythroblasts in the bone marrow.

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Documents bone marrow dyserythropoiesis with bi- and multinucleated erythroblasts and transfusion-dependent macrocytic anemia in FINCA patients.

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Histopathology

1

Pulmonary Granuloma-Like Lesions OCCASIONAL

Lung autopsy and biopsy specimens from infants with fatal cerebropulmonary FINCA syndrome show interstitial fibrosis accompanied by previously undescribed granuloma-like lesions in the lungs.

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents previously undescribed granuloma-like lesions alongside interstitial fibrosis in the lungs of FINCA patients.

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Pathograph

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Phenotypes

27

Blood 4

Macrocytic anemia FREQUENT HP:0001972

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Demonstrates macrocytic anemia in 5/5 patients of the series, with 4/5 requiring red blood cell transfusions in infancy.

Chronic hemolytic anemia OCCASIONAL HP:0004870

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."

Identifies chronic hemolytic anemia as one of the main clinical features in classic FINCA syndrome.

Multinucleated erythroblast OCCASIONAL HP:0034278

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Documents marked bi- and multinuclearity of erythroblasts on bone marrow aspirate in two patients.

Decreased circulating immunoglobulin concentration OCCASIONAL HP:0004313

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Documents decreased immunoglobulin levels in 2 of 5 patients in the cohort.

Cardiovascular 1

Abnormal cerebral vascular morphology OCCASIONAL HP:0100659

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"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."

Describes the defining cerebral angiomatosis (leptomeningeal, cortical, and superficial white matter hypervascularization and congestion).

Digestive 4

Hepatomegaly OCCASIONAL HP:0002240

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents hepatomegaly, hepatic steatosis, and liver collagen accumulation in affected children.

Hepatic steatosis OCCASIONAL HP:0001397

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents hepatic steatosis at autopsy in affected children.

Hepatic fibrosis OCCASIONAL HP:0001395

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Documents collagen accumulation in the liver of FINCA patients.

Malabsorption OCCASIONAL HP:0002024

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."

Documents malabsorption as one of the main infantile clinical features of FINCA syndrome.

Head and Neck 1

Microcephaly OCCASIONAL HP:0000252

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."

Documents microcephaly (SD below -2) in 4/15 patients.

Immune 1

Recurrent respiratory infections FREQUENT HP:0002205

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"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."

Identifies recurrent infections as a core clinical feature alongside neurodevelopmental delay and macrocytic anemia.

Musculoskeletal 2

Axial hypotonia VERY_FREQUENT HP:0008936

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait...."

Documents truncal hypotonia in 12/15 (80%) individuals.

Spasticity OCCASIONAL HP:0001257

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait...."

Documents spasticity or hyperreflexia in 4 of 15 individuals in the cohort.

Nervous System 9

Global developmental delay OBLIGATE HP:0001263

Show evidence (2 references)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression..."

Demonstrates universal global developmental delay (15/15 individuals) and severe expressive language impairment in the 15-patient cohort.

PMID:39328589 SUPPORT Human Clinical

"Among the 31 FINCA patients, including our newly reported patients, 14 patients (45.2%) were boys (1, 10–14). All FINCA patients experienced neurological symptoms including developmental delay, intellectual disability, behavior problems, movement disorder, hypotonia, dystonia, and seizures, among others"

Confirms that neurological symptoms including developmental delay occur across all 31 reviewed FINCA patients.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression..."

Documents moderate to severe intellectual disability in all 15 individuals of the cohort.

PMID:35255187 SUPPORT Human Clinical

"The clinical characteristics included intellectual disability with severely retarded speech expression, relatively preserved speech comprehension, and behavior problems. The last symptom combined aggression outbursts, attention deficit, and irritability."

Characterizes the cognitive and language profile in survivors into late childhood.

Seizure FREQUENT HP:0001250

Show evidence (2 references)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait...."

Reports seizures in 11/15 (73%) patients with onset between 9 months and 13 years.

PMID:35255187 SUPPORT Human Clinical

"Two girls have epilepsy with focal and generalized seizures that are not frequent however, may lead to status epilepticus."

Shows that focal and generalized seizures in FINCA survivors can lead to status epilepticus.

Atypical behavior FREQUENT HP:0000708

Show evidence (1 reference)

PMID:35255187 SUPPORT Human Clinical

"The clinical characteristics included intellectual disability with severely retarded speech expression, relatively preserved speech comprehension, and behavior problems. The last symptom combined aggression outbursts, attention deficit, and irritability."

Defines the behavioral phenotype combining aggression outbursts, attention deficit, and irritability.

Gait ataxia FREQUENT HP:0002066

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait...."

Documents unsteady, wide gait in 5/15 individuals and inability to walk in 5/15 individuals.

Developmental regression OCCASIONAL HP:0002376

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression..."

Documents speech regression in 4/15 patients and motor regression in 2/15 patients.

Dystonia OCCASIONAL HP:0001332

Show evidence (1 reference)

PMID:39328589 SUPPORT Human Clinical

"Among the 31 FINCA patients, including our newly reported patients, 14 patients (45.2%) were boys (1, 10–14). All FINCA patients experienced neurological symptoms including developmental delay, intellectual disability, behavior problems, movement disorder, hypotonia, dystonia, and seizures, among others"

Lists dystonia and movement disorders among the neurological manifestations of FINCA syndrome.

Cerebral atrophy FREQUENT HP:0002059

Show evidence (2 references)

PMID:37179546 SUPPORT Human Clinical

"Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."

Demonstrates severe progressive cerebral and cerebellar atrophy on brain MRI.

PMID:37188825 SUPPORT Human Clinical

"Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."

Documents cortical atrophy, dilated ventricles, and delayed myelination on MRI in 5 of 11 imaged individuals.

Thin corpus callosum FREQUENT HP:0033725

Show evidence (2 references)

PMID:37179546 SUPPORT Human Clinical

"Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."

Documents atrophy of the corpus callosum on brain MRI.

PMID:37188825 SUPPORT Human Clinical

"Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."

Reports corpus callosum hypoplasia on brain MRI.

Respiratory 3

Abnormal pulmonary interstitial morphology FREQUENT HP:0006530

Show evidence (2 references)

PMID:34165204 SUPPORT Human Clinical

"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..."

Shows pronounced infantile interstitial lung disease that stabilizes in surviving children.

PMID:39328589 SUPPORT Human Clinical

"About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."

Quantifies respiratory involvement (~50% of 31 patients) and chest CT-confirmed ILD (9/11 scanned patients) with ground-glass opacities and consolidations.

Pulmonary fibrosis FREQUENT HP:0002206

Show evidence (1 reference)

PMID:29423877 SUPPORT Human Clinical

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."

Demonstrates interstitial pulmonary fibrosis and granuloma-like lesions on lung histopathology.

Respiratory distress FREQUENT HP:0002098

Show evidence (1 reference)

PMID:39328589 SUPPORT Human Clinical

"About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."

Documents tachypnea, hypoxemia, and respiratory distress in approximately half of the 31 FINCA patients.

Growth 2

Failure to thrive FREQUENT HP:0001508

Show evidence (2 references)

PMID:29423877 SUPPORT Human Clinical

"The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."

Identifies progressive growth failure and malabsorption as core features in infantile FINCA syndrome.

PMID:37188825 SUPPORT Human Clinical

"At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."

Documents decreased body weight in 9/15 individuals and short stature in 7/15 individuals.

Short stature FREQUENT HP:0004322

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."

Documents short stature in 7/15 (47%) individuals.

🧬

Genetic Associations

1

NHLRC2 (Pathogenic Biallelic Variants)

Gene: NHLRC2 hgnc:24731

Show evidence (3 references)

PMID:29423877 SUPPORT Human Clinical

"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."

Identifies the original compound heterozygous NHLRC2 variants (p.Asp148Tyr and p.Arg201GlyfsTer6) causing FINCA syndrome.

PMID:32435055 SUPPORT Human Clinical

"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..."

Documents compound heterozygosity for p.Asp148Tyr and p.His143Pro in the conserved N-terminal Trx-like domain.

PMID:37188825 SUPPORT Human Clinical

"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..."

Expands the allelic spectrum of FINCA syndrome with nine novel NHLRC2 variants across 12 families.

💊

Medical Actions

4

Systemic Corticosteroid Therapy

Action: Systemic Corticosteroid Therapy NCIT:C122080

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Long-term systemic glucocorticoid therapy can improve respiratory symptoms, chest CT findings, and serum KL-6 levels in patients with FINCA-associated interstitial lung disease.

Mechanism Target:

Pulmonary Interstitial Fibrosis — Suppresses pulmonary interstitial inflammation and fibrotic disease activity in FINCA-associated interstitial lung disease.

Target Phenotypes: Abnormal pulmonary interstitial morphology HP:0006530 Pulmonary fibrosis HP:0002206 Respiratory distress HP:0002098

Show evidence (1 reference)

PMID:39328589 SUPPORT Human Clinical

"The elder brother died of infantile respiratory failure, while the younger brother showed improvement in respiratory symptoms, chest CT, and Krebs von den Lungen-6 levels after long-term systemic glucocorticoid therapy, indicating that anti-inflammatory treatment may be beneficial in the..."

Demonstrates clinical, radiological, and biomarker (KL-6) improvement of FINCA-associated ILD with long-term systemic glucocorticoid therapy.

Packed Red Blood Cell Transfusion

Action: Packed Red Blood Cell Transfusion NCIT:C15409

Red blood cell transfusions are frequently required during infancy to manage severe macrocytic and dyserythropoietic anemia.

Target Phenotypes: Macrocytic anemia HP:0001972 Chronic hemolytic anemia HP:0004870

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Documents the requirement for red blood cell transfusions during infancy in 4 of 5 patients with FINCA-associated macrocytic anemia.

Intravenous Immunoglobulin Therapy

Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Immunoglobulin replacement therapy and additional vaccinations (such as pneumococcal vaccine and varicella immunoglobulin) are recommended when humoral immunodeficiency is detected.

Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313 Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Immunoglobulin treatment and additional vaccinations (e.g., pneumococcal vaccine and varicella immunoglobulin) and antibiotic prophylaxis (for pneumocystis carinii, etc.) are recommended if immunodeficiency is detected."

Recommends immunoglobulin replacement and targeted vaccinations for FINCA patients with immunodeficiency.

Antibiotic Prophylaxis

Action: Antibiotic Prophylaxis NCIT:C51993

Platform: Small molecule

Antibiotic prophylaxis (including prophylaxis against Pneumocystis jirovecii and bacterial respiratory pathogens) is recommended in FINCA patients with immunodeficiency and recurrent infections.

Target Phenotypes: Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Immunoglobulin treatment and additional vaccinations (e.g., pneumococcal vaccine and varicella immunoglobulin) and antibiotic prophylaxis (for pneumocystis carinii, etc.) are recommended if immunodeficiency is detected."

Recommends antibiotic prophylaxis in FINCA patients with immunodeficiency and recurrent infections.

🔬

Biochemical Markers

3

Reduced Cellular NHLRC2 Protein Level (DECREASED)

Context: Patient-derived fibroblasts and peripheral blood cells

Show evidence (2 references)

PMID:29423877 SUPPORT Human Clinical

"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."

Demonstrates low cellular NHLRC2 protein levels in patient-derived fibroblasts.

PMID:37188825 SUPPORT Human Clinical

"Studying different non-truncating variants and linking their effects on NHLRC2 protein levels revealed a putative genotype-phenotype correlation: variants leading to severely reduced protein levels (either in homozygous or in compound-heterozygous state with another severe missense or..."

Establishes cellular NHLRC2 protein dosage as a biochemical correlate of respiratory disease severity.

Serum Krebs von den Lungen-6 (KL-6) (ELEVATED)

Context: Interstitial lung disease activity and treatment monitoring

Show evidence (1 reference)

PMID:39328589 SUPPORT Human Clinical

"The elder brother died of infantile respiratory failure, while the younger brother showed improvement in respiratory symptoms, chest CT, and Krebs von den Lungen-6 levels after long-term systemic glucocorticoid therapy, indicating that anti-inflammatory treatment may be beneficial in the..."

Documents serum Krebs von den Lungen-6 (KL-6) as a biomarker responsive to systemic glucocorticoid therapy in FINCA-related ILD.

Serum Immunoglobulins (DECREASED)

Context: Humoral immune evaluation

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Confirms decreased serum immunoglobulin levels in two of five patients evaluated.

🔬

Diagnosis

4

Whole Exome Sequencing (Confirmatory)

Molecular genetic testing via whole-exome or genome sequencing to identify biallelic pathogenic variants in NHLRC2 is the definitive diagnostic method and is recommended for infants and children presenting with cerebropulmonary manifestations or infantile-onset epileptic encephalopathies.

Whole Exome Sequencing NCIT:C101295

Results: Identification of homozygous or compound heterozygous pathogenic variants in NHLRC2.

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Based on the current knowledge on the phenotypic spectrum of FINCA disease, we recommend considering WES analysis for patients with a history of infantile-onset cerebropulmonary manifestations as well as infantile-onset epileptic encephalopathies without pulmonary manifestations."

Recommends whole-exome sequencing for suspected FINCA syndrome across both cerebropulmonary and isolated neurological presentations.

Chest Computed Tomography (Supportive)

High-resolution chest computed tomography to evaluate infantile interstitial lung disease, typically demonstrating ground-glass opacities and pulmonary consolidations.

Chest Computed Tomography NCIT:C191501

Results: Ground-glass opacities (GGOs) and pulmonary consolidations consistent with interstitial lung disease.

Show evidence (1 reference)

PMID:39328589 SUPPORT Human Clinical

"About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."

Establishes chest CT findings of ground-glass opacities and pulmonary consolidations in 9 of 11 scanned FINCA patients.

Brain Magnetic Resonance Imaging (Supportive)

Brain MRI to evaluate structural and neurodegenerative abnormalities, which may reveal corpus callosum hypoplasia or atrophy, dilated ventricles, delayed myelination, and progressive cerebral and cerebellar atrophy.

Magnetic Resonance Imaging NCIT:C16809

Results: Corpus callosum hypoplasia/atrophy, dilated ventricles, delayed myelination, and cortical/cerebellar atrophy.

Show evidence (1 reference)

PMID:37188825 SUPPORT Human Clinical

"Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."

Details characteristic brain MRI abnormalities in FINCA syndrome.

Bone Marrow Aspiration (Supportive)

Bone marrow aspiration in patients with severe infantile macrocytic anemia to assess for dyserythropoiesis and multinucleated erythroblasts.

Bone Marrow Aspiration NCIT:C15644

Results: Increased erythropoiesis or dyserythropoiesis with marked bi- and multinuclearity of erythroblasts and eosinophilia.

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils..."

Describes bone marrow aspirate findings of dyserythropoiesis and bi-/multinucleated erythroblasts in FINCA patients.

📈

Progression

1

Onset

Age: Infancy to childhood (2 months to 13 years)

Severe multisystem cases present around 2 months of age with progressive cerebropulmonary symptoms, anemia, and failure to thrive. Seizure onset ranges from 9 months to 13 years, and mortality is concentrated before age 3 years (overall mortality 25.8% across 31 patients, rising to 77.8% among the 9 patients with interstitial lung disease), whereas survivors range from 4 to 61 years of age with neurodevelopmental delay and progressive cerebral and cerebellar atrophy.

Show evidence (3 references)

PMID:29423877 SUPPORT Human Clinical

"The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."

Describes early infantile multisystem presentation of classic FINCA syndrome.

PMID:37179546 SUPPORT Human Clinical

"Combining the clinical features of our five novel patients with the previously described 13 patients (Uusimaa et al., 2018; Brodsky et al., 2020; Rapp et al., 2021; Badura-Stronka et al., 2022) reveals the following: 10 patients have been reported as being alive (age between 4 and 61 years at..."

Documents survival into adulthood (4 to 61 years) alongside infant/early-childhood mortality (10 months to 2 years 5 months).

PMID:39328589 SUPPORT Human Clinical

"The overall mortality rate among 31 FINCA patients is 25.8%, whereas the mortality rate for those 9 patients with comorbid ILD is significantly higher at 77.8%. All deceased children died before the age of 3 (1, 10–14)."

Establishes overall mortality (25.8%) and elevated mortality in patients with comorbid interstitial lung disease (77.8%), with all deaths occurring before age 3.

📊

Prevalence

1

Global published cases

Cases In Literature Ultra Rare

Ultra-rare disorder with 33 patients from various ethnic backgrounds reported in the literature following its initial characterization.

Show evidence (1 reference)

PMID:40510178 SUPPORT BACKGROUND Human Clinical

"Since our initial characterisation, 33 patients from various ethnic backgrounds have been reported with different combinations of recessive pathogenic variants in NHLRC2 broadening the phenotypic spectrum of the disease"

Documents 33 reported patients globally with biallelic NHLRC2 variants.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Fibrosis, Neurodegeneration, and Cerebral Angiomatosis:

Congenital Dyserythropoietic Anemia Type II Not Yet Curated MONDO:0009134

Overlapping Features Infants with FINCA syndrome may initially present with severe macrocytic anemia and bone marrow bi- and multinucleated erythroblasts mimicking congenital dyserythropoietic anemia type II (CDA II); distinguished by multisystem neurodevelopmental and pulmonary involvement and biallelic NHLRC2 variants rather than SEC23B mutations.

Distinguishing Features

Progressive neurodevelopmental delay, hypotonia, and seizures
Infantile interstitial lung disease
Biallelic pathogenic variants in NHLRC2 on exome sequencing

Show evidence (1 reference)

PMID:37179546 SUPPORT Human Clinical

"In patient six, the initial lead-pathologies were severe anemia associated with feeding problems, failure to thrive and muscular hypotonia; hence, hematologists should keep ultra-orphan diseases like CDAs, FINCA syndrome and CAD-associated uridine responsive epileptic encephalopathy in the..."

Highlights congenital dyserythropoietic anemias (CDAs) as a key differential diagnosis for FINCA syndrome presenting with severe infantile macrocytic anemia.

🐁

Animal Models

2

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote) Mus musculus

Compound heterozygous FINCA mouse model carrying the patient-equivalent missense variant p.Asp148Tyr combined with a null allele. Mice are viable and exhibit adolescent hyperactivity, decreased exploration of novel objects, altered innate immune interferon-gamma responses, dysregulated Rho GTPase signaling, vesicular trafficking defects, and accumulation of hnRNP C2 in developing neurons and adult female hippocampus.

Species

Mus musculus

Genotype

Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote)

Pathograph links

Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation recapitulates fidelity: high observes: tissue Nhlrc2^FINCA/- mice exhibit increased hnRNP C2 isoform levels in developing neurons and adult hippocampus.

Neuronal Vesicular Trafficking Dysfunction recapitulates fidelity: moderate observes: cellular Proteomic and cellular studies of Nhlrc2^FINCA/- mice demonstrate dysregulated neuronal vesicular trafficking.

Cytoskeletal and Rho GTPase Signaling Dysregulation recapitulates fidelity: moderate observes: cellular Transcriptomic and interactome comparisons in Nhlrc2^FINCA/- mice identify Rho GTPase signaling dysregulation.

Enhanced Fibroblast-to-Myofibroblast Differentiation fails to recapitulate Despite markedly decreased NHLRC2 protein levels, Nhlrc2^FINCA/- mice do not develop spontaneous pulmonary or multiorgan fibrosis.

Limitations: Despite markedly reduced NHLRC2 protein levels across tissues, Nhlrc2^FINCA/- mice do not spontaneously develop the severe early-onset multiorgan fibrosis, interstitial lung disease, or fatal neurodegeneration characteristic of human FINCA syndrome.

Show evidence (1 reference)

PMID:33297935 SUPPORT Model Organism

"Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex."

Documents that Nhlrc2^FINCA/- mice fail to recapitulate spontaneous severe early-onset multiorgan fibrosis/disease despite markedly reduced NHLRC2 levels.

Show evidence (3 references)

PMID:33297935 SUPPORT Model Organism

"Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex."

Documents that Nhlrc2^FINCA/- mice do not develop spontaneous severe early-onset multiorgan disease despite markedly reduced NHLRC2 levels.

PMID:33297935 SUPPORT Model Organism

"Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein."

Demonstrates hnRNP C2 accumulation in developing neurons and adult hippocampus of FINCA mice.

PMID:40510178 SUPPORT Model Organism

"FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells,..."

Characterizes behavioral, innate immune, and Rho GTPase signaling phenotypes in FINCA mice.

Nhlrc2-/- (homozygous null) Mus musculus

Homozygous Nhlrc2 null mouse embryos arrest prior to the morula stage, demonstrating that complete loss of NHLRC2 is embryonic lethal.

Species

Mus musculus

Genotype

Nhlrc2-/- (homozygous null)

Pathograph links

NHLRC2 Structural Destabilization and Protein Depletion perturbs fidelity: moderate observes: organism Complete ablation of Nhlrc2 in mice causes pre-morula embryonic arrest, establishing the requirement for residual NHLRC2 activity.

Show evidence (1 reference)

PMID:29423877 SUPPORT Model Organism

"Development of the Nhlrc2 null mouse strain stalled before the morula stage."

Demonstrates pre-morula embryonic lethality in homozygous Nhlrc2 null mice.

{ }

Source YAML

click to show

name: Fibrosis, Neurodegeneration, and Cerebral Angiomatosis
creation_date: "2026-10-14T00:00:00Z"
description: >-
  Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA syndrome) is an
  autosomal recessive multisystem disorder caused by biallelic pathogenic variants
  in NHLRC2. Affected individuals present with variable combinations of
  infantile-onset interstitial lung disease, global developmental delay,
  intellectual disability, hypotonia, seizures, movement disorders, progressive
  cerebral and cerebellar atrophy, cerebral angiomatosis, macrocytic or
  dyserythropoietic anemia, hepatomegaly with hepatic steatosis and fibrosis,
  recurrent infections, and growth failure. While early-onset respiratory failure
  can be fatal in infancy or early childhood, individuals with higher residual
  NHLRC2 protein levels often stabilize respiratory symptoms or present with a
  predominantly neurodevelopmental phenotype surviving into childhood or adulthood.
category: Genetic
parents:
  - Autosomal Recessive Disease
  - Multisystem Disorder
  - Neurodegenerative Disease
synonyms:
  - FINCA syndrome
  - FINCA disease
  - Fibrosis, neurodegeneration, and cerebral angiomatosis
disease_term:
  preferred_term: fibrosis, neurodegeneration, and cerebral angiomatosis
  term:
    id: MONDO:0032651
    label: fibrosis, neurodegeneration, and cerebral angiomatosis
classifications:
  harrisons_chapter:
    - classification_value: NEUROLOGIC
    - classification_value: RESPIRATORY
    - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
  - name: Autosomal Recessive
    description: >-
      FINCA syndrome is inherited in an autosomal recessive manner due to
      compound heterozygous or homozygous pathogenic variants in NHLRC2.
      Complete loss of NHLRC2 is embryonic lethal in mice prior to the morula
      stage, and affected individuals carry at least one hypomorphic missense
      allele such as p.Asp148Tyr.
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Confirms autosomal recessive inheritance of FINCA syndrome with biallelic NHLRC2 variants.
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Development of the Nhlrc2 null mouse strain stalled before the morula stage."
        explanation: Demonstrates that complete loss of Nhlrc2 is pre-morula embryonic lethal in mice, explaining why human patients carry at least one hypomorphic missense allele.
prevalence:
  - population: Global published cases
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >-
      Ultra-rare disorder with 33 patients from various ethnic backgrounds
      reported in the literature following its initial characterization.
    evidence:
      - reference: PMID:40510178
        reference_title: "Altered behaviour and immune response in mice with NHLRC2 p.Asp148Tyr variant."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        quote_role: BACKGROUND
        snippet: "Since our initial characterisation, 33 patients from various ethnic backgrounds have been reported with different combinations of recessive pathogenic variants in NHLRC2 broadening the phenotypic spectrum of the disease"
        explanation: Documents 33 reported patients globally with biallelic NHLRC2 variants.
progression:
  - phase: Onset
    age_range: Infancy to childhood (2 months to 13 years)
    notes: >-
      Severe multisystem cases present around 2 months of age with progressive
      cerebropulmonary symptoms, anemia, and failure to thrive. Seizure onset
      ranges from 9 months to 13 years, and mortality is concentrated before
      age 3 years (overall mortality 25.8% across 31 patients, rising to 77.8%
      among the 9 patients with interstitial lung disease), whereas survivors
      range from 4 to 61 years of age with neurodevelopmental delay and
      progressive cerebral and cerebellar atrophy.
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."
        explanation: Describes early infantile multisystem presentation of classic FINCA syndrome.
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Combining the clinical features of our five novel patients with the previously described 13 patients (Uusimaa et al., 2018; Brodsky et al., 2020; Rapp et al., 2021; Badura-Stronka et al., 2022) reveals the following: 10 patients have been reported as being alive (age between 4 and 61 years at the time of the publication), while eight were deceased (age at death between 10 months and 2 years, 5 months)."
        explanation: Documents survival into adulthood (4 to 61 years) alongside infant/early-childhood mortality (10 months to 2 years 5 months).
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The overall mortality rate among 31 FINCA patients is 25.8%, whereas the mortality rate for those 9 patients with comorbid ILD is significantly higher at 77.8%. All deceased children died before the age of 3 (1, 10–14)."
        explanation: Establishes overall mortality (25.8%) and elevated mortality in patients with comorbid interstitial lung disease (77.8%), with all deaths occurring before age 3.
pathophysiology:
  - name: NHLRC2 Structural Destabilization and Protein Depletion
    description: >-
      NHLRC2 comprises an N-terminal thioredoxin-like (Trx-like) domain, a
      six-bladed NHL repeat beta-propeller domain, and a C-terminal beta-stranded
      domain. Pathogenic missense variants such as p.Asp148Tyr in the Trx-like
      domain thermally destabilize the protein structure by 2 degrees Celsius and
      markedly reduce steady-state cellular NHLRC2 protein levels. Combined with
      null or hypomorphic second alleles, total cellular NHLRC2 falls below
      critical functional thresholds, with more severe depletion driving early
      multisystem and pulmonary disease.
    genes:
      - preferred_term: NHLRC2
        term:
          id: hgnc:24731
          label: NHLRC2
    molecular_functions:
      - preferred_term: protein binding
        modifier: DECREASED
        term:
          id: GO:0005515
          label: protein binding
    cell_types:
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
    evidence:
      - reference: PMID:30138417
        reference_title: "Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "NHLRC2 contains three domains; an N-terminal thioredoxin-like (Trx-like) domain, followed by a six-bladed NHL repeat containing β-propeller domain and then a C-terminal β-stranded domain."
        explanation: Defines the three-domain architecture of human NHLRC2.
      - reference: PMID:30138417
        reference_title: "Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The Asp148Tyr mutation destabilizes the structure of the protein by 2°C."
        explanation: Shows thermal destabilization of NHLRC2 by the recurrent p.Asp148Tyr variant.
      - reference: PMID:30138417
        reference_title: "Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "This in vitro data, taken together with the in vivo data that the D148Y mutation results in a large decrease of NHLRC2 levels in cells derived from patients"
        explanation: Links structural destabilization to severe depletion of NHLRC2 protein in patient cells.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Studying different non-truncating variants and linking their effects on NHLRC2 protein levels revealed a putative genotype-phenotype correlation: variants leading to severely reduced protein levels (either in homozygous or in compound-heterozygous state with another severe missense or frameshift/nonsense variant) were associated with an early onset multisystem phenotype including pulmonary disease. When the sum of NHLRC2 protein levels from both alleles appears to exceed a certain critical level, a phenotype without progressive respiratory symptoms was observed"
        explanation: Demonstrates that residual NHLRC2 protein dosage governs whether pulmonary and multisystem pathology develops.
    downstream:
      - target: Cytoskeletal and Rho GTPase Signaling Dysregulation
        description: >-
          Loss of functional NHLRC2 disrupts its interactions with cytoskeleton
          and RhoA regulators (including p190RhoGAP) and vesicle transport
          machinery.
      - target: Neuronal Vesicular Trafficking Dysfunction
        description: >-
          Deficiency of functional NHLRC2 in neural progenitor cells and neurons
          perturbs intracellular vesicular transport.
      - target: Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation
        description: >-
          Deficiency of functional NHLRC2 in neural progenitor cells and
          hippocampal neurons causes accumulation of the RNA-binding protein
          isoform hnRNP C2 and perturbed RNA metabolism.
      - target: Increased Susceptibility to ROS-Induced Caspase-8 Mediated Apoptosis
        description: >-
          Loss of NHLRC2 sensitizes cells to reactive oxygen species-induced
          apoptotic cell death linked to caspase-8 interaction with the
          thioredoxin-like domain.

  - name: Cytoskeletal and Rho GTPase Signaling Dysregulation
    description: >-
      NHLRC2 regulates cellular organization via actin/vimentin cytoskeleton
      dynamics, Rho GTPase signaling (through association with p190RhoGAP to
      modulate RhoA activation), and vesicle-mediated transport. In patient
      fibroblasts and mutant cells, NHLRC2 deficiency causes abnormal
      multilamellar bodies, altered vimentin filament organization, and
      dysregulated Rho GTPase signaling pathways.
    cell_types:
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
      - preferred_term: macrophage
        term:
          id: CL:0000235
          label: macrophage
    biological_processes:
      - preferred_term: cytoskeleton organization
        modifier: DYSREGULATED
        term:
          id: GO:0007010
          label: cytoskeleton organization
      - preferred_term: vesicle-mediated transport
        modifier: DYSREGULATED
        term:
          id: GO:0016192
          label: vesicle-mediated transport
    evidence:
      - reference: PMID:30239752
        reference_title: "Biallelic mutations in human NHLRC2 enhance myofibroblast differentiation in FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "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."
        explanation: Shows multilamellar bodies and abnormal vimentin cytoskeleton organization in FINCA patient fibroblasts.
      - reference: PMID:40510178
        reference_title: "Altered behaviour and immune response in mice with NHLRC2 p.Asp148Tyr variant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells, we identified Rho GTPase signalling as a common affected pathway."
        explanation: Identifies Rho GTPase signaling as a conserved pathway disrupted by the FINCA p.Asp148Tyr variant across mouse and human cells.
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: BACKGROUND
        snippet: "In addition, NHLRC2 associates with p190RhoGAP and alters the activation levels of the cytoskeleton regulator RhoA (Haney et al., 2018)."
        explanation: Connects NHLRC2 association with p190RhoGAP to RhoA cytoskeletal regulation.
    downstream:
      - target: Enhanced Fibroblast-to-Myofibroblast Differentiation
        description: >-
          Altered cytoskeletal organization, vesicle transport, and vimentin/IL-1beta
          regulation drive excessive fibroblast-to-myofibroblast differentiation.
      - target: Macrophage Morphological Defect and Impaired Phagocytosis
        description: >-
          Disrupted cytoskeletal remodeling prevents filopodia formation and
          phagocytic cup assembly in macrophages while promoting hyperinflammatory
          responses.

  - name: Enhanced Fibroblast-to-Myofibroblast Differentiation
    description: >-
      Compound heterozygous NHLRC2 mutations promote premature differentiation
      of fibroblasts into alpha-SMA-positive myofibroblasts and fail to restrain
      vimentin and IL-1beta expression, driving excessive extracellular matrix
      and collagen deposition across parenchymal organs.
    cell_types:
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
      - preferred_term: myofibroblast cell
        term:
          id: CL:0000186
          label: myofibroblast cell
    biological_processes:
      - preferred_term: cell differentiation
        modifier: INCREASED
        term:
          id: GO:0030154
          label: cell differentiation
      - preferred_term: extracellular matrix organization
        modifier: DYSREGULATED
        term:
          id: GO:0030198
          label: extracellular matrix organization
    evidence:
      - reference: PMID:30239752
        reference_title: "Biallelic mutations in human NHLRC2 enhance myofibroblast differentiation in FINCA disease."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "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."
        explanation: Demonstrates that biallelic NHLRC2 mutations cause tissue fibrosis by enhancing fibroblast-to-myofibroblast differentiation.
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: BACKGROUND
        snippet: "Overexpression of NHLRC2 has been shown to decrease the expression levels of vimentin and IL-1β, suggesting that NHLRC2 deficiency may be involved in the mechanism of fibrogenesis by regulating inflammatory pathways (8)."
        explanation: Links NHLRC2 deficiency to fibrogenesis via failure to suppress vimentin and IL-1beta inflammatory signaling.
    downstream:
      - target: Pulmonary Interstitial Fibrosis
        description: >-
          Excessive myofibroblast differentiation and inflammatory signaling in
          lung parenchyma drive interstitial pulmonary fibrosis.
      - target: Hepatic Fibrosis
        description: >-
          Excessive myofibroblast activation and collagen deposition in the
          liver drive hepatic fibrosis alongside steatosis.

  - name: Pulmonary Interstitial Fibrosis
    description: >-
      Progressive fibrotic remodeling of the pulmonary interstitium accompanied
      by granuloma-like lung lesions, ground-glass opacities, and pulmonary
      consolidations, leading to severe infantile interstitial lung disease and
      hypoxemic respiratory failure.
    locations:
      - preferred_term: lung
        term:
          id: UBERON:0002048
          label: lung
    biological_processes:
      - preferred_term: extracellular matrix organization
        modifier: DYSREGULATED
        term:
          id: GO:0030198
          label: extracellular matrix organization
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents pulmonary interstitial fibrosis and granuloma-like lung lesions in FINCA patients.
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."
        explanation: Documents interstitial lung disease with ground-glass opacities and consolidations in FINCA patients.
    downstream:
      - target: Pulmonary fibrosis
        description: >-
          Interstitial collagen deposition directly manifests as clinical and
          histopathological pulmonary fibrosis.
      - target: Abnormal pulmonary interstitial morphology
        description: >-
          Interstitial fibrotic remodeling produces ground-glass opacities and
          consolidations on chest imaging.
      - target: Respiratory distress
        description: >-
          Impaired alveolar gas exchange from interstitial lung disease causes
          tachypnea, hypoxemia, and respiratory distress.
      - target: Failure to thrive
        description: >-
          Chronic hypoxemic respiratory insufficiency increases metabolic demand
          and impairs postnatal weight gain.

  - name: Hepatic Fibrosis
    description: >-
      Collagen accumulation in the liver parenchyma accompanied by hepatic
      steatosis, hepatomegaly, and transient liver dysfunction.
    locations:
      - preferred_term: liver
        term:
          id: UBERON:0002107
          label: liver
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents hepatomegaly, hepatic steatosis, and collagen accumulation in the liver of FINCA patients.
    downstream:
      - target: Hepatomegaly
        description: >-
          Hepatic lipid accumulation and fibrotic remodeling cause liver
          enlargement.
      - target: Hepatic steatosis
        description: >-
          Disturbed hepatocellular lipid and vesicular homeostasis manifests as
          hepatic steatosis.
      - target: Hepatic fibrosis
        description: >-
          Hepatic collagen accumulation directly manifests as hepatic fibrosis.

  - name: Neuronal Vesicular Trafficking Dysfunction
    description: >-
      In developing neural progenitor cells and neurons, NHLRC2 deficiency
      disrupts intracellular vesicular trafficking networks and vacuolar
      homeostasis, creating a predisposition to progressive vacuolar
      neurodegeneration and myelin loss.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: vesicle-mediated transport
        modifier: DYSREGULATED
        term:
          id: GO:0016192
          label: vesicle-mediated transport
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
    evidence:
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Collectively, the dysfunction in vesicular trafficking may create a predisposition to neurodegeneration in FINCA disease."
        explanation: Identifies vesicular trafficking dysfunction as a driver of neurodegenerative vulnerability in FINCA disease.
    downstream:
      - target: Vacuolar Neurodegeneration and Neuronal Depletion
        description: >-
          Impaired neuronal vesicular transport leads to intraneuronal vacuolar
          degeneration and progressive neuronal loss.
      - target: White Matter Myelin Loss and Gliosis
        description: >-
          Disrupted vesicular trafficking of myelin components impairs myelin
          maintenance and promotes white matter degeneration.

  - name: Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation
    description: >-
      In developing neural progenitor cells and adult hippocampal neurons,
      NHLRC2 dysfunction causes accumulation of the RNA-binding protein isoform
      hnRNP C2. Perturbed neuronal RNA metabolism and downregulated
      myelination-associated proteins predispose neurons and white matter to
      progressive degeneration.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: RNA splicing
        modifier: DYSREGULATED
        term:
          id: GO:0008380
          label: RNA splicing
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
      - preferred_term: Ammon's horn
        term:
          id: UBERON:0001954
          label: Ammon's horn
    evidence:
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein."
        explanation: Shows accumulation of hnRNP C2 in developing neurons and hippocampus in the FINCA mouse model.
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The increase in the hnRNP C2 protein in Nhlrc2FINCA/− embryonic NPCs and adult mouse hippocampus suggests a perturbation in overall RNA metabolism, which in turn may contribute to the neurodegeneration seen in FINCA disease."
        explanation: Connects elevated hnRNP C2 and perturbed RNA metabolism to neurodegeneration in FINCA disease.
    downstream:
      - target: Vacuolar Neurodegeneration and Neuronal Depletion
        description: >-
          Perturbed neuronal RNA metabolism driven by hnRNP C2 accumulation
          promotes progressive neuronal degeneration.
      - target: White Matter Myelin Loss and Gliosis
        description: >-
          Altered RNA metabolism and reduced myelination protein expression
          contribute to white matter myelin loss.

  - name: Increased Susceptibility to ROS-Induced Caspase-8 Mediated Apoptosis
    description: >-
      In human HCT116 colon carcinoma cells, the N-terminal thioredoxin-like
      domain of NHLRC2 interacts with pro-caspase-8, and reactive oxygen species
      (ROS) trigger caspase-8-mediated cleavage of NHLRC2 at Asp580. Loss of
      NHLRC2 increases cellular sensitivity to ROS-induced apoptotic cell death,
      representing a candidate mechanism that may contribute to parenchymal and
      neuronal cell loss under oxidative stress.
    biological_processes:
      - preferred_term: apoptotic process
        modifier: INCREASED
        term:
          id: GO:0006915
          label: apoptotic process
    evidence:
      - reference: PMID:29242562
        reference_title: "ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and CRISPR-Cas9-mediated loss of NHLRC2 resulted in an increased susceptibility of HCT116 cells to ROS-induced apoptosis."
        explanation: Demonstrates that NHLRC2 interacts with pro-caspase-8 via its Trx-like domain and that NHLRC2 loss increases susceptibility to ROS-induced apoptosis in HCT116 cells.
    downstream:
      - target: Vacuolar Neurodegeneration and Neuronal Depletion
        description: >-
          Proposed candidate mechanism whereby heightened sensitivity to
          oxidative stress-induced apoptosis may promote neuronal loss across
          the cerebral cortex, cerebellum, and spinal cord anterior horns.
        hypothesis_groups:
          - ros_caspase8_apoptosis_hypothesis

  - name: Cerebral Angiomatosis
    description: >-
      Neuropathology in FINCA syndrome reveals increased angiomatosis-like
      leptomeningeal, cortical, and superficial white matter vascularization and
      congestion.
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Establishes leptomeningeal, cortical, and superficial white matter angiomatosis as a hallmark neuropathological feature of FINCA syndrome.
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        quote_role: BACKGROUND
        snippet: "Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."
        explanation: Summarizes cerebral angiomatosis among the core neuropathological findings in FINCA patients.
    downstream:
      - target: Abnormal cerebral vascular morphology
        description: >-
          Angiomatosis-like leptomeningeal and cortical hypervascularization
          directly manifests as abnormal cerebral vascular morphology.

  - name: White Matter Myelin Loss and Gliosis
    description: >-
      Progressive white matter degeneration in FINCA syndrome characterized by
      myelin loss, reactive gliosis, delayed myelination, and hypoplasia or
      atrophy of the corpus callosum.
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Demonstrates white matter myelin loss on neuropathology in FINCA patients.
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        quote_role: BACKGROUND
        snippet: "Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."
        explanation: Summarizes white matter myelin loss with gliosis in FINCA patients.
    downstream:
      - target: Thin corpus callosum
        description: >-
          Loss of interhemispheric white matter tracts and impaired myelination
          cause corpus callosum hypoplasia and atrophy.
      - target: Spasticity
        description: >-
          Corticospinal tract white matter demyelination and gliosis produce
          pyramidal tract signs including spasticity and hyperreflexia.
      - target: Gait ataxia
        description: >-
          Cerebellar and spinocerebellar white matter tract degeneration
          contributes to wide-based unsteady gait.
      - target: Axial hypotonia
        description: >-
          Central white matter and motor pathway dysfunction contribute to
          infantile truncal hypotonia.

  - name: Vacuolar Neurodegeneration and Neuronal Depletion
    description: >-
      Progressive vacuolar degeneration and neuronal depletion across the
      cerebral cortex, cerebellum, and spinal cord anterior horns, resulting in
      progressive cerebral and cerebellar atrophy and severe neurodevelopmental
      impairment.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
      - preferred_term: cerebellum
        term:
          id: UBERON:0002037
          label: cerebellum
      - preferred_term: spinal cord
        term:
          id: UBERON:0002240
          label: spinal cord
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Establishes vacuolar degeneration and neuronal degeneration in FINCA syndrome.
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        quote_role: BACKGROUND
        snippet: "Neuropathology of FINCA patients identified brain atrophy, vacuolar neurodegeneration, myelin loss with gliosis, cerebral angiomatosis, and neuronal depletion of the anterior horns of the spinal cord (Uusimaa et al. 2018)."
        explanation: Summarizes brain atrophy, vacuolar neurodegeneration, and anterior horn neuronal depletion in FINCA patients.
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."
        explanation: Confirms progressive general cerebral and cerebellar atrophy in surviving adolescents.
    downstream:
      - target: Cerebral atrophy
        description: >-
          Progressive cortical and subcortical neuronal loss manifests as
          cerebral and cerebellar atrophy on neuroimaging.
      - target: Microcephaly
        description: >-
          Impaired brain growth and progressive neurodegeneration result in
          postnatal microcephaly.
      - target: Global developmental delay
        description: >-
          Widespread cortical and cerebellar neuronal dysfunction causes severe
          global developmental delay.
      - target: Intellectual disability
        description: >-
          Cerebral cortical and hippocampal neuronal pathology leads to moderate
          to severe intellectual disability.
      - target: Developmental regression
        description: >-
          Ongoing vacuolar neurodegeneration drives loss of previously acquired
          speech and motor skills in childhood.
      - target: Seizure
        description: >-
          Cortical neuronal degeneration and gliosis create epileptogenic
          networks causing focal and generalized seizures.
      - target: Dystonia
        description: >-
          Subcortical and extrapyramidal neuronal involvement causes dystonia
          and hyperkinetic movement disorders.
      - target: Atypical behavior
        description: >-
          Frontotemporal and limbic neuronal dysfunction manifests as aggression
          outbursts, irritability, and attention deficit.
      - target: Gait ataxia
        description: >-
          Cerebellar and spinal cord neuronal depletion impairs motor
          coordination and gait.
      - target: Axial hypotonia
        description: >-
          Spinal cord anterior horn neuronal depletion and central motor
          dysfunction cause truncal hypotonia.

  - name: Macrophage Morphological Defect and Impaired Phagocytosis
    description: >-
      NHLRC2 interacts with FRYL, EIF2AK2, and KLHL13 during macrophage
      differentiation. Loss of NHLRC2 yields smaller macrophages lacking
      filopodia and membrane ruffling that fail to form phagocytic cups or
      engulf bacteria, accompanied by a hyperinflammatory phenotype and altered
      interferon-gamma innate immune responses. This predisposes individuals to
      recurrent respiratory and systemic infections.
    cell_types:
      - preferred_term: macrophage
        term:
          id: CL:0000235
          label: macrophage
    biological_processes:
      - preferred_term: phagocytosis
        modifier: DECREASED
        term:
          id: GO:0006909
          label: phagocytosis
    evidence:
      - reference: PMID:31594818
        reference_title: "A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13."
        explanation: Demonstrates that NHLRC2 loss in human macrophages causes hyperinflammation and inability to phagocytose bacteria.
      - reference: PMID:31594818
        reference_title: "A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Compared with WT macrophages, NHLRC2 mutant macrophages were smaller and lacked filopodia. In the presence of Salmonella, WT macrophages displayed increased membrane ruffling and engaged with Salmonella to form phagocytic cups, but the NHLRC2 mutant macrophage cell surface remained smooth and did not appear to engage with the bacteria in the environment."
        explanation: Shows loss of filopodia, membrane ruffling, and phagocytic cup formation in NHLRC2-deficient macrophages.
    downstream:
      - target: Recurrent respiratory infections
        description: >-
          Defective macrophage bacterial phagocytosis and dysregulated innate
          immune signaling predispose patients to recurrent respiratory tract
          infections.

  - name: Dyserythropoiesis and Multinucleated Erythroblast Formation
    description: >-
      Bone marrow aspirates in affected infants show increased erythropoiesis and
      dyserythropoiesis with marked bi- and multinuclearity of erythroblasts
      resembling congenital dyserythropoietic anemia type II, accompanied by
      transfusion-dependent infantile macrocytic anemia.
    cell_types:
      - preferred_term: erythroblast
        term:
          id: CL:0000765
          label: erythroblast
      - preferred_term: erythrocyte
        term:
          id: CL:0000232
          label: erythrocyte
    biological_processes:
      - preferred_term: erythrocyte differentiation
        modifier: DYSREGULATED
        term:
          id: GO:0030218
          label: erythrocyte differentiation
    locations:
      - preferred_term: bone marrow
        term:
          id: UBERON:0002371
          label: bone marrow
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Documents bone marrow dyserythropoiesis with bi- and multinucleated erythroblasts and transfusion-dependent macrocytic anemia in FINCA patients.
    downstream:
      - target: Macrocytic anemia
        description: >-
          Ineffective erythropoiesis and disordered erythroid maturation produce
          infantile macrocytic anemia.
      - target: Multinucleated erythroblast
        description: >-
          Dyserythropoiesis directly manifests as bi- and multinucleated
          erythroblasts in the bone marrow.

histopathology:
  - name: Pulmonary Granuloma-Like Lesions
    finding_term:
      preferred_term: Pulmonary Granuloma-Like Lesions
    frequency: OCCASIONAL
    description: >-
      Lung autopsy and biopsy specimens from infants with fatal cerebropulmonary
      FINCA syndrome show interstitial fibrosis accompanied by previously
      undescribed granuloma-like lesions in the lungs.
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents previously undescribed granuloma-like lesions alongside interstitial fibrosis in the lungs of FINCA patients.

phenotypes:
  - category: Nervous System
    name: Global developmental delay
    frequency: OBLIGATE
    description: >-
      Moderate to severe global developmental delay is observed across affected
      individuals surviving beyond early infancy, with many children remaining
      non-verbal or speaking only a few rudimentary words.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression occurred after 1–3 years of age, and the siblings (individual 1 and 2) had motor regression starting from the age of six."
        explanation: Demonstrates universal global developmental delay (15/15 individuals) and severe expressive language impairment in the 15-patient cohort.
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Among the 31 FINCA patients, including our newly reported patients, 14 patients (45.2%) were boys (1, 10–14). All FINCA patients experienced neurological symptoms including developmental delay, intellectual disability, behavior problems, movement disorder, hypotonia, dystonia, and seizures, among others"
        explanation: Confirms that neurological symptoms including developmental delay occur across all 31 reviewed FINCA patients.

  - category: Nervous System
    name: Intellectual disability
    frequency: VERY_FREQUENT
    description: >-
      Moderate to severe intellectual disability with severely impaired speech
      expression and relatively preserved speech comprehension in older
      survivors.
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression occurred after 1–3 years of age, and the siblings (individual 1 and 2) had motor regression starting from the age of six."
        explanation: Documents moderate to severe intellectual disability in all 15 individuals of the cohort.
      - reference: PMID:35255187
        reference_title: "FINCA syndrome-Defining neurobehavioral phenotype in survivors into late childhood."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The clinical characteristics included intellectual disability with severely retarded speech expression, relatively preserved speech comprehension, and behavior problems. The last symptom combined aggression outbursts, attention deficit, and irritability."
        explanation: Characterizes the cognitive and language profile in survivors into late childhood.

  - category: Nervous System
    name: Axial hypotonia
    frequency: VERY_FREQUENT
    description: >-
      Truncal and muscular hypotonia presenting in infancy, observed in 12 of
      15 individuals in the largest clinical series and contributing to delayed
      or absent independent ambulation.
    phenotype_term:
      preferred_term: Axial hypotonia
      term:
        id: HP:0008936
        label: Axial hypotonia
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait. Seizures occurred in 11 individuals, with age of onset ranging from nine months to 13 years."
        explanation: Documents truncal hypotonia in 12/15 (80%) individuals.

  - category: Nervous System
    name: Seizure
    frequency: FREQUENT
    description: >-
      Focal and generalized seizures occurring in 11 of 15 patients in the
      largest series (onset 9 months to 13 years), which may progress to status
      epilepticus.
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait. Seizures occurred in 11 individuals, with age of onset ranging from nine months to 13 years."
        explanation: Reports seizures in 11/15 (73%) patients with onset between 9 months and 13 years.
      - reference: PMID:35255187
        reference_title: "FINCA syndrome-Defining neurobehavioral phenotype in survivors into late childhood."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Two girls have epilepsy with focal and generalized seizures that are not frequent however, may lead to status epilepticus."
        explanation: Shows that focal and generalized seizures in FINCA survivors can lead to status epilepticus.

  - category: Nervous System
    name: Atypical behavior
    frequency: FREQUENT
    description: >-
      Behavioral disturbances in childhood survivors characterized by aggression
      outbursts, attention deficit, and severe irritability.
    phenotype_term:
      preferred_term: Atypical behavior
      term:
        id: HP:0000708
        label: Atypical behavior
    evidence:
      - reference: PMID:35255187
        reference_title: "FINCA syndrome-Defining neurobehavioral phenotype in survivors into late childhood."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The clinical characteristics included intellectual disability with severely retarded speech expression, relatively preserved speech comprehension, and behavior problems. The last symptom combined aggression outbursts, attention deficit, and irritability."
        explanation: Defines the behavioral phenotype combining aggression outbursts, attention deficit, and irritability.

  - category: Nervous System
    name: Gait ataxia
    frequency: FREQUENT
    description: >-
      Unsteady, wide-based gait observed in ambulant individuals (5 of 15
      patients in the largest cohort, while 5 of 15 never achieved independent
      walking).
    phenotype_term:
      preferred_term: Gait ataxia
      term:
        id: HP:0002066
        label: Gait ataxia
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait. Seizures occurred in 11 individuals, with age of onset ranging from nine months to 13 years."
        explanation: Documents unsteady, wide gait in 5/15 individuals and inability to walk in 5/15 individuals.

  - category: Nervous System
    name: Developmental regression
    frequency: OCCASIONAL
    description: >-
      Speech regression occurring after 1 to 3 years of age (4 of 15 patients)
      and motor regression starting around age 6 years (2 of 15 patients).
    phenotype_term:
      preferred_term: Developmental regression
      term:
        id: HP:0002376
        label: Developmental regression
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals showed global developmental delay and later intellectual disability (ID), which in most cases was classified as moderate or severe. Nine children were non-verbal at the last assessment, and five could speak only a few rudimentary words. In four cases, speech regression occurred after 1–3 years of age, and the siblings (individual 1 and 2) had motor regression starting from the age of six."
        explanation: Documents speech regression in 4/15 patients and motor regression in 2/15 patients.

  - category: Nervous System
    name: Dystonia
    frequency: OCCASIONAL
    description: >-
      Dystonia and hyperkinetic movement disorders occurring as part of the
      extrapyramidal neurological spectrum of FINCA syndrome.
    phenotype_term:
      preferred_term: Dystonia
      term:
        id: HP:0001332
        label: Dystonia
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Among the 31 FINCA patients, including our newly reported patients, 14 patients (45.2%) were boys (1, 10–14). All FINCA patients experienced neurological symptoms including developmental delay, intellectual disability, behavior problems, movement disorder, hypotonia, dystonia, and seizures, among others"
        explanation: Lists dystonia and movement disorders among the neurological manifestations of FINCA syndrome.

  - category: Nervous System
    name: Spasticity
    frequency: OCCASIONAL
    description: >-
      Pyramidal tract involvement with spasticity and hyperreflexia developing
      in a subset of affected children alongside movement disorders.
    phenotype_term:
      preferred_term: Spasticity
      term:
        id: HP:0001257
        label: Spasticity
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "All 15 individuals had variable neuromuscular involvement: 12 had truncal hypotonia, five individuals were never able to walk and four developed hyperkinetic movement disorder, spasticity or hyperreflexia. Two depended on a wheelchair for long distances and five had an unsteady, wide gait. Seizures occurred in 11 individuals, with age of onset ranging from nine months to 13 years."
        explanation: Documents spasticity or hyperreflexia in 4 of 15 individuals in the cohort.

  - category: Nervous System
    name: Cerebral atrophy
    frequency: FREQUENT
    description: >-
      Mild cortical atrophy to severe general cerebral and cerebellar atrophy
      with dilated ventricles and white matter myelin loss on neuroimaging and
      neuropathology.
    phenotype_term:
      preferred_term: Cerebral atrophy
      term:
        id: HP:0002059
        label: Cerebral atrophy
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."
        explanation: Demonstrates severe progressive cerebral and cerebellar atrophy on brain MRI.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."
        explanation: Documents cortical atrophy, dilated ventricles, and delayed myelination on MRI in 5 of 11 imaged individuals.

  - category: Nervous System
    name: Thin corpus callosum
    frequency: FREQUENT
    description: >-
      Hypoplasia or atrophy of the corpus callosum observed on brain MRI.
    phenotype_term:
      preferred_term: Thin corpus callosum
      term:
        id: HP:0033725
        label: Thin corpus callosum
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Chest radiography showed ARDS and chronic pneumonitis, with brain MRI revealing atrophy of the corpus callosum. A severe general cerebral and cerebellar atrophy in a patient at the age of 17 years suggested progressive neurodegeneration."
        explanation: Documents atrophy of the corpus callosum on brain MRI.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."
        explanation: Reports corpus callosum hypoplasia on brain MRI.

  - category: Nervous System
    name: Abnormal cerebral vascular morphology
    frequency: OCCASIONAL
    description: >-
      Cerebral angiomatosis characterized by increased angiomatosis-like
      leptomeningeal, cortical, and superficial white matter vascularization and
      congestion on neuropathological examination.
    phenotype_term:
      preferred_term: Abnormal cerebral vascular morphology
      term:
        id: HP:0100659
        label: Abnormal cerebral vascular morphology
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Describes the defining cerebral angiomatosis (leptomeningeal, cortical, and superficial white matter hypervascularization and congestion).

  - category: Head and Neck
    name: Microcephaly
    frequency: OCCASIONAL
    description: >-
      Postnatal microcephaly (head circumference more than 2 SD below the mean)
      documented in 4 of 15 individuals in the largest clinical cohort.
    phenotype_term:
      preferred_term: Microcephaly
      term:
        id: HP:0000252
        label: Microcephaly
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."
        explanation: Documents microcephaly (SD below -2) in 4/15 patients.

  - category: Respiratory
    name: Abnormal pulmonary interstitial morphology
    frequency: FREQUENT
    description: >-
      Infantile-onset interstitial lung disease (ILD) characterized by
      ground-glass opacities and pulmonary consolidations on chest CT, which may
      cause fatal infantile respiratory failure or stabilize over childhood.
    phenotype_term:
      preferred_term: Abnormal pulmonary interstitial morphology
      term:
        id: HP:0006530
        label: Abnormal pulmonary interstitial morphology
    evidence:
      - reference: PMID:34165204
        reference_title: "Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Shows pronounced infantile interstitial lung disease that stabilizes in surviving children.
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."
        explanation: Quantifies respiratory involvement (~50% of 31 patients) and chest CT-confirmed ILD (9/11 scanned patients) with ground-glass opacities and consolidations.

  - category: Respiratory
    name: Pulmonary fibrosis
    frequency: FREQUENT
    description: >-
      Interstitial pulmonary fibrosis accompanied by granuloma-like lung lesions
      in severe infantile cases.
    phenotype_term:
      preferred_term: Pulmonary fibrosis
      term:
        id: HP:0002206
        label: Pulmonary fibrosis
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Demonstrates interstitial pulmonary fibrosis and granuloma-like lesions on lung histopathology.

  - category: Respiratory
    name: Respiratory distress
    frequency: FREQUENT
    description: >-
      Tachypnea, cough, hypoxemia, and progressive respiratory distress or acute
      respiratory distress syndrome (ARDS) presenting in about half of reported
      FINCA patients during infancy.
    phenotype_term:
      preferred_term: Respiratory distress
      term:
        id: HP:0002098
        label: Respiratory distress
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."
        explanation: Documents tachypnea, hypoxemia, and respiratory distress in approximately half of the 31 FINCA patients.

  - category: Respiratory
    name: Recurrent respiratory infections
    frequency: FREQUENT
    description: >-
      Recurrent respiratory tract infections beginning in infancy, often
      triggering exacerbations of interstitial lung disease and anemia.
    phenotype_term:
      preferred_term: Recurrent respiratory infections
      term:
        id: HP:0002205
        label: Recurrent respiratory infections
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Identifies recurrent infections as a core clinical feature alongside neurodevelopmental delay and macrocytic anemia.

  - category: Blood
    name: Macrocytic anemia
    frequency: FREQUENT
    description: >-
      Macrocytic anemia presenting in infancy, frequently requiring multiple
      packed red blood cell transfusions.
    phenotype_term:
      preferred_term: Macrocytic anemia
      term:
        id: HP:0001972
        label: Macrocytic anemia
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Demonstrates macrocytic anemia in 5/5 patients of the series, with 4/5 requiring red blood cell transfusions in infancy.

  - category: Blood
    name: Chronic hemolytic anemia
    frequency: OCCASIONAL
    description: >-
      Chronic hemolytic anemia presenting in early infancy as part of the
      hematologic manifestation of FINCA syndrome.
    phenotype_term:
      preferred_term: Chronic hemolytic anemia
      term:
        id: HP:0004870
        label: Chronic hemolytic anemia
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."
        explanation: Identifies chronic hemolytic anemia as one of the main clinical features in classic FINCA syndrome.

  - category: Blood
    name: Multinucleated erythroblast
    frequency: OCCASIONAL
    description: >-
      Bone marrow dyserythropoiesis with marked bi- and multinuclearity of
      erythroblasts mimicking congenital dyserythropoietic anemia type II.
    phenotype_term:
      preferred_term: Multinucleated erythroblast
      term:
        id: HP:0034278
        label: Multinucleated erythroblast
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Documents marked bi- and multinuclearity of erythroblasts on bone marrow aspirate in two patients.

  - category: Immune
    name: Decreased circulating immunoglobulin concentration
    frequency: OCCASIONAL
    description: >-
      Humoral immunodeficiency with decreased serum immunoglobulin levels
      contributing to recurrent infections.
    phenotype_term:
      preferred_term: Decreased circulating immunoglobulin concentration
      term:
        id: HP:0004313
        label: Decreased circulating immunoglobulin concentration
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Documents decreased immunoglobulin levels in 2 of 5 patients in the cohort.

  - category: Growth
    name: Failure to thrive
    frequency: FREQUENT
    description: >-
      Progressive growth failure, feeding difficulties, and decreased body
      weight (9 of 15 patients in the largest cohort).
    phenotype_term:
      preferred_term: Failure to thrive
      term:
        id: HP:0001508
        label: Failure to thrive
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."
        explanation: Identifies progressive growth failure and malabsorption as core features in infantile FINCA syndrome.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."
        explanation: Documents decreased body weight in 9/15 individuals and short stature in 7/15 individuals.

  - category: Growth
    name: Short stature
    frequency: FREQUENT
    description: >-
      Postnatal short stature observed in 7 of 15 individuals in the largest
      clinical cohort.
    phenotype_term:
      preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "At the last clinical examination, four individuals (ages five, six, eight and 19) had microcephaly (SD below −2). Short stature and decreased body weight were observed in seven and nine individuals, respectively, with five individuals having both."
        explanation: Documents short stature in 7/15 (47%) individuals.

  - category: Digestive
    name: Hepatomegaly
    frequency: OCCASIONAL
    description: >-
      Hepatomegaly accompanied by hepatic steatosis, collagen accumulation, and
      transient liver dysfunction.
    phenotype_term:
      preferred_term: Hepatomegaly
      term:
        id: HP:0002240
        label: Hepatomegaly
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents hepatomegaly, hepatic steatosis, and liver collagen accumulation in affected children.

  - category: Digestive
    name: Hepatic steatosis
    frequency: OCCASIONAL
    description: >-
      Fatty infiltration (steatosis) of the liver observed alongside
      hepatomegaly and hepatic collagen accumulation.
    phenotype_term:
      preferred_term: Hepatic steatosis
      term:
        id: HP:0001397
        label: Hepatic steatosis
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents hepatic steatosis at autopsy in affected children.

  - category: Digestive
    name: Hepatic fibrosis
    frequency: OCCASIONAL
    description: >-
      Hepatic collagen accumulation and fibrotic remodeling of the liver.
    phenotype_term:
      preferred_term: Hepatic fibrosis
      term:
        id: HP:0001395
        label: Hepatic fibrosis
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver."
        explanation: Documents collagen accumulation in the liver of FINCA patients.

  - category: Digestive
    name: Malabsorption
    frequency: OCCASIONAL
    description: >-
      Intestinal malabsorption and chronic diarrhea presenting in infancy and
      contributing to progressive growth failure.
    phenotype_term:
      preferred_term: Malabsorption
      term:
        id: HP:0002024
        label: Malabsorption
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction."
        explanation: Documents malabsorption as one of the main infantile clinical features of FINCA syndrome.

biochemical:
  - name: Reduced Cellular NHLRC2 Protein Level
    presence: DECREASED
    context: Patient-derived fibroblasts and peripheral blood cells
    notes: >-
      Steady-state NHLRC2 protein levels are markedly reduced in patient-derived
      fibroblasts; severity of protein depletion correlates with early-onset
      pulmonary and multisystem involvement.
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Demonstrates low cellular NHLRC2 protein levels in patient-derived fibroblasts.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Studying different non-truncating variants and linking their effects on NHLRC2 protein levels revealed a putative genotype-phenotype correlation: variants leading to severely reduced protein levels (either in homozygous or in compound-heterozygous state with another severe missense or frameshift/nonsense variant) were associated with an early onset multisystem phenotype including pulmonary disease. When the sum of NHLRC2 protein levels from both alleles appears to exceed a certain critical level, a phenotype without progressive respiratory symptoms was observed"
        explanation: Establishes cellular NHLRC2 protein dosage as a biochemical correlate of respiratory disease severity.

  - name: Serum Krebs von den Lungen-6 (KL-6)
    presence: ELEVATED
    context: Interstitial lung disease activity and treatment monitoring
    notes: >-
      Serum KL-6 levels are elevated during active FINCA-associated interstitial
      lung disease and decrease in parallel with clinical and radiological
      improvement under systemic glucocorticoid therapy.
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The elder brother died of infantile respiratory failure, while the younger brother showed improvement in respiratory symptoms, chest CT, and Krebs von den Lungen-6 levels after long-term systemic glucocorticoid therapy, indicating that anti-inflammatory treatment may be beneficial in the treatment of ILD caused by FINCA syndrome."
        explanation: Documents serum Krebs von den Lungen-6 (KL-6) as a biomarker responsive to systemic glucocorticoid therapy in FINCA-related ILD.

  - name: Serum Immunoglobulins
    presence: DECREASED
    context: Humoral immune evaluation
    notes: >-
      Decreased circulating immunoglobulin levels are detected in a subset of
      patients presenting with recurrent infections.
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Confirms decreased serum immunoglobulin levels in two of five patients evaluated.

genetic:
  - name: NHLRC2
    association: Pathogenic Biallelic Variants
    gene_term:
      preferred_term: NHLRC2
      term:
        id: hgnc:24731
        label: NHLRC2
    features: >-
      Biallelic missense, frameshift, nonsense, or splice-site variants in
      NHLRC2. The recurrent hypomorphic missense variant c.442G>T (p.Asp148Tyr)
      in the conserved N-terminal thioredoxin-like domain is the most common
      disease allele, occurring in either homozygous state or compound
      heterozygosity with loss-of-function variants (such as p.Arg201GlyfsTer6)
      or additional missense variants (such as p.His143Pro). At least nine
      additional pathogenic variants across the gene have been identified in
      diverse populations, with residual NHLRC2 protein abundance correlating
      inversely with early-onset pulmonary disease.
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Identifies the original compound heterozygous NHLRC2 variants (p.Asp148Tyr and p.Arg201GlyfsTer6) causing FINCA syndrome.
      - reference: PMID:32435055
        reference_title: "Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Documents compound heterozygosity for p.Asp148Tyr and p.His143Pro in the conserved N-terminal Trx-like domain.
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "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."
        explanation: Expands the allelic spectrum of FINCA syndrome with nine novel NHLRC2 variants across 12 families.

animal_models:
  - species: Mus musculus
    genotype: Nhlrc2^FINCA/- (p.Asp148Tyr / null compound heterozygote)
    description: >-
      Compound heterozygous FINCA mouse model carrying the patient-equivalent
      missense variant p.Asp148Tyr combined with a null allele. Mice are viable
      and exhibit adolescent hyperactivity, decreased exploration of novel
      objects, altered innate immune interferon-gamma responses, dysregulated
      Rho GTPase signaling, vesicular trafficking defects, and accumulation of
      hnRNP C2 in developing neurons and adult female hippocampus.
    associated_phenotypes:
      - Hyperactivity and decreased novel object exploration
      - Altered innate immune interferon-gamma response
      - Hippocampal hnRNP C2 accumulation
    modeled_mechanisms:
      - target: Neuronal hnRNP C2 Accumulation and RNA Metabolism Perturbation
        relationship: RECAPITULATES
        fidelity: HIGH
        model_scale: TISSUE
        description: >-
          Nhlrc2^FINCA/- mice exhibit increased hnRNP C2 isoform levels in
          developing neurons and adult hippocampus.
      - target: Neuronal Vesicular Trafficking Dysfunction
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: CELLULAR
        description: >-
          Proteomic and cellular studies of Nhlrc2^FINCA/- mice demonstrate
          dysregulated neuronal vesicular trafficking.
      - target: Cytoskeletal and Rho GTPase Signaling Dysregulation
        relationship: RECAPITULATES
        fidelity: MODERATE
        model_scale: CELLULAR
        description: >-
          Transcriptomic and interactome comparisons in Nhlrc2^FINCA/- mice
          identify Rho GTPase signaling dysregulation.
      - target: Enhanced Fibroblast-to-Myofibroblast Differentiation
        relationship: FAILS_TO_RECAPITULATE
        description: >-
          Despite markedly decreased NHLRC2 protein levels, Nhlrc2^FINCA/- mice
          do not develop spontaneous pulmonary or multiorgan fibrosis.
        limitations: >-
          Despite markedly reduced NHLRC2 protein levels across tissues, Nhlrc2^FINCA/-
          mice do not spontaneously develop the severe early-onset multiorgan fibrosis,
          interstitial lung disease, or fatal neurodegeneration characteristic of human
          FINCA syndrome.
        evidence:
          - reference: PMID:33297935
            reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: "Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex."
            explanation: Documents that Nhlrc2^FINCA/- mice fail to recapitulate spontaneous severe early-onset multiorgan fibrosis/disease despite markedly reduced NHLRC2 levels.
    evidence:
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex."
        explanation: Documents that Nhlrc2^FINCA/- mice do not develop spontaneous severe early-onset multiorgan disease despite markedly reduced NHLRC2 levels.
      - reference: PMID:33297935
        reference_title: "Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA\u00a0disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein."
        explanation: Demonstrates hnRNP C2 accumulation in developing neurons and adult hippocampus of FINCA mice.
      - reference: PMID:40510178
        reference_title: "Altered behaviour and immune response in mice with NHLRC2 p.Asp148Tyr variant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells, we identified Rho GTPase signalling as a common affected pathway."
        explanation: Characterizes behavioral, innate immune, and Rho GTPase signaling phenotypes in FINCA mice.

  - species: Mus musculus
    genotype: Nhlrc2-/- (homozygous null)
    description: >-
      Homozygous Nhlrc2 null mouse embryos arrest prior to the morula stage,
      demonstrating that complete loss of NHLRC2 is embryonic lethal.
    associated_phenotypes:
      - Pre-morula embryonic lethality
    modeled_mechanisms:
      - target: NHLRC2 Structural Destabilization and Protein Depletion
        relationship: PERTURBS
        fidelity: MODERATE
        model_scale: ORGANISM
        description: >-
          Complete ablation of Nhlrc2 in mice causes pre-morula embryonic
          arrest, establishing the requirement for residual NHLRC2 activity.
    evidence:
      - reference: PMID:29423877
        reference_title: "NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Development of the Nhlrc2 null mouse strain stalled before the morula stage."
        explanation: Demonstrates pre-morula embryonic lethality in homozygous Nhlrc2 null mice.

mechanistic_hypotheses:
  - hypothesis_group_id: ros_caspase8_apoptosis_hypothesis
    hypothesis_label: ROS-Induced Caspase-8 Mediated Apoptosis in FINCA Neurodegeneration
    status: EMERGING
    description: >-
      In vitro studies in human HCT116 colon carcinoma cells showed that the
      thioredoxin-like domain of NHLRC2 binds pro-caspase-8, that ROS trigger
      caspase-8-mediated cleavage of NHLRC2 at Asp580, and that NHLRC2 loss
      sensitizes cells to ROS-induced apoptosis. While this mechanism has been
      proposed as a candidate driver of parenchymal and neuronal cell loss in
      FINCA syndrome, direct demonstration in patient neurons or FINCA animal
      brain tissue remains to be established.
    evidence:
      - reference: PMID:29242562
        reference_title: "ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and CRISPR-Cas9-mediated loss of NHLRC2 resulted in an increased susceptibility of HCT116 cells to ROS-induced apoptosis."
        explanation: Establishes the in vitro interaction between NHLRC2 and pro-caspase-8 and increased susceptibility to ROS-induced apoptosis in HCT116 cells.

treatments:
  - name: Systemic Corticosteroid Therapy
    description: >-
      Long-term systemic glucocorticoid therapy can improve respiratory
      symptoms, chest CT findings, and serum KL-6 levels in patients with
      FINCA-associated interstitial lung disease.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Systemic Corticosteroid Therapy
      term:
        id: NCIT:C122080
        label: Systemic Corticosteroid Therapy
      therapeutic_agent:
        - preferred_term: corticosteroid
          term:
            id: CHEBI:50858
            label: corticosteroid
    target_mechanisms:
      - target: Pulmonary Interstitial Fibrosis
        description: >-
          Suppresses pulmonary interstitial inflammation and fibrotic disease
          activity in FINCA-associated interstitial lung disease.
    target_phenotypes:
      - preferred_term: Abnormal pulmonary interstitial morphology
        term:
          id: HP:0006530
          label: Abnormal pulmonary interstitial morphology
      - preferred_term: Pulmonary fibrosis
        term:
          id: HP:0002206
          label: Pulmonary fibrosis
      - preferred_term: Respiratory distress
        term:
          id: HP:0002098
          label: Respiratory distress
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The elder brother died of infantile respiratory failure, while the younger brother showed improvement in respiratory symptoms, chest CT, and Krebs von den Lungen-6 levels after long-term systemic glucocorticoid therapy, indicating that anti-inflammatory treatment may be beneficial in the treatment of ILD caused by FINCA syndrome."
        explanation: Demonstrates clinical, radiological, and biomarker (KL-6) improvement of FINCA-associated ILD with long-term systemic glucocorticoid therapy.

  - name: Packed Red Blood Cell Transfusion
    description: >-
      Red blood cell transfusions are frequently required during infancy to
      manage severe macrocytic and dyserythropoietic anemia.
    treatment_term:
      preferred_term: Packed Red Blood Cell Transfusion
      term:
        id: NCIT:C15409
        label: Packed Red Blood Cell Transfusion
    target_phenotypes:
      - preferred_term: Macrocytic anemia
        term:
          id: HP:0001972
          label: Macrocytic anemia
      - preferred_term: Chronic hemolytic anemia
        term:
          id: HP:0004870
          label: Chronic hemolytic anemia
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Documents the requirement for red blood cell transfusions during infancy in 4 of 5 patients with FINCA-associated macrocytic anemia.

  - name: Intravenous Immunoglobulin Therapy
    description: >-
      Immunoglobulin replacement therapy and additional vaccinations (such as
      pneumococcal vaccine and varicella immunoglobulin) are recommended when
      humoral immunodeficiency is detected.
    treatment_term:
      preferred_term: Intravenous Immunoglobulin Therapy
      term:
        id: NCIT:C121331
        label: Intravenous Immunoglobulin Therapy
    target_phenotypes:
      - preferred_term: Decreased circulating immunoglobulin concentration
        term:
          id: HP:0004313
          label: Decreased circulating immunoglobulin concentration
      - preferred_term: Recurrent respiratory infections
        term:
          id: HP:0002205
          label: Recurrent respiratory infections
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immunoglobulin treatment and additional vaccinations (e.g., pneumococcal vaccine and varicella immunoglobulin) and antibiotic prophylaxis (for pneumocystis carinii, etc.) are recommended if immunodeficiency is detected."
        explanation: Recommends immunoglobulin replacement and targeted vaccinations for FINCA patients with immunodeficiency.

  - name: Antibiotic Prophylaxis
    description: >-
      Antibiotic prophylaxis (including prophylaxis against Pneumocystis
      jirovecii and bacterial respiratory pathogens) is recommended in FINCA
      patients with immunodeficiency and recurrent infections.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Antibiotic Prophylaxis
      term:
        id: NCIT:C51993
        label: Antibiotic Prophylaxis
    target_phenotypes:
      - preferred_term: Recurrent respiratory infections
        term:
          id: HP:0002205
          label: Recurrent respiratory infections
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immunoglobulin treatment and additional vaccinations (e.g., pneumococcal vaccine and varicella immunoglobulin) and antibiotic prophylaxis (for pneumocystis carinii, etc.) are recommended if immunodeficiency is detected."
        explanation: Recommends antibiotic prophylaxis in FINCA patients with immunodeficiency and recurrent infections.

diagnosis:
  - name: Whole Exome Sequencing
    presence: Confirmatory
    description: >-
      Molecular genetic testing via whole-exome or genome sequencing to identify
      biallelic pathogenic variants in NHLRC2 is the definitive diagnostic
      method and is recommended for infants and children presenting with
      cerebropulmonary manifestations or infantile-onset epileptic
      encephalopathies.
    diagnosis_term:
      preferred_term: Whole Exome Sequencing
      term:
        id: NCIT:C101295
        label: Whole Exome Sequencing
    results: Identification of homozygous or compound heterozygous pathogenic variants in NHLRC2.
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Based on the current knowledge on the phenotypic spectrum of FINCA disease, we recommend considering WES analysis for patients with a history of infantile-onset cerebropulmonary manifestations as well as infantile-onset epileptic encephalopathies without pulmonary manifestations."
        explanation: Recommends whole-exome sequencing for suspected FINCA syndrome across both cerebropulmonary and isolated neurological presentations.

  - name: Chest Computed Tomography
    presence: Supportive
    description: >-
      High-resolution chest computed tomography to evaluate infantile
      interstitial lung disease, typically demonstrating ground-glass opacities
      and pulmonary consolidations.
    diagnosis_term:
      preferred_term: Chest Computed Tomography
      term:
        id: NCIT:C191501
        label: Chest Computed Tomography
    results: Ground-glass opacities (GGOs) and pulmonary consolidations consistent with interstitial lung disease.
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "About half of the 31 FINCA patients presented with respiratory symptoms, such as tachypnea, cough, hypoxemia, and respiratory distress. Chest CT scans were performed on 11 patients, among whom 9 children were diagnosed with ILD, with the most prevalent findings being GGOs and pulmonary consolidations."
        explanation: Establishes chest CT findings of ground-glass opacities and pulmonary consolidations in 9 of 11 scanned FINCA patients.

  - name: Brain Magnetic Resonance Imaging
    presence: Supportive
    description: >-
      Brain MRI to evaluate structural and neurodegenerative abnormalities,
      which may reveal corpus callosum hypoplasia or atrophy, dilated ventricles,
      delayed myelination, and progressive cerebral and cerebellar atrophy.
    diagnosis_term:
      preferred_term: Magnetic Resonance Imaging
      term:
        id: NCIT:C16809
        label: Magnetic Resonance Imaging
    results: Corpus callosum hypoplasia/atrophy, dilated ventricles, delayed myelination, and cortical/cerebellar atrophy.
    evidence:
      - reference: PMID:37188825
        reference_title: "Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Brain abnormalities (dilated ventricles, corpus callosum hypoplasia, mild cortical atrophy and delayed myelination) were diagnosed in five individuals, while six had unremarkable brain MRI scans."
        explanation: Details characteristic brain MRI abnormalities in FINCA syndrome.

  - name: Bone Marrow Aspiration
    presence: Supportive
    description: >-
      Bone marrow aspiration in patients with severe infantile macrocytic anemia
      to assess for dyserythropoiesis and multinucleated erythroblasts.
    diagnosis_term:
      preferred_term: Bone Marrow Aspiration
      term:
        id: NCIT:C15644
        label: Bone Marrow Aspiration
    results: Increased erythropoiesis or dyserythropoiesis with marked bi- and multinuclearity of erythroblasts and eosinophilia.
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Laboratory investigations (Table 2) revealed macrocytic anemia in all five patients, with the bone marrow aspirates in two patients (patients five and six, Table 2) showing increased erythropoiesis or dyserythropoiesis, marked bi- and multinuclearity of erythroblasts and increased eosinophils suggestive of congenital dyserythropoietic anemia (CDA type II) (Figures 3A, B). Four out of five patients needed several red blood cell transfusions in infancy. Furthermore, immunodeficiency with decreased immunoglobulin levels was detected in two patients."
        explanation: Describes bone marrow aspirate findings of dyserythropoiesis and bi-/multinucleated erythroblasts in FINCA patients.

differential_diagnoses:
  - name: Congenital Dyserythropoietic Anemia Type II
    description: >-
      Infants with FINCA syndrome may initially present with severe macrocytic
      anemia and bone marrow bi- and multinucleated erythroblasts mimicking
      congenital dyserythropoietic anemia type II (CDA II); distinguished by
      multisystem neurodevelopmental and pulmonary involvement and biallelic
      NHLRC2 variants rather than SEC23B mutations.
    distinguishing_features:
      - Progressive neurodevelopmental delay, hypotonia, and seizures
      - Infantile interstitial lung disease
      - Biallelic pathogenic variants in NHLRC2 on exome sequencing
    disease_term:
      preferred_term: congenital dyserythropoietic anemia type 2
      term:
        id: MONDO:0009134
        label: congenital dyserythropoietic anemia type 2
    evidence:
      - reference: PMID:37179546
        reference_title: "Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "In patient six, the initial lead-pathologies were severe anemia associated with feeding problems, failure to thrive and muscular hypotonia; hence, hematologists should keep ultra-orphan diseases like CDAs, FINCA syndrome and CAD-associated uridine responsive epileptic encephalopathy in the differential diagnostic repertoire."
        explanation: Highlights congenital dyserythropoietic anemias (CDAs) as a key differential diagnosis for FINCA syndrome presenting with severe infantile macrocytic anemia.

  - name: Surfactant Metabolism Dysfunction / NKX2-1-Related Interstitial Lung Disease
    description: >-
      Surfactant dysfunction disorder caused by NKX2-1 mutation presents with
      early-onset interstitial lung disease and neurological involvement
      (choreoathetosis/hypotonia) closely resembling FINCA syndrome;
      distinguished by normal thyroid function in FINCA patients and molecular
      testing of NHLRC2 versus NKX2-1.
    distinguishing_features:
      - Normal thyroid function in FINCA syndrome (versus congenital hypothyroidism in brain-lung-thyroid syndrome)
      - Macrocytic/dyserythropoietic anemia
      - Biallelic NHLRC2 variants rather than heterozygous NKX2-1 variants
    disease_term:
      preferred_term: brain-lung-thyroid syndrome
      term:
        id: MONDO:0012593
        label: brain-lung-thyroid syndrome
    evidence:
      - reference: PMID:39328589
        reference_title: "Case Report: Clinical manifestations and treatment of two Chinese patients with FINCA syndrome carrying a novel variant of NHLRC2."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "For example, the clinical manifestations of surfactant dysfunction disorder caused by an NKX2-1 mutation are very similar to those of early-onset ILD and neurological involvement, which needs to be excluded as a differential diagnosis. Unlike in the NKX2-1 mutation, FINCA patients exhibit normal thyroid function."
        explanation: Identifies NKX2-1-related surfactant dysfunction disorder as a differential diagnosis for early-onset ILD with neurological involvement, distinguished by normal thyroid function in FINCA syndrome.

discussions:
  - discussion_id: finca_cerebral_angiomatosis_mechanism_gap
    kind: KNOWLEDGE_GAP
    prompt: >-
      What molecular mechanism links biallelic NHLRC2 deficiency to the
      angiomatosis-like leptomeningeal and superficial cortical vascular
      proliferation seen on neuropathology in FINCA syndrome?
    attaches_to:
      - pathophysiology#Cerebral Angiomatosis
    rationale: >-
      Although cerebral angiomatosis is one of the defining neuropathological
      features that gave FINCA syndrome its name (Uusimaa et al., 2018,
      PMID:29423877), the upstream molecular pathway connecting loss of NHLRC2
      to excess small thin-walled leptomeningeal and superficial cortical blood
      vessels remains uncharacterized. Functional studies to date have focused
      on fibroblast-to-myofibroblast differentiation, macrophage phagocytosis,
      and neuronal vesicular trafficking and hnRNP C2 accumulation, leaving the
      vascular morphogenesis defect as an open mechanistic question.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸

Fibrosis, Neurodegeneration, and Cerebral Angiomatosis (FINCA syndrome): research report

claude-haiku-4-5-20251001, claude-opus-5-5 8 citations 2026-10-14T15:52:21.895610

Gathering the last few facts (phagocytosis screen, Orphanet ID), then writing the report.

Fibrosis, Neurodegeneration, and Cerebral Angiomatosis (FINCA syndrome): research report

Scope and sources. This report draws mainly on the 13 PubMed abstracts already cached in references_cache/ (all quotes below are copied from those cached abstracts), plus a few web searches. The literature is small: about 33 to 35 published patients, one gene, and one compound-heterozygous mouse model. Many template sections have no data, and I say so where that applies rather than filling them in.

Ontology IDs need checking. Apart from MONDO:0032651 and the OMIM numbers, the HPO, GO, CL, UBERON and NCIT IDs below came from memory, not from a lookup. Treat them as leads only. Under this repository's rules, run each one through runoak or just validate-terms before binding it.

Connectors. The claude.ai PubMed and OLS connectors were not authorized in this session, so I could not use them. Authorizing them in claude.ai connector settings would make term and PMID checks easier next time.

1. Disease information

Overview. FINCA is an autosomal recessive multisystem disease caused by biallelic variants in NHLRC2. It was first described in 2018 in three Finnish children who died in early childhood. Since then the known phenotype has widened: there are now survivors into childhood and adulthood, and some patients have a mainly neurodevelopmental picture.

"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." — PMID:29423877 (Uusimaa et al., Acta Neuropathol 2018)

"FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene." — PMID:37179546 (Tallgren et al., Front Neurosci 2023)

Identifiers

Resource	ID
MONDO	MONDO:0032651 "fibrosis, neurodegeneration, and cerebral angiomatosis"
OMIM, disease	#618278
OMIM, gene (NHLRC2)	*618277 (PMID:34165204)
HGNC	NHLRC2; look up the hgnc: number (lowercase `hgnc:` form) before use
Orphanet	Not found. No ORPHA record mentioning NHLRC2 is in the local cache, and web search did not return one
ICD-10 / ICD-11 / MeSH	No disease-specific codes found

Synonyms. FINCA syndrome; FINCA disease; NHLRC2-related disease (Sczakiel 2023 uses "NHLRC2-related disease").

Type of evidence. All of it comes from aggregated case reports and series (individual-patient descriptions). There are no registry or EHR datasets, apart from the chILD-EU register search in Rapp et al. 2021.

2. Etiology

Cause. Biallelic (homozygous or compound heterozygous) germline variants in NHLRC2. The missense variant p.Asp148Tyr (c.442G>T) recurs, and in the early reports every patient carried it on at least one allele (PMID:37188825).
Hypomorphism. Complete loss of NHLRC2 is presumed lethal. Nhlrc2-null mouse embryos stop developing before the morula stage (PMID:29423877) or die during gastrulation (as summarized in PMID:37179546). Patients therefore carry at least one allele that keeps some function.
Genetic risk factors. None known beyond the causal gene. No modifier genes or GWAS loci have been reported.
Environmental and gene–environment factors. Nothing is established. Respiratory disease "was progressive or exacerbated during infections" (PMID:35255187). The FINCA mouse paper suggests environmental triggers as a research question: the model "serves as a tool for investigations on the role of environmental triggers in disease patho[genesis]" (PMID:40510178). This is a hypothesis, not a demonstrated factor.
Protective factors. None known. Higher residual NHLRC2 protein goes with milder disease (see section 4), which works like a protective allele effect.

3. Phenotypes

Frequencies are mostly qualitative. Pooled counts appear in Sczakiel 2023 and Tallgren 2023, but only the abstracts are cached, so exact per-feature percentages should be taken from the full texts.

Phenotype	Onset and course	Frequency and notes	Candidate HPO (verify)	Key PMID
Global developmental delay / intellectual disability	Infancy; becomes the main feature in survivors	Universal in the 15-patient series ("All patients… presented with moderate to severe global developmental delay")	Global developmental delay HP:0001263; Intellectual disability HP:0001249	37188825, 34165204
Interstitial lung disease / pulmonary fibrosis	Infancy; progressive in fatal cases, often stabilizes in survivors	Frequent; "pronounced in almost all patients during infancy" in Rapp's 6 patients	Interstitial pulmonary abnormality / Pulmonary fibrosis HP:0002206	34165204, 37179546
Respiratory distress / respiratory failure	Infancy	Main cause of early death	Respiratory distress HP:0002098; Respiratory failure HP:0002878	29423877, 39328589
Seizures	9 months to 13 years	"Frequently observed"	Seizure HP:0001250	37188825
Truncal hypotonia	Infancy	Frequent	Truncal hypotonia HP:0008936	37188825
Movement disorder	Childhood	Frequent; Rett-like features reported	Abnormality of movement HP:0100022	37188825, 35255187
Cerebral angiomatosis (leptomeningeal and cortical hypervascularization)	Seen at neuropathology	Autopsy cases	Look up a vascular malformation term	29423877
White-matter vacuolar degeneration, myelin loss, neuronal degeneration	Progressive	Autopsy cases	Look up leukodystrophy / white-matter abnormality terms	29423877
Cerebral and cerebellar atrophy	Progressive	Seen on imaging in survivors	Cerebral atrophy HP:0002059; Cerebellar atrophy HP:0001272	35255187
Chronic haemolytic or macrocytic anemia	Infancy	A "key feature" in Tallgren's patients	Hemolytic anemia HP:0001878; Macrocytic anemia HP:0001972	29423877, 37179546
Recurrent infections	Infancy and childhood	A key feature	Recurrent infections HP:0002719	29423877, 37179546
Malabsorption / chronic diarrhea	Infancy	Classic severe cases	Malabsorption HP:0002024	29423877, 35255187
Growth failure / failure to thrive	Infancy; progressive	Classic severe cases	Failure to thrive HP:0001508	29423877
Hepatomegaly, steatosis, hepatic fibrosis; transient liver dysfunction	Infancy	Autopsy and lab findings	Hepatomegaly HP:0002240; Hepatic steatosis HP:0001397; Hepatic fibrosis HP:0001395	29423877
Muscle fibrosis	—	Reported in the earlier cases	Look up	37188825
Cardiac fibrosis	—	Autopsy	Look up	37179546
Congenital heart defects (CoA, VSD, ASD, PDA)	Congenital	Single Chinese sibling; may be coincidental	Look up	39328589
Raised KL-6 (laboratory)	—	Lung injury marker, single case report	—	39328589

Supporting quotes:

"The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction." — PMID:29423877

"Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver." — PMID:29423877

"Seizures, truncal hypotonia and movement disorders were frequently observed." — PMID:37188825

"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." — PMID:37179546

Quality of life. No QoL instrument (EQ-5D, SF-36, PROMIS) has been used. Survivors have severe neurodevelopmental disability and long-term care needs.

4. Genetic and molecular information

Gene. NHLRC2 (NHL repeat-containing protein 2), chromosome 10q25.3, gene OMIM *618277. The protein has three domains:
an N-terminal thioredoxin-like (Trx-like) domain;
a six-bladed NHL-repeat β-propeller;
a non-conserved C-terminal domain.

"The structure reveals two domains adjacent to each other that form a cleft containing a conserved CCINC motif." — PMID:30138417

The Trx-like domain has no measurable thioredoxin activity: "an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity" (PMID:29423877).

Variants reported

Variant	Type	Notes	PMID
c.442G>T p.Asp148Tyr	Missense, hypomorphic	Recurrent; destabilizes the protein by 2 °C; Asp148 is not conserved across species	29423877, 30138417
c.601_602del p.Arg201GlyfsTer6	Frameshift	Not expressed in patient fibroblasts, so likely null	29423877
c.428C>A p.His143Pro	Missense in the Trx-like domain	Absent from gnomAD	32435055
Nine novel variants (missense and truncating)	Mixed	Includes 8 patients without p.Asp148Tyr	37188825
c.1610dupT p.Leu537PhefsTer17	Frameshift	Chinese siblings	39328589
Novel missense (Polish patient)	Missense	Rett-like phenotype	35255187

The c.601_602del coordinate for the frameshift comes from my recollection of the full text and is not in the cached abstract, so confirm it. Brodsky 2020 writes the recurrent variant as "c.442T>G"; this is a notation inconsistency, and c.442G>T is what PMID:37179546 and PMID:33297935 use.

Classification. ClinVar and ClinGen status was not checked in this session. There is no CGGV record in the local cache.
Origin. Germline.
Functional effect. Partial loss of function (hypomorphic), with protein level tracking severity:

"we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype." — PMID:37188825

Modifier genes, epigenetics, chromosomal abnormalities. None reported.

5. Environmental information

Not applicable as a cause. Intercurrent respiratory infections make the lung disease worse (PMID:35255187). There is no infectious agent and no toxicant link.

6. Mechanism and pathophysiology

Causal chain

Biallelic hypomorphic NHLRC2 variants (often p.Asp148Tyr in trans with a null allele) lead to reduced, destabilized NHLRC2 protein. This is demonstrated: low NHLRC2 in patient fibroblasts (PMID:29423877), 2 °C destabilization (PMID:30138417), and lower expression in HEK293 assays (PMID:37188825).
Reduced NHLRC2 leads to abnormal Rho GTPase (RhoA–Rac1) signalling and actin-cytoskeleton dynamics. Proximity-labelling MS in human cells and mESC transcriptomics both point to Rho GTPase signalling (PMID:40510178). A genome-wide CRISPR screen identified NHLRC2 as a regulator of RhoA–Rac1, actin polymerization and filopodia in phagocytosis (Haney et al., Nat Genet 2018, PMID:30397336; cited from web search, not cached). This step is demonstrated in cells; its contribution to patient disease is inferred.
The disturbed cytoskeleton and vesicle transport branch into four outcomes:
3a. Fibroblasts are more likely to become myofibroblasts, which leads to interstitial fibrosis of the lung, liver, muscle and heart. Shown in patient-derived fibroblasts; the link to organ fibrosis is inferred. > "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." — PMID:30239752

Patient cells also show "multilamellar bodies and distinctly organized vimentin filaments" (PMID:30239752). - 3b. Macrophage differentiation and phagocytosis fail, and innate immune responses change, which leads to recurrent infections. This is also a plausible source of inflammatory lung injury, though that link is inferred.

"NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles." — PMID:31594818 (THP-1 knockout)

FINCA mice show "an altered innate immune response, particularly in interferon γ production" (PMID:40510178). - 3c. Neuronal development is disturbed: altered vesicular-transport and actin proteins, and accumulation of hnRNP C2, which leads to neurodevelopmental delay, then progressive neurodegeneration, white-matter vacuolization and myelin loss, seizures and movement disorder. The evidence is from mice; the human link is inferred.

"isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice" — PMID:33297935 - 3d. Cerebral vascular abnormality (angiomatosis-like leptomeningeal and cortical hypervascularization) leads to congestion. The mechanism is unknown. A loose lead: PDGFB showed up next to NHLRC2 in the Salmonella screen (PMID:31594818), but nothing connects it to the angiomatosis. 4. Anemia (haemolytic, macrocytic, dyserythropoietic) has no known mechanism. 5. Redox and apoptosis (peripheral). In HCT116 colon cancer cells, ROS trigger caspase-8 cleavage of NHLRC2 at Asp580, and losing NHLRC2 makes the cells more prone to ROS-induced apoptosis (PMID:29242562). This has not been shown in FINCA tissue. 6. Clinical end-point. The severity of lung fibrosis decides early mortality, and the neurological course decides long-term outcome.

Candidate terms (verify each)

GO biological processes: regulation of Rho protein signal transduction; actin cytoskeleton organization; phagocytosis (GO:0006909); myofibroblast differentiation; macrophage differentiation (GO:0030225); vesicle-mediated transport (GO:0016192); extracellular matrix organization; interferon-gamma production (GO:0032609).
GO cellular component: cytosol (GO:0005829). NHLRC2 is described as "an essential cytosolic protein" in PMID:30138417.
CL cell types: fibroblast (CL:0000057); myofibroblast (CL:0000186); macrophage (CL:0000235); neuron (CL:0000540); oligodendrocyte (CL:0000128, for the myelin loss, inferred); erythrocyte (CL:0000232); hepatocyte (CL:0000182); endothelial cell (CL:0000115, for the angiomatosis, inferred).

Omics data

Transcriptomics of mESCs carrying the variant or the knockout: changes in genes for metabolism, adhesion, neurodevelopment and immune response (PMID:40510178).
2D-DIGE proteomics of E13.5 cortical precursors: 19 altered proteins (PMID:33297935).
BioID proximity-labelling interactomes (PMID:30239752, 40510178).
Interaction partners from immunoprecipitation: FRYL, EIF2AK2, KLHL13 (PMID:31594818).
No single-cell or spatial studies, and no GEO datasets found specific to the disease.

7. Anatomical structures affected

Primary organs: brain, including cerebral cortex, white matter, leptomeninges and cerebellum; lung (interstitium); liver.
Secondary organs: skeletal muscle, heart (fibrosis), gut (malabsorption), bone marrow and erythroid lineage, immune system.
Candidate UBERON terms (verify): brain (UBERON:0000955), lung (UBERON:0002048), liver (UBERON:0002107), leptomeninx (UBERON:0000391), cerebral cortex (UBERON:0000956), cerebellum (UBERON:0002037), white matter.
Subcellular: cytosol, actin cytoskeleton, vimentin intermediate filaments, and multilamellar bodies as an ultrastructural finding.
Laterality: bilateral and diffuse. Chest CT shows bilateral ground-glass opacities (PMID:39328589).

8. Temporal development

Onset. Patients are well at birth, with onset around 2 months in the severe form (PMID:29423877). Onset is in infancy to early childhood across the spectrum.
Course. Two broad trajectories:
Severe: rapidly progressive cerebropulmonary disease with death before about 3 years.
Attenuated: interstitial lung disease stabilizes, and developmental delay becomes the main feature.

"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." — PMID:34165204

Neurological course. Progressive cerebral and cerebellar atrophy has been documented in survivors.
Remission. No spontaneous remission. One child's lung disease improved on long-term glucocorticoids (PMID:39328589).
Critical period. Infancy, for respiratory survival.

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007).
Prevalence: ultra-rare. About 33 published patients by 2025:

"Since our initial characterisation, 33 patients from various ethnic backgrounds have been reported" — PMID:40510178

Later case reports may add a few more. No population prevalence estimate exists, so prevalence_class would be about literature case counts (CASES_IN_LITERATURE) or unknown, not a numeric band. - Populations reported: Finnish (the first families), Ukrainian, German/European chILD register, Jordanian/Middle Eastern, Iranian, Pakistani, Canadian, US, Polish, Austrian, Chinese. - Founder effect: possible for p.Asp148Tyr in Finland (the first families were non-consanguineous). The allele recurs across ancestries, so it is not purely a founder allele. I have not found a formal haplotype analysis. - Consanguinity: present in some of the later homozygous families, for example the Middle Eastern and Iranian families in PMID:37188825 (from the full text; check before use). - Penetrance and expressivity: penetrance appears complete for biallelic genotypes. Expressivity varies widely and tracks residual protein level. - Anticipation and mosaicism: none reported. - Carrier frequency: not established; gnomAD was not queried. - Sex ratio: no sex bias reported.

10. Diagnostics

Genetic testing. Exome sequencing found every reported case, with Sanger confirmation and segregation analysis. No single-gene test is in routine use. NHLRC2 belongs on childhood interstitial lung disease (chILD) panels and on neurodevelopmental, epilepsy and Rett-like panels:

"NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disor[ders]…" — PMID:37188825

"the NHLRC2 gene should be considered in patients with symptoms of atypical Rett syndrome" — PMID:35255187 - Imaging. - Chest CT: ground-glass opacities and consolidation. - Brain MRI: cerebral and cerebellar atrophy, white-matter changes. - Pathology. - Lung: interstitial fibrosis with granuloma-like lesions. - Liver: steatosis and collagen deposition. - Brain: angiomatosis-like vascularization, vacuolar white-matter degeneration. - Fibroblast electron microscopy: multilamellar bodies. - Laboratory. Full blood count (macrocytic or haemolytic anemia), liver function tests, KL-6 (PMID:39328589). There is no disease-specific biomarker. Western blot of NHLRC2 in fibroblasts is a research test. - Differential diagnosis. - Surfactant dysfunction disorders (SFTPB, SFTPC, ABCA3, NKX2-1). NKX2-1 is the brain–lung–thyroid syndrome and also combines a CNS and a lung picture. - MARS1-related pulmonary alveolar proteinosis. - COPA syndrome. - STING-associated vasculopathy (SAVI). - Rett and atypical Rett syndromes. - Mitochondrial disease. - Screening. No newborn screening. Cascade carrier testing and prenatal or preimplantation testing are possible once the familial variants are known.

11. Outcome and prognosis

Mortality. The existing KB entry gives 25.8% overall mortality across 31 patients, and 77.8% among the 9 patients with interstitial lung disease. Those figures need a source quote from the full text: they do not appear in the cached abstracts.
Timing of deaths. Most deaths happen before 3 years, from respiratory failure:

"Patients described by the Finnish and Ukrainian group, and two patients described by Rapp et al. (2021) died before reaching the age of 3" — PMID:35255187
Survivors. Reported survivors have reached late childhood and adulthood (KB entry: 4 to 61 years; check against the full text). They live with moderate to severe intellectual disability, epilepsy and movement disorder.
Prognostic factors. Early interstitial lung disease predicts a poor outcome. Lower residual NHLRC2 expression goes with greater severity (PMID:37188825).

12. Treatment

There is no disease-modifying therapy. Management is supportive.

Intervention	Evidence	Candidate NCIT (verify)
Systemic glucocorticoids for ILD	One case report: respiratory symptoms, CT and KL-6 improved in the younger sibling (PMID:39328589)	Pharmacotherapy NCIT:C15986, plus a therapeutic_agent glucocorticoid such as CHEBI:24261 (verify)
Respiratory support (oxygen, ventilation)	Standard care	Supportive Care NCIT:C15747
Antiseizure medication	Standard care	Pharmacotherapy NCIT:C15986
Nutritional support for malabsorption and growth failure	Standard care	Nutritional Support NCIT:C15433. Per CLAUDE.md, do not tag this BEHAVIORAL without reading the treatment
Physical, occupational and speech therapy	Standard care	NCIT:C15302 / C121351 / C159273
Genetic counseling	Standard care	NCIT:C15240

"the younger brother showed improvement in respiratory symptoms, chest CT, and Krebs von den Lungen-6 levels after long-term systemic glucocorticoid therapy, indicating that anti-inflammatory treatment may be beneficial in the treatment of ILD caused by FINCA syndrome." — PMID:39328589

Clinical trials. None found. No gene therapy, ASO or other targeted approach has been reported.
Pharmacogenomics. None.

13. Prevention

Primary prevention: genetic counseling, with carrier, prenatal or preimplantation testing in families with known variants.
Secondary prevention: early exome sequencing in infants who have chILD together with neurological signs.
Tertiary prevention: prevent and treat infections early, given the infection-related worsening of lung disease. Vaccination is reasonable but has not been studied for this disease. Monitor anemia, liver and nutrition.
Public health and environmental measures: not applicable.

14. Other species and natural disease

No naturally occurring animal disease is known; no OMIA entry was found.
Orthologs: mouse Nhlrc2 and zebrafish nhlrc2. NHLRC2 homologs are "across a range of eukaryotic and prokaryotic species", and the conserved residues sit in the cleft between the Trx-like and β-propeller domains (PMID:30138417).
No zoonotic relevance.

15. Model organisms

Model	Genotype	What it reproduces	Limitations	PMID
Mouse, null	Nhlrc2−/−	Shows the gene is essential: development stops before the morula stage or during gastrulation	Cannot model the postnatal disease	29423877
Mouse, "FINCA mouse"	Knock-in p.Asp148Tyr over a knockout allele (compound heterozygous)	Neurodevelopmental and behavioural changes (adolescent hyperactivity, less exploration of a new object), altered IFN-γ and innate immunity, raised hippocampal hnRNP C2	No severe early multiorgan disease and no fibrosis: "Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex" (PMID:33297935)	33297935, 40510178
Zebrafish	nhlrc2−/−	Early larval lethality; injected nhlrc2 mRNA delays onset and reduces severity	Not yet peer-reviewed (Oulu thesis / conference abstract)	web: Oulu thesis
Patient-derived immortalized skin fibroblasts	Compound heterozygous	Myofibroblast features, multilamellar bodies, vimentin reorganization	Cell culture only; no organ context	30239752
THP-1 macrophages	CRISPR knockout	Failed differentiation, loss of phagocytosis, hyperinflammation	Complete knockout, not hypomorphic; cancer cell line	31594818
HEK293 expression	Variant constructs	Protein-level assay behind the genotype–phenotype correlation	Overexpression system	37188825
mESCs	Homozygous p.Asp148Tyr or knockout	Transcriptomic changes	Embryonic stem-cell context	40510178

For KB curation, the FINCA mouse fits animal_models: with PARTIALLY_RECAPITULATES against the neurodevelopmental and immune nodes and FAILS_TO_RECAPITULATE against the fibrosis node. The abstract quote above can serve as the required evidence for that negative link. This is also a natural HUMAN_MODEL_MISMATCH discussion: the mouse has reduced protein and no fibrosis, while patients have severe fibrosis.

Notes for curation against the existing entry

An untracked entry kb/disorders/Fibrosis_Neurodegeneration_And_Cerebral_Angiomatosis.yaml already exists in this worktree. It cites most of the PMIDs above and has two problems under current rules:
It carries updated_date, which is deprecated.
It uses the deprecated percentage field in prevalence. That should become measure_type: CASES_IN_LITERATURE with structured slots.
Haney et al. 2018 (PMID:30397336) is the main evidence for the RhoA–Rac1 node and is not in references_cache/. Fetch it with just fetch-reference PMID:30397336 before citing it.
Three numbers in the existing entry are not in any cached abstract: the mortality figures (25.8% / 77.8%), the survivor age range (4 to 61 years) and the seizure-onset range. Each needs a full-text source.

Sources

Cached abstracts: PMID:29423877, 30138417, 30239752, 31594818, 32435055, 33297935, 34165204, 35255187, 37179546, 37188825, 39328589, 40510178, 29242562.
Haney et al. 2018, Nat Genet, doi:10.1038/s41588-018-0254-1 and BioGRID ORCS dataset
Hiltunen et al. 2025, PMC12159220; bioRxiv preprint
Oulu thesis: NHLRC2 in embryonic development and FINCA modelling (zebrafish)
Tallgren et al. 2023, PMC10173879; Sczakiel et al. 2023, PMC10400545; Biterova et al. 2018, PMC6107167

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Fibrosis, Neurodegeneration, and Cerebral Angiomatosis (FINCA syndrome): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Candidate terms (verify each)

Omics data

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Notes for curation against the existing entry

Sources