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

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.

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

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

1. 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).
2. 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.
3. The disturbed cytoskeleton and vesicle transport branch into four outcomes:

4. 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.

"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

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