Cardiospondylocarpofacial syndrome

Mendelian MONDO:0008005 Pathograph 25

Cardiospondylocarpofacial syndrome (CSCFS) is an ultrarare autosomal dominant developmental disorder caused by heterozygous pathogenic MAP3K7 variants. The syndrome combines growth impairment, craniofacial dysmorphism, vertebral and carpal-tarsal fusion, congenital heart disease with valve dysplasia, and hearing loss with inner ear malformations. Mechanistically, CSCFS is defined by MAP3K7/TAK1 loss of function with impaired non-canonical TGF-beta/BMP-MAPK signaling, downstream connective tissue dysregulation, and defective cardiomyogenic developmental programs. This entry is scoped to the MAP3K7-related CSCFS loss-of-function phenotype, distinct from allelic MAP3K7 frontometaphyseal dysplasia type 2.

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1
Inheritance
6
Pathophys.
17
Phenotypes
25
Pathograph
1
Genes
6
Treatments
4
Differentials
1
Datasets
12
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
CSCFS is an autosomal dominant MAP3K7 disorder that is usually caused by a de novo heterozygous pathogenic variant.
Autosomal dominant inheritance
Show evidence (2 references)
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"Cardiospondylocarpofacial syndrome (CSCFS) is an extremely rare autosomal dominant disorder resulting from variant in the MAP3K7 gene"
This directly supports autosomal dominant inheritance for CSCFS.
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"The variant was confirmed by Sanger sequencing to be absent in other family members and is de novo."
This provides direct evidence that at least some CSCFS cases arise de novo.
⚙

Pathophysiology

6
MAP3K7 haploinsufficiency
CSCFS is initiated by heterozygous pathogenic MAP3K7 variants that reduce TAK1 function, distinguishing the syndrome from allelic gain-of-function frontometaphyseal dysplasia biology.
MAP3K7 link
Downstream
Impaired non-canonical TGF-beta/BMP-MAPK-p38 signaling Reduced TAK1 dosage impairs the developmental signaling outputs that normally connect TGF-beta and BMP inputs to MAPK-p38 transcriptional responses.
Connective tissue dysregulation Reduced TAK1 activity perturbs tissue-homeostasis programs that manifest clinically as a syndromic connective tissue disorder.
Show evidence (2 references)
PMID:27426734 SUPPORT Human Clinical
"Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families"
This causative series establishes heterozygous MAP3K7 variation as the initiating genetic lesion in CSCFS.
PMID:35730652 SUPPORT Human Clinical
"Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect."
This directly establishes loss of TAK1 function as the central CSCFS mechanism.
Impaired non-canonical TGF-beta/BMP-MAPK-p38 signaling
TAK1 normally transduces TGF-beta and BMP inputs into downstream MAPK-p38 responses. In CSCFS this signaling axis is dysregulated in patient-derived cells, altering developmental transcriptional control.
fibroblast link
MAP3K7 link
transforming growth factor beta receptor signaling pathway link BMP signaling pathway link MAPK cascade link
Downstream
Defective fibroblast cytoskeleton assembly and autophagy Impaired TAK1 signaling in fibroblasts disrupts alpha-SMA cytoskeletal responses and autophagic homeostasis.
Primary-cilium-dependent cardiomyogenesis defect Disrupted TAK1 signaling impairs cardiac developmental signaling programs.
Abnormal skeletal segmentation and fusion Altered developmental signaling drives vertebral and carpal-tarsal fusion phenotypes.
Show evidence (2 references)
PMID:35700636 SUPPORT In Vitro
"TAK1 is a serine threonine kinase that mediates signal transduction induced by TGFβ and bone morphogenetic proteins, and controls a variety of cell functions by modulating the downstream activation of NF-kkB, JNK, and p38."
This iPSC-resource paper directly supports the affected signaling axes downstream of MAP3K7/TAK1.
PMID:27426734 SUPPORT Human Clinical
"These findings support the loss of transcriptional control of the TGF-β-MAPK-p38 pathway in fibroblasts obtained from affected individuals."
This supports dysregulated non-canonical TGF-beta/MAPK-p38 signaling in patient-derived fibroblasts.
Defective fibroblast cytoskeleton assembly and autophagy
Patient-derived fibroblast studies support impaired TGF-beta-mediated alpha-SMA cytoskeleton assembly, reduced cell migration, and defective autophagy as a discrete cellular consequence of CSCFS-causing MAP3K7 dysfunction.
fibroblast link
autophagy link
Downstream
Connective tissue dysregulation Impaired fibroblast stress-fiber and autophagy responses provide a cellular basis for connective tissue fragility and hypermobility.
Show evidence (1 reference)
DOI:10.1016/j.bbadis.2020.165742 SUPPORT In Vitro
"alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy"
The article title provides direct verifiable support for altered cytoskeletal assembly and autophagy in CSCFS-associated MAP3K7 dysfunction.
Primary-cilium-dependent cardiomyogenesis defect
TAK1-dependent signaling at the primary cilium is required for normal cardiomyocyte differentiation and heart development; CSCFS-associated TAK1 dysfunction is linked to syndromic congenital heart disease.
cardiac muscle cell link
MAP3K7 link
cardiomyocyte differentiation link ↓ DECREASED
Downstream
Atrial septal defect Abnormal cardiogenesis predisposes to structural congenital heart defects.
Dilated cardiomyopathy Severe developmental and signaling disruption can extend to cardiomyopathic remodeling.
Show evidence (2 references)
GEO:GSE279246 SUPPORT In Vitro
"Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or administration of small molecule inhibitors targeting TAK1 inhibited ciliary signaling and cardiomyocyte differentiation in vitro"
This directly links TAK1 disruption to defective cardiomyocyte differentiation.
GEO:GSE279246 SUPPORT Model Organism
"RNA sequencing of tak1-/- mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins."
This supports transcriptional cardiac developmental failure downstream of TAK1 loss.
Connective tissue dysregulation
CSCFS overlaps with connective tissue disorder phenotypes, including skin, joint, gastrointestinal, and valvular manifestations, consistent with abnormal TAK1-dependent matrix and tissue-homeostasis signaling.
fibroblast link
Downstream
Joint hypermobility Connective tissue fragility contributes to marked joint laxity.
Show evidence (2 references)
PMID:29467388 SUPPORT Human Clinical
"The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility."
This directly supports a connective tissue dysregulation node in CSCFS.
PMID:35730652 SUPPORT Human Clinical
"Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease, and we show overlap in clinical phenotypes of CSCF with Noonan syndrome (NS)."
Cohort-level evidence supports connective tissue disease overlap as a core part of the syndrome.
Abnormal skeletal segmentation and fusion
Developmental disturbance of the axial and appendicular skeleton leads to progressive vertebral, carpal, and tarsal fusion patterns in CSCFS.
skeletal system development link
Downstream
Vertebral fusion Abnormal segmentation of the spine produces vertebral fusion.
Carpal synostosis Abnormal wrist skeletal patterning leads to carpal fusion.
Tarsal synostosis Developmental fusion also affects tarsal bones.
Show evidence (2 references)
PMID:34558790 SUPPORT Human Clinical
"Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by growth impairment, failure to thrive in infancy, multiple valvular disease, carpal and tarsal fusions, vertebral fusions, and joint hypermobility."
This directly supports fused axial and appendicular skeletal development as a core mechanism-linked phenotype cluster.
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"AbstractWe report on two unrelated cases born to nonconsanguineous parents with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation, facial dysmorphism, congenital cardiac defects (septal defect and non progressive multiple..."
The original syndrome report supports extensive vertebral and carpal/tarsal synostosis as defining developmental outcomes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiospondylocarpofacial syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

17
Cardiovascular 3
Atrial septal defect OCCASIONAL Atrial septal defect (HP:0001631)
Show evidence (1 reference)
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"The main manifestations are growth retardation, hypotonia, dysmorphic facial features, skeletal and limb abnormalities, cardiac septal defects with valve dysplasia, cardiomyopathy, and deafness with inner ear malformations."
This supports atrial septal defect within the broader septal-defect phenotype spectrum of CSCFS.
Polyvalvular heart disease FREQUENT Abnormal heart valve morphology (HP:0001654)
Show evidence (1 reference)
PMID:29467388 SUPPORT Human Clinical
"The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility."
This directly supports polyvalvular heart disease as a core CSCFS cardiac phenotype.
Dilated cardiomyopathy OCCASIONAL Dilated cardiomyopathy (HP:0001644)
Show evidence (1 reference)
DOI:10.4103/apc.apc_235_24 SUPPORT Human Clinical
"We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy (DCM) and congenital heart disease (CHD) and presented with acute heart failure (HF)."
This supports dilated cardiomyopathy as an important severe cardiac phenotype in CSCFS.
Ear 1
Hearing impairment FREQUENT Hearing impairment (HP:0000365)
Show evidence (1 reference)
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"AbstractWe report on two unrelated cases born to nonconsanguineous parents with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation, facial dysmorphism, congenital cardiac defects (septal defect and non progressive multiple..."
This directly supports hearing impairment/deafness in the original syndrome description.
Head and Neck 1
Craniofacial dysmorphism VERY_FREQUENT Abnormal facial shape (HP:0001999)
Show evidence (1 reference)
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"The main manifestations are growth retardation, hypotonia, dysmorphic facial features, skeletal and limb abnormalities, cardiac septal defects with valve dysplasia, cardiomyopathy, and deafness with inner ear malformations."
This directly identifies dysmorphic facial features as a core CSCFS manifestation.
Limbs 2
Carpal synostosis VERY_FREQUENT Carpal synostosis (HP:0009702)
Show evidence (1 reference)
PMID:34558790 SUPPORT Human Clinical
"Another major achievement of this research is to successfully capture the process of carpal fusion in a CSCF case radiographically."
This directly supports carpal synostosis and its radiographic evolution in CSCFS.
Tarsal synostosis FREQUENT Tarsal synostosis (HP:0008368)
Show evidence (1 reference)
DOI:10.1002/pd.6358 SUPPORT Human Clinical
"The characteristic features of CSCF include growth retardation, facial dysmorphism, carpal-tarsal fusion, dorsal spine synostosis, deafness, inner ear malformation, cardiac septal defect and valve dysplasia."
This directly supports tarsal synostosis as part of the characteristic CSCFS skeletal pattern.
Musculoskeletal 3
Hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (1 reference)
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"The main manifestations are growth retardation, hypotonia, dysmorphic facial features, skeletal and limb abnormalities, cardiac septal defects with valve dysplasia, cardiomyopathy, and deafness with inner ear malformations."
This supports hypotonia as part of the recurrent CSCFS phenotype spectrum.
Vertebral fusion VERY_FREQUENT Vertebral fusion (HP:0002948)
Show evidence (1 reference)
PMID:34558790 SUPPORT Human Clinical
"Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by growth impairment, failure to thrive in infancy, multiple valvular disease, carpal and tarsal fusions, vertebral fusions, and joint hypermobility."
This directly supports vertebral fusion as a defining skeletal phenotype.
Joint hypermobility FREQUENT Joint hypermobility (HP:0001382)
Show evidence (1 reference)
PMID:29467388 SUPPORT Human Clinical
"The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility."
This directly supports pronounced joint hypermobility in CSCFS.
Nervous System 3
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"At the age of 4 months and 22 days, the Gesell Developmental Diagnostic Scale was used to assess his Developmental Quotient (DQ, DQ < 70 as low score) (gross motor 29, fine motor 63, adaptive 60, language 41 and personal-social 49)."
Multi-domain low developmental quotients support global developmental delay in the reported CSCFS patient.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"He had hypotonia and delays in developmental milestones."
The case report directly documents delayed developmental milestones.
Delayed speech and language development OCCASIONAL Delayed speech and language development (HP:0000750)
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"The short lingual frenulum, first observed in our patients, may also be a factor affecting speech development."
The 2025 case report discusses impaired speech development in the context of CSCFS-associated craniofacial findings.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"Our patients exhibited mild intellectual disability, delayed language and motor development."
This directly supports delayed language development as part of the expanded CSCFS phenotype.
Mild intellectual disability OCCASIONAL Mild intellectual disability (HP:0001256)
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"He was diagnosed with a mild intellectual disability."
The full-text 2025 case directly documents mild intellectual disability.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"When assessed at the age of 7 years and 3 months using the Wechsler Intelligence Scale for Children, his Full Scale IQ score was determined to be 71."
A borderline-low full-scale IQ score supports the mild intellectual disability phenotype.
Growth 1
Short stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"AbstractWe report on two unrelated cases born to nonconsanguineous parents with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation"
This directly supports postnatal growth retardation and short stature in the original syndrome description.
Other 3
Failure to thrive in infancy VERY_FREQUENT Failure to thrive in infancy (HP:0001531)
Show evidence (2 references)
PMID:34558790 SUPPORT Human Clinical
"Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by growth impairment, failure to thrive in infancy, multiple valvular disease, carpal and tarsal fusions, vertebral fusions, and joint hypermobility."
The molecularly confirmed Asian case review identifies failure to thrive in infancy as a characteristic CSCFS manifestation.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"He was admitted to the Pediatric Rehabilitation Department of Guangxi Maternal and Child Health Hospital for developmental delay and failure to thrive when he was 5 months old."
The full-text 2025 case provides patient-level evidence of early failure to thrive.
Brain imaging abnormality OCCASIONAL Brain imaging abnormality (HP:0410263)
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"Brain Magnetic resonance imaging at 5 months of age showed bilateral hemispheric asymmetry and widening of the right frontotemporal extracerebral space."
This directly supports brain MRI abnormalities as an occasional expanded phenotype.
Inner ear malformation FREQUENT Abnormal inner ear morphology (HP:0011390)
Show evidence (1 reference)
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"AbstractWe report on two unrelated cases born to nonconsanguineous parents with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation, facial dysmorphism, congenital cardiac defects (septal defect and non progressive multiple..."
This directly supports inner-ear malformations as a separate structural CSCFS phenotype.
🧬

Genetic Associations

1
MAP3K7 (Causative)
Show evidence (2 references)
PMID:29467388 SUPPORT Human Clinical
"Heterozygous variants in MAP3K7, encoding the transforming growth factor-β-activated kinase 1 (TAK1), are associated with the ultrarare cardiospondylocarpofacial syndrome (CSCFS)."
This directly establishes MAP3K7 as the disease gene.
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"Whole exome sequencing revealed a novel heterozygous variant, c.142G > A[p. (Gly48Arg)], in the MAP3K7 gene. The variant was confirmed by Sanger sequencing to be absent in other family members and is de novo."
This supports the typical de novo autosomal dominant inheritance pattern in CSCFS.
💊

Treatments

6
Cardiology surveillance and management
Action: supportive care MAXO:0000950
Baseline and serial cardiology assessment should monitor septal defects, valve dysplasia or regurgitation, arrhythmia, pulmonary hypertension, and cardiomyopathy; cardiac MRI or rhythm monitoring may be used when echocardiography or symptoms indicate.
Target Phenotypes: Polyvalvular heart disease ↗ Dilated cardiomyopathy ↗
Show evidence (2 references)
PMID:35730652 SUPPORT Human Clinical
"patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease"
The MAP3K7 cohort explicitly supports ongoing cardiac risk surveillance.
DOI:10.4103/apc.apc_235_24 SUPPORT Human Clinical
"We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy (DCM) and congenital heart disease (CHD) and presented with acute heart failure (HF)."
Severe neonatal cardiomyopathy and congenital heart disease justify cardiology surveillance and prompt management of cardiac decompensation.
Audiology and hearing support
Action: hearing aid usage MAXO:0009030
Audiologic evaluation and otolaryngology follow-up should assess conductive or sensorineural hearing loss, inner-ear malformations, and recurrent otitis media; hearing aids or other hearing support should be provided when indicated.
Target Phenotypes: Hearing impairment ↗ Inner ear malformation ↗
Show evidence (2 references)
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"deafness, and inner ear malformations."
The original syndrome report supports dedicated hearing evaluation and hearing support.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"He was also diagnosed with conductive hearing impairment with an average hearing threshold of 52.6 dB."
Quantified hearing loss in a recent patient supports audiology follow-up and hearing support.
Orthopedic and spine surveillance
Action: orthopedic procedure MAXO:0000477
Orthopedic follow-up with spine and extremity imaging should monitor vertebral fusion, carpal/tarsal synostosis, scoliosis, pectus deformity, delayed bone age, foot deformity, and joint hypermobility.
Target Phenotypes: Vertebral fusion ↗ Carpal synostosis ↗ Tarsal synostosis ↗
Show evidence (2 references)
PMID:34558790 SUPPORT Human Clinical
"Another major achievement of this research is to successfully capture the process of carpal fusion in a CSCF case radiographically."
Radiographic progression of carpal fusion supports serial skeletal imaging and orthopedic surveillance.
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"shortened extremities, carpal/tarsal and extensive vertebral synostosis, delayed carpal bone age"
The original report supports orthopedic monitoring for axial and appendicular skeletal abnormalities.
Developmental, speech, and rehabilitation therapies
Action: supportive care MAXO:0000950
Developmental assessment should guide early intervention, physical therapy for hypotonia and motor delay, occupational therapy for adaptive and fine motor needs, and speech-language therapy for delayed language or speech affected by hearing impairment or oral structural differences.
Target Phenotypes: Global developmental delay ↗ Delayed speech and language development ↗ Hypotonia ↗
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"He had hypotonia and delays in developmental milestones."
Motor and developmental delays support early developmental and rehabilitation services.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"The short lingual frenulum, first observed in our patients, may also be a factor affecting speech development."
Speech-development impact supports speech-language evaluation and therapy when indicated.
Feeding and growth support
Action: nutrition intervention MAXO:0000009
Infants and children with poor growth should receive nutrition assessment, feeding therapy, and gastroenterology support; gastrostomy or surgical management may be required for severe feeding or gastrointestinal complications.
Target Phenotypes: Failure to thrive in infancy ↗
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/ SUPPORT Human Clinical
"Most patients experienced growth issues, largely attributed to feeding difficulties and gastrointestinal problems, with the majority undergoing gastrostomy."
Feeding and gastrointestinal problems as a common driver of growth issues support feeding and nutrition intervention.
PMID:34558790 SUPPORT Human Clinical
"growth impairment, failure to thrive in infancy, multiple valvular disease, carpal and tarsal fusions, vertebral fusions, and joint hypermobility."
Failure to thrive in infancy supports active growth and nutrition support.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling should address autosomal dominant inheritance, the frequent de novo presentation, recurrence risk when a parent is affected or mosaic, and reproductive testing options for families with an identified MAP3K7 variant.
Show evidence (2 references)
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"Cardiospondylocarpofacial syndrome (CSCFS) is an extremely rare autosomal dominant disorder resulting from variant in the MAP3K7 gene"
Autosomal dominant inheritance supports counseling about transmission and recurrence risk.
DOI:10.3389/fped.2025.1651803 SUPPORT Human Clinical
"The variant was confirmed by Sanger sequencing to be absent in other family members and is de novo."
De novo occurrence supports counseling about typical recurrence risk and the possibility of parental mosaicism.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Cardiospondylocarpofacial syndrome:

Frontometaphyseal dysplasia type 2
Overlapping Features MAP3K7 gain-of-function disease is allelic to CSCFS but has a distinct frontometaphyseal dysplasia phenotype.
Distinguishing Features
  • CSCFS-associated MAP3K7 variants act through loss of function, whereas FMD2-associated variants show a different functional fingerprint.
  • Prominent cardioskeletal-connective tissue overlap with valve disease and carpal-tarsal fusion favors CSCFS over the metaphyseal/frontometaphyseal dysplasia pattern.
Show evidence (1 reference)
PMID:29467388 SUPPORT Human Clinical
"Specific gain-of-function variants in the same gene cause the allelic frontometaphyseal dysplasia type 2."
This directly supports FMD2 as an allelic differential diagnosis for CSCFS.
Noonan syndrome MONDO:0018997
Overlapping Features Noonan syndrome overlaps through short stature, congenital heart disease, and syndromic facies, but CSCFS adds characteristic vertebral and carpal-tarsal fusion.
Distinguishing Features
  • Carpal/tarsal fusion and extensive vertebral synostosis favor CSCFS over Noonan syndrome.
  • MAP3K7-associated connective tissue findings and deafness with inner-ear malformation also support CSCFS.
Show evidence (1 reference)
PMID:35730652 SUPPORT Human Clinical
"Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders,..."
This cohort study directly names Noonan syndrome as a differential diagnosis.
Ehlers-Danlos syndrome MONDO:0020066
Overlapping Features CSCFS overlaps with EDS through connective tissue manifestations and joint hypermobility, but fused vertebrae and carpal/tarsal synostosis support CSCFS.
Distinguishing Features
  • Extensive vertebral and carpal-tarsal fusion are not typical defining features of Ehlers-Danlos syndrome.
  • Congenital septal and valvular heart disease with MAP3K7 causation favor CSCFS.
Show evidence (1 reference)
PMID:34558790 SUPPORT Human Clinical
"In addition to the main symptoms of CSCF, the present case had a mixed phenotype of Ehlers-Danlos syndrome (EDS) and Noonan syndrome."
This directly supports EDS as an important phenotypic differential.
Spondylocarpotarsal synostosis syndrome MONDO:0010094
Overlapping Features Spondylocarpotarsal synostosis syndrome overlaps through vertebral and carpal-tarsal fusion, but CSCFS adds congenital heart disease, deafness, and distinctive craniofacial findings.
Distinguishing Features
  • Congenital cardiac defects with valve dysplasia and inner-ear malformations support CSCFS over isolated spondylocarpotarsal synostosis syndrome.
  • The original CSCFS description specifically excluded FLNB in the overlapping skeletal disorder differential.
Show evidence (1 reference)
DOI:10.1002/ajmg.a.33277 SUPPORT Human Clinical
"Although some features are similar to spondylocarpotarsal synostosis syndrome, the exclusion of FLNB and this constellation of findings suggest a new entity"
This directly supports spondylocarpotarsal synostosis syndrome as a key skeletal differential diagnosis.
📊

Related Datasets

1
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development geo:GSE279246
Bulk transcriptomic and mechanistic developmental dataset linking TAK1/MAP3K7 dysfunction to syndromic congenital heart disease, cardiomyocyte differentiation failure, and altered cardiac developmental gene expression.
zebrafish BULK RNA SEQ
heart
Conditions: cardiospondylocarpofacial syndrome congenital heart disease MAP3K7/TAK1 dysfunction
Findings
TAK1 loss downregulates core cardiac transcriptional programs, sarcomeric genes, and extracellular matrix genes in mutant hearts.
Show evidence (1 reference)
GEO:GSE279246 SUPPORT Model Organism
"RNA sequencing of tak1-/- mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins."
This directly supports the dataset's relevance to CSCFS cardiac developmental mechanisms.
TAK1 perturbation inhibits ciliary signaling and cardiomyocyte differentiation in vitro.
Show evidence (1 reference)
GEO:GSE279246 SUPPORT In Vitro
"Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or administration of small molecule inhibitors targeting TAK1 inhibited ciliary signaling and cardiomyocyte differentiation in vitro"
This complements the zebrafish transcriptomic finding with cell-based evidence of impaired cardiomyogenesis.
Show evidence (1 reference)
GEO:GSE279246 SUPPORT Model Organism
"RNA sequencing of tak1-/- mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins."
This supports GEO:GSE279246 as a disease-relevant zebrafish cardiac transcriptomic dataset for TAK1 biology.
{ }

Source YAML

click to show 
name: Cardiospondylocarpofacial syndrome
creation_date: "2026-04-21T14:07:20Z"
updated_date: "2026-04-21T23:48:00Z"
category: Mendelian
description: >-
  Cardiospondylocarpofacial syndrome (CSCFS) is an ultrarare autosomal dominant
  developmental disorder caused by heterozygous pathogenic MAP3K7 variants.
  The syndrome combines growth impairment, craniofacial dysmorphism, vertebral
  and carpal-tarsal fusion, congenital heart disease with valve dysplasia, and
  hearing loss with inner ear malformations. Mechanistically, CSCFS is defined
  by MAP3K7/TAK1 loss of function with impaired non-canonical TGF-beta/BMP-MAPK
  signaling, downstream connective tissue dysregulation, and defective
  cardiomyogenic developmental programs. This entry is scoped to the
  MAP3K7-related CSCFS loss-of-function phenotype, distinct from allelic
  MAP3K7 frontometaphyseal dysplasia type 2.
synonyms:
- CSCFS
- CSCF syndrome
disease_term:
  preferred_term: cardiospondylocarpofacial syndrome
  term:
    id: MONDO:0008005
    label: cardiospondylocarpofacial syndrome
notes: >-
  CSCFS is allelic with frontometaphyseal dysplasia type 2 but has a distinct
  loss-of-function TAK1 fingerprint and a syndromic combination of skeletal,
  connective tissue, and cardiac developmental abnormalities. Published case
  series also note phenotypic overlap with Noonan syndrome and Ehlers-Danlos
  syndrome.
prevalence:
- population: Published literature through 2025
  percentage: 26 reported cases worldwide
  notes: >-
    This is a literature case count rather than a population-based prevalence
    estimate.
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only 26 cases of CSCFS have been reported worldwide.
    explanation: >-
      This contemporary case review supports the current literature-reported
      rarity of CSCFS.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    CSCFS is an autosomal dominant MAP3K7 disorder that is usually caused by a
    de novo heterozygous pathogenic variant.
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiospondylocarpofacial syndrome (CSCFS) is an extremely rare autosomal
      dominant disorder resulting from variant in the MAP3K7 gene
    explanation: >-
      This directly supports autosomal dominant inheritance for CSCFS.
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was confirmed by Sanger sequencing to be absent in other
      family members and is de novo.
    explanation: >-
      This provides direct evidence that at least some CSCFS cases arise de novo.
pathophysiology:
- name: MAP3K7 haploinsufficiency
  description: >-
    CSCFS is initiated by heterozygous pathogenic MAP3K7 variants that reduce
    TAK1 function, distinguishing the syndrome from allelic gain-of-function
    frontometaphyseal dysplasia biology.
  genes:
  - preferred_term: MAP3K7
    term:
      id: hgnc:6859
      label: MAP3K7
  evidence:
  - reference: PMID:27426734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified heterozygous MAP3K7 mutations in six
      distinct CSCF-affected individuals from four families
    explanation: >-
      This causative series establishes heterozygous MAP3K7 variation as the
      initiating genetic lesion in CSCFS.
  - reference: PMID:35730652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings support that in contrast to FMD2-causing mutations, CSCF-causing
      mutations in MAP3K7 have a loss-of-function effect.
    explanation: >-
      This directly establishes loss of TAK1 function as the central CSCFS
      mechanism.
  downstream:
  - target: Impaired non-canonical TGF-beta/BMP-MAPK-p38 signaling
    description: >-
      Reduced TAK1 dosage impairs the developmental signaling outputs that
      normally connect TGF-beta and BMP inputs to MAPK-p38 transcriptional
      responses.
    evidence:
    - reference: PMID:27426734
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MAPK-p38 signaling was markedly altered when expression of
        non-canonical TGF-beta-driven target genes was impaired.
      explanation: >-
        This supports the direct causal step from MAP3K7 haploinsufficiency to
        impaired non-canonical TGF-beta/MAPK-p38 signaling.
  - target: Connective tissue dysregulation
    description: >-
      Reduced TAK1 activity perturbs tissue-homeostasis programs that manifest
      clinically as a syndromic connective tissue disorder.
    evidence:
    - reference: PMID:29467388
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study confirms locus homogeneity for CSCFS, expands the mutational
        spectrum of MAP3K7, and adds data on the existence of a community of
        connective tissue disorders caused by abnormalities of the TAK1-dependent
        signaling pathway.
      explanation: >-
        This directly supports connective tissue dysregulation as a downstream
        consequence of abnormal TAK1 signaling.
- name: Impaired non-canonical TGF-beta/BMP-MAPK-p38 signaling
  description: >-
    TAK1 normally transduces TGF-beta and BMP inputs into downstream MAPK-p38
    responses. In CSCFS this signaling axis is dysregulated in patient-derived
    cells, altering developmental transcriptional control.
  genes:
  - preferred_term: MAP3K7
    term:
      id: hgnc:6859
      label: MAP3K7
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
  evidence:
  - reference: PMID:35700636
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TAK1 is a serine threonine kinase that mediates signal transduction induced
      by TGFβ and bone morphogenetic proteins, and controls a variety of cell
      functions by modulating the downstream activation of NF-kkB, JNK, and p38.
    explanation: >-
      This iPSC-resource paper directly supports the affected signaling axes
      downstream of MAP3K7/TAK1.
  - reference: PMID:27426734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings support the loss of transcriptional control of the
      TGF-β-MAPK-p38 pathway in fibroblasts obtained from affected individuals.
    explanation: >-
      This supports dysregulated non-canonical TGF-beta/MAPK-p38 signaling in
      patient-derived fibroblasts.
  downstream:
  - target: Defective fibroblast cytoskeleton assembly and autophagy
    description: >-
      Impaired TAK1 signaling in fibroblasts disrupts alpha-SMA cytoskeletal
      responses and autophagic homeostasis.
    evidence:
    - reference: DOI:10.1016/j.bbadis.2020.165742
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy
      explanation: >-
        The article title directly supports altered fibroblast cytoskeletal and
        autophagy responses downstream of CSCFS-causing MAP3K7 dysfunction.
  - target: Primary-cilium-dependent cardiomyogenesis defect
    description: >-
      Disrupted TAK1 signaling impairs cardiac developmental signaling programs.
    evidence:
    - reference: GEO:GSE279246
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Detailed characterization of tak1-/- and tab2-/- zebrafish mutants
        revealed cardiac defects (dilated atrium, trabeculation defects,
        tachycardia and reduced contractility) as well as extracardiac
        developmental anomalies.
      explanation: >-
        Zebrafish loss-of-function data support a developmental cardiac defect
        downstream of TAK1 disruption.
    - reference: GEO:GSE279246
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or
        administration of small molecule inhibitors targeting TAK1 inhibited
        ciliary signaling and cardiomyocyte differentiation in vitro
      explanation: >-
        In vitro perturbation data directly support a cardiomyogenic defect tied
        to TAK1-dependent ciliary signaling.
  - target: Abnormal skeletal segmentation and fusion
    description: >-
      Altered developmental signaling drives vertebral and carpal-tarsal fusion
      phenotypes.
    evidence:
    - reference: DOI:10.4103/apc.apc_235_24
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It encodes transforming growth factor-β activated kinase1 (TAK1), a member
        of the mitogen-activated protein kinase (MAPK) family, and is responsible
        for abnormal skeletal and cardiac morphogenesis.
      explanation: >-
        This supports abnormal skeletal morphogenesis downstream of MAP3K7
        dysfunction.
- name: Defective fibroblast cytoskeleton assembly and autophagy
  description: >-
    Patient-derived fibroblast studies support impaired TGF-beta-mediated
    alpha-SMA cytoskeleton assembly, reduced cell migration, and defective
    autophagy as a discrete cellular consequence of CSCFS-causing MAP3K7
    dysfunction.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: DOI:10.1016/j.bbadis.2020.165742
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy
    explanation: >-
      The article title provides direct verifiable support for altered
      cytoskeletal assembly and autophagy in CSCFS-associated MAP3K7
      dysfunction.
  downstream:
  - target: Connective tissue dysregulation
    description: >-
      Impaired fibroblast stress-fiber and autophagy responses provide a
      cellular basis for connective tissue fragility and hypermobility.
    evidence:
    - reference: PMID:29467388
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was originally ascertained for a presumed hereditary connective
        tissue disorder due to soft/dystrophic skin, extreme joint hypermobility,
        polyvalvular heart disease, and upper gastrointestinal dismotility.
      explanation: >-
        This clinical phenotype supports connective tissue consequences
        downstream of fibroblast dysfunction.
- name: Primary-cilium-dependent cardiomyogenesis defect
  description: >-
    TAK1-dependent signaling at the primary cilium is required for normal
    cardiomyocyte differentiation and heart development; CSCFS-associated TAK1
    dysfunction is linked to syndromic congenital heart disease.
  genes:
  - preferred_term: MAP3K7
    term:
      id: hgnc:6859
      label: MAP3K7
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiomyocyte differentiation
    term:
      id: GO:0055007
      label: cardiac muscle cell differentiation
    modifier: DECREASED
  evidence:
  - reference: GEO:GSE279246
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or
      administration of small molecule inhibitors targeting TAK1 inhibited ciliary
      signaling and cardiomyocyte differentiation in vitro
    explanation: >-
      This directly links TAK1 disruption to defective cardiomyocyte
      differentiation.
  - reference: GEO:GSE279246
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA sequencing of tak1-/- mutant hearts showed downregulation of genes
      encoding core cardiac transcription factors, sarcomeric proteins and
      extracellular matrix proteins.
    explanation: >-
      This supports transcriptional cardiac developmental failure downstream of
      TAK1 loss.
  downstream:
  - target: Atrial septal defect
    description: >-
      Abnormal cardiogenesis predisposes to structural congenital heart defects.
    evidence:
    - reference: DOI:10.3389/fped.2025.1651803
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main manifestations are growth retardation, hypotonia, dysmorphic
        facial features, skeletal and limb abnormalities, cardiac septal defects
        with valve dysplasia, cardiomyopathy, and deafness with inner ear
        malformations.
      explanation: >-
        This supports septal heart defects as a downstream consequence of CSCFS
        cardiac developmental pathology.
  - target: Dilated cardiomyopathy
    description: >-
      Severe developmental and signaling disruption can extend to cardiomyopathic
      remodeling.
    evidence:
    - reference: DOI:10.4103/apc.apc_235_24
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene
        c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy
        (DCM) and congenital heart disease (CHD) and presented with acute heart
        failure (HF).
      explanation: >-
        This supports dilated cardiomyopathy as a clinically important downstream
        cardiac consequence in some CSCFS patients.
- name: Connective tissue dysregulation
  description: >-
    CSCFS overlaps with connective tissue disorder phenotypes, including skin,
    joint, gastrointestinal, and valvular manifestations, consistent with abnormal
    TAK1-dependent matrix and tissue-homeostasis signaling.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:29467388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was originally ascertained for a presumed hereditary connective
      tissue disorder due to soft/dystrophic skin, extreme joint hypermobility,
      polyvalvular heart disease, and upper gastrointestinal dismotility.
    explanation: >-
      This directly supports a connective tissue dysregulation node in CSCFS.
  - reference: PMID:35730652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, patients with pathogenic mutations in MAP3K7 are at risk for
      (severe) cardiac disease, have symptoms associated with connective tissue
      disease, and we show overlap in clinical phenotypes of CSCF with Noonan
      syndrome (NS).
    explanation: >-
      Cohort-level evidence supports connective tissue disease overlap as a core
      part of the syndrome.
  downstream:
  - target: Joint hypermobility
    description: Connective tissue fragility contributes to marked joint laxity.
    evidence:
    - reference: PMID:34558790
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by
        growth impairment, failure to thrive in infancy, multiple valvular disease,
        carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
      explanation: >-
        This directly supports joint hypermobility as a downstream connective tissue
        phenotype.
- name: Abnormal skeletal segmentation and fusion
  description: >-
    Developmental disturbance of the axial and appendicular skeleton leads to
    progressive vertebral, carpal, and tarsal fusion patterns in CSCFS.
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by
      growth impairment, failure to thrive in infancy, multiple valvular disease,
      carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
    explanation: >-
      This directly supports fused axial and appendicular skeletal development as a
      core mechanism-linked phenotype cluster.
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AbstractWe report on two unrelated cases born to nonconsanguineous parents
      with a similar clinical presentation: hypotonia since the neonatal period,
      severe failure to thrive, postnatal growth retardation, facial dysmorphism,
      congenital cardiac defects (septal defect and non progressive multiple valve
      dysplasia), shortened extremities, carpal/tarsal and extensive vertebral
      synostosis, delayed carpal bone age, deafness, and inner ear malformations.
    explanation: >-
      The original syndrome report supports extensive vertebral and carpal/tarsal
      synostosis as defining developmental outcomes.
  downstream:
  - target: Vertebral fusion
    description: Abnormal segmentation of the spine produces vertebral fusion.
    evidence:
    - reference: PMID:34558790
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by
        growth impairment, failure to thrive in infancy, multiple valvular disease,
        carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
      explanation: >-
        This supports vertebral fusion as a direct downstream skeletal outcome.
  - target: Carpal synostosis
    description: Abnormal wrist skeletal patterning leads to carpal fusion.
    evidence:
    - reference: PMID:34558790
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Another major achievement of this research is to successfully capture the
        process of carpal fusion in a CSCF case radiographically.
      explanation: >-
        This directly supports carpal fusion as a mechanistically linked skeletal
        phenotype.
  - target: Tarsal synostosis
    description: Developmental fusion also affects tarsal bones.
    evidence:
    - reference: DOI:10.1002/pd.6358
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The characteristic features of CSCF include growth retardation, facial
        dysmorphism, carpal-tarsal fusion, dorsal spine synostosis, deafness, inner
        ear malformation, cardiac septal defect and valve dysplasia.
      explanation: >-
        This prenatal case report directly supports tarsal fusion within the
        syndrome pattern.
phenotypes:
- category: Growth
  name: Short stature
  frequency: VERY_FREQUENT
  description: >-
    Postnatal growth retardation and short stature are among the most consistent
    CSCFS manifestations.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AbstractWe report on two unrelated cases born to nonconsanguineous parents
      with a similar clinical presentation: hypotonia since the neonatal period,
      severe failure to thrive, postnatal growth retardation
    explanation: >-
      This directly supports postnatal growth retardation and short stature in the
      original syndrome description.
- category: Growth
  name: Failure to thrive in infancy
  frequency: VERY_FREQUENT
  description: >-
    Feeding difficulty and poor infant growth are common early manifestations of
    CSCFS and may drive later short stature.
  phenotype_term:
    preferred_term: Failure to thrive in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by
      growth impairment, failure to thrive in infancy, multiple valvular disease,
      carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
    explanation: >-
      The molecularly confirmed Asian case review identifies failure to thrive in
      infancy as a characteristic CSCFS manifestation.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was admitted to the Pediatric Rehabilitation Department of Guangxi
      Maternal and Child Health Hospital for developmental delay and failure to
      thrive when he was 5 months old.
    explanation: >-
      The full-text 2025 case provides patient-level evidence of early failure to
      thrive.
- category: Neurologic
  name: Hypotonia
  frequency: FREQUENT
  description: >-
    Hypotonia is a recurrent early-life neurologic feature of CSCFS.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main manifestations are growth retardation, hypotonia, dysmorphic
      facial features, skeletal and limb abnormalities, cardiac septal defects
      with valve dysplasia, cardiomyopathy, and deafness with inner ear
      malformations.
    explanation: >-
      This supports hypotonia as part of the recurrent CSCFS phenotype spectrum.
- category: Neurologic
  name: Global developmental delay
  frequency: FREQUENT
  description: >-
    Some affected children have delayed motor, language, adaptive, and
    personal-social developmental milestones.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 4 months and 22 days, the Gesell Developmental Diagnostic
      Scale was used to assess his Developmental Quotient (DQ, DQ < 70 as low
      score) (gross motor 29, fine motor 63, adaptive 60, language 41 and
      personal-social 49).
    explanation: >-
      Multi-domain low developmental quotients support global developmental
      delay in the reported CSCFS patient.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had hypotonia and delays in developmental milestones.
    explanation: >-
      The case report directly documents delayed developmental milestones.
- category: Neurologic
  name: Delayed speech and language development
  frequency: OCCASIONAL
  description: >-
    Delayed expressive language has been reported in CSCFS and may be
    compounded by hearing impairment and short lingual frenulum.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short lingual frenulum, first observed in our patients, may also be a
      factor affecting speech development.
    explanation: >-
      The 2025 case report discusses impaired speech development in the context
      of CSCFS-associated craniofacial findings.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients exhibited mild intellectual disability, delayed language and
      motor development.
    explanation: >-
      This directly supports delayed language development as part of the
      expanded CSCFS phenotype.
- category: Neurologic
  name: Mild intellectual disability
  frequency: OCCASIONAL
  description: >-
    Mild intellectual disability has been reported in at least some CSCFS
    patients, expanding the neurodevelopmental spectrum.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was diagnosed with a mild intellectual disability.
    explanation: >-
      The full-text 2025 case directly documents mild intellectual disability.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When assessed at the age of 7 years and 3 months using the Wechsler
      Intelligence Scale for Children, his Full Scale IQ score was determined to
      be 71.
    explanation: >-
      A borderline-low full-scale IQ score supports the mild intellectual
      disability phenotype.
- category: Neurologic
  name: Brain imaging abnormality
  frequency: OCCASIONAL
  description: >-
    Rare CSCFS patients may show structural brain MRI abnormalities.
  phenotype_term:
    preferred_term: Brain imaging abnormality
    term:
      id: HP:0410263
      label: Brain imaging abnormality
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain Magnetic resonance imaging at 5 months of age showed bilateral
      hemispheric asymmetry and widening of the right frontotemporal
      extracerebral space.
    explanation: >-
      This directly supports brain MRI abnormalities as an occasional expanded
      phenotype.
- category: Craniofacial
  name: Craniofacial dysmorphism
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Dysmorphic facial features are a defining syndromic component of CSCFS and
    contribute to the recognizable craniofacial presentation.
  phenotype_term:
    preferred_term: Craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main manifestations are growth retardation, hypotonia, dysmorphic
      facial features, skeletal and limb abnormalities, cardiac septal defects
      with valve dysplasia, cardiomyopathy, and deafness with inner ear
      malformations.
    explanation: >-
      This directly identifies dysmorphic facial features as a core CSCFS
      manifestation.
- category: Musculoskeletal
  name: Vertebral fusion
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Extensive vertebral fusion or dorsal spine synostosis is a defining skeletal
    manifestation.
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) is characterized by
      growth impairment, failure to thrive in infancy, multiple valvular disease,
      carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
    explanation: >-
      This directly supports vertebral fusion as a defining skeletal phenotype.
- category: Musculoskeletal
  name: Carpal synostosis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Carpal fusion is a characteristic radiographic abnormality in CSCFS.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another major achievement of this research is to successfully capture the
      process of carpal fusion in a CSCF case radiographically.
    explanation: >-
      This directly supports carpal synostosis and its radiographic evolution in
      CSCFS.
- category: Musculoskeletal
  name: Tarsal synostosis
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Tarsal fusion accompanies carpal fusion and helps distinguish CSCFS from some
    other syndromic skeletal disorders.
  phenotype_term:
    preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  evidence:
  - reference: DOI:10.1002/pd.6358
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic features of CSCF include growth retardation, facial
      dysmorphism, carpal-tarsal fusion, dorsal spine synostosis, deafness, inner
      ear malformation, cardiac septal defect and valve dysplasia.
    explanation: >-
      This directly supports tarsal synostosis as part of the characteristic CSCFS
      skeletal pattern.
- category: Musculoskeletal
  name: Joint hypermobility
  frequency: FREQUENT
  description: >-
    Extreme or marked joint hypermobility is a recurrent connective-tissue feature
    in CSCFS.
  phenotype_term:
    preferred_term: Joint Hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:29467388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was originally ascertained for a presumed hereditary connective
      tissue disorder due to soft/dystrophic skin, extreme joint hypermobility,
      polyvalvular heart disease, and upper gastrointestinal dismotility.
    explanation: >-
      This directly supports pronounced joint hypermobility in CSCFS.
- category: Otolaryngologic
  name: Hearing impairment
  frequency: FREQUENT
  description: >-
    Deafness or hearing impairment with inner-ear malformations is part of the
    syndromic phenotype.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AbstractWe report on two unrelated cases born to nonconsanguineous parents
      with a similar clinical presentation: hypotonia since the neonatal period,
      severe failure to thrive, postnatal growth retardation, facial dysmorphism,
      congenital cardiac defects (septal defect and non progressive multiple valve
      dysplasia), shortened extremities, carpal/tarsal and extensive vertebral
      synostosis, delayed carpal bone age, deafness, and inner ear malformations.
    explanation: >-
      This directly supports hearing impairment/deafness in the original syndrome
      description.
- category: Otolaryngologic
  name: Inner ear malformation
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Structural inner-ear abnormalities accompany deafness in the characteristic
    CSCFS otologic phenotype.
  phenotype_term:
    preferred_term: Inner ear malformation
    term:
      id: HP:0011390
      label: Abnormal inner ear morphology
  evidence:
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AbstractWe report on two unrelated cases born to nonconsanguineous parents
      with a similar clinical presentation: hypotonia since the neonatal period,
      severe failure to thrive, postnatal growth retardation, facial dysmorphism,
      congenital cardiac defects (septal defect and non progressive multiple valve
      dysplasia), shortened extremities, carpal/tarsal and extensive vertebral
      synostosis, delayed carpal bone age, deafness, and inner ear malformations.
    explanation: >-
      This directly supports inner-ear malformations as a separate structural
      CSCFS phenotype.
- category: Cardiovascular
  name: Atrial septal defect
  frequency: OCCASIONAL
  description: >-
    Septal heart defects are part of the congenital cardiac spectrum in CSCFS.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main manifestations are growth retardation, hypotonia, dysmorphic
      facial features, skeletal and limb abnormalities, cardiac septal defects
      with valve dysplasia, cardiomyopathy, and deafness with inner ear
      malformations.
    explanation: >-
      This supports atrial septal defect within the broader septal-defect phenotype
      spectrum of CSCFS.
- category: Cardiovascular
  name: Polyvalvular heart disease
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Valve dysplasia or disease affecting multiple cardiac valves is a recurrent
    cardiovascular feature of CSCFS, distinct from septal defects.
  phenotype_term:
    preferred_term: Polyvalvular heart disease
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
  evidence:
  - reference: PMID:29467388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was originally ascertained for a presumed hereditary connective
      tissue disorder due to soft/dystrophic skin, extreme joint hypermobility,
      polyvalvular heart disease, and upper gastrointestinal dismotility.
    explanation: >-
      This directly supports polyvalvular heart disease as a core CSCFS cardiac
      phenotype.
- category: Cardiovascular
  name: Dilated cardiomyopathy
  frequency: OCCASIONAL
  description: >-
    Severe cases can include neonatal dilated cardiomyopathy in addition to
    congenital structural heart disease.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: DOI:10.4103/apc.apc_235_24
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene
      c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy
      (DCM) and congenital heart disease (CHD) and presented with acute heart
      failure (HF).
    explanation: >-
      This supports dilated cardiomyopathy as an important severe cardiac phenotype
      in CSCFS.
biochemical: []
genetic:
- name: MAP3K7
  association: Causative
  gene_term:
    preferred_term: MAP3K7
    term:
      id: hgnc:6859
      label: MAP3K7
  notes: >-
    CSCFS is an autosomal dominant MAP3K7 disorder that is usually caused by de
    novo heterozygous pathogenic variants affecting TAK1.
  evidence:
  - reference: PMID:29467388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous variants in MAP3K7, encoding the transforming growth
      factor-β-activated kinase 1 (TAK1), are associated with the ultrarare
      cardiospondylocarpofacial syndrome (CSCFS).
    explanation: >-
      This directly establishes MAP3K7 as the disease gene.
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed a novel heterozygous variant, c.142G > A[p.
      (Gly48Arg)], in the MAP3K7 gene. The variant was confirmed by Sanger
      sequencing to be absent in other family members and is de novo.
    explanation: >-
      This supports the typical de novo autosomal dominant inheritance pattern in
      CSCFS.
environmental: []
treatments:
- name: Cardiology surveillance and management
  description: >-
    Baseline and serial cardiology assessment should monitor septal defects,
    valve dysplasia or regurgitation, arrhythmia, pulmonary hypertension, and
    cardiomyopathy; cardiac MRI or rhythm monitoring may be used when
    echocardiography or symptoms indicate.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Polyvalvular heart disease
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35730652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with pathogenic mutations in MAP3K7 are at risk for (severe)
      cardiac disease
    explanation: >-
      The MAP3K7 cohort explicitly supports ongoing cardiac risk surveillance.
  - reference: DOI:10.4103/apc.apc_235_24
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene
      c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy
      (DCM) and congenital heart disease (CHD) and presented with acute heart
      failure (HF).
    explanation: >-
      Severe neonatal cardiomyopathy and congenital heart disease justify
      cardiology surveillance and prompt management of cardiac decompensation.
- name: Audiology and hearing support
  description: >-
    Audiologic evaluation and otolaryngology follow-up should assess conductive
    or sensorineural hearing loss, inner-ear malformations, and recurrent otitis
    media; hearing aids or other hearing support should be provided when
    indicated.
  treatment_term:
    preferred_term: hearing aid usage
    term:
      id: MAXO:0009030
      label: hearing aid usage
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Inner ear malformation
    term:
      id: HP:0011390
      label: Abnormal inner ear morphology
  evidence:
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      deafness, and inner ear malformations.
    explanation: >-
      The original syndrome report supports dedicated hearing evaluation and
      hearing support.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was also diagnosed with conductive hearing impairment with an average
      hearing threshold of 52.6 dB.
    explanation: >-
      Quantified hearing loss in a recent patient supports audiology follow-up
      and hearing support.
- name: Orthopedic and spine surveillance
  description: >-
    Orthopedic follow-up with spine and extremity imaging should monitor
    vertebral fusion, carpal/tarsal synostosis, scoliosis, pectus deformity,
    delayed bone age, foot deformity, and joint hypermobility.
  treatment_term:
    preferred_term: orthopedic procedure
    term:
      id: MAXO:0000477
      label: orthopedic procedure
  target_phenotypes:
  - preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  - preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  - preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another major achievement of this research is to successfully capture the
      process of carpal fusion in a CSCF case radiographically.
    explanation: >-
      Radiographic progression of carpal fusion supports serial skeletal imaging
      and orthopedic surveillance.
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      shortened extremities, carpal/tarsal and extensive vertebral synostosis,
      delayed carpal bone age
    explanation: >-
      The original report supports orthopedic monitoring for axial and appendicular
      skeletal abnormalities.
- name: Developmental, speech, and rehabilitation therapies
  description: >-
    Developmental assessment should guide early intervention, physical therapy
    for hypotonia and motor delay, occupational therapy for adaptive and fine
    motor needs, and speech-language therapy for delayed language or speech
    affected by hearing impairment or oral structural differences.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had hypotonia and delays in developmental milestones.
    explanation: >-
      Motor and developmental delays support early developmental and
      rehabilitation services.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short lingual frenulum, first observed in our patients, may also be a
      factor affecting speech development.
    explanation: >-
      Speech-development impact supports speech-language evaluation and therapy
      when indicated.
- name: Feeding and growth support
  description: >-
    Infants and children with poor growth should receive nutrition assessment,
    feeding therapy, and gastroenterology support; gastrostomy or surgical
    management may be required for severe feeding or gastrointestinal
    complications.
  treatment_term:
    preferred_term: nutrition intervention
    term:
      id: MAXO:0000009
      label: nutrition intervention
  target_phenotypes:
  - preferred_term: Failure to thrive in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients experienced growth issues, largely attributed to feeding
      difficulties and gastrointestinal problems, with the majority undergoing
      gastrostomy.
    explanation: >-
      Feeding and gastrointestinal problems as a common driver of growth issues
      support feeding and nutrition intervention.
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      growth impairment, failure to thrive in infancy, multiple valvular disease,
      carpal and tarsal fusions, vertebral fusions, and joint hypermobility.
    explanation: >-
      Failure to thrive in infancy supports active growth and nutrition support.
- name: Genetic counseling
  description: >-
    Genetic counseling should address autosomal dominant inheritance, the
    frequent de novo presentation, recurrence risk when a parent is affected or
    mosaic, and reproductive testing options for families with an identified
    MAP3K7 variant.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiospondylocarpofacial syndrome (CSCFS) is an extremely rare autosomal
      dominant disorder resulting from variant in the MAP3K7 gene
    explanation: >-
      Autosomal dominant inheritance supports counseling about transmission and
      recurrence risk.
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was confirmed by Sanger sequencing to be absent in other
      family members and is de novo.
    explanation: >-
      De novo occurrence supports counseling about typical recurrence risk and
      the possibility of parental mosaicism.
diagnosis:
- name: MAP3K7 molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >-
    Molecular confirmation relies on identifying a heterozygous pathogenic MAP3K7
    variant in a patient with compatible skeletal, cardiac, and craniofacial
    findings.
  results: A pathogenic heterozygous MAP3K7 variant supports the diagnosis of CSCFS.
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed a novel heterozygous variant, c.142G > A[p.
      (Gly48Arg)], in the MAP3K7 gene.
    explanation: >-
      This directly supports molecular genetic testing as the diagnostic method.
- name: Sanger confirmation of MAP3K7 variant
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >-
    Sanger sequencing is used to confirm the candidate variant and assess de novo
    status in the family.
  results: Confirmation of the MAP3K7 variant with absence in relatives supports a de novo syndromic diagnosis.
  evidence:
  - reference: DOI:10.3389/fped.2025.1651803
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was confirmed by Sanger sequencing to be absent in other family
      members and is de novo.
    explanation: >-
      This directly supports Sanger confirmation in CSCFS diagnosis.
- name: Echocardiography
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: MAXO:0010203
      label: echocardiography
  description: >-
    Echocardiography defines septal defects, valve dysplasia, and severe prenatal
    or postnatal structural cardiac disease in CSCFS.
  results: Structural septal or valvular abnormalities support syndromic cardiac involvement consistent with CSCFS.
  evidence:
  - reference: DOI:10.1002/pd.6358
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal echocardiography revealed tricuspid regurgitation with valve prolapse.
    explanation: >-
      This directly supports echocardiography as a useful diagnostic procedure in
      CSCFS.
- name: Skeletal radiography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >-
    Serial radiographic assessment can document carpal fusion and vertebral
    segmentation abnormalities.
  results: Carpal or vertebral fusion on radiographs supports the diagnosis.
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another major achievement of this research is to successfully capture the
      process of carpal fusion in a CSCF case radiographically.
    explanation: >-
      This directly supports skeletal radiography as a diagnostic procedure in
      CSCFS.
- name: Audiologic evaluation
  diagnosis_term:
    preferred_term: diagnostic procedure of auditory system
    term:
      id: MAXO:0001445
      label: diagnostic procedure of auditory system
  description: >-
    Formal audiology is used to identify conductive or sensorineural hearing
    impairment and to guide hearing support.
  results: >-
    Conductive or sensorineural hearing impairment supports syndromic otologic
    involvement in CSCFS.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was also diagnosed with conductive hearing impairment with an average
      hearing threshold of 52.6 dB.
    explanation: >-
      Quantified hearing impairment supports audiologic evaluation.
- name: Developmental assessment
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  description: >-
    Standardized developmental testing helps define motor, language, adaptive,
    and cognitive support needs.
  results: Low developmental quotients or IQ scores document neurodevelopmental involvement.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 4 months and 22 days, the Gesell Developmental Diagnostic
      Scale was used to assess his Developmental Quotient
    explanation: >-
      The reported use of standardized developmental testing supports
      developmental assessment as part of clinical evaluation.
- name: Brain MRI
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  description: >-
    Brain MRI can evaluate infants or children with developmental delay,
    hypotonia, or neurologic concerns.
  results: Structural brain abnormalities may expand the recognized CSCFS phenotype.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain Magnetic resonance imaging at 5 months of age showed bilateral
      hemispheric asymmetry and widening of the right frontotemporal
      extracerebral space.
    explanation: >-
      This directly supports brain MRI as a clinically informative diagnostic
      procedure in at least some CSCFS patients.
differential_diagnoses:
- name: Frontometaphyseal dysplasia type 2
  description: >-
    MAP3K7 gain-of-function disease is allelic to CSCFS but has a distinct
    frontometaphyseal dysplasia phenotype.
  distinguishing_features:
  - CSCFS-associated MAP3K7 variants act through loss of function, whereas FMD2-associated variants show a different functional fingerprint.
  - Prominent cardioskeletal-connective tissue overlap with valve disease and carpal-tarsal fusion favors CSCFS over the metaphyseal/frontometaphyseal dysplasia pattern.
  evidence:
  - reference: PMID:29467388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific gain-of-function variants in the same gene cause the allelic
      frontometaphyseal dysplasia type 2.
    explanation: >-
      This directly supports FMD2 as an allelic differential diagnosis for CSCFS.
- name: Noonan syndrome
  description: >-
    Noonan syndrome overlaps through short stature, congenital heart disease, and
    syndromic facies, but CSCFS adds characteristic vertebral and carpal-tarsal
    fusion.
  distinguishing_features:
  - Carpal/tarsal fusion and extensive vertebral synostosis favor CSCFS over Noonan syndrome.
  - MAP3K7-associated connective tissue findings and deafness with inner-ear malformation also support CSCFS.
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  evidence:
  - reference: PMID:35730652
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing
      MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered
      in the differential diagnosis of patients with syndromic congenital cardiac
      defects and/or cardiomyopathy, syndromic connective tissue disorders, and in
      the differential diagnosis of NS.
    explanation: >-
      This cohort study directly names Noonan syndrome as a differential diagnosis.
- name: Ehlers-Danlos syndrome
  description: >-
    CSCFS overlaps with EDS through connective tissue manifestations and joint
    hypermobility, but fused vertebrae and carpal/tarsal synostosis support CSCFS.
  distinguishing_features:
  - Extensive vertebral and carpal-tarsal fusion are not typical defining features of Ehlers-Danlos syndrome.
  - Congenital septal and valvular heart disease with MAP3K7 causation favor CSCFS.
  disease_term:
    preferred_term: Ehlers-Danlos syndrome
    term:
      id: MONDO:0020066
      label: Ehlers-Danlos syndrome
  evidence:
  - reference: PMID:34558790
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the main symptoms of CSCF, the present case had a mixed
      phenotype of Ehlers-Danlos syndrome (EDS) and Noonan syndrome.
    explanation: >-
      This directly supports EDS as an important phenotypic differential.
- name: Spondylocarpotarsal synostosis syndrome
  description: >-
    Spondylocarpotarsal synostosis syndrome overlaps through vertebral and
    carpal-tarsal fusion, but CSCFS adds congenital heart disease, deafness, and
    distinctive craniofacial findings.
  distinguishing_features:
  - Congenital cardiac defects with valve dysplasia and inner-ear malformations support CSCFS over isolated spondylocarpotarsal synostosis syndrome.
  - The original CSCFS description specifically excluded FLNB in the overlapping skeletal disorder differential.
  disease_term:
    preferred_term: spondylocarpotarsal synostosis syndrome
    term:
      id: MONDO:0010094
      label: spondylocarpotarsal synostosis syndrome
  evidence:
  - reference: DOI:10.1002/ajmg.a.33277
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although some features are similar to spondylocarpotarsal synostosis
      syndrome, the exclusion of FLNB and this constellation of findings suggest a
      new entity
    explanation: >-
      This directly supports spondylocarpotarsal synostosis syndrome as a key
      skeletal differential diagnosis.
clinical_trials: []
datasets:
- accession: geo:GSE279246
  title: TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
  description: >-
    Bulk transcriptomic and mechanistic developmental dataset linking TAK1/MAP3K7
    dysfunction to syndromic congenital heart disease, cardiomyocyte
    differentiation failure, and altered cardiac developmental gene expression.
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
    tissue_term:
      preferred_term: heart
      term:
        id: UBERON:0000948
        label: heart
  conditions:
  - cardiospondylocarpofacial syndrome
  - congenital heart disease
  - MAP3K7/TAK1 dysfunction
  evidence:
  - reference: GEO:GSE279246
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA sequencing of tak1-/- mutant hearts showed downregulation of genes
      encoding core cardiac transcription factors, sarcomeric proteins and
      extracellular matrix proteins.
    explanation: >-
      This supports GEO:GSE279246 as a disease-relevant zebrafish cardiac
      transcriptomic dataset for TAK1 biology.
  findings:
  - statement: TAK1 loss downregulates core cardiac transcriptional programs, sarcomeric genes, and extracellular matrix genes in mutant hearts.
    evidence:
    - reference: GEO:GSE279246
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        RNA sequencing of tak1-/- mutant hearts showed downregulation of genes
        encoding core cardiac transcription factors, sarcomeric proteins and
        extracellular matrix proteins.
      explanation: >-
        This directly supports the dataset's relevance to CSCFS cardiac
        developmental mechanisms.
  - statement: TAK1 perturbation inhibits ciliary signaling and cardiomyocyte differentiation in vitro.
    evidence:
    - reference: GEO:GSE279246
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or
        administration of small molecule inhibitors targeting TAK1 inhibited
        ciliary signaling and cardiomyocyte differentiation in vitro
      explanation: >-
        This complements the zebrafish transcriptomic finding with cell-based
        evidence of impaired cardiomyogenesis.
references:
- reference: PMID:27426734
  title: "Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome."
  findings: []
- reference: PMID:29467388
  title: A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder.
  findings: []
- reference: PMID:34558790
  title: "Expanding the phenotypic spectrum of cardiospondylocarpofacial syndrome: From a detailed clinical and radiological observation of a boy with a novel missense variant in MAP3K7."
  findings: []
- reference: PMID:35700636
  title: "Generation of the induced pluripotent stem cell line UNIBSi017-A from an individual with cardiospondylocarpofacial syndrome and the MAP3K7 c.737-7A > G variant."
  findings: []
- reference: PMID:35730652
  title: "The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations."
  findings: []
- reference: DOI:10.1002/ajmg.a.33277
  title: "Postnatal growth retardation, facial dysmorphism, spondylocarpal synostosis, cardiac defect, and inner ear malformation (cardiospondylocarpofacial syndrome?)-A distinct syndrome?"
  findings: []
- reference: DOI:10.1002/pd.6358
  title: "Early and severe tricuspid valve dysplasia in a fetus with cardiospondylocarpofacial syndrome due to a variant c.616T>G p.(Tyr206Asp) in MAP3K7"
  findings: []
- reference: DOI:10.1016/j.bbadis.2020.165742
  title: "Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy"
  findings: []
- reference: DOI:10.3389/fped.2025.1651803
  title: Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family
  findings: []
- reference: DOI:10.4103/apc.apc_235_24
  title: Neonatal dilated cardiomyopathy and cardiospondylocarpofacial syndrome linked to a novel MAP3K7 gene mutation
  findings: []
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
  title: Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family - PMC
  findings: []
- reference: GEO:GSE279246
  title: TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
  findings: []
📚

References & Deep Research

References

12
PMID:27426734
Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome.
No top-level findings curated for this source.
PMID:29467388
A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder.
No top-level findings curated for this source.
PMID:34558790
Expanding the phenotypic spectrum of cardiospondylocarpofacial syndrome: From a detailed clinical and radiological observation of a boy with a novel missense variant in MAP3K7.
No top-level findings curated for this source.
PMID:35700636
Generation of the induced pluripotent stem cell line UNIBSi017-A from an individual with cardiospondylocarpofacial syndrome and the MAP3K7 c.737-7A > G variant.
No top-level findings curated for this source.
PMID:35730652
The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.
No top-level findings curated for this source.
DOI:10.1002/ajmg.a.33277
Postnatal growth retardation, facial dysmorphism, spondylocarpal synostosis, cardiac defect, and inner ear malformation (cardiospondylocarpofacial syndrome?)-A distinct syndrome?
No top-level findings curated for this source.
DOI:10.1002/pd.6358
Early and severe tricuspid valve dysplasia in a fetus with cardiospondylocarpofacial syndrome due to a variant c.616T>G p.(Tyr206Asp) in MAP3K7
No top-level findings curated for this source.
DOI:10.1016/j.bbadis.2020.165742
Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy
No top-level findings curated for this source.
DOI:10.3389/fped.2025.1651803
Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family
No top-level findings curated for this source.
DOI:10.4103/apc.apc_235_24
Neonatal dilated cardiomyopathy and cardiospondylocarpofacial syndrome linked to a novel MAP3K7 gene mutation
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12405365/
Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family - PMC
No top-level findings curated for this source.
GEO:GSE279246
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
No top-level findings curated for this source.

Deep Research

1
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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Cardiospondylocarpofacial syndrome. Core disease mechanisms, molecular and...
Asta Scientific Corpus Retrieval 20 citations 2026-04-21T17:03:30.234951

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Cardiospondylocarpofacial syndrome. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[2] An overview on cardiac involvement in Inborn Errors of Metabolism: from clinical clues to nutritional management strategies

  • Authors: C. Montanari, V. Tagi, Martina Tosi, Eliana Stucchi, Eleonora Pisano et al.
  • Year: 2025
  • Venue: Frontiers in Cardiovascular Medicine
  • URL: https://www.semanticscholar.org/paper/53edcd65284033a78e81633fbeb8012f21599561
  • DOI: 10.3389/fcvm.2025.1648010
  • PMID: 41425985
  • PMCID: 12711851
  • Summary: This review examines nutritional strategies for managing patients affected by IEMs with cardiac involvement, providing clinicians with research-backed guidance to support cardiological care, since specific nutritional strategies have shown promise in reversing or improving cardiac function in specific IEMs.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Approximately 10% to 30% of the known causes of cardiomyopathy in childhood are attributable to IEMs (10, 130,131). In IEMs, cardiac manifestations can be indicative symptoms discovered during regular multisystem screening. While in disorders like MPS, heart manifestations may dominate the clinical presentation, in others, such as PD, they represent the sole clinical manifestation. Four fundamental mechanisms underlie the pathophysiology of cardiac involvement. First, cardiac symptoms can be linked to a reduction in energy production resulting from genetic mutations in proteins involved in energy homeostasis, molecular transport, or cellular organelles. Second, the intracellular accumulation of intermediates or storage substrates within cardiac myocytes can lead to structural and functional damage of the cardiac tissue. Third, the accumulation of intermediate metabolites may exert toxic effects on cardiac and surrounding tissues, for example, by triggering apoptosis in cardiac myocytes. Fourth, altered cellular functions such as signal transduction, depolarization, and cell adhesion, caused by the absence or alteration of glyconjugates, can compromise tissue integrity and cardiac function. It is important to note that pathogenetic mechanisms, summarized in Figure 3, may often overlap, particularly in later stages of the illness progression (33). In this review, we offered a comprehensive description of the cardiovascular diseases primarily associated with various types of IEMs, to guide cardiologists in the differential diagnosis (Figure 4). Moreover, the diagnosis of an underlying metabolic disorder should rely on the recognition of associated signs and symptoms characteristic of each specific disease. > IEMs have a wide phenotypic spectrum and may be characterized by a late onset or mild organ involvement, remaining misdiagnosed. Following the diagnosis of heart complications, the cardiologist should first conduct a detailed investigation of the patient's and family's medical history, including an assessment of consanguinity and/or the presence of rare inherited disorders. The patient's history should include age of onset of each clinically relevant symptom, the presence of associated pathological conditions and/or symptoms (hypoglycemia, myalgia, neurological issues or liver problems) and the result of neonatal screening.

[3] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[4] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

  • Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
  • DOI: 10.3390/ijms22031161
  • PMID: 33503868
  • PMCID: 7865492
  • Citations: 16
  • Influential citations: 1
  • Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[5] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

  • Authors: K. Lourida, G. Louridas
  • Year: 2022
  • Venue: Cardiogenetics
  • URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
  • DOI: 10.3390/cardiogenetics12020015
  • Citations: 4
  • Influential citations: 1
  • Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[6] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

  • Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
  • DOI: 10.3390/ijms22083930
  • PMID: 33920294
  • PMCID: 8069124
  • Citations: 6
  • Influential citations: 1
  • Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[7] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

  • Authors: O. Tsukamoto
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
  • DOI: 10.3390/ijms21010226
  • PMID: 31905684
  • PMCID: 6982115
  • Citations: 16
  • Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[8] Cardiac Phenotype and Gene Mutations in RASopathies

  • Authors: M. Faienza, G. Meliota, D. Mentino, R. Ficarella, Mattia Gentile et al.
  • Year: 2024
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/a4087d3b73d20a6e2f46b7fb87eed4017ec9a9be
  • DOI: 10.3390/genes15081015
  • PMID: 39202376
  • PMCID: 11353738
  • Citations: 9
  • Influential citations: 1
  • Summary: The molecular mechanisms underlying the development of cardiac diseases associated particularly with NS are clarified, and the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

[9] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[10] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

  • Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
  • DOI: 10.3390/genes14091734
  • PMID: 37761876
  • PMCID: 10531442
  • Citations: 11
  • Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.369) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[11] Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

  • Authors: J. Hansen, J. Galatioto, Cristina I. Caescu, P. Arnaud, R. C. Calizo et al.
  • Year: 2019
  • Venue: JCI insight
  • URL: https://www.semanticscholar.org/paper/261628418de4c8b21daeb694301dc1b8759b622d
  • DOI: 10.1172/jci.insight.127652
  • PMID: 31167969
  • Citations: 20
  • Summary: System pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy. Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14). > An overview of regulatory pathways and networks associated with a given pathology can often be obtained by examining changes in gene expression during disease progression. Systems pharmacology approaches that consider drug targets as nodes within cellular regulatory networks can use differentially expressed genes (DEGs) to predict dysregulated SCPs that underlie cell-level mechanisms (1,3). Further, computational analyses of the pharmacologically induced perturbations of gene expression listed in the Connectivity Map (CMap) database can predict drugs to be repurposed to normalize dysregulated SCPs (15).

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[13] Epigenetic Insights into Tuberous Sclerosis Complex, Von Hippel–Lindau Syndrome, and Ataxia–Telangiectasia

  • Authors: Gavriel Hadjigavriel, Christina Stylianides, Evangelos Axarloglou, M. Manthou, E. Vakirlis et al.
  • Year: 2025
  • Venue: Epigenomes
  • URL: https://www.semanticscholar.org/paper/5643fde916e6d150423d2be7a32508e11fb6b6f8
  • DOI: 10.3390/epigenomes9020020
  • PMID: 40558831
  • PMCID: 12191455
  • Citations: 1
  • Summary: Current evidence on the epigenetic landscape of these syndromes is consolidated, elucidating how modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations by integrating epigenetic insights with known molecular pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.358) > Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation.

[14] Placing joint hypermobility in context: traits, disorders and syndromes

  • Authors: S. Morlino, M. Castori
  • Year: 2023
  • Venue: British Medical Bulletin
  • URL: https://www.semanticscholar.org/paper/dfc6a2564a6ebb5bf7b04e626232162747748a6b
  • DOI: 10.1093/bmb/ldad013
  • PMID: 37350130
  • PMCID: 10689077
  • Citations: 17
  • Summary: In the clinical context, elucidation of the pathophysiology of pain related to JHM should develop in parallel with the analysis of pleiotropic manifestations of syndromes with JHM, and current limitations and disagreements concerning the ‘spectrum’, HSD and HEDS are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.358) > Treating JHM-related MSK pain can be difficult because people are often referred to the 'expert' after years of evolving symptoms. Current understanding of the mechanisms which underlie JHMrelated MSK pain identifies a progression from soft tissue/joint traumas facilitated by JHM, to pain chronicity, to fluctuating disability (Fig. 3). Treatment follows an integrated, biopsychosocial approach 42 that considers pain as the summation of a multitude of intermingled mechanisms. Available strategies, such as physiotherapy, painkiller drugs and cognitive-behavioral therapy, are not always effective in the medium and long terms, and accessibility to tailored programs is not guaranteed in all healthcare systems. The availability of patient pathways emerging from the coordinated work of transnational initiatives, such as the European Reference Networks for rare and complex diseases and international foundations like the Ehlers-Danlos Society, facilitates standardization of treatment accessibility and delivery within the various healthcare systems. Similar needs are found for the syndromic patient who requests periodic follow-up for the early detection and treatment of late-onset complications related to the pleiotropic manifestations of the identified genetic mutation. > Cardiovascular and hollow organ involvement and, in particular, the risk of life-threatening events represent the most severe, though relatively rare manifestation of specific EDS subtypes. Spontaneous arterial ruptures are a major feature of vascular EDS but may occur at lower rates in other EDS clinical subtypes. 45 Preliminary genotype-phenotype correlations suggest a variable severity of cardiovascular involvement in vascular EDS according to the mutation type. 33 Much less information is available for the other EDS subtypes with a documented or presumed increased risk of vascular events. 46 Given the unpredictability of arterial and hollow organ ruptures in EDS, and the complexities generated by the tissue fragility in the emergency room, risk prediction according to patients' stratification and availability of risk reduction procedures are aims for the future. The identification of innovative drugs for treating pain and improving tissue fragility should become an emerging field of pre-clinical and clinical research in EDS and related disorders.

[15] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.358) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[16] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

  • Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
  • Year: 2015
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
  • DOI: 10.1186/s13023-015-0242-9
  • PMID: 25874378
  • PMCID: 4358699
  • Citations: 93
  • Influential citations: 5
  • Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[17] Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective

  • Authors: J. Gervasoni, A. Primiano, M. Cicchinelli, L. Santucci, Serenella Servidei et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07c164ce4ffbef88bb87a0761bc653dfb74eeeb0
  • DOI: 10.3390/ijms25094855
  • PMID: 38732076
  • PMCID: 11084339
  • Citations: 4
  • Summary: Omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > Mitochondrial diseases represent a large collection of rare neurometabolic syndromes characterized by extremely difficult clinical management, both chronically and during acute events. This condition is due to a lack of complete understanding of the metabolic and molecular mechanisms involved in the pathogenesis, and also to the absence of reliable diagnostic and prognostic biomarkers that are able to identify the disease in its multiple clinical manifestations and monitor its progression. Although genetic testing provides secure diagnoses, heteroplasmy, and gaps in knowledge of pathological mechanisms limit genomics in offering a comprehensive spectrum of diseases and their variations in severity and progression. Additionally, the absence of validated biomarkers has made identifying new therapies a challenge [24,25]. > Several techniques have developed to interrogate this complex process in multiple dimensions (DNA, RNA, proteins, and metabolites), known as "omics". These disciplines allow to investigate the different classes of biological components (genes-genomic, proteinsproteomic, and metabolites-metabolomic) that determine the phenotype of an organism. Different analytical techniques (Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) are used to identify either the metabolite patterns that are significant for the determination of the metabolic phenotype of the system under investigation, or the proteins used to determine of the alteration in the proteomic asset that can be identified as a possible marker of disease. Metabolomics and proteomic studies can be conducted with targeted, semi-targeted, and untargeted analytical approaches. Analysis is usually performed on multiple biological fluids: urine, saliva, plasma or serum, cerebrospinal fluid, cell cultures, tissue extracts, or biopsies. Through metabolic analysis, we can measure the metabolic profile, obtaining a fingerprint determined by the perturbation that is characteristic of the pathogenetic process [26].

[18] Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

  • Authors: Noelia Benetó, L. Vilageliu, D. Grinberg, I. Canals
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/80f8e4e1b87f7a316de9bd4e7fbd5ac14ed7af1c
  • DOI: 10.3390/ijms21217819
  • PMID: 33105639
  • PMCID: 7659972
  • Citations: 41
  • Influential citations: 2
  • Summary: An update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > With this review, we provided an overview of the molecular basis of Sanfilippo syndrome and a summary of the main animal and cellular models available to date, which can be used to test the different therapeutic approaches.For many years, animal models have been the gold-standard to investigate disease mechanisms and to develop and test therapeutic options.However, the fundamental differences between animal and human brain structure and development, as well as the higher complexity of human organs and cells, are major factors that should be taken into account when performing a study.Findings relevant in animal models might not be important in the context of human physiology, pointing out the importance of generating human cellular models to complement the existing animal models.In the last years, several Sanfilippo-iPSC lines have been established and, in combination with faster and improved protocols to generate relevant cell types in 2D and 3D cultures [125][126][127], will contribute to expand our understanding of the molecular and cellular mechanisms of the disease.In addition, iPSC-derived brain cells will be very useful in drug screening studies to identify possible drug candidates with the potential to treat human brain cells.To date, several potential therapies have been tested, however gene therapy seems to be the approach generating a better outcome.It is crucial to follow the ongoing clinical trials for this therapy considering the very promising results of previous studies.Nevertheless, efforts should also be made to develop and assess other possible approaches for the treatment of patients suffering from this devastating disorder.

[19] Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

  • Authors: L. Velicki, D. Jakovljevic, A. Preveden, M. Golubovic, M. Bjelobrk et al.
  • Year: 2020
  • Venue: BMC Cardiovascular Disorders
  • URL: https://www.semanticscholar.org/paper/5b4558af699aad557a802ddc5c280ae601c2d56f
  • DOI: 10.1186/s12872-020-01807-4
  • PMID: 33297970
  • PMCID: 7727200
  • Citations: 55
  • Influential citations: 2
  • Summary: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > ]. Technological progress has made it possible to identify new genes associated with HCM-numerous other genes that do not encode sarcomere proteins but rather genes encoding the synthesis of Z-disk proteins and proteins involved in the calcium signaling pathway. With the introduction and implementation of the next-generation sequencing solutions, the identification of nearly 50 gene mutations associated with some form of HCM throughout literature has become possible [12]. > Regardless of the mutation type, the same pathophysiology mechanisms are responsible for the development of typical HCM phenotype and disease progression. Disrupted sarcomere properties due to the mutations cause impaired relaxation and lead to diastolic dysfunction, which is followed by hyperdynamic contractility and hypertrophy of the LV in the later course [9,11]. > Due to variable penetrance and expressivity, the phenotypic characteristics of HCM are multifaceted and may be influenced by other factors beyond single pathogenic mutations [13]. In addition to LV hypertrophy, phenotypic HCM expression also includes myocardial hypercontractivity, myofibril disorganization, fibrosis, as well as the presence of mild myocardial inflammation. Although the clinical phenotype can partially differ depending on the affected gene, no distinctive correlation between disease severity and specific genes has been established. Moreover, clinical features such as disease penetration, hypertrophy severity, and patient prognosis are known to vary depending on different mutations within the same gene [11]. > The precise link between determined underlying gene mutation and the clinical course remains elusive in this heterogeneous condition. The motivation to compile this HCM patient registry was to try to define what patient features are more prevalent with specific gene mutations and to establish whether the level of disease expression might be linked to one of the two most common mutations responsible for HCM. The goal was to reveal and distinguish subtle differences that may exist in clinical presentation and, more importantly, in heart structure and function recorded by cardiac imaging (i.e. echocardiography) between different gene mutations, thus providing essential information for the computational model development. Moreover, data from this study will also complement the clinical trial (NCT03832660 at clinicaltrials.gov) evaluating the effects of pharmacological (sacub

[20] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.