CPSFS1A is the autosomal dominant form of a MYH3-related congenital contracture syndrome that sits at the skeletal end of the distal arthrogryposis spectrum. MYH3 encodes embryonic myosin heavy chain, the motor isoform that powers skeletal muscle contraction during the fetal window in which limb joints acquire their range of motion. What distinguishes CPSFS from its allelic neighbours - Freeman-Sheldon (DA2A), Sheldon-Hall (DA2B) and DA1 - is not a different gene but the addition of extensive bony abnormality: vertebral, carpal and tarsal fusions and severe early-onset scoliosis on top of the contractures and pterygia those conditions share. The mechanism is contested, and this entry does not settle it. The best-characterized MYH3 alleles are motor-domain missense variants that behave as a gain of mechanical function rather than a loss - mutant embryonic myosin binds actin too tightly and cycles too slowly, so the muscle is stiff and poorly powered rather than absent - and on that model it is sustained abnormal tension across developing joints, not weakness, that fixes them. But that work was done on distal arthrogryposis alleles, and the pterygium and skeletal-fusion end of the spectrum that CPSFS occupies has instead been described as loss of function, with a recurrent 5'UTR splice allele rather than a missense. Both readings are carried here with their evidence.
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Conditions with similar clinical presentations that must be differentiated from Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A:
name: Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A
creation_date: "2026-09-03T20:10:00Z"
category: Musculoskeletal Disorder
parents:
- Distal Arthrogryposis
- Congenital Limb Malformation
disease_term:
preferred_term: contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A
term:
id: MONDO:0008338
label: contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A
synonyms:
- CPSFS1A
- CPSFS1, autosomal dominant
- contractures, pterygia, and variable skeletal fusions syndrome 1A
description: >-
CPSFS1A is the autosomal dominant form of a MYH3-related congenital contracture
syndrome that sits at the skeletal end of the distal arthrogryposis spectrum. MYH3
encodes embryonic myosin heavy chain, the motor isoform that powers skeletal muscle
contraction during the fetal window in which limb joints acquire their range of
motion. What distinguishes CPSFS from its allelic neighbours - Freeman-Sheldon
(DA2A), Sheldon-Hall (DA2B) and DA1 - is not a different gene but the addition of
extensive bony abnormality: vertebral, carpal and tarsal fusions and severe
early-onset scoliosis on top of the contractures and pterygia those conditions
share. The mechanism is contested, and this entry does not settle it. The
best-characterized MYH3 alleles are motor-domain missense variants that behave as a
gain of mechanical function rather than a loss - mutant embryonic myosin binds actin
too tightly and cycles too slowly, so the muscle is stiff and poorly powered rather
than absent - and on that model it is sustained abnormal tension across developing
joints, not weakness, that fixes them. But that work was done on distal
arthrogryposis alleles, and the pterygium and skeletal-fusion end of the spectrum
that CPSFS occupies has instead been described as loss of function, with a recurrent
5'UTR splice allele rather than a missense. Both readings are carried here with their
evidence.
inheritance:
- name: Autosomal dominant inheritance
description: >-
CPSFS1A is the dominantly inherited form; heterozygous MYH3 variants are sufficient.
A separate recessive form (CPSFS1B) is caused by biallelic variants in the same gene,
so MYH3 dose and allele class, not the gene itself, set the inheritance pattern.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 variants underlie both dominantly and recessively inherited Contractures, \nPterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are \ncharacterized by extensive bony abnormalities in addition to congenital \ncontractures."
explanation: >-
States that CPSFS occurs in both dominant and recessive forms, which is what
separates CPSFS1A from CPSFS1B, and names the extensive bony abnormality that
distinguishes CPSFS from the other MYH3 arthrogryposes.
genetic:
- name: MYH3
gene_term:
preferred_term: MYH3
term:
id: hgnc:7573
label: MYH3
association: Pathogenic Variants
relationship_type: CAUSATIVE
inheritance:
- name: Autosomal Dominant
notes: >-
Embryonic myosin heavy chain. The same gene causes DA1, DA2A (Freeman-Sheldon),
DA2B (Sheldon-Hall), multiple pterygium syndrome and both CPSFS forms, so the
gene alone does not predict which phenotype a patient has.
evidence:
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 variants underlie both dominantly and recessively inherited Contractures, \nPterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are \ncharacterized by extensive bony abnormalities in addition to congenital \ncontractures."
explanation: Identifies MYH3 as the gene underlying CPSFS, including the dominant form.
- reference: PMID:21531865
reference_title: Exome sequencing identifies an MYH3 mutation in a family with distal arthrogryposis type 1.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Identification of an MYH3 mutation in this family with distal \narthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to \ninclude distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B \n(Sheldon-Hall syndrome)."
explanation: >-
Establishes the breadth of the MYH3 allelic series. Indirect for CPSFS1A
specifically: the families studied had DA1, not CPSFS, so this supports the
claim that one gene produces several contracture phenotypes rather than
characterizing CPSFS itself.
- reference: PMID:25256237
reference_title: Genotype-phenotype relationships in Freeman-Sheldon syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Phenotypic \nseverity varied significantly by genotype (P=0.0055)."
explanation: >-
Shows that within one MYH3 disorder the specific allele, not merely the presence
of a variant, sets severity. Indirect: the cohort was DA2A, so this motivates
rather than demonstrates an allele-specific explanation for why some MYH3
variants produce the CPSFS skeletal-fusion phenotype.
pathophysiology:
- name: MYH3 Motor Domain Dysfunction
biological_scale: MOLECULAR
description: >-
Missense variants alter residue interactions within the embryonic myosin motor
domain, changing how it engages actin and nucleotide. This is the studied lesion
class and the one the mechanistic work below rests on - a change in motor behaviour
rather than an absence of motor. It is not the only allele class reported in this
part of the MYH3 spectrum: the recurrent CPSFS/spondylocarpotarsal allele is
c.-9+1G>A, a 5'UTR splice variant that cannot alter motor-domain residue
interactions at all and points instead at reduced expression. Note that where it has
been described alongside this phenotype it was compound heterozygous, in trans with
a head-region missense - so it is not established as a dominant-acting allele, and
the dominant disease this entry covers may not be the setting in which it operates.
See the REFUTE items below and the knowledge gap.
molecular_functions:
- preferred_term: embryonic myosin motor activity
term:
id: GO:0000146
label: microfilament motor activity
modifier: DECREASED
- preferred_term: actin binding by embryonic myosin
term:
id: GO:0003779
label: actin binding
modifier: INCREASED
evidence:
- reference: PMID:32799913
reference_title: Drosophila myosin mutants model the disparate severity of type 1 and type 2B distal arthrogryposis and indicate an enhanced actin affinity mechanism.
supports: SUPPORT
directness: INDIRECT
evidence_source: COMPUTATIONAL
snippet: "molecular modeling \nstudies, which indicate that the F437I and A234T mutations affect specific amino \nacid residue interactions within the myosin motor domain that may alter \ninteraction with actin and nucleotide"
explanation: >-
Locates the lesion in the motor domain's actin and nucleotide interfaces. Indirect
and computational: this is in silico modeling of two DA alleles, not CPSFS alleles.
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: REFUTE
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "pathogenic variants in CHRNG, MYH3 and TPM2 described to date have been associated with loss of function mutations"
explanation: >-
Contradicts this node as a general account of CPSFS. On the pterygium and
skeletal-fusion end of the MYH3 spectrum the reported allele class is loss of
function, which a gain-of-mechanical-function motor lesion does not describe.
Indirect because the statement is made of a multiple pterygium syndrome cohort
rather than of CPSFS1A. Retained rather than reconciled because both readings
have support.
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: REFUTE
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "the MYH3 c.-9+1G > A variant was initially described in individuals with spondylocarpotarsal synostosis syndrome"
explanation: >-
Names the recurrent allele on the spondylocarpotarsal side as a 5'UTR splice
variant. A 5'UTR splice lesion cannot alter residue interactions in the motor
domain, so for that allele this node's mechanism does not apply. Indirect, and by
two steps: the observation is made in a multiple pterygium syndrome cohort, and
the patient carrying it was compound heterozygous (c.-9+1G>A in trans with
p.Ala183Pro), so it is a biallelic presentation rather than the dominant disease
this entry is scoped to.
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "This missense is not present in gnomAD and affects the head region of MYH3, a domain where pathogenic missense variants are frequently observed"
explanation: >-
The counterweight to the two REFUTE items above, from the same paper and the same
patient: motor-domain (head region) missense is a recognized and frequent
pathogenic class in MYH3. This is why the entry carries both readings rather than
replacing one with the other.
downstream:
- target: Prolonged Actomyosin Interaction
causal_link_type: DIRECT
description: >-
Tighter actin binding with slower nucleotide turnover keeps myosin heads attached
through a larger fraction of the cycle.
- name: Prolonged Actomyosin Interaction
biological_scale: MOLECULAR
description: >-
Mutant embryonic myosin hydrolyses ATP more slowly and stays bound to actin longer,
with the rate-limiting step falling around phosphate release and the power stroke.
The functional consequence is a muscle that is stiffer and stronger per unit but
produces less usable power.
molecular_functions:
- preferred_term: actin-activated myosin ATPase cycling
term:
id: GO:0000146
label: microfilament motor activity
modifier: DECREASED
evidence:
- reference: PMID:32799913
reference_title: Drosophila myosin mutants model the disparate severity of type 1 and type 2B distal arthrogryposis and indicate an enhanced actin affinity mechanism.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "These data in conjunction with our sinusoidal analysis of fibers \nsuggest prolonged myosin binding to actin and a slowed step associated with Pi \nrelease and/or the power stroke."
explanation: >-
Directly measures the prolonged actomyosin interaction this node asserts. Indirect
for CPSFS1A: the measurement is in transgenic Drosophila carrying DA alleles.
- reference: PMID:32799913
reference_title: Drosophila myosin mutants model the disparate severity of type 1 and type 2B distal arthrogryposis and indicate an enhanced actin affinity mechanism.
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "isolated DA1 myosin \nshowed significantly reduced myosin ATPase activity and in vitro actin filament \nmotility"
explanation: >-
Biochemical measurement on isolated mutant myosin, separate from the fiber
mechanics above. Graded IN_VITRO because the assay is on purified protein.
downstream:
- target: Myofibril Assembly and Stability Defect
causal_link_type: DIRECT
description: >-
Abnormal cross-bridge kinetics degrade sarcomere assembly and maintenance in the
developing muscle.
- name: Myofibril Assembly and Stability Defect
biological_scale: CELLULAR
description: >-
Developing muscle fibers assemble myofibrils poorly and fail to maintain them,
with reduced power output alongside increased stiffness and passive force - the
combination that makes this a mechanically abnormal rather than simply weak muscle.
cell_types:
- preferred_term: fetal skeletal muscle fiber
term:
id: CL:0008002
label: skeletal muscle fiber
- preferred_term: differentiating myotube
term:
id: CL:0002372
label: myotube
biological_processes:
- preferred_term: myofibril assembly
term:
id: GO:0030239
label: myofibril assembly
modifier: DECREASED
- preferred_term: skeletal muscle contraction
term:
id: GO:0006936
label: muscle contraction
modifier: ABNORMAL
evidence:
- reference: PMID:32799913
reference_title: Drosophila myosin mutants model the disparate severity of type 1 and type 2B distal arthrogryposis and indicate an enhanced actin affinity mechanism.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "We observed significant defects in DA1 and DA2B Drosophila flight and \njump ability, as well as myofibril assembly and stability"
explanation: >-
Reports the myofibril assembly and stability defect this node asserts, in an
invertebrate model of two DA alleles.
- reference: PMID:32799913
reference_title: Drosophila myosin mutants model the disparate severity of type 1 and type 2B distal arthrogryposis and indicate an enhanced actin affinity mechanism.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Mechanical studies of indirect flight muscle fibers from DA1 \nheterozygotes revealed reduced power output along with increased stiffness and \nforce production, compared to wild-type controls."
explanation: >-
Quantifies the stiff-but-underpowered fiber phenotype, and does so in
heterozygotes, which is the relevant dose for a dominant disorder.
downstream:
- target: Reduced Fetal Movement
causal_link_type: DIRECT
description: >-
Mechanically compromised fetal muscle moves the limbs less through the period when
joint mobility is established.
- name: Reduced Fetal Movement
biological_scale: ORGANISM
description: >-
Diminished fetal movement during the window in which embryonic myosin is the
dominant sarcomeric isoform. This is the convergence point at which a molecular
motor defect becomes a structural birth defect, and it is the step shared with the
other akinesia-related contracture syndromes.
biological_processes:
- preferred_term: skeletal muscle tissue development
term:
id: GO:0007519
label: skeletal muscle tissue development
modifier: ABNORMAL
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Multiple pterygium syndrome (MPS) is a genetically heterogeneous \nrare form of arthrogryposis multiplex congenita characterized by joint \ncontractures and webbing or pterygia, as well as distinctive facial features \nrelated to diminished fetal movement."
explanation: >-
Attributes the contracture-plus-pterygium-plus-facial phenotype to diminished
fetal movement. Indirect: stated for multiple pterygium syndrome, an allelic and
clinically overlapping MYH3 condition, not for CPSFS1A.
downstream:
- target: Congenital contracture
causal_link_type: DIRECT
description: Joints held immobile through development become fixed in flexion.
- target: Periarticular Soft Tissue Webbing
causal_link_type: DIRECT
description: >-
Skin and soft tissue across a persistently flexed joint fail to expand, producing
a web.
- target: Axial and Appendicular Bony Fusion
causal_link_type: DIRECT
description: >-
Absent joint motion permits adjacent skeletal elements to fuse rather than
cavitate and separate.
- name: Periarticular Soft Tissue Webbing
biological_scale: TISSUE
description: >-
Soft tissue spanning a chronically flexed joint becomes a fixed web, most often
across the popliteal, antecubital and cervical regions.
downstream:
- target: Pterygium
causal_link_type: DIRECT
- name: Axial and Appendicular Bony Fusion
biological_scale: TISSUE
description: >-
Vertebral, carpal and tarsal elements fuse. This is the node that distinguishes
CPSFS from the other MYH3 contracture syndromes, and it is also what makes the
resulting spinal deformity structural rather than positional.
downstream:
- target: Vertebral fusion
causal_link_type: DIRECT
- target: Carpal synostosis
causal_link_type: DIRECT
- target: Tarsal synostosis
causal_link_type: DIRECT
- target: Scoliosis
causal_link_type: DIRECT
description: >-
Asymmetric vertebral fusion produces a curve that progresses with growth rather
than responding to bracing alone.
evidence:
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 variants underlie both dominantly and recessively inherited Contractures, \nPterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are \ncharacterized by extensive bony abnormalities in addition to congenital \ncontractures."
explanation: >-
Names extensive bony abnormality as the defining feature of CPSFS over the other
MYH3 contracture syndromes, which is what this node asserts.
phenotypes:
- category: Musculoskeletal
name: Congenital contracture
phenotype_term:
preferred_term: Congenital contracture
term:
id: HP:0002803
label: Congenital contracture
description: >-
Multiple congenital joint contractures, distally predominant, present at birth.
evidence:
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 variants underlie both dominantly and recessively inherited Contractures, \nPterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are \ncharacterized by extensive bony abnormalities in addition to congenital \ncontractures."
explanation: Names congenital contractures as a defining feature of CPSFS.
- category: Musculoskeletal
name: Pterygium
phenotype_term:
preferred_term: Pterygium
term:
id: HP:0001059
label: Pterygium
description: Webbing across chronically flexed joints.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "fingers with camptodactyly, interdigital pterygia and thumb-in-palm deformities"
explanation: >-
An observed pterygium finding rather than the word appearing in a syndrome name.
Indirect because the cohort is multiple pterygium syndrome.
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 variants underlie both dominantly and recessively inherited Contractures, \nPterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are \ncharacterized by extensive bony abnormalities in addition to congenital \ncontractures."
explanation: >-
Pterygia appear here only inside the syndrome's name, so this establishes that
pterygia are definitional for CPSFS rather than reporting the finding in patients.
Graded INDIRECT for that reason.
- category: Musculoskeletal
name: Vertebral fusion
phenotype_term:
preferred_term: Vertebral fusion
term:
id: HP:0002948
label: Vertebral fusion
description: >-
Fusion of vertebral bodies or posterior elements; the spondylo- component of the
syndrome name.
evidence:
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by vertebral\nfusions, a disproportionately short stature, and synostosis of carpal and tarsal\nbones"
explanation: >-
Names the fusion triad. Indirect: stated for spondylocarpotarsal synostosis
syndrome, whose phenotype MYH3 is reported to cause alongside FLNB, rather than
for CPSFS1A specifically.
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "with pathogenic variants in FLNB, MYH3, and the more recently proposed RFLNA, being reported to cause this condition"
explanation: >-
Connects MYH3 to that fusion phenotype, which is what makes the preceding quote
bear on this entry at all.
- category: Musculoskeletal
name: Carpal synostosis
phenotype_term:
preferred_term: Carpal synostosis
term:
id: HP:0009702
label: Carpal synostosis
description: Fusion of carpal bones; the carpo- component of the syndrome name.
evidence:
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by vertebral\nfusions, a disproportionately short stature, and synostosis of carpal and tarsal\nbones"
explanation: >-
Names the fusion triad. Indirect: stated for spondylocarpotarsal synostosis
syndrome, whose phenotype MYH3 is reported to cause alongside FLNB, rather than
for CPSFS1A specifically.
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "with pathogenic variants in FLNB, MYH3, and the more recently proposed RFLNA, being reported to cause this condition"
explanation: >-
Connects MYH3 to that fusion phenotype, which is what makes the preceding quote
bear on this entry at all.
- category: Musculoskeletal
name: Tarsal synostosis
phenotype_term:
preferred_term: Tarsal synostosis
term:
id: HP:0008368
label: Tarsal synostosis
description: Fusion of tarsal bones; the tarsal component of the syndrome name.
evidence:
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by vertebral\nfusions, a disproportionately short stature, and synostosis of carpal and tarsal\nbones"
explanation: >-
Names the fusion triad. Indirect: stated for spondylocarpotarsal synostosis
syndrome, whose phenotype MYH3 is reported to cause alongside FLNB, rather than
for CPSFS1A specifically.
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "with pathogenic variants in FLNB, MYH3, and the more recently proposed RFLNA, being reported to cause this condition"
explanation: >-
Connects MYH3 to that fusion phenotype, which is what makes the preceding quote
bear on this entry at all.
- category: Musculoskeletal
name: Scoliosis
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
clinical_course: PROGRESSIVE
description: >-
Early-onset scoliosis that in MYH3-related disease tends to the malignant end of
the spectrum - a curve reaching 50 degrees before age four - rather than the mild
curves seen in other arthrogryposis genotypes.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "the two patients with MYH3 mutations presented with malignant \nscoliosis"
explanation: >-
Both MYH3-mutant children in this series had malignant scoliosis while the CHRNG
patients spanned the mild-to-malignant range. Indirect and small: n=2, and the
cohort was ascertained as multiple pterygium syndrome rather than CPSFS.
- category: Musculoskeletal
name: Camptodactyly
phenotype_term:
preferred_term: Camptodactyly
term:
id: HP:0012385
label: Camptodactyly
description: Flexion contracture of the interphalangeal joints of the fingers.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "fingers with camptodactyly, interdigital pterygia and thumb-in-palm deformities"
explanation: >-
Reports camptodactyly in the hand phenotype. Indirect: the cohort is multiple
pterygium syndrome, which includes MYH3 patients but is not CPSFS.
- category: Musculoskeletal
name: Talipes equinovarus
phenotype_term:
preferred_term: Talipes equinovarus
term:
id: HP:0001762
label: Talipes equinovarus
description: Clubfoot, a common distal contracture in MYH3-related disease.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "foot deformities include both clubfoot and congenital vertical talus"
explanation: >-
Reports clubfoot in the foot phenotype of this overlapping MYH3-inclusive cohort.
- category: Craniofacial
name: Micrognathia
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
description: >-
Small mandible, part of the facial phenotype attributed to diminished fetal
movement across the MYH3 contracture syndromes.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "distinctive facial features including micrognathia"
explanation: >-
Reports micrognathia among the distinctive facial features of this overlapping
cohort, and attributes them to diminished fetal movement.
- category: Growth
name: Short stature
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
description: >-
Reduced height, driven substantially by the spinal deformity and vertebral fusion
rather than by a primary growth defect.
evidence:
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by vertebral\nfusions, a disproportionately short stature, and synostosis of carpal and tarsal\nbones"
explanation: >-
Names the fusion triad. Indirect: stated for spondylocarpotarsal synostosis
syndrome, whose phenotype MYH3 is reported to cause alongside FLNB, rather than
for CPSFS1A specifically.
- reference: PMID:33916386
reference_title: Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "with pathogenic variants in FLNB, MYH3, and the more recently proposed RFLNA, being reported to cause this condition"
explanation: >-
Connects MYH3 to that fusion phenotype, which is what makes the preceding quote
bear on this entry at all.
treatments:
- name: Spinal Bracing and Serial Casting
description: >-
Non-operative management of early-onset scoliosis. It buys time rather than
correcting the deformity, and in the malignant curves characteristic of MYH3
disease that window is short.
treatment_term:
preferred_term: spinal bracing and serial casting
term:
id: NCIT:C15315
label: Rehabilitation
therapeutic_modality: DEVICE
target_phenotypes:
- preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
target_mechanisms:
- target: Axial and Appendicular Bony Fusion
description: >-
Bracing and casting act on the curve produced by asymmetric vertebral fusion. They
do not act on the fusion itself, which is why the benefit is time-limited.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Bracing and serial spine casting appear to be beneficial for a few \nyears; non-fusion spinal instrumentation may be needed to modulate more severe \ncurves during growth and spontaneous spine fusions may occur in those cases."
explanation: >-
Reports the benefit and its time limit, and the escalation to instrumentation.
Indirect: observed in a multiple pterygium syndrome series that included MYH3
patients rather than a CPSFS cohort.
- name: Non-Fusion Spinal Instrumentation
description: >-
Growth-friendly instrumentation to modulate a severe curve while the spine is still
growing. Spontaneous fusion may occur in these cases, which is a consideration
specific to a disease whose mechanism already favours fusion.
treatment_term:
preferred_term: non-fusion spinal instrumentation
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
therapeutic_modality: SURGERY
target_phenotypes:
- preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
target_mechanisms:
- target: Axial and Appendicular Bony Fusion
description: >-
Growth-friendly instrumentation modulates the curve arising from vertebral fusion.
Spontaneous fusion may follow, so the intervention shares a direction with the
mechanism it is managing.
evidence:
- reference: PMID:34440395
reference_title: "The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Bracing and serial spine casting appear to be beneficial for a few \nyears; non-fusion spinal instrumentation may be needed to modulate more severe \ncurves during growth and spontaneous spine fusions may occur in those cases."
explanation: >-
Names non-fusion instrumentation as the escalation for curves that outrun bracing.
- name: Physical Therapy
description: >-
Stretching, splinting and range-of-motion work for the congenital contractures.
Standard of care across the distal arthrogryposes; no CPSFS-specific outcome data
was citable here.
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
therapeutic_modality: BEHAVIORAL
target_phenotypes:
- preferred_term: Congenital contracture
term:
id: HP:0002803
label: Congenital contracture
target_mechanisms:
- target: Congenital contracture
description: >-
Stretching and splinting act on the established contracture. Nothing in current
management reaches the myosin lesion upstream of it.
notes: >-
Left without an evidence item on purpose. Generic arthrogryposis rehabilitation
literature was not reachable in the environment this entry was curated in, and a
quote about a different disorder would not support the claim.
differential_diagnoses:
- name: Freeman-Sheldon syndrome (DA2A)
description: >-
The severe end of the MYH3 distal arthrogryposis spectrum, with facial contractures
and congenital scoliosis but without the carpal and tarsal fusions that define
CPSFS. Three recurrent alleles explain most cases.
evidence:
- reference: PMID:25256237
reference_title: Genotype-phenotype relationships in Freeman-Sheldon syndrome.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "MYH3 mutations were found in 43/46 (93%) kindreds, with three mutations \n(p.T178I, p.R672C, and p.R672H) explaining 39/43 (91%) of cases."
explanation: >-
Establishes the recurrent-allele architecture of DA2A, which is the practical
basis for distinguishing it from CPSFS on sequencing.
- name: Sheldon-Hall syndrome (DA2B)
description: >-
Moderate-severity MYH3 distal arthrogryposis, again without the CPSFS bony fusions.
evidence:
- reference: PMID:38856159
reference_title: Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Heterozygous variants in MYH3 have been identified to \ncause the dominantly-inherited distal arthrogryposis conditions, Freeman-Sheldon \nsyndrome, Sheldon-Hall syndrome, and multiple pterygium syndrome."
explanation: >-
Lists the dominant MYH3 conditions that must be separated from CPSFS1A clinically,
since all are heterozygous MYH3.
- name: Spondylocarpotarsal synostosis syndrome (FLNB)
disease_term:
preferred_term: spondylocarpotarsal synostosis syndrome
term:
id: MONDO:0010094
label: spondylocarpotarsal synostosis syndrome
description: >-
The closest mimic, and the reason the naming is confusing: it produces the same
vertebral, carpal and tarsal fusions but is usually a recessive FLNB defect rather
than a MYH3 one. Contractures and pterygia are less prominent. Already curated in
dismech as Spondylocarpotarsal_Synostosis_Syndrome.
- name: Multiple pterygium syndrome, Escobar variant (CHRNG)
description: >-
Overlaps closely enough to be diagnosed as CPSFS clinically; CHRNG is the more
common cause in a molecularly solved pterygium cohort, with MYH3 the main
alternative to exclude. Already curated in dismech as
Autosomal_Recessive_Multiple_Pterygium_Syndrome.
discussions:
- discussion_id: cpsfs1a_mechanism_is_borrowed_from_da_alleles
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does the enhanced-actin-affinity mechanism established for DA1 and DA2B alleles
actually hold for the MYH3 alleles that cause CPSFS1A, and if so what makes those
alleles produce bony fusion rather than contractures alone?
attaches_to:
- pathophysiology#Prolonged Actomyosin Interaction
- pathophysiology#Axial and Appendicular Bony Fusion
rationale: >-
Every mechanistic evidence item on the molecular and cellular nodes of this entry
comes from work on DA1 (F437I) and DA2B (A234T) alleles in transgenic Drosophila
and on purified myosin - not from CPSFS alleles, and not from human muscle. The
causal chain from motor defect to contracture is therefore borrowed from allelic
neighbours. That borrowing is defensible for the shared contracture phenotype, but
it explains nothing about the feature that actually defines CPSFS: the vertebral,
carpal and tarsal fusions.
There is now a concrete candidate for the distinct-allele-class possibility, and it
is the reason this gap is not merely an absence of evidence. PMID:34440395 states
that MYH3 variants on the pterygium end of the spectrum have been associated with
loss of function, and names the recurrent CPSFS/spondylocarpotarsal allele as
c.-9+1G>A, a 5'UTR splice variant. A 5'UTR splice lesion cannot produce enhanced
actin affinity in the motor domain, so if it is the representative CPSFS allele then
the chain on this entry describes a different disorder than the one it is filed
under. The same paper's other MYH3 patient carried a head-region missense, and notes
that motor-domain missense is a frequent pathogenic class - so the honest position
is two competing allele classes, not a settled answer either way. Both are carried
structurally on the MYH3 Motor Domain Dysfunction node, as SUPPORT and REFUTE.
Curators should not read the INDIRECT gradings on this entry as a formality.
proposed_experiments:
- experiment_id: cpsfs1a_allele_biochemistry
name: CPSFS allele biochemistry against DA alleles
description: >-
Express CPSFS1A-associated MYH3 alleles alongside F437I and A234T and compare
actin affinity, ATPase rate and in vitro motility. Include c.-9+1G>A, which the
biochemical assay cannot address directly and which needs an expression-level
readout instead - that asymmetry is itself the point.
would_support:
- pathophysiology#Prolonged Actomyosin Interaction
supporting_outcome:
- >-
CPSFS alleles show the same enhanced actin affinity and reduced ATPase rate as
the DA alleles, placing the skeletal difference downstream of this node.
refuting_outcome:
- >-
CPSFS alleles show normal actin affinity and ATPase kinetics, in which case the
borrowed DA mechanism on this node needs replacing rather than annotating.
notes: >-
Scope: MONDO:0008338 is the autosomal dominant form (CPSFS1A). The recessive form
(CPSFS1B) and the parent term contractures, pterygia, and variable skeletal fusions
syndrome (MONDO:0020937) are separate concepts; the parent appears in dismech today
only as a differential_diagnoses entry on Autosomal_Recessive_Multiple_Pterygium_Syndrome
and is not curated in its own right.
review_notes: >-
Curated in an environment with no outbound access to PubMed, Crossref or OLS, so
every reference here was already present in references_cache/ and nothing new could
be fetched. Three things a reviewer should weigh.
First, there is no CPSFS-specific clinical series among the citable sources. The only
source naming CPSFS is PMID:38856159, whose own subject is a recessive distal
arthrogryposis family, so phenotype and treatment evidence leans on allelic MYH3
conditions and is graded INDIRECT wherever the source speaks about a neighbouring
condition rather than CPSFS. DIRECT is reserved for the handful of claims a source
makes about CPSFS itself - the inheritance split, MYH3 causation, the defining bony
abnormality and the congenital contractures.
Second, the mechanism is genuinely contested and the entry carries both sides rather
than picking one. The molecular chain rests on motor-domain missense alleles studied
in Drosophila and purified protein; PMID:34440395 reports loss of function on the
pterygium end of the spectrum and a recurrent 5'UTR splice allele on the CPSFS side.
Those appear as REFUTE items on the initiating node, with the same paper's
head-region-missense observation as the counterweight. Do not collapse this to one
reading without new evidence.
Third, MONDO:0008338 was absent from cache/mondo/terms.csv and from the diseaseterm
enum cache, and OLS was unreachable, so that one CURIE could not be validated locally
and its two generated cache rows could not be produced. It comes from the stub's
enrich-stubs MONDO extract; CI, or any curator with network, resolves it. Prevalence
is omitted because no CPSFS1A figure was citable, and no ISDS skeletal category or
OMIM mapping is asserted because neither was verifiable from the cache - the ISDS
nosology (PMID:31633310) is cached abstract-only and does not mention MYH3.