Temtamy Preaxial Brachydactyly Syndrome
Temtamy preaxial brachydactyly syndrome (TPBS; MIM 605282) is a rare autosomal recessive skeletal/developmental disorder caused by biallelic loss-of-function mutations in CHSY1, the gene encoding chondroitin sulfate synthase 1. CHSY1 is a secreted Fringe-domain glycosyltransferase required for chondroitin sulfate biosynthesis. Loss of CHSY1 reduces chondroitin sulfate moieties and triggers excess JAG1 production with increased NOTCH signaling, while CHSY1 has also been proposed as a downstream target of BMP signaling during limb and inner-ear development. The clinical phenotype is characterized by bilateral preaxial brachydactyly with hyperphalangism and partial duplication of proximal phalanges (especially digits 1-3), symphalangism, carpal/tarsal and radioulnar synostoses, facial dysmorphism, dental anomalies, sensorineural hearing loss, short stature, and delayed motor and mental development. TPBS is distinct from C12orf57-related Temtamy syndrome (a separate intellectual disability/corpus callosum disorder).
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Limbs 3
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Source YAML
click to showname: Temtamy Preaxial Brachydactyly Syndrome
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >
Temtamy preaxial brachydactyly syndrome (TPBS; MIM 605282) is a rare
autosomal recessive skeletal/developmental disorder caused by biallelic
loss-of-function mutations in CHSY1, the gene encoding chondroitin sulfate
synthase 1. CHSY1 is a secreted Fringe-domain glycosyltransferase required
for chondroitin sulfate biosynthesis. Loss of CHSY1 reduces chondroitin
sulfate moieties and triggers excess JAG1 production with increased NOTCH
signaling, while CHSY1 has also been proposed as a downstream target of BMP
signaling during limb and inner-ear development. The clinical phenotype is
characterized by bilateral preaxial brachydactyly with hyperphalangism and
partial duplication of proximal phalanges (especially digits 1-3),
symphalangism, carpal/tarsal and radioulnar synostoses, facial dysmorphism,
dental anomalies, sensorineural hearing loss, short stature, and delayed
motor and mental development. TPBS is distinct from C12orf57-related Temtamy
syndrome (a separate intellectual disability/corpus callosum disorder).
disease_term:
preferred_term: Temtamy preaxial brachydactyly syndrome
term:
id: MONDO:0011533
label: temtamy preaxial brachydactyly syndrome
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:21129728
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
TPBS is a Mendelian autosomal-recessive disorder caused by biallelic
CHSY1 loss-of-function mutations, placing it in Harrison's
Genetics/Environment Part.
- classification_value: DISORDER_OF_EAR
evidence:
- reference: PMID:24269551
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Sensorineural hearing loss is a consistent core feature of TPBS,
supporting an ear-disorder classification.
parents:
- Skeletal Dysplasia
synonyms:
- TPBS
- preaxial brachydactyly syndrome, TEMTAMY type
inheritance:
- name: Autosomal Recessive
description: >
TPBS is inherited in an autosomal recessive pattern. Affected individuals
are typically homozygous for CHSY1 loss-of-function variants and were
identified in multiple consanguineous families through homozygosity/linkage
mapping to chromosome 15q26-qter.
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After mapping the TPBS locus to chromosome 15q26-qterm, we identified
causative mutations in five consanguineous TPBS families.
explanation: >-
Identification of biallelic CHSY1 mutations in five consanguineous
families establishes autosomal recessive inheritance.
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene
in two TPBS patients from a consanguineous Pakistani family.
explanation: >-
A homozygous CHSY1 missense variant segregating in a consanguineous
Pakistani family confirms recessive inheritance and extends the
mutational spectrum.
genetic:
- name: CHSY1 Loss-of-Function Mutations
gene_term:
preferred_term: CHSY1
term:
id: hgnc:17198
label: CHSY1
association: Causative
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Establishes CHSY1 loss of function as the cause of TPBS and summarizes
the core phenotype.
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High-throughput sequencing of all 177 candidate genes detected a
truncating frameshift mutation in the gene CHSY1 encoding a chondroitin
synthase with a Fringe domain.
explanation: >-
Independent identification of a truncating CHSY1 frameshift mutation in
syndromic preaxial brachydactyly confirms the gene-disease relationship.
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation predicted substitution of a highly conserved aspartate amino
acid residue to asparagine at position 633 in the protein (D633N).
explanation: >-
A novel conserved-residue missense variant (p.D633N) broadens the CHSY1
pathogenic variant spectrum beyond truncating alleles.
notes: >
Reported pathogenic CHSY1 alleles include in-frame deletions, frameshifts,
nonsense, splice-site, and missense variants, consistent with a
loss-of-function disease mechanism. Open Targets summarizes the allelic
requirement as biallelic with loss-of-function/absent gene product
consequence.
pathophysiology:
- name: CHSY1 Deficiency and Reduced Chondroitin Sulfate Biosynthesis
description: >
CHSY1 is a secreted glycosyltransferase, bearing a Fringe domain, that is
required for the synthesis of chondroitin sulfate chains on proteoglycans.
Biallelic loss-of-function mutations eliminate CHSY1 activity, reducing
chondroitin sulfate moieties and altering the extracellular matrix and
proteoglycan context that supports cartilage, bone, and craniofacial
development. TPBS is therefore part of the spectrum of disorders caused by
defects in glycosaminoglycan/proteoglycan biosynthesis.
genes:
- preferred_term: CHSY1
term:
id: hgnc:17198
label: CHSY1
biological_processes:
- preferred_term: Chondroitin sulfate proteoglycan biosynthesis
term:
id: GO:0050650
label: chondroitin sulfate proteoglycan biosynthetic process
modifier: DECREASED
- preferred_term: Glycosaminoglycan biosynthesis
term:
id: GO:0006024
label: glycosaminoglycan biosynthetic process
modifier: DECREASED
chemical_entities:
- preferred_term: chondroitin sulfate
term:
id: CHEBI:37397
label: chondroitin sulfate
modifier: DECREASED
cell_types:
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
CHSY1 was secreted from patients' fibroblasts and was required for
synthesis of chondroitin sulfate moieties.
explanation: >-
Patient fibroblast studies establish that CHSY1 is secreted and required
for chondroitin sulfate synthesis, the proximate biochemical defect.
downstream:
- target: Increased JAG1-NOTCH Signaling
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Noticeably, its absence triggered massive production of JAG1 and
subsequent NOTCH activation, which could only be reversed with a wild-type
but not a Fringe catalytically dead CHSY1 construct.
explanation: >-
CHSY1 absence directly causes increased JAG1 and NOTCH activation,
establishing the causal link from CHSY1 deficiency to NOTCH dysregulation.
- target: Dysregulated BMP-CHSY1 Limb and Inner-Ear Patterning
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to
reduced chsy1 expression and, during epithelial morphogenesis, defects
similar to those that occur upon Chsy1 inactivation, indicating that Bmp
signaling affects inner-ear development by repressing chsy1.
explanation: >-
The BMP-CHSY1 regulatory axis links the chondroitin sulfate defect to
BMP-dependent inner-ear and limb patterning.
- name: Increased JAG1-NOTCH Signaling
description: >
Loss of CHSY1 triggers massive production of the Notch ligand JAG1 and
subsequent activation of NOTCH signaling. This effect requires CHSY1's
catalytic Fringe activity, as it is reversed by wild-type but not a
catalytically dead CHSY1 construct. Dysregulated NOTCH output disturbs
skeletal patterning, particularly during limb development, and CHSY1
depletion also enhances osteogenesis in fetal osteoblasts and upregulates
JAG2 in other cell types.
genes:
- preferred_term: CHSY1
term:
id: hgnc:17198
label: CHSY1
biological_processes:
- preferred_term: Notch signaling pathway
term:
id: GO:0007219
label: Notch signaling pathway
modifier: INCREASED
- preferred_term: Limb morphogenesis
term:
id: GO:0035108
label: limb morphogenesis
modifier: ABNORMAL
cell_types:
- preferred_term: Osteoblast
term:
id: CL:0000062
label: osteoblast
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Noticeably, its absence triggered massive production of JAG1 and
subsequent NOTCH activation, which could only be reversed with a wild-type
but not a Fringe catalytically dead CHSY1 construct.
explanation: >-
Demonstrates that CHSY1 loss increases JAG1 and NOTCH activation in a
Fringe-catalysis-dependent manner, the core signaling mechanism.
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro, depletion of CHSY1 by RNAi knockdown resulted in enhanced
osteogenesis in fetal osteoblasts and remarkable upregulation of JAG2 in
glioblastoma cells.
explanation: >-
RNAi knockdown links CHSY1 loss to enhanced osteogenesis and JAG2
upregulation, supporting altered Notch-ligand-driven skeletal cell
behavior.
downstream:
- target: Abnormal Limb and Skeletal Patterning
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the
human disorder; it increased NOTCH output and impaired skeletal,
pectoral-fin, and retinal development.
explanation: >-
Increased NOTCH output in vivo drives the impaired skeletal/limb
development that produces the TPBS patterning phenotype.
- name: Dysregulated BMP-CHSY1 Limb and Inner-Ear Patterning
description: >
CHSY1 has been identified as a potential mediator/target of BMP signaling.
In zebrafish, unrestricted Bmp2b signaling or loss of the BMP inhibitor Dan
reduces chsy1 expression, and Chsy1 perturbation produces inner-ear and
other developmental defects similar to those seen with altered BMP
signaling. Both loss and gain of chsy1 produce comparable zebrafish
phenotypes, paralleling how human brachydactyly can result from either
reduced or excessive BMP signaling. This BMP-CHSY1 axis links the chondroitin
sulfate defect to limb, craniofacial, and inner-ear (hearing) phenotypes.
genes:
- preferred_term: CHSY1
term:
id: hgnc:17198
label: CHSY1
biological_processes:
- preferred_term: BMP signaling pathway
term:
id: GO:0030509
label: BMP signaling pathway
modifier: ABNORMAL
- preferred_term: Skeletal system development
term:
id: GO:0001501
label: skeletal system development
modifier: ABNORMAL
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to
reduced chsy1 expression and, during epithelial morphogenesis, defects
similar to those that occur upon Chsy1 inactivation, indicating that Bmp
signaling affects inner-ear development by repressing chsy1.
explanation: >-
Zebrafish data establish that BMP signaling represses chsy1 and that the
BMP-CHSY1 axis governs inner-ear development, linking the gene defect to
the hearing phenotype.
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In addition, we obtained strikingly similar zebrafish phenotypes after
chsy1 overexpression, which might explain why, in humans, brachydactyly
can be caused by mutations leading either to loss or to gain of BMP
signaling.
explanation: >-
Both loss and gain of chsy1 produce similar zebrafish phenotypes,
mirroring the dual relationship between BMP signaling level and
brachydactyly.
downstream:
- target: Abnormal Limb and Skeletal Patterning
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In zebrafish, antisense-mediated chsy1 knockdown causes defects in
multiple developmental processes, some of which are likely to also be
causative in the etiology of TPBS.
explanation: >-
Dysregulated BMP-CHSY1 developmental signaling produces the
multi-process developmental defects underlying TPBS limb/skeletal
patterning.
- name: Abnormal Limb and Skeletal Patterning
description: >
Convergent dysregulation of NOTCH and BMP signaling, downstream of reduced
chondroitin sulfate biosynthesis, produces abnormal limb and skeletal
patterning and ossification. The result is the characteristic preaxial
brachydactyly with hyperphalangism and partial duplication/splitting of
proximal phalanges in digits 1-3, symphalangism, and carpal/tarsal and
radioulnar synostoses, together with craniofacial and inner-ear anomalies.
cell_types:
- preferred_term: Chondrocyte
term:
id: CL:0000138
label: chondrocyte
- preferred_term: Osteoblast
term:
id: CL:0000062
label: osteoblast
biological_processes:
- preferred_term: Limb morphogenesis
term:
id: GO:0035108
label: limb morphogenesis
modifier: ABNORMAL
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the
human disorder; it increased NOTCH output and impaired skeletal,
pectoral-fin, and retinal development.
explanation: >-
Zebrafish chsy1 knockdown increases NOTCH output and impairs skeletal and
appendage development, recapitulating the human limb-patterning defect.
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We conclude that CHSY1 is a secreted FRINGE enzyme required for adjustment
of NOTCH signaling throughout human and fish embryogenesis and
particularly during limb patterning.
explanation: >-
Establishes CHSY1's role in tuning NOTCH signaling during limb patterning,
the developmental process disrupted in TPBS.
downstream:
- target: Preaxial Brachydactyly with Proximal Phalangeal Duplication
causal_link_type: DIRECT
- target: Brachydactyly
causal_link_type: DIRECT
- target: Finger Hyperphalangy
causal_link_type: DIRECT
- target: Proximal Finger Symphalangism
causal_link_type: DIRECT
- target: Radioulnar Synostosis
causal_link_type: DIRECT
- target: Carpal Synostosis
causal_link_type: DIRECT
- target: Tarsal Synostosis
causal_link_type: DIRECT
- target: Sensorineural Hearing Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Facial Dysmorphism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Dental Anomalies
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Delayed Motor and Mental Development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Short Stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Severe Sensorineural Hearing Impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Hypodontia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Talon Cusp
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Widely-Spaced Maxillary Central Incisors
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Abnormally Large Globe
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Abnormal Facial Shape
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Duplication of Thumb Phalanx
causal_link_type: DIRECT
- target: Synostosis of Carpals and Tarsals
causal_link_type: DIRECT
phenotypes:
- category: Skeletal
name: Preaxial Brachydactyly with Proximal Phalangeal Duplication
description: >
Hallmark feature is bilateral, symmetric preaxial brachydactyly with partial
duplication/splitting of proximal phalanges, particularly in digits 1-3.
phenotype_term:
preferred_term: Preaxial brachydactyly with proximal phalangeal duplication
term:
id: HP:0009613
label: Duplication of the proximal phalanx of the thumb
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We delineated a syndromic recessive preaxial brachydactyly with partial
duplication of proximal phalanges to 16.8 Mb over 4 chromosomes.
explanation: >-
Describes the cardinal limb phenotype of preaxial brachydactyly with
partial duplication of proximal phalanges.
- category: Skeletal
name: Brachydactyly
description: >
Generalized brachydactyly (shortened digits) accompanies the preaxial
phalangeal anomalies and limb malformations.
phenotype_term:
preferred_term: Brachydactyly
term:
id: HP:0001156
label: Brachydactyly
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple
developmental defects, including brachydactyly and deafness.
explanation: >-
Brachydactyly (and deafness) are identified as core developmental defects
in this BMP/CHSY1-related disorder.
- category: Skeletal
name: Finger Hyperphalangy
description: >
Hyperphalangism, with accessory phalanges arranged linearly within affected
digits (especially digits 1-3), is a characteristic radiographic finding.
phenotype_term:
preferred_term: Finger hyperphalangy
term:
id: HP:0030367
label: Finger hyperphalangy
evidence:
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Clinical description explicitly lists hyperphalangism of digits as a
defining TPBS feature.
- category: Skeletal
name: Proximal Finger Symphalangism
description: >
Symphalangism (fusion of phalanges) affecting the fingers contributes to the
digital malformation spectrum of TPBS.
phenotype_term:
preferred_term: Proximal finger symphalangism
term:
id: HP:0006152
label: Proximal finger symphalangism
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We delineated a syndromic recessive preaxial brachydactyly with partial
duplication of proximal phalanges to 16.8 Mb over 4 chromosomes.
explanation: >-
Symphalangism is a well-documented TPBS feature in the full-text
literature; the available abstract does not name it explicitly, so this
snippet supports the broader syndromic digital malformation spectrum
(preaxial brachydactyly with proximal phalangeal anomalies) of which
finger symphalangism is part.
- category: Skeletal
name: Radioulnar Synostosis
description: >
Fusion of the radius and ulna (radioulnar synostosis) is among the
characteristic skeletal fusions reported in TPBS.
phenotype_term:
preferred_term: Radioulnar synostosis
term:
id: HP:0002974
label: Radioulnar synostosis
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Radioulnar synostosis is part of the limb malformation spectrum
characterizing TPBS in the gene-discovery report.
- category: Skeletal
name: Carpal Synostosis
description: >
Fusion of carpal bones is part of the skeletal fusion phenotype, alongside
tarsal and radioulnar synostoses.
phenotype_term:
preferred_term: Synostosis of carpal bones
term:
id: HP:0005048
label: Synostosis of carpal bones
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Carpal synostosis is part of the broad limb malformation spectrum
characterizing TPBS.
- category: Skeletal
name: Tarsal Synostosis
description: >
Fusion of tarsal bones in the feet parallels the carpal fusion seen in the
hands.
phenotype_term:
preferred_term: Tarsal synostosis
term:
id: HP:0008368
label: Tarsal synostosis
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Tarsal synostosis is part of the limb malformation spectrum characterizing
TPBS.
- category: Auditory
name: Sensorineural Hearing Loss
description: >
Moderate to profound sensorineural hearing impairment is a consistent
extra-skeletal manifestation, mechanistically linked to BMP-CHSY1
dysregulation during inner-ear development.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Hearing loss is identified as a core feature of TPBS in the gene-discovery
report.
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Independent clinical description confirms sensorineural hearing loss as a
defining TPBS feature.
- category: Craniofacial
name: Facial Dysmorphism
description: >
Affected individuals display characteristic facial dysmorphism as part of
the syndromic presentation.
phenotype_term:
preferred_term: Facial dysmorphism
term:
id: HP:0000271
label: Abnormality of the face
evidence:
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Clinical description lists facial dysmorphism among the defining TPBS
features.
- category: Dental
name: Dental Anomalies
description: >
Orodental anomalies are part of the syndromic phenotype of TPBS.
phenotype_term:
preferred_term: Dental anomalies
term:
id: HP:0000164
label: Abnormality of the dentition
evidence:
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Clinical description lists dental anomalies among the defining TPBS
features.
- category: Neurodevelopmental
name: Delayed Motor and Mental Development
description: >
Delayed motor and mental development (global developmental delay) is
reported in affected individuals.
phenotype_term:
preferred_term: Delayed motor and mental development
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Clinical description lists delayed motor and mental development among the
defining TPBS features.
- category: Growth
name: Short Stature
description: >
Short stature/growth retardation accompanies the skeletal phenotype.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
Short stature is identified as a core feature of TPBS in the gene-discovery
report.
- category: Neurodevelopmental
name: Intellectual Disability
description: >
Intellectual disability is a frequent extra-skeletal manifestation of TPBS,
accompanying the motor and mental developmental delay.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
explanation: >-
Orphanet lists intellectual disability as a frequent feature of
Temtamy preaxial brachydactyly syndrome.
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive
rare disorder characterized by hyperphalangism of digits, facial
dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor
and mental development, and growth retardation.
explanation: >-
Delayed mental development in this clinical description reflects the
underlying intellectual disability in TPBS.
- category: Auditory
name: Severe Sensorineural Hearing Impairment
description: >
Severe sensorineural hearing impairment is a frequent feature of TPBS,
representing a more specific characterization of the hearing loss that
is typically profound in affected individuals.
phenotype_term:
preferred_term: Severe sensorineural hearing impairment
term:
id: HP:0008625
label: Severe sensorineural hearing impairment
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0008625 | Severe sensorineural hearing impairment | Frequent (79-30%)"
explanation: >-
Orphanet lists severe sensorineural hearing impairment as a frequent
feature of Temtamy preaxial brachydactyly syndrome.
- category: Dental
name: Hypodontia
description: >
Hypodontia (fewer than normal number of teeth) is a frequent dental anomaly
in TPBS, part of the orodental phenotype that includes talon cusps and
misaligned teeth.
phenotype_term:
preferred_term: Hypodontia
term:
id: HP:0000668
label: Hypodontia
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0000668 | Hypodontia | Frequent (79-30%)"
explanation: >-
Orphanet lists hypodontia as a frequent dental feature of
Temtamy preaxial brachydactyly syndrome.
- category: Dental
name: Talon Cusp
description: >
Talon cusps (accessory cusps on the lingual surface of teeth) are a
characteristic dental finding in TPBS, part of the dental anomaly spectrum.
phenotype_term:
preferred_term: Talon cusp
term:
id: HP:0011087
label: Talon cusp
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0011087 | Talon cusp | Frequent (79-30%)"
explanation: >-
Orphanet lists talon cusp as a frequent dental feature of
Temtamy preaxial brachydactyly syndrome.
- category: Dental
name: Widely-Spaced Maxillary Central Incisors
description: >
Widely-spaced maxillary central incisors are a frequent dental anomaly
in TPBS, contributing to the characteristic dental phenotype.
phenotype_term:
preferred_term: Widely-spaced maxillary central incisors
term:
id: HP:0001566
label: Widely-spaced maxillary central incisors
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0001566 | Widely-spaced maxillary central incisors | Frequent (79-30%)"
explanation: >-
Orphanet lists widely-spaced maxillary central incisors as a frequent
dental feature of Temtamy preaxial brachydactyly syndrome.
- category: Eye
name: Abnormally Large Globe
description: >
Enlarged globes (megalocornea/buphthalmos) are an occasional-to-frequent
ocular feature of TPBS, reflecting the multi-system nature of the
developmental syndrome.
phenotype_term:
preferred_term: Abnormally large globe
term:
id: HP:0001090
label: Abnormally large globe
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0001090 | Abnormally large globe | Frequent (79-30%)"
explanation: >-
Orphanet lists abnormally large globe as a frequent ocular feature of
Temtamy preaxial brachydactyly syndrome.
- category: Craniofacial
name: Abnormal Facial Shape
description: >
Affected individuals have an abnormal facial shape as part of the syndromic
dysmorphism, including round face, malar hypoplasia, and other features
described in the Orphanet definition.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0001999 | Abnormal facial shape | Frequent (79-30%)"
explanation: >-
Orphanet lists abnormal facial shape as a frequent craniofacial feature
of Temtamy preaxial brachydactyly syndrome.
- category: Skeletal
name: Duplication of Thumb Phalanx
description: >
Duplication of one or more phalanges of the thumb is a very frequent
hallmark of TPBS, encompassing both complete and partial duplications
of the proximal phalanx of the thumb.
phenotype_term:
preferred_term: Duplication of thumb phalanx
term:
id: HP:0009942
label: Duplication of thumb phalanx
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0009942 | Duplication of thumb phalanx | Very frequent (99-80%)"
explanation: >-
Orphanet lists duplication of thumb phalanx as a very frequent feature
of Temtamy preaxial brachydactyly syndrome.
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We delineated a syndromic recessive preaxial brachydactyly with partial
duplication of proximal phalanges to 16.8 Mb over 4 chromosomes.
explanation: >-
The gene-discovery paper delineates the preaxial brachydactyly with
phalangeal duplication that defines TPBS.
- category: Skeletal
name: Synostosis of Carpals and Tarsals
description: >
Combined carpal and tarsal synostoses are a frequent skeletal fusion
phenotype in TPBS, reflecting widespread abnormal joint fusion affecting
both hands and feet.
phenotype_term:
preferred_term: Synostosis of carpals/tarsals
term:
id: HP:0100266
label: Synostosis of carpals/tarsals
frequency: FREQUENT
evidence:
- reference: ORPHA:363417
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0100266 | Synostosis of carpals/tarsals | Frequent (79-30%)"
explanation: >-
Orphanet lists synostosis of carpals/tarsals as a frequent skeletal
feature of Temtamy preaxial brachydactyly syndrome.
animal_models:
- species: Danio rerio
genotype: chsy1 antisense morpholino knockdown
description: >
Antisense morpholino knockdown of chsy1 in zebrafish embryos partially
phenocopies the human disorder, increasing NOTCH output and impairing
skeletal, pectoral-fin, retinal, and inner-ear development. chsy1
overexpression produces strikingly similar phenotypes, paralleling the human
observation that brachydactyly can arise from either loss or gain of BMP
signaling.
genes:
- preferred_term: CHSY1
term:
id: hgnc:17198
label: CHSY1
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the
human disorder; it increased NOTCH output and impaired skeletal,
pectoral-fin, and retinal development.
explanation: >-
Zebrafish chsy1 knockdown recapitulates key TPBS features and confirms the
increased-NOTCH mechanism in vivo.
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In zebrafish, antisense-mediated chsy1 knockdown causes defects in
multiple developmental processes, some of which are likely to also be
causative in the etiology of TPBS.
explanation: >-
Independent zebrafish knockdown produces developmental defects modeling
TPBS etiology.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
description: >-
TPBS is recognized clinically and radiographically from bilateral preaxial
brachydactyly with hyperphalangism and partial duplication/splitting of
proximal phalanges (digits 1-3), symphalangism, carpal/tarsal and radioulnar
synostoses, facial dysmorphism, dental anomalies, and sensorineural hearing
loss (assessed by audiometry). Diagnosis is confirmed by identification of
biallelic CHSY1 loss-of-function variants on molecular genetic testing.
Differential diagnosis includes other syndromic brachydactylies with
hyperphalangism (e.g., Catel-Manzke syndrome). TPBS must be distinguished
from the unrelated C12orf57-related Temtamy syndrome.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After mapping the TPBS locus to chromosome 15q26-qterm, we identified
causative mutations in five consanguineous TPBS families.
explanation: >-
Identification of causative CHSY1 mutations underpins molecular genetic
confirmation of TPBS.
treatments:
- name: Genetic Counseling
description: >
Autosomal recessive inheritance of TPBS warrants genetic counseling for
affected individuals and at-risk families. Identification of the familial
CHSY1 variant enables carrier testing and prenatal/preimplantation genetic
testing for at-risk couples, which is especially relevant in consanguineous
families.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:24269551
reference_title: "A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene
in two TPBS patients from a consanguineous Pakistani family.
explanation: >-
Identification of the familial CHSY1 variant in a consanguineous family
enables carrier testing and counseling for at-risk relatives.
- name: Hearing Aid Therapy
description: >
Sensorineural hearing loss in TPBS is managed supportively with audiologic
rehabilitation, including hearing aids.
treatment_term:
preferred_term: hearing aid usage
term:
id: MAXO:0009030
label: hearing aid usage
evidence:
- reference: PMID:21129728
reference_title: "Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that loss of human CHSY1 function causes autosomal-recessive
Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by
limb malformations, short stature, and hearing loss.
explanation: >-
The hearing loss documented in TPBS is the indication for audiologic
management with hearing aids.
target_mechanisms:
- target: Dysregulated BMP-CHSY1 Limb and Inner-Ear Patterning
treatment_effect: MODULATES
description: >-
Hearing aids compensate for the sensorineural hearing loss resulting from
CHSY1-deficiency-driven patterning defects in inner-ear development without
correcting the underlying BMP-NOTCH signaling imbalance.
- name: Orthopedic Surgery
description: >
Limb malformations including the digital anomalies and synostoses may be
addressed with orthopedic/hand surgical procedures as part of multidisciplinary
supportive management.
treatment_term:
preferred_term: orthopedic surgery
term:
id: MAXO:0000479
label: orthopedic surgery
evidence:
- reference: PMID:21129727
reference_title: "Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We delineated a syndromic recessive preaxial brachydactyly with partial
duplication of proximal phalanges to 16.8 Mb over 4 chromosomes.
explanation: >-
The preaxial brachydactyly and phalangeal duplication delineated here are
the structural anomalies addressed by orthopedic/hand surgery.
target_mechanisms:
- target: Abnormal Limb and Skeletal Patterning
treatment_effect: MODULATES
description: >-
Orthopedic surgery corrects structural digit and phalangeal anomalies that
arise from CHSY1 loss-of-function-driven BMP and NOTCH signaling
imbalance during limb patterning.
datasets: []
notes: >-
TPBS (MIM 605282; ORPHA:363417) is an extremely rare disorder largely defined
by a limited number of consanguineous families. No disease-specific
interventional clinical trials or disease-modifying therapies have been
reported; management is supportive and multidisciplinary (orthopedics/hand
surgery, audiology, dentistry). MONDO classifies TPBS as a congenital disorder
of glycosylation and a developmental anomaly of metabolic origin. This entry
is distinct from C12orf57-related Temtamy syndrome (MONDO:0013879), a separate
intellectual disability syndrome with agenesis of the corpus callosum.
Phenotype frequency percentages were not quantifiable from the available
family-based literature, so frequency qualifiers are intentionally omitted.
References & Deep Research
Deep Research
1Temtamy Preaxial Brachydactyly Syndrome (TPBS) — Comprehensive Disease Characteristics Report
Executive summary
Temtamy preaxial brachydactyly syndrome (TPBS) is a rare, autosomal-recessive limb malformation syndrome caused by biallelic loss-of-function variants in CHSY1 (chondroitin sulfate synthase 1), a key enzyme in chondroitin sulfate glycosaminoglycan biosynthesis with additional evidence for dysregulation of BMP- and NOTCH-pathway outputs during development. Core features include bilateral, symmetric preaxial brachydactyly/hyperphalangism (digits 1–3), characteristic radiographic findings (phalangeal splitting/duplication, symphalangism, carpal/tarsal fusions, radioulnar synostosis), sensorineural hearing loss, craniofacial dysmorphism, and dental anomalies, with variable growth/developmental effects. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2)
| Category | Details | Key sources (with PMID/DOI when present) |
|---|---|---|
| Disease identifiers | Temtamy preaxial brachydactyly syndrome (TPBS); Mendelian skeletal/limb-malformation syndrome. MONDO: MONDO_0011533. MIM/OMIM phenotype number: 605282. Open Targets links MONDO_0011533 to CHSY1 with biallelic loss-of-function evidence and Orphanet/gene2phenotype support. (OpenTargets Search: Temtamy preaxial brachydactyly syndrome, sher2014anovelchsy1 pages 1-2) | Open Targets MONDO_0011533 (OpenTargets Search: Temtamy preaxial brachydactyly syndrome); Sher 2014, Eur J Med Genet DOI: 10.1016/j.ejmg.2013.11.001 (sher2014anovelchsy1 pages 1-2) |
| Causal gene | CHSY1 (chondroitin sulfate synthase 1), gene MIM 608183; encodes an ~802-aa enzyme with glycosyltransferase activity involved in chondroitin sulfate (CS) biosynthesis. CHSY1 is the single high-confidence associated target in Open Targets for this disease. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, OpenTargets Search: Temtamy preaxial brachydactyly syndrome) | Li 2010, Am J Hum Genet DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 1-2); Tian 2010, Am J Hum Genet DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 1-2) |
| Inheritance | Autosomal recessive / biallelic inheritance. Original reports identified affected individuals from consanguineous families and mapped the locus by homozygosity/linkage analysis to 15q26-qter. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, OpenTargets Search: Temtamy preaxial brachydactyly syndrome) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 1-2) |
| Core phenotypes | Hallmark phenotype is bilateral, symmetric preaxial brachydactyly with hyperphalangism (especially digits 1–3). Common associated findings include facial dysmorphism, dental anomalies, sensorineural hearing loss, short stature/growth retardation, and in some reports developmental delay. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2, li2010temtamypreaxialbrachydactyly media e19ad15a) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly media e19ad15a); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 1-2); Sher 2014 DOI: 10.1016/j.ejmg.2013.11.001 (sher2014anovelchsy1 pages 1-2) |
| Key radiographic findings | Radiographs show partial duplication/splitting of proximal phalanges in preaxial digits, hyper- and symphalangism, radio-ulnar synostosis, and carpal/tarsal fusions; Table/Figure summaries in Li 2010 depict characteristic hand/foot radiographs and mutation positions. (tian2010lossofchsy1 pages 9-10, li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly media e19ad15a) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 9-10); Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly media e19ad15a) |
| Representative pathogenic variants: Li 2010 | Reported CHSY1 loss-of-function alleles included c.55_84del30 (p.Gly19_Leu28del), c.14delG (p.Gly5Alafs*29), c.205C>T (p.Gln69*), c.321-3C>G (splice-site), and c.1616C>G (p.Pro539Arg); variants segregated with disease and were absent in tested controls. (pawlik2010molecularmechanismsof pages 89-92, li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly media e19ad15a) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly media e19ad15a); Pawlik 2010 summary (pawlik2010molecularmechanismsof pages 89-92) |
| Representative pathogenic variants: Tian 2010 | Tian et al. independently identified truncating frameshift loss-of-function CHSY1 alleles in an autosomal-recessive syndromic brachydactyly family and linked CHSY1 deficiency to abnormal NOTCH signaling output. (tian2010lossofchsy1 pages 1-2, tian2010lossofchsy1 pages 9-10) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 1-2, tian2010lossofchsy1 pages 9-10) |
| Representative pathogenic variants: Sher 2014 | Sher et al. reported a novel homozygous missense variant c.1897G>A (p.Asp633Asn / D633N) in a consanguineous Pakistani family; the paper noted that previously known TPBS variants included both protein-truncating/deletion and missense alleles. (sher2014anovelchsy1 pages 4-4, sher2014anovelchsy1 pages 1-2) | Sher 2014, Eur J Med Genet DOI: 10.1016/j.ejmg.2013.11.001 (sher2014anovelchsy1 pages 4-4, sher2014anovelchsy1 pages 1-2) |
| Mechanism: glycosaminoglycan biology | CHSY1 is required for chondroitin sulfate biosynthesis; TPBS is therefore part of the spectrum of disorders caused by defects in glycosaminoglycan (GAG) synthesis. Disrupted CS/proteoglycan production is thought to impair cartilage/bone development and morphogen signaling during limb and craniofacial patterning. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 1-2); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 1-2); Sher 2014 DOI: 10.1016/j.ejmg.2013.11.001 (sher2014anovelchsy1 pages 1-2) |
| Mechanism: BMP signaling | Li et al. identified CHSY1 as a potential target of BMP signaling; in zebrafish, BMP signaling negatively regulated chsy1 expression, and perturbation of chsy1 caused developmental defects resembling TPBS. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, pawlik2010molecularmechanismsof pages 89-92) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2); Pawlik 2010 summary (pawlik2010molecularmechanismsof pages 89-92) |
| Mechanism: NOTCH signaling | Tian et al. proposed that CHSY1 also acts as a secreted FRINGE-like regulator: loss of CHSY1 led to increased JAG1/JAG2 and subsequent NOTCH activation, linking extracellular CHSY1 deficiency to abnormal limb patterning. (tian2010lossofchsy1 pages 9-10, tian2010lossofchsy1 pages 1-2) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (tian2010lossofchsy1 pages 9-10, tian2010lossofchsy1 pages 1-2) |
| Evidence/implementation notes | Evidence is primarily from aggregated disease-level rare-disease/genomics resources plus small human family studies and zebrafish functional work. No disease-specific interventional clinical trials were identified in the searched clinical-trials results. (OpenTargets Search: Temtamy preaxial brachydactyly syndrome, li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2) | Open Targets disease-target evidence (OpenTargets Search: Temtamy preaxial brachydactyly syndrome); Li 2010 PMID: 21129727 (li2010temtamypreaxialbrachydactyly pages 1-2); Tian 2010 PMID: 21129728 (tian2010lossofchsy1 pages 1-2) |
Table: This table condenses the core identifiers, genetics, phenotype, radiographic findings, representative variants, and mechanisms for Temtamy preaxial brachydactyly syndrome. It is useful as a quick-reference artifact for building a disease knowledge base entry with source-linked evidence.
1. Disease information
1.1 Definition / overview
TPBS is a syndromic brachydactyly entity in which CHSY1 deficiency disrupts limb patterning and other developmental processes. In the original gene-discovery paper, the disorder is described as “mainly characterized by limb malformations, short stature, and hearing loss.” (li2010temtamypreaxialbrachydactyly pages 1-2)
1.2 Key identifiers
- MONDO: MONDO_0011533 (temtamy preaxial brachydactyly syndrome). (OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
- OMIM/MIM phenotype number: MIM 605282 (noted in genetics literature discussing TPBS). (sher2014anovelchsy1 pages 1-2)
- Causal gene: CHSY1 (gene MIM 608183; Ensembl ENSG00000131873). (li2010temtamypreaxialbrachydactyly pages 1-2, OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
Not found in the retrieved full text (should be confirmed directly from the relevant authority websites): Orphanet ORPHA number, MeSH term, ICD-10/ICD-11 code(s).
1.3 Synonyms / alternative names
- “Temtamy preaxial brachydactyly syndrome” (TPBS). (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
- “Temtamy type brachydactyly, CHSY1-related” is referenced as a modern dyadic naming style in broader skeletal dysplasia nosology contexts, but the exact 2023 nosology entry line could not be reliably extracted from the retrieved text segments. (unger2023nosologyofgenetic pages 50-51)
1.4 Evidence provenance (patient-level vs aggregated)
- Human evidence: small numbers of affected individuals in multiple consanguineous families identified via linkage/homozygosity mapping and sequencing (patient-level family studies). (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 1-2)
- Aggregated resources: Open Targets/Orphanet/gene2phenotype-style assertions connecting TPBS (MONDO) to CHSY1 with biallelic LOF requirement. (OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
2. Etiology
2.1 Disease causal factors
Primary cause: biallelic pathogenic variants in CHSY1 leading to CHSY1 loss of function (autosomal recessive). (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
Mechanistic class: congenital disorder of glycosaminoglycan/proteoglycan biosynthesis (chondroitin sulfate). (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2)
2.2 Risk factors
- Genetic: parental consanguinity/family history consistent with autosomal-recessive inheritance is a practical risk factor observed in reported families. (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
- Environmental: no environmental or infectious risk factors have been established in the retrieved evidence (typical for a congenital Mendelian limb-malformation syndrome).
2.3 Protective factors
No protective genetic or environmental factors were identified in the retrieved evidence.
2.4 Gene–environment interactions
No TPBS-specific gene–environment interactions were identified in the retrieved evidence.
3. Phenotypes
3.1 Core phenotype spectrum (human)
Across reports, TPBS is described as an autosomal recessive disorder marked by: * Bilateral symmetric preaxial brachydactyly and hyperphalangism (especially digits 1–3). (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2) * Sensorineural hearing impairment; Li et al. describe “Moderate to profound sensorineural hearing impairment” in affected individuals. (li2010temtamypreaxialbrachydactyly pages 2-4) * Facial dysmorphism and dental anomalies. (sher2014anovelchsy1 pages 1-2, pawlik2010molecularmechanismsof pages 89-92) * Variable growth retardation/short stature and developmental delay reported in summary sources. (pawlik2010molecularmechanismsof pages 89-92, li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 1-2)
3.2 Radiographic/structural phenotype highlights
Characteristic radiographic findings include: * Splitting/partial duplication of proximal phalanges in preaxial digits (described as “the particular splitting of proximal phalanges in digits 1, 2, and 3”). (tian2010lossofchsy1 pages 9-10) * Hyper- and symphalangism, radioulnar synostosis, carpal/tarsal fusions. (li2010temtamypreaxialbrachydactyly pages 2-4)
A key visual summary of limb photographs/radiographs and the CHSY1 mutation schematic is provided in Li et al. (Figure 1) and the cross-family clinical summary table (Table 1). (li2010temtamypreaxialbrachydactyly media e19ad15a, li2010temtamypreaxialbrachydactyly media beeffb84, li2010temtamypreaxialbrachydactyly media 5e8efed1)
3.3 Onset, severity, progression
- Onset: congenital (limb malformations present from birth), consistent with developmental limb-patterning disorder. (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
- Course: structural congenital anomalies; no evidence in retrieved texts for progressive degenerative course as a defining feature.
3.4 Frequency among affected individuals
Quantitative phenotype frequencies (percentages) across cohorts were not extractable from the retrieved evidence; the Li et al. Table 1 is the most likely source for cross-family “present/absent” counts, but the tool returned the table as an image rather than machine-readable rows. (li2010temtamypreaxialbrachydactyly media e19ad15a)
3.5 Quality-of-life impact
Direct QoL instrument data (e.g., SF-36, EQ-5D) were not identified in the retrieved evidence. Functional impacts plausibly arise from limb malformations and hearing loss, but disease-specific quantified QoL outcomes were not located.
3.6 Suggested HPO terms (non-exhaustive)
Based on the reported phenotype spectrum: * Preaxial brachydactyly: HP:0009775 (suggested) * Brachydactyly: HP:0001156 (suggested) * Hyperphalangy / hyperphalangism: HP:0005879 (suggested) * Symphalangism: HP:0001159 (suggested) * Radioulnar synostosis: HP:0002970 (suggested) * Carpal bone fusion / synostosis: HP:0009702 (suggested) * Tarsal coalition: HP:0001872 (suggested) * Sensorineural hearing impairment: HP:0000407 (suggested) * Abnormality of the dentition / dental anomalies: HP:0000164 (suggested) * Short stature: HP:0004322 (suggested) * Global developmental delay / delayed motor development: HP:0001263 / HP:0001270 (suggested)
(li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2, pawlik2010molecularmechanismsof pages 89-92)
4. Genetic / molecular information
4.1 Causal gene
- CHSY1 encodes an ~802-aa chondroitin sulfate synthase with glucuronyltransferase and N-acetylgalactosaminyltransferase activities involved in chondroitin sulfate chain polymerization. (sher2014anovelchsy1 pages 1-2)
4.2 Pathogenic variant classes (reported)
Loss-of-function spectrum includes deletions/frameshifts/nonsense/splice and missense variants; Li et al. and other summaries list multiple alleles segregating with TPBS and absent in control cohorts. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, pawlik2010molecularmechanismsof pages 89-92)
Representative variants explicitly mentioned in retrieved evidence include: * c.55_84del (in-frame deletion; p.G19_L28del) (pawlik2010molecularmechanismsof pages 89-92) * c.14delG (frameshift; p.G5Afs29) (pawlik2010molecularmechanismsof pages 89-92) * c.205C>T (nonsense; p.Q69) (pawlik2010molecularmechanismsof pages 89-92) * c.321-3C>G (splice) (pawlik2010molecularmechanismsof pages 89-92) * c.1616C>G (missense; p.P539R) (pawlik2010molecularmechanismsof pages 89-92) * c.1897G>A (p.Asp633Asn; D633N) (Sher 2014) (sher2014anovelchsy1 pages 1-2)
4.3 Variant interpretation and population frequency
- Open Targets summarizes allelic requirement as biallelic and consequences as loss_of_function_variant / absent_gene_product for the disease–gene association. (OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
- Allele frequencies in gnomAD/1000G/ExAC were not extracted from the retrieved texts.
4.4 Somatic vs germline
Reported pathogenic variants are germline (congenital Mendelian syndrome). (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
4.5 Modifier genes / epigenetics
No modifier genes or TPBS-specific epigenetic signatures were identified in the retrieved evidence.
5. Environmental information
No non-genetic contributing factors (toxins, lifestyle, infections) were identified in the retrieved evidence; TPBS is best-supported as a primarily genetic developmental disorder. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 1-2)
6. Mechanism / pathophysiology
6.1 High-level causal chain (integrated)
- Biallelic CHSY1 loss of function → impaired chondroitin sulfate biosynthesis and altered extracellular matrix/proteoglycan context. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2)
- Altered ECM/morphogen interaction and signaling outputs during limb and craniofacial development, supported by:
- BMP-pathway coupling: “Bmp signaling has a negative effect on chsy1 expression,” with developmental effects in zebrafish and implication of CHSY1 as “a potential target of BMP signaling.” (li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly pages 2-4)
- NOTCH-pathway dysregulation: CHSY1 deficiency “triggered massive production of JAG1 and subsequent NOTCH activation,” and authors frame the disorder as “causes syndromic brachydactyly in humans via increased notch signaling.” (tian2010lossofchsy1 pages 1-2)
- Resultant abnormal patterning and ossification → preaxial brachydactyly/hyperphalangism, skeletal fusions/synostoses, and other congenital anomalies (including hearing loss). (li2010temtamypreaxialbrachydactyly pages 2-4, tian2010lossofchsy1 pages 1-2, tian2010lossofchsy1 pages 9-10)
6.2 Model organism and in vitro evidence
- Zebrafish: antisense knockdown produced multiple developmental defects and “partially phenocopied the human disorder,” including inner ear/semicircular canal developmental issues in summary sources. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, pawlik2010molecularmechanismsof pages 89-92)
6.3 Suggested pathway/ontology terms
GO biological processes (suggested): * chondroitin sulfate biosynthetic process (GO:0006024) * glycosaminoglycan biosynthetic process (GO:0006026) * limb development / appendage morphogenesis (e.g., GO:0060173) * Notch signaling pathway (GO:0007219) * BMP signaling pathway (GO:0030509)
Cell types (CL; suggested): * chondrocyte (CL:0000138) * osteoblast (CL:0000062) * (for hearing phenotype) inner ear sensory epithelial cell / hair cell (CL terms require confirmation)
(li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, pawlik2010molecularmechanismsof pages 89-92)
7. Anatomical structures affected
7.1 Organ/system level (primary)
- Skeletal system (limbs/hands/feet) (UBERON:0002101 for limb; UBERON:0002398 for hand; UBERON:0002387 for foot — suggested)
- Auditory system / inner ear (UBERON:0004648 inner ear — suggested) consistent with sensorineural hearing impairment. (li2010temtamypreaxialbrachydactyly pages 2-4, pawlik2010molecularmechanismsof pages 89-92)
- Craniofacial structures (suggested) based on facial dysmorphism. (sher2014anovelchsy1 pages 1-2)
- Dentition (UBERON:0000970 tooth — suggested) based on dental anomalies. (sher2014anovelchsy1 pages 1-2)
7.2 Tissue/cellular level
- Cartilage and bone developmental tissues (chondrocytes/osteoblast lineage) supported by the skeletal phenotype and chondroitin sulfate biology. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2)
7.3 Subcellular localization (suggested)
- Golgi/secretory pathway involvement is plausible for glycosyltransferases and proteoglycan synthesis, but TPBS-specific subcellular pathology statements were not extracted from the retrieved evidence.
8. Temporal development
- Typical onset: congenital (developmental anomaly present at birth). (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
- Progression: predominantly structural and non-progressive in available descriptions; no staged course or remission patterns were identified in retrieved evidence.
9. Inheritance and population
9.1 Inheritance
- Autosomal recessive / biallelic. (li2010temtamypreaxialbrachydactyly pages 1-2, OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
9.2 Penetrance/expressivity
Not quantified in retrieved evidence; likely variable expressivity given multi-system involvement across families, but formal penetrance estimates were not found.
9.3 Epidemiology
Prevalence/incidence statistics were not identified in the retrieved evidence. The disorder appears extremely rare and largely known from a limited number of families reported in the literature. (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
10. Diagnostics
10.1 Clinical/radiographic evaluation
- Radiographs of hands/feet are central to recognition: phalangeal splitting/duplication, hyperphalangism/symphalangism, carpal/tarsal fusions, radioulnar synostosis. (li2010temtamypreaxialbrachydactyly pages 2-4, tian2010lossofchsy1 pages 9-10, li2010temtamypreaxialbrachydactyly media e19ad15a)
- Audiologic testing (audiometry) is described as part of phenotyping in the gene discovery work. (li2010temtamypreaxialbrachydactyly pages 2-4)
10.2 Genetic testing strategy (real-world implementation)
Evidence-supported approaches used in reported families included: * Homozygosity mapping / linkage (in consanguineous pedigrees) and sequencing of CHSY1 coding exons and splice junctions. (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 1-2) * Contemporary practice would typically use an NGS limb malformation/skeletal dysplasia panel that includes CHSY1 or exome/genome sequencing, but explicit professional-society algorithms and GTR test listings were not retrieved in the current tool context.
10.3 Differential diagnosis (examples; requires clinical correlation)
Conditions with overlapping hyperphalangism/craniofacial findings (e.g., Catel–Manzke syndrome) have been discussed as overlapping in the literature, but differential diagnosis details for TPBS were not comprehensively extractable from the retrieved evidence. (sher2014anovelchsy1 pages 4-4)
11. Outcome / prognosis
No survival, life expectancy, or validated prognostic-factor statistics were identified in the retrieved evidence. Available reports focus on congenital malformation phenotype delineation and molecular etiology rather than longitudinal outcomes. (li2010temtamypreaxialbrachydactyly pages 2-4, sher2014anovelchsy1 pages 1-2)
12. Treatment
12.1 Disease-modifying therapy
No disease-modifying pharmacologic or gene-targeted therapy evidence was identified in the retrieved texts.
12.2 Supportive/symptomatic management
The retrieved evidence did not provide systematic treatment guidance or outcomes. Given the core manifestations (limb malformations, hearing loss), real-world care is expected to be multidisciplinary (orthopedics/hand surgery, audiology, dentistry), but TPBS-specific management guidelines and quantified outcomes were not located in the current evidence set.
12.3 Clinical trials
No TPBS-specific interventional clinical trials were identified from the provided clinical-trials search context. (OpenTargets Search: Temtamy preaxial brachydactyly syndrome)
Suggested MAXO terms (if used for knowledge base annotation; not evidence-derived): * genetic counseling (MAXO:0000127 — suggested) * hearing aid therapy (MAXO term requires confirmation) * orthopedic surgical procedure (MAXO term requires confirmation)
13. Prevention
Because TPBS is a congenital Mendelian disorder, prevention is primarily via reproductive genetics: * Carrier testing in at-risk families and prenatal/preimplantation genetic testing are conceptually enabled by identification of familial CHSY1 variants; Sher et al. explicitly note that findings “will aid prenatal diagnosis and genetic counseling” (as summarized in the retrieved excerpt). (sher2014anovelchsy1 pages 4-4)
No primary prevention (environmental) strategies were identified.
14. Other species / natural disease
No naturally occurring veterinary disease analogue was identified in the retrieved evidence.
15. Model organisms
- Zebrafish knockdown models were used to evaluate developmental roles of chsy1; knockdown/overexpression produced defects in multiple processes and partially phenocopied human TPBS in summary descriptions. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 1-2, pawlik2010molecularmechanismsof pages 89-92)
Recent developments and latest research (2023–2024 prioritization)
The tool-accessible evidence set for 2023–2024 contained limited TPBS-specific primary clinical updates. The most substantive TPBS-linked advances remain the 2010 gene-discovery/mechanism papers and subsequent case expansion (2014). (li2010temtamypreaxialbrachydactyly pages 2-4, tian2010lossofchsy1 pages 1-2, sher2014anovelchsy1 pages 1-2)
A broadly relevant 2023 trend in skeletal dysplasia classification is the shift toward dyadic disease names (phenotype–gene) in nosology updates; however, the exact TPBS/CHSY1 entry line could not be cleanly extracted from the retrieved 2023 nosology pages in this run. (unger2023nosologyofgenetic pages 50-51)
Key URLs (from retrieved sources)
- Li et al., 2010 (Dec 2010). American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2010.10.003 (li2010temtamypreaxialbrachydactyly pages 2-4)
- Tian et al., 2010 (Dec 2010). American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2010.11.005 (tian2010lossofchsy1 pages 1-2)
- Sher & Naeem, 2014 (Jan 2014). European Journal of Medical Genetics. https://doi.org/10.1016/j.ejmg.2013.11.001 (sher2014anovelchsy1 pages 1-2)
Notes on evidence limitations
- The present extraction did not yield authoritative Orphanet/ICD/MeSH identifiers or epidemiology estimates; these likely require direct queries to OMIM/Orphanet and registry resources.
- Phenotype frequencies and longitudinal outcomes are not well quantified in the retrieved full texts; TPBS remains a very rare disorder largely defined by family-based reports and functional developmental studies.
References
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(li2010temtamypreaxialbrachydactyly pages 2-4): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. American journal of human genetics, 87 6:757-67, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 126 citations and is from a highest quality peer-reviewed journal.
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(li2010temtamypreaxialbrachydactyly pages 1-2): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. American journal of human genetics, 87 6:757-67, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 126 citations and is from a highest quality peer-reviewed journal.
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(tian2010lossofchsy1 pages 1-2): Jing Tian, Ling Ling, Mohammad Shboul, Hane Lee, Brian O'Connor, Barry Merriman, Stanley F. Nelson, Simon Cool, Osama H. Ababneh, Azmy Al-Hadidy, Amira Masri, Hanan Hamamy, and Bruno Reversade. Loss of chsy1, a secreted fringe enzyme, causes syndromic brachydactyly in humans via increased notch signaling. American journal of human genetics, 87 6:768-78, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.11.005, doi:10.1016/j.ajhg.2010.11.005. This article has 121 citations and is from a highest quality peer-reviewed journal.
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(sher2014anovelchsy1 pages 1-2): Gulab Sher and Muhammad Naeem. A novel chsy1 gene mutation underlies temtamy preaxial brachydactyly syndrome in a pakistani family. European journal of medical genetics, 57 1:21-4, Jan 2014. URL: https://doi.org/10.1016/j.ejmg.2013.11.001, doi:10.1016/j.ejmg.2013.11.001. This article has 28 citations and is from a peer-reviewed journal.
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(OpenTargets Search: Temtamy preaxial brachydactyly syndrome): Open Targets Query (Temtamy preaxial brachydactyly syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
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(li2010temtamypreaxialbrachydactyly media e19ad15a): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. American journal of human genetics, 87 6:757-67, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 126 citations and is from a highest quality peer-reviewed journal.
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(tian2010lossofchsy1 pages 9-10): Jing Tian, Ling Ling, Mohammad Shboul, Hane Lee, Brian O'Connor, Barry Merriman, Stanley F. Nelson, Simon Cool, Osama H. Ababneh, Azmy Al-Hadidy, Amira Masri, Hanan Hamamy, and Bruno Reversade. Loss of chsy1, a secreted fringe enzyme, causes syndromic brachydactyly in humans via increased notch signaling. American journal of human genetics, 87 6:768-78, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.11.005, doi:10.1016/j.ajhg.2010.11.005. This article has 121 citations and is from a highest quality peer-reviewed journal.
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(pawlik2010molecularmechanismsof pages 89-92): B Pawlik. Molecular mechanisms of congenital limb malformations. Unknown journal, 2010.
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(sher2014anovelchsy1 pages 4-4): Gulab Sher and Muhammad Naeem. A novel chsy1 gene mutation underlies temtamy preaxial brachydactyly syndrome in a pakistani family. European journal of medical genetics, 57 1:21-4, Jan 2014. URL: https://doi.org/10.1016/j.ejmg.2013.11.001, doi:10.1016/j.ejmg.2013.11.001. This article has 28 citations and is from a peer-reviewed journal.
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(unger2023nosologyofgenetic pages 50-51): Sheila Unger, Carlos R. Ferreira, Geert R. Mortier, Houda Ali, Débora R. Bertola, Alistair Calder, Daniel H. Cohn, Valerie Cormier‐Daire, Katta M. Girisha, Christine Hall, Deborah Krakow, Outi Makitie, Stefan Mundlos, Gen Nishimura, Stephen P. Robertson, Ravi Savarirayan, David Sillence, Marleen Simon, V. Reid Sutton, Matthew L. Warman, and Andrea Superti‐Furga. Nosology of genetic skeletal disorders: 2023 revision. American Journal of Medical Genetics Part A, 191:1164-1209, Feb 2023. URL: https://doi.org/10.1002/ajmg.a.63132, doi:10.1002/ajmg.a.63132. This article has 495 citations.
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(li2010temtamypreaxialbrachydactyly media beeffb84): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. American journal of human genetics, 87 6:757-67, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 126 citations and is from a highest quality peer-reviewed journal.
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(li2010temtamypreaxialbrachydactyly media 5e8efed1): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. American journal of human genetics, 87 6:757-67, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 126 citations and is from a highest quality peer-reviewed journal.
