Frank-Ter Haar Syndrome

👪

Inheritance

1

Autosomal recessive HP:0000007

Homozygous or compound heterozygous loss-of-function variants or deletions of SH3PXD2B. The founding study used homozygosity mapping across consanguineous families to localise the gene.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33234702 SUPPORT Other

"FTHS is caused by homozygous or compound heterozygous loss-of-function mutation or deletion of SH3PXD2B"

States the biallelic loss-of-function mechanism and therefore the recessive inheritance.

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Pathophysiology

5

TKS4 Adaptor Loss of Function

SH3PXD2B encodes TKS4, a phox homology (PX) and SH3 domain-containing adaptor protein and Src substrate. Homozygosity mapping across FTHS families localised the disease to 5q35.1, and a homozygous deletion in one family mapped exactly to the smallest region of overlapping homozygosity, which contains SH3PXD2B alone. Patient fibroblasts from Borrone-phenotype families show complete loss of the protein on western blot, confirming that the molecular lesion is absence of functional TKS4.

SH3PXD2B hgnc:29242

Downstream

Incomplete Podosome Formation and Failed MT1-MMP Recruitment

Show evidence (3 references)

PMID:20137777 SUPPORT Human Clinical

"For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contains a single gene, SH3PXD2B."

Positional evidence isolating SH3PXD2B as the single gene in the critical interval.

PMID:20137777 SUPPORT Human Clinical

"This gene encodes the TKS4 protein, a phox homology (PX) and Src homology 3 (SH3) domain-containing adaptor protein and Src substrate."

Identifies the gene product and its adaptor/Src-substrate nature, the molecular entity lost in this disease.

PMID:24105366 SUPPORT In Vitro

"Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B."

Direct protein-level demonstration that the causative variants abolish TKS4, establishing loss of function.

Incomplete Podosome Formation and Failed MT1-MMP Recruitment

TKS4 is required for podosomes and invadopodia, actin-rich membrane protrusions that coordinate pericellular proteolysis with cell migration. Fibroblasts lacking Tks4 form only incomplete podosomes, and crucially fail to recruit membrane type-1 matrix metalloproteinase (MT1-MMP) to them. The rescue experiments locate the defect precisely: reintroducing Tks4 restores both podosome formation and matrix degradation, whereas overexpressing the related Tks5 restores podosome formation only. TKS4 therefore carries a non-redundant role in the proteolytic arm specifically, which is the step that fails in this disease.

fibroblast CL:0000057

podosome GO:0002102

Downstream

Defective Pericellular Matrix Remodelling

Show evidence (3 references)

PMID:19144821 SUPPORT In Vitro

"We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation."

Directly demonstrates that TKS4 loss impairs podosome formation and matrix degradation.

PMID:19144821 SUPPORT In Vitro

"Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes."

Identifies failed MT1-MMP recruitment as the specific molecular consequence, linking this disease to the MMP14/collagen-remodelling axis.

PMID:19144821 SUPPORT In Vitro

"Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5."

The differential rescue establishes that TKS4's role in matrix degradation is non-redundant with TKS5, explaining why its loss alone causes disease.

Defective Pericellular Matrix Remodelling

Without podosome-localised proteolysis, cells cannot degrade and remodel the extracellular matrix immediately around them. Extracellular matrix therefore accumulates rather than turning over, which is the proposed explanation for the progressive coarsening of facial features and for glaucoma refractory to treatment. This places FTHS within the defective collagen remodelling spectrum, whose other members carry MMP14 lesions — the protease that TKS4 fails to deliver.

fibroblast CL:0000057 osteoclast CL:0000092

extracellular matrix disassembly GO:0022617 ↓ DECREASED cell migration GO:0016477 ↓ DECREASED

Downstream

Skeletal and Craniofacial Malformation

Fibrotic Soft-Tissue Change

Megalocornea

Glaucoma

Show evidence (2 references)

PMID:33234702 SUPPORT Other

"SH3PXD2B encodes an adaptor protein with the same name, which is required for full functionality of podosomes, specialised membrane structures involved in extracellular matrix (ECM) remodelling."

States the ECM-remodelling role of podosomes that is lost in this disease.

PMID:31978614 SUPPORT INDIRECT Human Clinical

"we hypothesize that the alteration of podosomes function could lead to a reduction of the extracellular matrix degradation and accumulation of the latter in the extracellular space, which might explain the coarsening of the facial features and the severe refractory glaucoma"

Proposes matrix accumulation as the link from the podosome defect to two specific clinical features. Explicitly a hypothesis, and recorded as such.

Skeletal and Craniofacial Malformation

Failure of matrix remodelling during development produces the skeletal dysplasia and craniofacial phenotype: coarse facies, hypertelorism, wide anterior fontanelle, camptodactyly and vertebral abnormalities including scoliosis. Cardiac malformation arises in the same developmental window and is reproduced in the Tks4-null mouse.

Animal models

Tks4-null mouse Mouse recapitulates Reproduces the three-organ-system malformation phenotype of the human disease from the orthologous gene knockout.

Downstream

Camptodactyly

Coarse Facial Features

Hypertelorism

Wide Anterior Fontanelle

Scoliosis

Ventricular Septal Defect

Show evidence (1 reference)

PMID:20137777 SUPPORT Human Clinical

"Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is an autosomal-recessive disorder characterized by skeletal, cardiovascular, and eye abnormalities"

Defines the three-system malformation phenotype produced by the mechanism.

Fibrotic Soft-Tissue Change

Beyond malformation, retained matrix drives dermal and musculoskeletal fibrosis with joint contractures. The zebrafish sh3pxd2b mutant isolates this arm particularly clearly, developing dermal and musculoskeletal fibrosis whose contraction produces gross deformity, with comparatively mild skeletal change.

fibroblast CL:0000057

Animal models

pretzel zebrafish (sh3pxd2b mutant) Zebrafish partially recapitulates Reproduces the dermal and musculoskeletal fibrosis and contractures, but only mild skeletal abnormalities, so it models one arm of the disease rather than the whole.

Downstream

Joint Contractures

Show evidence (1 reference)

PMID:33234702 SUPPORT Other

"which is characterised by craniofacial abnormalities, skeletal malformations and fibrotic soft tissues changes including dermal fibrosis and joint contractures"

Records dermal fibrosis and joint contractures as part of the human phenotype, not only the model phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 1

Ventricular Septal Defect FREQUENT HP:0001629

Onset: CONGENITAL

Show evidence (2 references)

PMID:31978614 SUPPORT Human Clinical

"camptodactyly, ventricular septal defect, thin corpus callosum and craniofacial features suggestive of FTHS"

Documents a ventricular septal defect in a molecularly confirmed patient.

PMID:21453629 SUPPORT INDIRECT Human Clinical

"small chin, congenital heart defects, kyphoscoliosis"

Lists congenital heart defects among the main clinical features, supporting the frequency beyond the single documented case.

Eye 3

Megalocornea VERY_FREQUENT HP:0000485

Onset: CONGENITAL

Show evidence (2 references)

PMID:31978614 SUPPORT Human Clinical

"FTHS is characterized by facial dysmorphism, megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies."

Lists megalocornea among the defining features of the syndrome.

PMID:21453629 SUPPORT Human Clinical

"macrocornea with or without glaucoma"

Independent feature list confirming corneal enlargement as characteristic, and recording that glaucoma accompanies it only variably.

Glaucoma FREQUENT HP:0000501

Show evidence (2 references)

PMID:20137777 SUPPORT Human Clinical

"such as increased intraocular pressure, prominent eyes, and hypertelorism"

Records raised intraocular pressure among the defining ocular features.

PMID:31978614 SUPPORT Human Clinical

"with intrauterine growth retardation, hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect"

Documents congenital glaucoma in a molecularly confirmed patient.

Hypertelorism FREQUENT HP:0000316

Show evidence (2 references)

PMID:20137777 SUPPORT Human Clinical

"such as increased intraocular pressure, prominent eyes, and hypertelorism"

Lists hypertelorism among the defining craniofacial features.

PMID:21453629 SUPPORT Human Clinical

"prominent forehead, hypertelorism, prominent eyes"

Second independent feature list naming hypertelorism, supporting it as a characteristic rather than a single-case finding.

Head and Neck 2

Coarse Facial Features VERY_FREQUENT HP:0000280

Course: PROGRESSIVE

Show evidence (3 references)

PMID:31978614 SUPPORT Human Clinical

"Clinical evolution resulted in buphthalmos worsening, coarsening of the facial features and respiratory failure leading to death at 4,5 months."

Documents progressive facial coarsening in an affected patient.

PMID:31978614 SUPPORT Human Clinical

"FTHS is characterized by facial dysmorphism"

Establishes facial dysmorphism as a characteristic feature of the syndrome, supporting the frequency beyond the single documented case.

PMID:21453629 SUPPORT Human Clinical

"The main clinical features are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin"

Independent statement of the syndrome's main clinical features, naming the facial components (prominent forehead, full cheeks, small chin) that make up the characteristic facies.

Wide Anterior Fontanelle FREQUENT HP:0000260

Onset: CONGENITAL

Show evidence (1 reference)

PMID:21453629 SUPPORT Human Clinical

"The main clinical features are brachycephaly, wide fontanels, prominent forehead, hypertelorism"

Lists wide fontanels among the main clinical features of the syndrome.

Musculoskeletal 3

Camptodactyly FREQUENT HP:0012385

Show evidence (2 references)

PMID:21453629 SUPPORT Human Clinical

"coccygeal skin folds and flexion deformity of the fingers"

Lists flexion deformity of the fingers among the main clinical features of the syndrome.

PMID:31978614 SUPPORT Human Clinical

"congenital glaucoma, caudal appendix, scoliosis, camptodactyly"

Documents camptodactyly in a molecularly confirmed FTHS patient.

Scoliosis FREQUENT HP:0002650

Show evidence (2 references)

PMID:31978614 SUPPORT Human Clinical

"hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect"

Documents scoliosis in a molecularly confirmed FTHS patient.

PMID:21453629 SUPPORT INDIRECT Human Clinical

"kyphoscoliosis, skeletal dysplasia, developmental delay"

Lists kyphoscoliosis among the main clinical features, supporting spinal curvature as characteristic rather than a single-case finding. Kyphoscoliosis entails the scoliotic component this phenotype records.

Joint Contractures FREQUENT HP:0034392

Show evidence (1 reference)

PMID:33234702 SUPPORT Other

"fibrotic soft tissues changes including dermal fibrosis and joint contractures"

Records joint contractures as part of the fibrotic soft-tissue phenotype.

Nervous System 1

Developmental Delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:31978614 SUPPORT Human Clinical

"megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies"

Records developmental delay as a variable rather than obligate feature.

PMID:21453629 SUPPORT Human Clinical

"skeletal dysplasia, developmental delay, coccygeal skin folds"

Independent feature list including developmental delay among the main clinical features.

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Genetic Associations

1

SH3PXD2B loss of function

Gene: SH3PXD2B hgnc:29242 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:20137777 SUPPORT Human Clinical

"Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families."

Establishes the causative allelic spectrum across multiple families.

PMID:20137777 SUPPORT Human Clinical

"No SH3PXD2B mutations were detected in six other FTHS families, demonstrating the genetic heterogeneity of this condition."

Documents that SH3PXD2B does not account for all clinically diagnosed FTHS, an important limit on the gene-disease claim.

PMID:20137777 SUPPORT In Vitro

"dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation"

Supports a shared TKS4-deficient final mechanism even in mutation-negative patients, which is why the pathograph is keyed on TKS4 loss rather than on the genotype.

+ 1 more reference

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Medical Actions

2

Supportive and Multidisciplinary Care

Action: Supportive Care NCIT:C15747

Platform: Other

There is no therapy directed at the underlying podosome defect. The pathogenesis of the defective collagen remodelling disorders is incompletely understood and therapeutic options are correspondingly limited, so management is supportive and organised around the affected systems. This entry claims no target_mechanisms link because no reported intervention acts on the mechanism.

Show evidence (1 reference)

PMID:33234702 SUPPORT Other

"The pathogenesis of DECORS is still incompletely understood and, as a result, therapeutic options are limited."

States directly that therapeutic options for this disease group are limited, which is the basis for supportive-only management.

Glaucoma and Intraocular Pressure Management

Action: Supportive Care NCIT:C15747

Platform: Other

Treatment of the raised intraocular pressure that accompanies the ocular phenotype. The entry records this as frequently unsatisfactory rather than curative: in the severe reported case the glaucoma was refractory and buphthalmos progressed despite treatment, which is consistent with the proposed matrix-accumulation mechanism continuing to operate.

Target Phenotypes: Glaucoma HP:0000501

Show evidence (1 reference)

PMID:31978614 SUPPORT Human Clinical

"which might explain the coarsening of the facial features and the severe refractory glaucoma"

Records the glaucoma as refractory, establishing the limits of ocular pressure management in this disease.

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Diagnosis

1

Molecular confirmation by SH3PXD2B sequencing

Clinical suspicion from the craniofacial, ocular, skeletal and cardiac features is confirmed by identifying biallelic SH3PXD2B variants. Because SH3PXD2B accounts for only part of clinically diagnosed FTHS, a negative result does not exclude the diagnosis, and exome sequencing has been used to reach it in suspected cases.

Show evidence (2 references)

PMID:31978614 SUPPORT Human Clinical

"Diagnosis was confirmed by the identification of a previously known homozygous mutation c.969delG, p.(Arg324Glyfs*19) in SH3PXD2B."

Documents molecular confirmation as the diagnostic step in a reported patient.

PMID:28694206 SUPPORT Human Clinical

"exome sequencing is a powerful and a cost-effective tool for the diagnosis of a supposed genetically heterogeneous disorder such FTHS"

Supports exome sequencing as the practical diagnostic route given the genetic heterogeneity of the syndrome.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Forty patients reported with a clinical diagnosis as of 2020, of whom only 20 had an identified mutation. The gap between the two counts reflects the genetic heterogeneity recorded in the genetic block, not incomplete testing alone -- SH3PXD2B accounted for only 7 of 13 families in the founding study.

Show evidence (1 reference)

PMID:31978614 SUPPORT Human Clinical

"To date, 40 patients have been reported in the literature with a clinical diagnosis of FTHS, only 20 patients having identified mutations."

Gives the total reported case count and the molecularly confirmed subset, establishing the ultra-rare band.

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Animal Models

2

Tks4-null mouse

Mice lacking Tks4 develop skeletal, eye and cardiac abnormalities, phenocopying most of the human syndrome. This is the model that established the gene-disease relationship as causal rather than positional.

Species

Mouse

Genotype

Tks4 (Sh3pxd2b) null

Publication

PMID:20137777

Pathograph links

Skeletal and Craniofacial Malformation recapitulates fidelity: high observes: organism Reproduces the three-organ-system malformation phenotype of the human disease from the orthologous gene knockout.

Limitations: Phenocopies the majority, not all, of the human defects; the report does not claim complete reproduction of the phenotype.

Show evidence (1 reference)

PMID:20137777 SUPPORT Model Organism

"Mice lacking Tks4 also showed pronounced skeletal, eye, and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS."

Reports the knockout phenotype and the extent of its correspondence to the human disease.

pretzel zebrafish (sh3pxd2b mutant)

A sh3pxd2b mutant zebrafish that develops dermal and musculoskeletal fibrosis with contraction-driven deformity, isolating the fibrotic arm of the disease with comparatively mild skeletal change.

Species

Zebrafish

Genotype

sh3pxd2b mutant (pretzel)

Publication

PMID:33234702

Pathograph links

Fibrotic Soft-Tissue Change partially recapitulates fidelity: moderate observes: organism Reproduces the dermal and musculoskeletal fibrosis and contractures, but only mild skeletal abnormalities, so it models one arm of the disease rather than the whole.

Limitations: The authors note that the discrepancy between the sh3pxd2b and mmp14a/b zebrafish mutants implies the spatiotemporal dependence of ECM remodelling on these genes differs between fish and humans, so the division of labour seen in this model may not transfer. Skeletal involvement, prominent in human disease, is relatively mild here.

Divergences from the human mechanism

species mismatch qualifying

In zebrafish, ECM remodelling depends on sh3pxd2b and mmp14a/b with a different spatiotemporal division than in humans, which is the authors' own explanation for why this mutant is fibrosis-dominant while the mmp14a/b mutant is bone-dominant.

boundary omission qualifying

The skeletal dysplasia that defines the human syndrome is effectively outside what this model represents: skeletal abnormalities in pretzel are relatively mild, so bone phenotypes cannot be read off it and the sibling mmp14a/b mutant carries that arm instead.

Show evidence (2 references)

PMID:33234702 SUPPORT Model Organism

"In addition to relatively mild skeletal abnormalities, pretzel mutants develop dermal and musculoskeletal fibrosis"

Reports the model's fibrotic phenotype and the mildness of its skeletal involvement, supporting both the link and its limitation.

+ 1 more reference

{ }

Source YAML

click to show

name: Frank-Ter Haar Syndrome
creation_date: "2026-09-04T03:30:00Z"
category: Genetic
description: >-
  Frank-Ter Haar syndrome is a rare autosomal recessive skeletal dysplasia caused
  by biallelic loss-of-function variants in SH3PXD2B, which encodes the adaptor
  protein TKS4. TKS4 is required for functional podosomes — actin-rich membrane
  protrusions that couple pericellular proteolysis to cell migration — and its
  loss leaves podosome formation incomplete and prevents recruitment of the
  membrane-tethered protease MT1-MMP to those structures. The consequence is a
  cell that can no longer degrade and remodel extracellular matrix at its own
  surface, which places the disease in the defective collagen remodelling
  spectrum alongside the MMP14-related multicentric osteolytic syndromes.
  Clinically it presents with craniofacial dysmorphism, megalocornea with
  frequently severe glaucoma, camptodactyly and other skeletal malformations,
  congenital heart defects, and fibrotic soft-tissue change with joint
  contractures. Severity varies widely, from survival into adulthood to lethal
  respiratory failure in infancy, and the same variant has produced both.
disease_term:
  preferred_term: Frank-Ter Haar syndrome
  term:
    id: MONDO:0009579
    label: Frank-Ter Haar syndrome
synonyms:
- FTHS
- Ter Haar syndrome
- Borrone dermato-cardio-skeletal syndrome
- megalocornea, multiple skeletal anomalies, and developmental delay
parents:
- Defective Collagen Remodelling Spectrum
notes: >-
  Two synonyms carried on the stub need different treatment, and conflating them
  would corrupt the entry.

  "Borrone dermato-cardio-skeletal syndrome" is a genuine synonym for the
  SH3PXD2B-mutant cases. Linkage and sequencing in two BDCS kindreds found
  homozygous SH3PXD2B mutations with complete loss of protein, establishing that
  a proportion of BDCS and FTHS are allelic. Its case reports are usable here.
  Note the qualifier "a proportion": a third published BDCS family was excluded
  from the locus, so BDCS is not wholly the same entity.

  "Melnick-Needles syndrome, autosomal recessive" is a historical misattribution
  and must NOT be treated as a synonym for evidence purposes. Melnick-Needles
  syndrome is X-linked and caused by FLNA variants; it is a different disease
  with a different gene and inheritance. Do not import its literature.

  Genetic heterogeneity is real and should not be smoothed over: SH3PXD2B
  mutations were found in only 7 of 13 FTHS families in the founding study.
  One mutation-negative individual nevertheless had reduced TKS4 protein in
  dermal fibroblasts, which suggests a shared final mechanism reached by more
  than one genetic route.
references:
- reference: PMID:20137777
  title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
- reference: PMID:19144821
  title: "The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation."
- reference: PMID:24105366
  title: "Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome."
- reference: PMID:31978614
  title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
- reference: PMID:33234702
  title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
- reference: PMID:21453629
  title: "Frank-Ter Haar Syndrome."
inheritance:
- name: Autosomal recessive
  description: >-
    Homozygous or compound heterozygous loss-of-function variants or deletions of
    SH3PXD2B. The founding study used homozygosity mapping across consanguineous
    families to localise the gene.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33234702
    reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FTHS is caused by homozygous or compound heterozygous loss-of-function mutation or deletion of SH3PXD2B"
    explanation: >-
      States the biallelic loss-of-function mechanism and therefore the recessive
      inheritance.
pathophysiology:
- name: TKS4 Adaptor Loss of Function
  biological_scale: MOLECULAR
  description: >-
    SH3PXD2B encodes TKS4, a phox homology (PX) and SH3 domain-containing adaptor
    protein and Src substrate. Homozygosity mapping across FTHS families
    localised the disease to 5q35.1, and a homozygous deletion in one family
    mapped exactly to the smallest region of overlapping homozygosity, which
    contains SH3PXD2B alone. Patient fibroblasts from Borrone-phenotype families
    show complete loss of the protein on western blot, confirming that the
    molecular lesion is absence of functional TKS4.
  gene:
    preferred_term: SH3PXD2B
    term:
      id: hgnc:29242
      label: SH3PXD2B
  evidence:
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contains a single gene, SH3PXD2B."
    explanation: >-
      Positional evidence isolating SH3PXD2B as the single gene in the critical
      interval.
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene encodes the TKS4 protein, a phox homology (PX) and Src homology 3 (SH3) domain-containing adaptor protein and Src substrate."
    explanation: >-
      Identifies the gene product and its adaptor/Src-substrate nature, the
      molecular entity lost in this disease.
  - reference: PMID:24105366
    reference_title: "Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B."
    explanation: >-
      Direct protein-level demonstration that the causative variants abolish
      TKS4, establishing loss of function.
  downstream:
  - target: Incomplete Podosome Formation and Failed MT1-MMP Recruitment
    causal_link_type: DIRECT
- name: Incomplete Podosome Formation and Failed MT1-MMP Recruitment
  biological_scale: CELLULAR
  description: >-
    TKS4 is required for podosomes and invadopodia, actin-rich membrane
    protrusions that coordinate pericellular proteolysis with cell migration.
    Fibroblasts lacking Tks4 form only incomplete podosomes, and crucially fail
    to recruit membrane type-1 matrix metalloproteinase (MT1-MMP) to them. The
    rescue experiments locate the defect precisely: reintroducing Tks4 restores
    both podosome formation and matrix degradation, whereas overexpressing the
    related Tks5 restores podosome formation only. TKS4 therefore carries a
    non-redundant role in the proteolytic arm specifically, which is the step
    that fails in this disease.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cellular_components:
  - preferred_term: podosome
    term:
      id: GO:0002102
      label: podosome
    modifier: DECREASED
  evidence:
  - reference: PMID:19144821
    reference_title: "The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation."
    explanation: >-
      Directly demonstrates that TKS4 loss impairs podosome formation and matrix
      degradation.
  - reference: PMID:19144821
    reference_title: "The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes."
    explanation: >-
      Identifies failed MT1-MMP recruitment as the specific molecular
      consequence, linking this disease to the MMP14/collagen-remodelling axis.
  - reference: PMID:19144821
    reference_title: "The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5."
    explanation: >-
      The differential rescue establishes that TKS4's role in matrix degradation
      is non-redundant with TKS5, explaining why its loss alone causes disease.
  downstream:
  - target: Defective Pericellular Matrix Remodelling
    causal_link_type: DIRECT
- name: Defective Pericellular Matrix Remodelling
  biological_scale: TISSUE
  description: >-
    Without podosome-localised proteolysis, cells cannot degrade and remodel the
    extracellular matrix immediately around them. Extracellular matrix therefore
    accumulates rather than turning over, which is the proposed explanation for
    the progressive coarsening of facial features and for glaucoma refractory to
    treatment. This places FTHS within the defective collagen remodelling
    spectrum, whose other members carry MMP14 lesions — the protease that TKS4
    fails to deliver.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: DECREASED
  - preferred_term: cell migration
    term:
      id: GO:0016477
      label: cell migration
    modifier: DECREASED
  evidence:
  - reference: PMID:33234702
    reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SH3PXD2B encodes an adaptor protein with the same name, which is required for full functionality of podosomes, specialised membrane structures involved in extracellular matrix (ECM) remodelling."
    explanation: >-
      States the ECM-remodelling role of podosomes that is lost in this disease.
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we hypothesize that the alteration of podosomes function could lead to a reduction of the extracellular matrix degradation and accumulation of the latter in the extracellular space, which might explain the coarsening of the facial features and the severe refractory glaucoma"
    explanation: >-
      Proposes matrix accumulation as the link from the podosome defect to two
      specific clinical features. Explicitly a hypothesis, and recorded as such.
    directness: INDIRECT
  downstream:
  - target: Skeletal and Craniofacial Malformation
    causal_link_type: DIRECT
  - target: Fibrotic Soft-Tissue Change
    causal_link_type: DIRECT
  - target: Megalocornea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Glaucoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Skeletal and Craniofacial Malformation
  biological_scale: ORGANISM
  description: >-
    Failure of matrix remodelling during development produces the skeletal
    dysplasia and craniofacial phenotype: coarse facies, hypertelorism, wide
    anterior fontanelle, camptodactyly and vertebral abnormalities including
    scoliosis. Cardiac malformation arises in the same developmental window and
    is reproduced in the Tks4-null mouse.
  evidence:
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is an autosomal-recessive disorder characterized by skeletal, cardiovascular, and eye abnormalities"
    explanation: >-
      Defines the three-system malformation phenotype produced by the mechanism.
  downstream:
  - target: Camptodactyly
    causal_link_type: DIRECT
  - target: Coarse Facial Features
    causal_link_type: DIRECT
  - target: Hypertelorism
    causal_link_type: DIRECT
  - target: Wide Anterior Fontanelle
    causal_link_type: DIRECT
  - target: Scoliosis
    causal_link_type: DIRECT
  - target: Ventricular Septal Defect
    causal_link_type: DIRECT
- name: Fibrotic Soft-Tissue Change
  biological_scale: TISSUE
  description: >-
    Beyond malformation, retained matrix drives dermal and musculoskeletal
    fibrosis with joint contractures. The zebrafish sh3pxd2b mutant isolates this
    arm particularly clearly, developing dermal and musculoskeletal fibrosis
    whose contraction produces gross deformity, with comparatively mild skeletal
    change.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:33234702
    reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "which is characterised by craniofacial abnormalities, skeletal malformations and fibrotic soft tissues changes including dermal fibrosis and joint contractures"
    explanation: >-
      Records dermal fibrosis and joint contractures as part of the human
      phenotype, not only the model phenotype.
  downstream:
  - target: Joint Contractures
    causal_link_type: DIRECT
phenotypes:
- category: Phenotypic
  name: Megalocornea
  description: >-
    Enlarged cornea, a cardinal ocular feature, frequently accompanied by raised
    intraocular pressure and prominent eyes.
  phenotype_term:
    preferred_term: Megalocornea
    term:
      id: HP:0000485
      label: Megalocornea
    onset:
      onset_category: CONGENITAL
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FTHS is characterized by facial dysmorphism, megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies."
    explanation: >-
      Lists megalocornea among the defining features of the syndrome.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocornea with or without glaucoma"
    explanation: >-
      Independent feature list confirming corneal enlargement as characteristic,
      and recording that glaucoma accompanies it only variably.
- category: Phenotypic
  name: Glaucoma
  description: >-
    Raised intraocular pressure, often congenital and in severe cases refractory
    to treatment with progression to buphthalmos. Described as inconstant, so it
    is not universal.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  frequency: FREQUENT
  evidence:
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as increased intraocular pressure, prominent eyes, and hypertelorism"
    explanation: >-
      Records raised intraocular pressure among the defining ocular features.
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with intrauterine growth retardation, hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect"
    explanation: >-
      Documents congenital glaucoma in a molecularly confirmed patient.
- category: Phenotypic
  name: Coarse Facial Features
  description: >-
    Facial dysmorphism that coarsens progressively, attributed to extracellular
    matrix accumulation in soft tissue.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical evolution resulted in buphthalmos worsening, coarsening of the facial features and respiratory failure leading to death at 4,5 months."
    explanation: >-
      Documents progressive facial coarsening in an affected patient.
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FTHS is characterized by facial dysmorphism"
    explanation: >-
      Establishes facial dysmorphism as a characteristic feature of the
      syndrome, supporting the frequency beyond the single documented case.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin"
    explanation: >-
      Independent statement of the syndrome's main clinical features, naming the
      facial components (prominent forehead, full cheeks, small chin) that make
      up the characteristic facies.
- category: Phenotypic
  name: Hypertelorism
  description: Increased interpupillary distance, part of the craniofacial phenotype.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: FREQUENT
  evidence:
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as increased intraocular pressure, prominent eyes, and hypertelorism"
    explanation: >-
      Lists hypertelorism among the defining craniofacial features.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent forehead, hypertelorism, prominent eyes"
    explanation: >-
      Second independent feature list naming hypertelorism, supporting it as a
      characteristic rather than a single-case finding.
- category: Phenotypic
  name: Camptodactyly
  description: >-
    Fixed flexion deformity of the fingers, listed among the main clinical
    features of the syndrome and documented in molecularly confirmed patients.
    This replaced an earlier "brachydactyly" entry: no source in this entry's
    reference set reports short digits, and the digital anomaly the literature
    actually describes is a flexion deformity.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  frequency: FREQUENT
  evidence:
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coccygeal skin folds and flexion deformity of the fingers"
    explanation: >-
      Lists flexion deformity of the fingers among the main clinical features of
      the syndrome.
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital glaucoma, caudal appendix, scoliosis, camptodactyly"
    explanation: >-
      Documents camptodactyly in a molecularly confirmed FTHS patient.
- category: Phenotypic
  name: Wide Anterior Fontanelle
  description: >-
    Delayed closure and widening of the anterior fontanelle, part of the
    craniofacial phenotype.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
    onset:
      onset_category: CONGENITAL
  frequency: FREQUENT
  evidence:
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features are brachycephaly, wide fontanels, prominent forehead, hypertelorism"
    explanation: >-
      Lists wide fontanels among the main clinical features of the syndrome.
- category: Phenotypic
  name: Scoliosis
  description: Vertebral abnormality with lateral spinal curvature.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect"
    explanation: >-
      Documents scoliosis in a molecularly confirmed FTHS patient.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "kyphoscoliosis, skeletal dysplasia, developmental delay"
    explanation: >-
      Lists kyphoscoliosis among the main clinical features, supporting spinal
      curvature as characteristic rather than a single-case finding.
      Kyphoscoliosis entails the scoliotic component this phenotype records.
    directness: INDIRECT
- category: Phenotypic
  name: Ventricular Septal Defect
  description: >-
    Congenital cardiac malformation; cardiovascular abnormality is one of the
    three defining organ systems and is reproduced in the Tks4-null mouse. The
    cardiac spectrum is broader than VSD alone -- atrial septal defect and patent
    ductus arteriosus are reported in other patients -- so this phenotype records
    the specific defect documented in a molecularly confirmed case, while the
    frequency reflects congenital heart defects being a characteristic feature.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
    onset:
      onset_category: CONGENITAL
  frequency: FREQUENT
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "camptodactyly, ventricular septal defect, thin corpus callosum and craniofacial features suggestive of FTHS"
    explanation: >-
      Documents a ventricular septal defect in a molecularly confirmed patient.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "small chin, congenital heart defects, kyphoscoliosis"
    explanation: >-
      Lists congenital heart defects among the main clinical features,
      supporting the frequency beyond the single documented case.
    directness: INDIRECT
- category: Phenotypic
  name: Joint Contractures
  description: >-
    Contractures arising from fibrotic change in dermal and musculoskeletal soft
    tissue rather than from primary joint disease.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  frequency: FREQUENT
  evidence:
  - reference: PMID:33234702
    reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "fibrotic soft tissues changes including dermal fibrosis and joint contractures"
    explanation: >-
      Records joint contractures as part of the fibrotic soft-tissue phenotype.
- category: Phenotypic
  name: Developmental Delay
  description: >-
    Developmental delay, listed among the main clinical features but described
    as variable. No frequency is assigned: the sources say "variable", which
    describes varying severity rather than a reported proportion of patients,
    and neither gives a denominator.

    Deliberately left unconnected in the pathograph. Unlike the skeletal, ocular
    and cardiac features, no source in this entry's reference set proposes a
    route from defective pericellular matrix remodelling to impaired
    neurodevelopment, and the one patient with detailed neuroimaging had a thin
    corpus callosum without a mechanism offered. Inventing a causal edge here
    would assert more than the literature supports.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies"
    explanation: >-
      Records developmental delay as a variable rather than obligate feature.
  - reference: PMID:21453629
    reference_title: "Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal dysplasia, developmental delay, coccygeal skin folds"
    explanation: >-
      Independent feature list including developmental delay among the main
      clinical features.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Forty patients reported with a clinical diagnosis as of 2020, of whom only
    20 had an identified mutation. The gap between the two counts reflects the
    genetic heterogeneity recorded in the genetic block, not incomplete testing
    alone -- SH3PXD2B accounted for only 7 of 13 families in the founding study.
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 40 patients have been reported in the literature with a clinical diagnosis of FTHS, only 20 patients having identified mutations."
    explanation: >-
      Gives the total reported case count and the molecularly confirmed subset,
      establishing the ultra-rare band.
diagnosis:
- name: Molecular confirmation by SH3PXD2B sequencing
  description: >-
    Clinical suspicion from the craniofacial, ocular, skeletal and cardiac
    features is confirmed by identifying biallelic SH3PXD2B variants. Because
    SH3PXD2B accounts for only part of clinically diagnosed FTHS, a negative
    result does not exclude the diagnosis, and exome sequencing has been used to
    reach it in suspected cases.
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis was confirmed by the identification of a previously known homozygous mutation c.969delG, p.(Arg324Glyfs*19) in SH3PXD2B."
    explanation: >-
      Documents molecular confirmation as the diagnostic step in a reported
      patient.
  - reference: PMID:28694206
    reference_title: "Identification of two novel SH3PXD2B gene mutations in Frank-Ter Haar syndrome by exome sequencing: Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exome sequencing is a powerful and a cost-effective tool for the diagnosis of a supposed genetically heterogeneous disorder such FTHS"
    explanation: >-
      Supports exome sequencing as the practical diagnostic route given the
      genetic heterogeneity of the syndrome.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    There is no therapy directed at the underlying podosome defect. The
    pathogenesis of the defective collagen remodelling disorders is
    incompletely understood and therapeutic options are correspondingly limited,
    so management is supportive and organised around the affected systems. This
    entry claims no target_mechanisms link because no reported intervention acts
    on the mechanism.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33234702
    reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathogenesis of DECORS is still incompletely understood and, as a result, therapeutic options are limited."
    explanation: >-
      States directly that therapeutic options for this disease group are
      limited, which is the basis for supportive-only management.
- name: Glaucoma and Intraocular Pressure Management
  description: >-
    Treatment of the raised intraocular pressure that accompanies the ocular
    phenotype. The entry records this as frequently unsatisfactory rather than
    curative: in the severe reported case the glaucoma was refractory and
    buphthalmos progressed despite treatment, which is consistent with the
    proposed matrix-accumulation mechanism continuing to operate.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:31978614
    reference_title: "A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which might explain the coarsening of the facial features and the severe refractory glaucoma"
    explanation: >-
      Records the glaucoma as refractory, establishing the limits of ocular
      pressure management in this disease.

genetic:
- name: SH3PXD2B loss of function
  gene_term:
    preferred_term: SH3PXD2B
    term:
      id: hgnc:29242
      label: SH3PXD2B
  relationship_type: CAUSATIVE
  notes: >-
    Homozygous or compound heterozygous loss-of-function variants and deletions
    at 5q35.1. Genetic heterogeneity is established: only 7 of 13 FTHS families
    in the founding study carried SH3PXD2B mutations, and one mutation-negative
    individual still had reduced TKS4 protein in dermal fibroblasts, implying a
    shared final mechanism reachable by other genetic routes. A proportion of
    Borrone dermato-cardio-skeletal syndrome is allelic with FTHS, though a third
    published BDCS family was excluded from this locus.
  evidence:
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families."
    explanation: >-
      Establishes the causative allelic spectrum across multiple families.
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No SH3PXD2B mutations were detected in six other FTHS families, demonstrating the genetic heterogeneity of this condition."
    explanation: >-
      Documents that SH3PXD2B does not account for all clinically diagnosed FTHS,
      an important limit on the gene-disease claim.
  - reference: PMID:20137777
    reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation"
    explanation: >-
      Supports a shared TKS4-deficient final mechanism even in mutation-negative
      patients, which is why the pathograph is keyed on TKS4 loss rather than on
      the genotype.
  - reference: PMID:24105366
    reference_title: "Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FTHS and BDCS share some overlapping clinical features; therefore, our results demonstrate that a proportion of BDCS and FTHS cases are allelic."
    explanation: >-
      Establishes the allelic relationship with Borrone syndrome, justifying its
      treatment as a synonym for the SH3PXD2B-mutant subset.
animal_models:
- name: Tks4-null mouse
  species: Mouse
  genotype: Tks4 (Sh3pxd2b) null
  publication: PMID:20137777
  description: >-
    Mice lacking Tks4 develop skeletal, eye and cardiac abnormalities,
    phenocopying most of the human syndrome. This is the model that established
    the gene-disease relationship as causal rather than positional.
  modeled_mechanisms:
  - target: Skeletal and Craniofacial Malformation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Reproduces the three-organ-system malformation phenotype of the human
      disease from the orthologous gene knockout.
    limitations: >-
      Phenocopies the majority, not all, of the human defects; the report does
      not claim complete reproduction of the phenotype.
    evidence:
    - reference: PMID:20137777
      reference_title: "Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice lacking Tks4 also showed pronounced skeletal, eye, and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS."
      explanation: >-
        Reports the knockout phenotype and the extent of its correspondence to
        the human disease.
- name: pretzel zebrafish (sh3pxd2b mutant)
  species: Zebrafish
  genotype: sh3pxd2b mutant (pretzel)
  publication: PMID:33234702
  description: >-
    A sh3pxd2b mutant zebrafish that develops dermal and musculoskeletal fibrosis
    with contraction-driven deformity, isolating the fibrotic arm of the disease
    with comparatively mild skeletal change.
  modeled_mechanisms:
  - target: Fibrotic Soft-Tissue Change
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the dermal and musculoskeletal fibrosis and contractures, but
      only mild skeletal abnormalities, so it models one arm of the disease
      rather than the whole.
    limitations: >-
      The authors note that the discrepancy between the sh3pxd2b and mmp14a/b
      zebrafish mutants implies the spatiotemporal dependence of ECM remodelling
      on these genes differs between fish and humans, so the division of labour
      seen in this model may not transfer. Skeletal involvement, prominent in
      human disease, is relatively mild here.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        In zebrafish, ECM remodelling depends on sh3pxd2b and mmp14a/b with a
        different spatiotemporal division than in humans, which is the authors'
        own explanation for why this mutant is fibrosis-dominant while the
        mmp14a/b mutant is bone-dominant.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The skeletal dysplasia that defines the human syndrome is effectively
        outside what this model represents: skeletal abnormalities in pretzel are
        relatively mild, so bone phenotypes cannot be read off it and the
        sibling mmp14a/b mutant carries that arm instead.
    evidence:
    - reference: PMID:33234702
      reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition to relatively mild skeletal abnormalities, pretzel mutants develop dermal and musculoskeletal fibrosis"
      explanation: >-
        Reports the model's fibrotic phenotype and the mildness of its skeletal
        involvement, supporting both the link and its limitation.
    - reference: PMID:33234702
      reference_title: "The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The discrepancy in phenotypes between mmp14a/b and sh3pxd2b mutants suggests that in fish, as opposed to humans, there are differences in spatiotemporal dependence of ECM remodelling on either sh3pxd2b or mmp14a/b"
      explanation: >-
        The authors' own statement of the species divergence recorded in the
        divergences block.

📚

References & Deep Research

References

6

PMID:20137777

Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome.

No top-level findings curated for this source.

PMID:19144821

The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation.

No top-level findings curated for this source.

PMID:24105366

Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.

No top-level findings curated for this source.

PMID:31978614

A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum.

No top-level findings curated for this source.

PMID:33234702

The novel zebrafish model pretzel demonstrates a central role for SH3PXD2B in defective collagen remodelling and fibrosis in Frank-Ter Haar syndrome.

No top-level findings curated for this source.

PMID:21453629

Frank-Ter Haar Syndrome.

No top-level findings curated for this source.

Frank-Ter Haar Syndrome

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