Kyphoscoliotic Ehlers-Danlos Syndrome

Mendelian MONDO:0016002 Pathograph 44 Show in embeddings browser Ehlers-Danlos Syndrome Connective Tissue Disorder

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective-tissue disorder characterized by congenital or early-onset hypotonia, progressive kyphoscoliosis, generalized joint hypermobility, and skin fragility. It is genetically heterogeneous, with two known causal genes acting at different steps of collagen biosynthesis: PLOD1 (kEDS-PLOD1, formerly EDS type VIA, ~90% of molecularly confirmed cases), encoding lysyl hydroxylase 1, which hydroxylates telopeptide lysine residues required for mature collagen crosslink formation; and FKBP14 (kEDS-FKBP14, formerly EDS type VIB), encoding an ER-resident peptidyl-prolyl isomerase/chaperone implicated in procollagen folding, whose deficiency additionally causes myopathy and hearing impairment not typical of kEDS-PLOD1. MONDO retired the single umbrella term for this disease (MONDO:0034024) in favor of two gene-specific child concepts; this entry is anchored on MONDO:0016002 ("Ehlers-Danlos syndrome, kyphoscoliotic type 1"), which now carries the general "kyphoscoliotic Ehlers-Danlos syndrome"/"kEDS"/"EDS VI" synonyms and represents the common PLOD1-related form, with the FKBP14-related form modeled as a subtype anchored on its own MONDO:0013800 term.

Ask OpenScientist

Ask a research question about Kyphoscoliotic Ehlers-Danlos Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
11
Pathophys.
1
Histopath.
24
Phenotypes
44
Pathograph
2
Genes
4
Medical Actions
2
Subtypes
1
Models
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-kEDS is inherited in an autosomal recessive manner."
GeneReviews states the autosomal recessive inheritance pattern for PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"FKBP14-kEDS is inherited in an autosomal recessive manner."
GeneReviews states the autosomal recessive inheritance pattern for FKBP14-kEDS.
◆

Subtypes

2
kEDS-PLOD1 (kyphoscoliotic type 1, EDS VIA) MONDO:0016002
PLOD1 hgnc:9081 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PLOD1 (hgnc:9081). hgnc:9081 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic loss-of-function variants in PLOD1, encoding lysyl hydroxylase 1 (LH1). This is the common form of kEDS, characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality, with a distinctive risk of arterial rupture and dissection.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews summary establishes the core PLOD1-kEDS phenotype.
kEDS-FKBP14 (kyphoscoliotic type 2, EDS VIB) MONDO:0013800
FKBP14 hgnc:18625 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FKBP14 (hgnc:18625). hgnc:18625 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic loss-of-function variants in FKBP14, encoding an ER-resident FK506-binding-protein-family peptidyl-prolyl isomerase. Distinguished from kEDS-PLOD1 by additional myopathy and sensorineural hearing impairment, with congenital hypotonia that typically improves during childhood.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews summary establishes the core FKBP14-kEDS phenotype, distinguishing it from PLOD1-kEDS by myopathy and hearing impairment.
⚙

Pathophysiology

11
PLOD1 Loss-of-Function
Biallelic loss-of-function variants in PLOD1 abolish or markedly reduce lysyl hydroxylase 1 activity.
PLOD1 hgnc:9081 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLOD1 (hgnc:9081). hgnc:9081 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
procollagen-lysine 5-dioxygenase activity GO:0008475 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased procollagen-lysine 5-dioxygenase activity (GO:0008475). GO:0008475 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Warmblood Fragile Foal Syndrome (WFFS) horse Horse partially recapitulates A naturally occurring recessive PLOD1 missense variant in Warmblood horses causes Warmblood fragile foal syndrome type 1 (WFFS), a fatal connective-tissue fragility disorder and the equine counterpart of human kEDS-PLOD1.
Downstream
Deficient Telopeptide Lysyl Hydroxylation
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"It is caused by a deficiency of the collagen-modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (LH1; EC 1.14.11.4; MIM 153454; PLOD1 or lysyl hydroxylase 1)"
Establishes PLOD1/LH1 enzymatic identity and its loss as the cause of kEDS-PLOD1.
Deficient Telopeptide Lysyl Hydroxylation
Loss of LH1 activity prevents hydroxylation of lysine residues in the telopeptide regions of fibrillar procollagens, so the resulting crosslinks are lysine-derived rather than hydroxylysine-derived.
peptidyl-lysine hydroxylation GO:0017185 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidyl-lysine hydroxylation (GO:0017185). GO:0017185 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Collagen Crosslink Maturation
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"lysyl hydroxylase deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens and, hence, impaired cross-link formation with consequent mechanical instability of the affected tissues"
Establishes that LH1 deficiency causes underhydroxylation of collagen lysyl residues.
FKBP14 Loss-of-Function
Biallelic loss-of-function variants in FKBP14 disrupt its peptidyl-prolyl isomerase/chaperone activity in the endoplasmic reticulum.
FKBP14 hgnc:18625 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FKBP14 (hgnc:18625). hgnc:18625 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
peptidyl-prolyl cis-trans isomerase activity GO:0003755 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased peptidyl-prolyl cis-trans isomerase activity (GO:0003755). GO:0003755 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Procollagen Folding and Secretion
Show evidence (3 references)
PMID:24821723 SUPPORT In Vitro
"The absence of FKBP22 leads to a kyphoscoliotic type of Ehlers-Danlos syndrome (EDS), and this type of EDS is classified as EDS type VI, which can also be caused by a deficiency in lysyl-hydroxylase 1."
Establishes FKBP22 (FKBP14) loss as a cause of kEDS, alongside PLOD1 deficiency.
PMID:22265013 SUPPORT In Vitro
"We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro."
The original FKBP14 disease-gene report directly demonstrates that FKBP14 loss disrupts ER structure and extracellular matrix assembly in patient fibroblasts.
PMID:31949249 SUPPORT In Vitro
"these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens"
Documents the collagen-type substrate preference of FKBP22 (FKBP14) that underlies which collagens are affected by its loss of function.
Impaired Procollagen Folding and Secretion
Loss of FKBP14 chaperone/isomerase activity impairs correct folding and ER-to-Golgi trafficking of procollagen molecules, with a substrate preference for type III, type VI, and type X collagen rather than the type I/II/V collagens handled by lysyl hydroxylase 1 -- a difference proposed to explain why kEDS-FKBP14 has a broader phenotype (myopathy, hearing loss) than kEDS-PLOD1.
protein folding in endoplasmic reticulum GO:0034975 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein folding in endoplasmic reticulum (GO:0034975). GO:0034975 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Collagen Crosslink Maturation
Myopathy
Hearing Impairment
Show evidence (3 references)
PMID:36054293 SUPPORT In Vitro
"With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14."
Direct cellular evidence that FKBP14 loss causes intracellular retention (impaired secretion) of procollagen.
PMID:24821723 SUPPORT In Vitro
"These restrictive interactions might help explain the broader phenotype observed in patients that lack FKBP22."
Proposes that FKBP22's restricted collagen-type substrate preference underlies the broader kEDS-FKBP14 phenotype relative to kEDS-PLOD1.
PMID:31288483 SUPPORT In Vitro
"we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls"
RNA sequencing of FKBP14-kEDS patient fibroblasts shows ER-stress and protein-trafficking transcriptional changes downstream of the impaired procollagen folding/secretion node, alongside inner-ear and vascular remodeling changes plausibly linked to the hearing and vascular manifestations distinguishing FKBP14-kEDS.
Disorganized Dermal and Vascular Collagen Fibrils
Poorly crosslinked collagen fibrils are structurally weaker and abnormally organized in skin, joint capsule/ligament, vascular wall, and scleral connective tissue, reducing their tensile strength.
dermal fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Skin Fragility and Poor Wound Healing
Joint Hypermobility and Instability
Arterial Wall Fragility
Ocular Globe Fragility
Weakened Musculoskeletal and Paraspinal Connective Tissue
Mitral Valve Prolapse
Inguinal Hernia
Bladder Diverticulum
Subdural Hygroma
Bifid Uvula
Rectal Prolapse
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"Abnormal electron microscopy findings (Figure 1) included variable diameters of the collagen fibrils, irregular interfibrillar space in addition to irregular ragged outlines in cross sections."
Direct electron-microscopic documentation of disorganized dermal collagen fibrils in kEDS skin biopsies.
Weakened Musculoskeletal and Paraspinal Connective Tissue
Poorly crosslinked collagen in skeletal muscle fascia, spinal ligaments, and paraspinal connective tissue reduces its mechanical support of the trunk and axial skeleton.
Downstream
Congenital or Early-Onset Hypotonia
Kyphoscoliosis
Osteopenia
Clubfoot
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
Documents weakened musculoskeletal and paraspinal connective tissue as an early manifestation of the disorder.
Skin Fragility and Poor Wound Healing
Weakened dermal collagen produces hyperextensible, easily bruised, friable skin with atrophic scarring and impaired wound healing.
Downstream
Hyperextensible Skin
Fragile Skin
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"dermal wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously; cutaneous stitches should be left in place twice as long as usual, and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar"
GeneReviews management guidance documents the friable, poor-healing skin that requires special wound-closure precautions.
Joint Hypermobility and Instability
Reduced tensile strength of periarticular connective tissue (joint capsule, ligament) produces generalized joint laxity and dislocations.
Downstream
Generalized Joint Hypermobility
Recurrent Joint Dislocations
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
Documents generalized joint hyperextensibility as a manifestation of periarticular connective tissue weakness.
Arterial Wall Fragility
Defective collagen crosslinking weakens the arterial wall, predisposing to spontaneous rupture and dissection of medium-sized arteries.
fibroblast of the aortic adventitia CL:0002547 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast of the aortic adventitia (CL:0002547). CL:0002547 is a cell type from the Cell Ontology.
Downstream
Arterial Rupture and Dissection
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries."
GeneReviews establishes arterial wall fragility as a defining risk in kEDS.
PMID:21699693 SUPPORT BACKGROUND Model Organism
"15% of PLOD1-/- mice died at the age of 1-4 months due to aortic dissections, caused most likely by degenerated smooth muscle cells and abnormal collagen fibrils of aortic wall"
A PLOD1 knockout mouse study, cited in this human clinical paper's discussion, gives the mechanistic detail (smooth muscle degeneration and abnormal aortic collagen fibrils) behind the arterial wall fragility node.
Ocular Globe Fragility
Scleral and corneal connective tissue weakness produces blue sclerae, refractive error, and risk of globe rupture or retinal detachment.
Downstream
Refractive Error
Retinal Detachment
Blue Sclerae
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews lists ocular abnormality as a defining feature of PLOD1-kEDS.
✶

Histopathology

1
Abnormal Dermal Collagen Fibril Ultrastructure
Transmission electron microscopy of skin biopsies shows collagen fibrils of variable, abnormally increased diameter with loss of the normal circular cross-sectional contour and irregular interfibrillar spacing, a finding reported as distinct from other EDS subtypes; elastic fibers are structurally normal.
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"Diameters of the collagen fibrils were significantly increased with loss of the normal circular shape. In particular those fibrils with abnormally increased diameters showed a greater deviation from circular shape (Figure 1). The elastic fibers presented normal ultrastructural features."
Direct electron-microscopic description of the dermal collagen fibril abnormality in kEDS-PLOD1 skin biopsies.
⬡

Pathograph

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

Phenotypes

24
Cardiovascular 3
Arterial Rupture and Dissection HP:0025019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arterial rupture (HP:0025019). HP:0025019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries."
GeneReviews describes arterial rupture and dissection as a life-threatening risk in PLOD1-kEDS.
Mitral Valve Prolapse HP:0001634 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral valve prolapse (HP:0001634). HP:0001634 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse"
GeneReviews management recommendations document mitral valve prolapse as a cardiac manifestation of PLOD1-kEDS.
Cardiac Failure Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
GeneReviews documents cardiac failure as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
Digestive 2
Inguinal Hernia HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"annual examination for inguinal hernia"
GeneReviews surveillance recommendations document inguinal hernia as a manifestation of PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy"
GeneReviews lists inguinal or umbilical herniae among occasional systemic connective tissue features of FKBP14-kEDS.
Rectal Prolapse HP:0002035 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rectal prolapse (HP:0002035). HP:0002035 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
GeneReviews lists rectal prolapse among rarer findings in FKBP14-kEDS.
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews lists hearing impairment as a feature distinguishing FKBP14-kEDS from PLOD1-kEDS.
Eye 3
Refractive Error Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"corrective lenses for myopia and/or astigmatism"
GeneReviews management recommendations for PLOD1-kEDS document myopia and/or astigmatism as a manifestation requiring corrective lenses.
PMID:31132235 SUPPORT Human Clinical
"standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate"
GeneReviews management recommendations document refractive error as a manifestation of FKBP14-kEDS also requiring standard treatment.
Retinal Detachment HP:0000541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal detachment (HP:0000541). HP:0000541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"laser treatment of the retina for those with imminent detachment"
GeneReviews management recommendations for PLOD1-kEDS document retinal detachment risk requiring prophylactic laser treatment.
Blue Sclerae HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
GeneReviews lists bluish sclerae among the occasional systemic connective tissue features of FKBP14-kEDS.
Genitourinary 1
Bladder Diverticulum HP:0000015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bladder diverticulum (HP:0000015). HP:0000015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy"
GeneReviews lists bladder diverticula among occasional systemic connective tissue features of FKBP14-kEDS.
Head and Neck 1
Bifid Uvula HP:0000193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid uvula (HP:0000193). HP:0000193 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
GeneReviews lists bifid uvula with submucous or frank cleft palate among rarer findings in FKBP14-kEDS.
Immune 1
Recurrent Pneumonia HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
GeneReviews documents recurrent pneumonia as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
Integument 2
Fragile Skin HP:0001030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fragile skin (HP:0001030). HP:0001030 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews lists skin fragility as a defining feature of PLOD1-kEDS.
Hyperextensible Skin HP:0000974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperextensible skin (HP:0000974). HP:0000974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews lists hyperelastic (hyperextensible) skin as a feature of FKBP14-kEDS.
Limbs 1
Clubfoot Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate"
GeneReviews management recommendations document clubbed foot as a manifestation of FKBP14-kEDS requiring standard treatment.
Musculoskeletal 6
Congenital or Early-Onset Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252), qualified as temporality chronic. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews lists hypotonia as a defining feature of PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews lists congenital hypotonia as a defining feature of FKBP14-kEDS, typically improving in childhood.
Kyphoscoliosis HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751). HP:0002751 is a phenotype from the Human Phenotype Ontology.
Sequelae: Restrictive Ventilatory Defect Recurrent Pneumonia Cardiac Failure
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews establishes early-onset kyphoscoliosis as a defining feature of PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews lists progressive scoliosis as a defining feature of FKBP14-kEDS.
Generalized Joint Hypermobility HP:0002761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized joint hypermobility (HP:0002761). HP:0002761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
GeneReviews lists generalized joint hypermobility as a defining feature of PLOD1-kEDS.
Recurrent Joint Dislocations HP:0001373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint dislocation (HP:0001373). HP:0001373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Annual physical therapy assessment for weakness and motor issues and orthopedic assessment for management of kyphoscoliosis and recurrent dislocations"
GeneReviews surveillance recommendations for PLOD1-kEDS document recurrent joint dislocations as a disease manifestation requiring orthopedic assessment.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Sequelae: Gross Motor Developmental Delay
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
GeneReviews lists myopathy as a feature distinguishing FKBP14-kEDS from PLOD1-kEDS.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"assessment for osteopenia as needed beginning at age ten to 12 years"
GeneReviews surveillance recommendations document osteopenia as a manifestation of PLOD1-kEDS requiring assessment from age 10-12.
Nervous System 2
Gross Motor Developmental Delay Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"Most affected children achieve independent walking between ages two and four years."
GeneReviews documents delayed independent walking as evidence of gross motor developmental delay in FKBP14-kEDS.
Subdural Hygroma HP:6001070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subdural hygroma (HP:6001070). HP:6001070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31132235 SUPPORT Human Clinical
"Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
GeneReviews lists subdural hygroma among occasional systemic connective tissue features of FKBP14-kEDS.
Respiratory 1
Restrictive Ventilatory Defect HP:0002091 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive lung disease, annotated with Restrictive ventilatory defect (HP:0002091). HP:0002091 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
GeneReviews documents restrictive lung disease as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
🧬

Genetic Associations

2
PLOD1
Gene: PLOD1 hgnc:9081 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLOD1 (hgnc:9081). hgnc:9081 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"The diagnosis of PLOD1-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1 identified by molecular genetic testing."
GeneReviews establishes biallelic PLOD1 pathogenic variants as diagnostic of PLOD1-kEDS.
PMID:21699693 SUPPORT Human Clinical
"among them an 8.9-kb duplication of seven exons (exon 10-16) is the most common cause of the disorder"
Identifies the recurrent 8.9-kb exon 10-16 duplication as the most common PLOD1 pathogenic variant.
FKBP14
Gene: FKBP14 hgnc:18625 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FKBP14 (hgnc:18625). hgnc:18625 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:31132235 SUPPORT Human Clinical
"The diagnosis of FKBP14-kEDS is established in a proband by the identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing."
GeneReviews establishes biallelic FKBP14 pathogenic variants as diagnostic of FKBP14-kEDS.
PMID:36054293 SUPPORT Human Clinical
"the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?)"
Documents reported FKBP14 pathogenic variant types, including the recurrent c.362dupC frameshift founder allele.
PMID:41366145 SUPPORT Human Clinical
"A female patient with genetically confirmed FKBP14-associated EDS (homozygous c.362dupG p.E122RfsX7 mutation) was followed from infancy through age 10 at a tertiary pediatric center."
An independent case report documenting the identical p.(Glu122Argfs*7)/p.E122RfsX7 frameshift protein consequence in an unrelated patient (the cDNA change is given here as c.362dupG rather than c.362dupC; whether this is the same recurrent variant under a notation discrepancy or a distinct change producing the same frameshift could not be confirmed from the cached text).
💊

Medical Actions

4
Physical and Occupational Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Physical therapy to strengthen large muscle groups and address age-dependent decline in muscular strength.
Mechanism Target:
MODULATES Weakened Musculoskeletal and Paraspinal Connective Tissue — Strengthens the large muscle groups to partially compensate for the reduced mechanical support of weakened paraspinal and musculoskeletal connective tissue; it does not correct the underlying collagen defect.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Treatment of manifestations: Physical therapy to strengthen large muscle groups; swimming"
GeneReviews recommends physical therapy as a core management measure for PLOD1-kEDS.
Orthopedic Management of Kyphoscoliosis
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Orthopedic surveillance and surgical management of progressive kyphoscoliosis and joint instability.
Mechanism Target:
MODULATES Kyphoscoliosis — Surgical instrumentation and fusion mechanically stabilizes and corrects the progressive spinal curvature; it addresses the structural consequence rather than the underlying collagen crosslink defect, and carries an elevated complication risk from the same tissue fragility.
Show evidence (3 references)
PMID:20301635 SUPPORT Human Clinical
"management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed"
GeneReviews recommends orthopedic surgical management of kyphoscoliosis in PLOD1-kEDS.
PMID:21667916 SUPPORT Human Clinical
"Our experience supports that a satisfactory correction of scoliosis can be achieved by posterior spinal fusion only in patients with Ehlers-Danlos syndrome, kyphoscoliosis type."
A small case series documents posterior spinal fusion as a surgical management option achieving satisfactory correction in kEDS-associated scoliosis.
PMID:41366145 SUPPORT Human Clinical
"Nine-year follow-up demonstrated successful deformity control with solid arthrodesis at multiple levels, though ongoing challenges include hardware adaptation and the need for mobility assistance."
A long-term case report documents successful multi-stage surgical deformity control in FKBP14-kEDS, alongside ongoing hardware and mobility challenges from the underlying tissue fragility.
Beta-Blocker Therapy for Aortic Dilatation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: beta-adrenergic antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses beta-adrenergic antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Beta-blockers to reduce hemodynamic stress and prevent aortic dilatation or progression of vascular dissection.
Mechanism Target:
MODULATES Arterial Wall Fragility — Lowers hemodynamic stress on the mechanically weakened arterial wall to slow dilatation and reduce dissection risk; it does not correct the underlying collagen crosslink defect.
Show evidence (2 references)
PMID:20301635 SUPPORT Human Clinical
"treatment with beta-blockers as needed to prevent aortic dilatation"
GeneReviews recommends beta-blocker therapy to prevent aortic dilatation in PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"In those with aortic dilatation or vascular dissection, use of beta-blockers may be considered"
GeneReviews recommends beta-blocker consideration for aortic dilatation or vascular dissection in FKBP14-kEDS.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling regarding autosomal recessive inheritance, recurrence risk, and availability of carrier and prenatal/preimplantation testing.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"If both PLOD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews describes genetic counseling and testing options for at-risk relatives in PLOD1-kEDS.
🌍

Environmental Factors

2
Joint-Stressing and High-Impact Physical Activity
joint-stressing or high-impact physical activity Relation: this environmental factor is this exposure This environmental factor is joint-stressing or high-impact physical activity.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting"
GeneReviews lists these activities as agents/circumstances to avoid in PLOD1-kEDS because of joint stress.
Mechanism Target:
EXACERBATES Joint Hypermobility and Instability — Gymnastics, long-distance running, collision sports, and heavy lifting place mechanical stress on already unstable joints, increasing the risk of subluxation and dislocation.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting"
GeneReviews lists these activities as agents/circumstances to avoid in PLOD1-kEDS because of joint stress.
Diagnostic Arteriography
diagnostic arteriography Relation: this environmental factor is this exposure This environmental factor is diagnostic arteriography.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"
GeneReviews identifies arteriography as a procedure to avoid in PLOD1-kEDS because of vascular injury risk.
Mechanism Target:
EXACERBATES Arterial Wall Fragility — Catheter-based arteriography carries a risk of iatrogenic vascular injury in an already fragile arterial wall and is discouraged except to localize life-threatening bleeding.
Show evidence (1 reference)
PMID:20301635 SUPPORT Human Clinical
"arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"
GeneReviews identifies arteriography as a procedure to avoid in PLOD1-kEDS because of vascular injury risk.
🔬

Biochemical Markers

1
Urinary lysyl-pyridinoline to hydroxylysyl-pyridinoline ratio (INCREASED)
Context: Deficient lysyl hydroxylase 1 activity in kEDS-PLOD1 skews collagen crosslinking toward lysine-derived (lysyl-pyridinoline) rather than hydroxylysine-derived (hydroxylysyl-pyridinoline) crosslinks, raising the urinary total LP:HP ratio; this is a fast, non-invasive, and diagnostic biochemical test for kEDS-PLOD1.
Pathograph Readouts
Readout Of Defective Collagen Crosslink Maturation Positive Diagnostic
An elevated urinary LP:HP ratio reports the shift away from mature hydroxylysine-derived collagen crosslinks caused by LH1 deficiency.
Show evidence (2 references)
PMID:21699693 SUPPORT Human Clinical
"The ratio of urinary total LP to HP in patients with EDS type VIA is high as compared with normal controls"
Establishes the elevated urinary LP:HP ratio compared to normal controls in kEDS-PLOD1.
PMID:21699693 SUPPORT Human Clinical
"is diagnostic for EDS type VIA"
Establishes the urinary LP:HP ratio as a diagnostic biochemical marker for kEDS-PLOD1.
🔬

Diagnosis

3
Molecular Genetic Testing of PLOD1 or FKBP14
The definitive diagnostic test for kEDS. PLOD1-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1; FKBP14-kEDS is established by biallelic pathogenic variants in FKBP14. Sequence analysis alone misses structural variants (notably the recurrent PLOD1 exon 10-16 duplication), so deletion/duplication analysis is needed when only one or no pathogenic variant is found by sequencing.
Show evidence (3 references)
PMID:20301635 SUPPORT Human Clinical
"The diagnosis of PLOD1-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1 identified by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion for PLOD1-kEDS.
PMID:31132235 SUPPORT Human Clinical
"The diagnosis of FKBP14-kEDS is established in a proband by the identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion for FKBP14-kEDS.
PMID:37433679 SUPPORT Human Clinical
"Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only."
Case report of a patient clinically misdiagnosed with Larsen syndrome for over 40 years, later found by molecular testing to have FKBP14-kEDS, illustrating why molecular confirmation rather than clinical impression alone is required.
Clinical Suggestive Criteria (2017 International EDS Classification)
kEDS is one of the 13 EDS subtypes for which the 2017 International EDS Classification defines a set of clinical criteria suggestive of the diagnosis. As with nearly all non-hypermobile EDS subtypes, these clinical criteria are suggestive only: definitive diagnosis of both kEDS-PLOD1 and kEDS-FKBP14 requires molecular confirmation of biallelic pathogenic variants. For FKBP14-kEDS specifically, the clinical criteria require congenital muscular hypotonia together with congenital or early-onset kyphoscoliosis, plus generalized joint hypermobility or further gene-specific/supportive features; a subsequent 23-patient cohort refined these into explicit major criteria (severe generalized hypotonia at birth with improvement in infancy and delayed motor milestones; early-onset progressive kyphoscoliosis; joint hypermobility without pronounced contractures; foot deformities; and a normal or decreased urinary lysyl:hydroxylysyl pyridinoline ratio) and minor criteria (hyperelastic skin with follicular hyperkeratosis and easy bruising; myopathy; and hearing impairment).
Show evidence (3 references)
DOI:10.1002/ajmg.c.31552 SUPPORT Other
"For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite..."
The international consensus nosology establishes that kEDS has suggestive clinical criteria but, like all non-hypermobile EDS subtypes, requires molecular confirmation for definitive diagnosis.
PMID:31132235 SUPPORT Human Clinical
"Clinical diagnostic criteria rely on the finding of congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis in addition to generalized joint hypermobility or further gene-specific and/or supportive clinical features."
GeneReviews states the specific clinical suggestive criteria for FKBP14-kEDS.
PMID:28617417 SUPPORT Human Clinical
"the major diagnostic criteria are (i) severe generalized hypotonia at birth with marked muscle weakness that improves in infancy, and delayed gross motor milestones; (ii) early-onset progressive (kypho)scoliosis; (iii) joint hypermobility without pronounced contractures; (iv) foot deformities;..."
This 23-patient cohort study defines the explicit major and minor clinical diagnostic criteria for FKBP14-kEDS, stated to have informed the redraft of the 2017 International Nosology of EDS.
📊

Prevalence

1
kEDS-PLOD1 (EDS type VIA)
Birth Prevalence 1.0 per 100,000 live births 1–9 per 100,000 (births)
FKBP14-related disease (kEDS-FKBP14) is markedly rarer than PLOD1-related disease, but no separate population-based incidence estimate for kEDS-FKBP14 was found in the cited sources.
Show evidence (1 reference)
PMID:21699693 SUPPORT Human Clinical
"a rare autosomal recessively inherited connective tissue disorder with a disease incidence of approximately 1;100,000 live births"
Reports the estimated birth incidence of kEDS-PLOD1 (EDS type VIA).
🐁

Animal Models

1
Warmblood Fragile Foal Syndrome (WFFS) horse
Species
Horse
Genotype
PLOD1 c.2032G>A (homozygous)
Publication
PMID:31502696
Pathograph links
PLOD1 Loss-of-Function partially recapitulates fidelity: moderate observes: organism A naturally occurring recessive PLOD1 missense variant in Warmblood horses causes Warmblood fragile foal syndrome type 1 (WFFS), a fatal connective-tissue fragility disorder and the equine counterpart of human kEDS-PLOD1.
Limitations: Homozygous WFFS foals typically show severe perinatal/neonatal connective-tissue rupture and do not survive, a substantially more severe and earlier-lethal course than human kEDS-PLOD1, which is generally compatible with survival to adulthood; the cited study is a Thoroughbred allele-frequency and racing-injury screening report rather than a primary phenotypic characterization of WFFS.
Show evidence (1 reference)
PMID:31502696 SUPPORT BACKGROUND Model Organism
"A variant in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase1 gene (PLOD1 c.2032G>A) was shown to cause Warmblood fragile foal syndrome type 1 (WFFS), a fatal recessive defect of the connective tissue."
Background sentence in this Thoroughbred-screening paper establishing that the cited PLOD1 variant causes a fatal recessive equine connective-tissue disorder, the naturally-occurring animal counterpart of kEDS-PLOD1.
Notes
This naturally-occurring equine variant is the only PLOD1- or FKBP14-specific animal model identified in the cached literature; no engineered PLOD1 or FKBP14 knockout/knock-in mouse model with published phenotyping data was found. PMID:34712265, a narrative review of animal models across all EDS subtypes, confirms that engineered mouse and zebrafish models exist for many EDS-associated genes, but its abstract does not itself supply reproducible genotype/phenotype data for a PLOD1- or FKBP14-specific model suitable for a modeled_mechanisms entry here. A separately-cached PMID:34850861 (a CRISPR/Cas9 mouse model) is for musculocontractural EDS caused by CHST14/dermatan-sulfate-pathway variants -- a different EDS subtype and an unrelated gene/pathway -- and is deliberately not cited here to avoid Named Entity Confusion.
{ }

Source YAML

click to show 
name: Kyphoscoliotic Ehlers-Danlos Syndrome
category: Mendelian
creation_date: "2026-09-15T21:15:24Z"
description: >
  Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive
  connective-tissue disorder characterized by congenital or early-onset
  hypotonia, progressive kyphoscoliosis, generalized joint hypermobility, and
  skin fragility. It is genetically heterogeneous, with two known causal
  genes acting at different steps of collagen biosynthesis: PLOD1 (kEDS-PLOD1,
  formerly EDS type VIA, ~90% of molecularly confirmed cases), encoding lysyl
  hydroxylase 1, which hydroxylates telopeptide lysine residues required for
  mature collagen crosslink formation; and FKBP14 (kEDS-FKBP14, formerly EDS
  type VIB), encoding an ER-resident peptidyl-prolyl isomerase/chaperone
  implicated in procollagen folding, whose deficiency additionally causes
  myopathy and hearing impairment not typical of kEDS-PLOD1. MONDO retired the
  single umbrella term for this disease (MONDO:0034024) in favor of two
  gene-specific child concepts; this entry is anchored on MONDO:0016002
  ("Ehlers-Danlos syndrome, kyphoscoliotic type 1"), which now carries the
  general "kyphoscoliotic Ehlers-Danlos syndrome"/"kEDS"/"EDS VI" synonyms and
  represents the common PLOD1-related form, with the FKBP14-related form
  modeled as a subtype anchored on its own MONDO:0013800 term.
disease_term:
  preferred_term: Kyphoscoliotic Ehlers-Danlos Syndrome
  term:
    id: MONDO:0016002
    label: Ehlers-Danlos syndrome, kyphoscoliotic type 1
synonyms:
- kEDS
- EDS VI
- EDS type VI
- Ehlers-Danlos syndrome, kyphoscoliotic type
- PLOD1-kEDS
- kyphoscoliotic EDS due to lysyl hydroxylase 1 deficiency
notes: >
  The generic MONDO umbrella term for kyphoscoliotic EDS (MONDO:0034024) is
  obsolete, with no single non-obsolete replacement; MONDO instead provides
  two sibling gene-specific children (MONDO:0016002 for PLOD1-related type 1,
  MONDO:0013800 for FKBP14-related type 2), both direct subclasses of
  MONDO:0020066 (Ehlers-Danlos syndrome). This entry anchors on MONDO:0016002
  because it carries the general kEDS/EDS-VI synonyms and PLOD1-kEDS accounts
  for the large majority of reported cases; FKBP14-kEDS is curated as a
  has_subtypes entry with its own MONDO term, following the precedent set by
  Musculocontractural_Ehlers-Danlos_Syndrome.yaml for a genetically
  heterogeneous EDS subtype.
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
references:
- reference: PMID:20301635
  title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
  tags:
  - GeneReviews
- reference: PMID:31132235
  title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
  tags:
  - GeneReviews
has_subtypes:
- name: kEDS-PLOD1
  display_name: kEDS-PLOD1 (kyphoscoliotic type 1, EDS VIA)
  subtype_term:
    preferred_term: PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome
    term:
      id: MONDO:0016002
      label: Ehlers-Danlos syndrome, kyphoscoliotic type 1
  genes:
  - preferred_term: PLOD1
    term:
      id: hgnc:9081
      label: PLOD1
  description: >
    Caused by biallelic loss-of-function variants in PLOD1, encoding lysyl
    hydroxylase 1 (LH1). This is the common form of kEDS, characterized by
    hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis,
    skin fragility, and ocular abnormality, with a distinctive risk of
    arterial rupture and dissection.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews summary establishes the core PLOD1-kEDS phenotype.
- name: kEDS-FKBP14
  display_name: kEDS-FKBP14 (kyphoscoliotic type 2, EDS VIB)
  subtype_term:
    preferred_term: FKBP14-related kyphoscoliotic Ehlers-Danlos syndrome
    term:
      id: MONDO:0013800
      label: Ehlers-Danlos syndrome, kyphoscoliotic type, 2
  genes:
  - preferred_term: FKBP14
    term:
      id: hgnc:18625
      label: FKBP14
  description: >
    Caused by biallelic loss-of-function variants in FKBP14, encoding an
    ER-resident FK506-binding-protein-family peptidyl-prolyl isomerase.
    Distinguished from kEDS-PLOD1 by additional myopathy and sensorineural
    hearing impairment, with congenital hypotonia that typically improves
    during childhood.
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews summary establishes the core FKBP14-kEDS phenotype, distinguishing it from PLOD1-kEDS by myopathy and hearing impairment.
pathophysiology:
- name: PLOD1 Loss-of-Function
  biological_scale: MOLECULAR
  subtypes:
  - kEDS-PLOD1
  description: >
    Biallelic loss-of-function variants in PLOD1 abolish or markedly reduce
    lysyl hydroxylase 1 activity.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: PLOD1
    term:
      id: hgnc:9081
      label: PLOD1
  molecular_functions:
  - preferred_term: procollagen-lysine 5-dioxygenase activity
    modifier: DECREASED
    term:
      id: GO:0008475
      label: procollagen-lysine 5-dioxygenase activity
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by a deficiency of the collagen-modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (LH1; EC 1.14.11.4; MIM 153454; PLOD1 or lysyl hydroxylase 1)"
    explanation: Establishes PLOD1/LH1 enzymatic identity and its loss as the cause of kEDS-PLOD1.
  downstream:
  - target: Deficient Telopeptide Lysyl Hydroxylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This enzyme plays an important role as a post-translational modifying enzyme in collagen biosynthesis through both hydroxylation of lysyl residues in -Xaa-Lys-Gly- collagen sequences to hydroxylysyl residues"
      explanation: Directly links loss of LH1 enzymatic activity to failure of collagen lysyl hydroxylation.
- name: Deficient Telopeptide Lysyl Hydroxylation
  biological_scale: MOLECULAR
  subtypes:
  - kEDS-PLOD1
  description: >
    Loss of LH1 activity prevents hydroxylation of lysine residues in the
    telopeptide regions of fibrillar procollagens, so the resulting
    crosslinks are lysine-derived rather than hydroxylysine-derived.
  biological_processes:
  - preferred_term: peptidyl-lysine hydroxylation
    modifier: DECREASED
    term:
      id: GO:0017185
      label: peptidyl-lysine hydroxylation
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lysyl hydroxylase deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens and, hence, impaired cross-link formation with consequent mechanical instability of the affected tissues"
    explanation: Establishes that LH1 deficiency causes underhydroxylation of collagen lysyl residues.
  downstream:
  - target: Defective Collagen Crosslink Maturation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "lysyl hydroxylase deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens and, hence, impaired cross-link formation with consequent mechanical instability of the affected tissues"
      explanation: Directly links underhydroxylation to impaired collagen crosslink formation.
- name: FKBP14 Loss-of-Function
  biological_scale: MOLECULAR
  subtypes:
  - kEDS-FKBP14
  description: >
    Biallelic loss-of-function variants in FKBP14 disrupt its
    peptidyl-prolyl isomerase/chaperone activity in the endoplasmic
    reticulum.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: FKBP14
    term:
      id: hgnc:18625
      label: FKBP14
  molecular_functions:
  - preferred_term: peptidyl-prolyl cis-trans isomerase activity
    modifier: DECREASED
    term:
      id: GO:0003755
      label: peptidyl-prolyl cis-trans isomerase activity
  evidence:
  - reference: PMID:24821723
    reference_title: "A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The absence of FKBP22 leads to a kyphoscoliotic type of Ehlers-Danlos syndrome (EDS), and this type of EDS is classified as EDS type VI, which can also be caused by a deficiency in lysyl-hydroxylase 1."
    explanation: Establishes FKBP22 (FKBP14) loss as a cause of kEDS, alongside PLOD1 deficiency.
  - reference: PMID:22265013
    reference_title: "Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro."
    explanation: The original FKBP14 disease-gene report directly demonstrates that FKBP14 loss disrupts ER structure and extracellular matrix assembly in patient fibroblasts.
  - reference: PMID:31949249
    reference_title: "The novel missense mutation Met48Lys in FKBP22 changes its structure and functions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens"
    explanation: Documents the collagen-type substrate preference of FKBP22 (FKBP14) that underlies which collagens are affected by its loss of function.
  downstream:
  - target: Impaired Procollagen Folding and Secretion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24821723
      reference_title: "A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen, and type X collagen, but not with type I collagen, type II collagen, or type V collagen"
      explanation: Directly shows FKBP22/FKBP14 catalyzes procollagen folding, so its loss impairs that folding step.
- name: Impaired Procollagen Folding and Secretion
  biological_scale: CELLULAR
  subtypes:
  - kEDS-FKBP14
  description: >
    Loss of FKBP14 chaperone/isomerase activity impairs correct folding and
    ER-to-Golgi trafficking of procollagen molecules, with a substrate
    preference for type III, type VI, and type X collagen rather than the
    type I/II/V collagens handled by lysyl hydroxylase 1 -- a difference
    proposed to explain why kEDS-FKBP14 has a broader phenotype (myopathy,
    hearing loss) than kEDS-PLOD1.
  biological_processes:
  - preferred_term: protein folding in endoplasmic reticulum
    modifier: DECREASED
    term:
      id: GO:0034975
      label: protein folding in endoplasmic reticulum
  evidence:
  - reference: PMID:36054293
    reference_title: "Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14."
    explanation: Direct cellular evidence that FKBP14 loss causes intracellular retention (impaired secretion) of procollagen.
  - reference: PMID:24821723
    reference_title: "A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These restrictive interactions might help explain the broader phenotype observed in patients that lack FKBP22."
    explanation: Proposes that FKBP22's restricted collagen-type substrate preference underlies the broader kEDS-FKBP14 phenotype relative to kEDS-PLOD1.
  - reference: PMID:31288483
    reference_title: "Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls"
    explanation: RNA sequencing of FKBP14-kEDS patient fibroblasts shows ER-stress and protein-trafficking transcriptional changes downstream of the impaired procollagen folding/secretion node, alongside inner-ear and vascular remodeling changes plausibly linked to the hearing and vascular manifestations distinguishing FKBP14-kEDS.
  downstream:
  - target: Defective Collagen Crosslink Maturation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36054293
      reference_title: "Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14."
      explanation: Impaired procollagen folding leads to intracellular retention rather than proper secretion and downstream crosslink maturation.
  - target: Myopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31949249
      reference_title: "The novel missense mutation Met48Lys in FKBP22 changes its structure and functions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens"
      explanation: FKBP22's substrate preference includes type VI collagen, a key component of the muscle endomysium/basal lamina also disrupted in the type-VI-collagenopathy muscular dystrophies, providing a candidate mechanism for the myopathy distinguishing FKBP14-kEDS from PLOD1-kEDS.
    - reference: PMID:28617417
      reference_title: "A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical symptoms suggesting a myopathy are most likely caused by secondary effects of the connective alterations in and around muscle, with secondary effects on muscle fibers themselves, as is in fact the case in the COL6-related dystrophies"
      explanation: This cohort study attributes the FKBP14-kEDS myopathy to secondary effects of the collagen matrix defect on muscle, drawing the same mechanistic parallel to COL6-related dystrophies as the substrate-preference finding above.
  - target: Hearing Impairment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31288483
      reference_title: "Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls"
      explanation: Differential expression of inner-ear development genes in FKBP14-kEDS patient fibroblasts is a candidate molecular link to the hearing impairment distinguishing FKBP14-kEDS from PLOD1-kEDS, though this is a skin-fibroblast transcriptomic association rather than direct cochlear evidence.
- name: Defective Collagen Crosslink Maturation
  biological_scale: MOLECULAR
  description: >
    Whether from deficient telopeptide hydroxylation (kEDS-PLOD1) or impaired
    procollagen folding (kEDS-FKBP14), fibrillar collagen molecules fail to
    form mature, stable crosslinks, converging on the same downstream defect
    in collagen fibril assembly shared by both molecular subtypes.
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lysyl hydroxylase deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens and, hence, impaired cross-link formation with consequent mechanical instability of the affected tissues"
    explanation: Establishes that the collagen crosslink defect is the point of convergence producing mechanically unstable connective tissue.
  downstream:
  - target: Disorganized Dermal and Vascular Collagen Fibrils
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Abnormal electron microscopy findings (Figure 1) included variable diameters of the collagen fibrils, irregular interfibrillar space in addition to irregular ragged outlines in cross sections."
      explanation: Direct ultrastructural evidence that impaired crosslink maturation produces disorganized, abnormally shaped collagen fibrils in skin biopsies.
- name: Disorganized Dermal and Vascular Collagen Fibrils
  biological_scale: TISSUE
  description: >
    Poorly crosslinked collagen fibrils are structurally weaker and abnormally
    organized in skin, joint capsule/ligament, vascular wall, and scleral
    connective tissue, reducing their tensile strength.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal electron microscopy findings (Figure 1) included variable diameters of the collagen fibrils, irregular interfibrillar space in addition to irregular ragged outlines in cross sections."
    explanation: Direct electron-microscopic documentation of disorganized dermal collagen fibrils in kEDS skin biopsies.
  downstream:
  - target: Skin Fragility and Poor Wound Healing
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Typical clinical features included muscular hypotonia at birth and smooth velvety skin."
      explanation: Documents the characteristic skin texture change that accompanies the disorganized dermal collagen fibrils.
  - target: Joint Hypermobility and Instability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
      explanation: Links the connective tissue defect to joint hyperextensibility observed from infancy.
  - target: Arterial Wall Fragility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vascular rupture is by far the major life-threatening complication in this disorder"
      explanation: Documents vascular wall involvement as a major consequence of the disorganized collagen fibril defect.
  - target: Ocular Globe Fragility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
      explanation: GeneReviews lists ocular abnormality as a defining feature arising from the same connective tissue defect.
  - target: Weakened Musculoskeletal and Paraspinal Connective Tissue
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
      explanation: Documents musculoskeletal and paraspinal involvement traceable to the collagen fibril defect from early infancy.
  - target: Mitral Valve Prolapse
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse"
      explanation: GeneReviews documents mitral valve prolapse, a manifestation of weakened cardiac valve connective tissue, as a feature of PLOD1-kEDS requiring management.
  - target: Inguinal Hernia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "annual examination for inguinal hernia"
      explanation: GeneReviews documents inguinal hernia, a manifestation of weakened abdominal wall connective tissue, as a feature of PLOD1-kEDS requiring surveillance.
  - target: Bladder Diverticulum
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy"
      explanation: GeneReviews lists bladder diverticula among the systemic connective tissue features of FKBP14-kEDS.
  - target: Subdural Hygroma
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
      explanation: GeneReviews lists subdural hygroma among the systemic connective tissue features of FKBP14-kEDS.
  - target: Bifid Uvula
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
      explanation: GeneReviews lists bifid uvula/cleft palate among the rarer connective tissue findings of FKBP14-kEDS.
  - target: Rectal Prolapse
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
      explanation: GeneReviews lists rectal prolapse among the rarer connective tissue findings of FKBP14-kEDS.
- name: Weakened Musculoskeletal and Paraspinal Connective Tissue
  biological_scale: TISSUE
  description: >
    Poorly crosslinked collagen in skeletal muscle fascia, spinal ligaments,
    and paraspinal connective tissue reduces its mechanical support of the
    trunk and axial skeleton.
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
    explanation: Documents weakened musculoskeletal and paraspinal connective tissue as an early manifestation of the disorder.
  downstream:
  - target: Congenital or Early-Onset Hypotonia
    evidence:
    - reference: PMID:21699693
      reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
      explanation: Documents hypotonia as a consequence of weakened musculoskeletal connective tissue support from birth.
  - target: Kyphoscoliosis
    evidence:
    - reference: PMID:21667916
      reference_title: "Posterior spinal fusion for scoliosis in Ehlers-Danlos syndrome, kyphoscoliosis type."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Surgical treatment of scoliosis associated with Ehlers-Danlos syndrome poses a challenge to spine surgeons because of the high risk of major complications."
      explanation: Documents that the weakened paraspinal connective tissue produces a spinal curvature that is mechanically difficult to stabilize surgically.
  - target: Osteopenia
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "assessment for osteopenia as needed beginning at age ten to 12 years"
      explanation: GeneReviews surveillance guidance documents osteopenia as a manifestation of the weakened skeletal connective tissue matrix in PLOD1-kEDS.
  - target: Clubfoot
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate"
      explanation: GeneReviews documents clubbed foot as a musculoskeletal manifestation of FKBP14-kEDS, and foot deformity is one of the major diagnostic criteria for the disorder.
- name: Skin Fragility and Poor Wound Healing
  biological_scale: TISSUE
  description: >
    Weakened dermal collagen produces hyperextensible, easily bruised,
    friable skin with atrophic scarring and impaired wound healing.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dermal wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously; cutaneous stitches should be left in place twice as long as usual, and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar"
    explanation: GeneReviews management guidance documents the friable, poor-healing skin that requires special wound-closure precautions.
  downstream:
  - target: Hyperextensible Skin
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
      explanation: GeneReviews lists hyperelastic skin as a defining feature of the skin fragility node's downstream phenotype.
  - target: Fragile Skin
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
      explanation: GeneReviews lists skin fragility as a defining feature reached by this node.
- name: Joint Hypermobility and Instability
  biological_scale: TISSUE
  description: >
    Reduced tensile strength of periarticular connective tissue (joint
    capsule, ligament) produces generalized joint laxity and dislocations.
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants affected with EDS type VIA present with moderate to severe generalized muscle hypotonia, and with skeletal findings such as kyphoscoliosis and joint hyperextensibility"
    explanation: Documents generalized joint hyperextensibility as a manifestation of periarticular connective tissue weakness.
  downstream:
  - target: Generalized Joint Hypermobility
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
      explanation: GeneReviews lists generalized joint hypermobility as a defining feature reached by this node.
  - target: Recurrent Joint Dislocations
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Annual physical therapy assessment for weakness and motor issues and orthopedic assessment for management of kyphoscoliosis and recurrent dislocations"
      explanation: GeneReviews surveillance guidance documents recurrent dislocations as a manifestation of joint instability.
- name: Arterial Wall Fragility
  biological_scale: TISSUE
  description: >
    Defective collagen crosslinking weakens the arterial wall, predisposing
    to spontaneous rupture and dissection of medium-sized arteries.
  cell_types:
  - preferred_term: fibroblast of the aortic adventitia
    term:
      id: CL:0002547
      label: fibroblast of the aortic adventitia
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries."
    explanation: GeneReviews establishes arterial wall fragility as a defining risk in kEDS.
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: "15% of PLOD1-/- mice died at the age of 1-4 months due to aortic dissections, caused most likely by degenerated smooth muscle cells and abnormal collagen fibrils of aortic wall"
    explanation: A PLOD1 knockout mouse study, cited in this human clinical paper's discussion, gives the mechanistic detail (smooth muscle degeneration and abnormal aortic collagen fibrils) behind the arterial wall fragility node.
  downstream:
  - target: Arterial Rupture and Dissection
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36860721
      reference_title: "A severe case of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome associated with several arterial and venous complications: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vascular fragility is another characteristic of the disease rarely described. We report a severe case of kEDS-PLOD1 with several vascular complications leading to difficulties in disease management."
      explanation: Case report documenting arterial wall fragility progressing to multiple vascular complications in kEDS-PLOD1.
    - reference: PMID:41613374
      reference_title: "Kyphoscoliotic Ehlers-Danlos syndrome associated with superior mesenteric artery aneurysm and abdominal aortic rupture: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we report a 15-year-old Chinese boy with kEDS-PLOD1 who presented with a superior mesenteric aneurysm and severe vascular complications."
      explanation: Case report documenting fatal arterial rupture (superior mesenteric aneurysm and aortic rupture) arising from arterial wall fragility in kEDS-PLOD1.
- name: Ocular Globe Fragility
  biological_scale: TISSUE
  description: >
    Scleral and corneal connective tissue weakness produces blue sclerae,
    refractive error, and risk of globe rupture or retinal detachment.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews lists ocular abnormality as a defining feature of PLOD1-kEDS.
  downstream:
  - target: Refractive Error
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "corrective lenses for myopia and/or astigmatism"
      explanation: GeneReviews management guidance documents refractive error as a manifestation of ocular globe fragility.
  - target: Retinal Detachment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "laser treatment of the retina for those with imminent detachment"
      explanation: GeneReviews management guidance documents retinal detachment risk as a manifestation of ocular globe fragility.
  - target: Blue Sclerae
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
      explanation: GeneReviews lists bluish sclerae among the systemic connective tissue features of FKBP14-kEDS.
phenotypes:
- name: Congenital or Early-Onset Hypotonia
  category: Neurologic
  description: >
    Muscular hypotonia present from birth or early infancy, a defining
    feature of both molecular subtypes.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    temporality: CHRONIC
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews lists hypotonia as a defining feature of PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews lists congenital hypotonia as a defining feature of FKBP14-kEDS, typically improving in childhood.
- name: Kyphoscoliosis
  category: Musculoskeletal
  description: >
    Progressive, often congenital or early-onset curvature of the spine in
    both coronal (scoliosis) and sagittal (kyphosis) planes.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  sequelae:
  - target: Restrictive Ventilatory Defect
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
      explanation: GeneReviews identifies restrictive lung disease as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
  - target: Recurrent Pneumonia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
      explanation: GeneReviews identifies recurrent pneumonia as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
  - target: Cardiac Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
      explanation: GeneReviews identifies cardiac failure as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews establishes early-onset kyphoscoliosis as a defining feature of PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews lists progressive scoliosis as a defining feature of FKBP14-kEDS.
- name: Generalized Joint Hypermobility
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Generalized joint hypermobility
    term:
      id: HP:0002761
      label: Generalized joint hypermobility
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews lists generalized joint hypermobility as a defining feature of PLOD1-kEDS.
- name: Fragile Skin
  category: Dermatologic
  phenotype_term:
    preferred_term: Fragile skin
    term:
      id: HP:0001030
      label: Fragile skin
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality."
    explanation: GeneReviews lists skin fragility as a defining feature of PLOD1-kEDS.
- name: Recurrent Joint Dislocations
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual physical therapy assessment for weakness and motor issues and orthopedic assessment for management of kyphoscoliosis and recurrent dislocations"
    explanation: GeneReviews surveillance recommendations for PLOD1-kEDS document recurrent joint dislocations as a disease manifestation requiring orthopedic assessment.
- name: Hyperextensible Skin
  category: Dermatologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews lists hyperelastic (hyperextensible) skin as a feature of FKBP14-kEDS.
- name: Arterial Rupture and Dissection
  category: Cardiovascular
  description: >
    Life-threatening spontaneous rupture and dissection of medium-sized
    arteries, an important and distinctive risk in kEDS.
  phenotype_term:
    preferred_term: Arterial rupture
    term:
      id: HP:0025019
      label: Arterial rupture
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections of medium-sized arteries."
    explanation: GeneReviews describes arterial rupture and dissection as a life-threatening risk in PLOD1-kEDS.
- name: Refractive Error
  category: Ophthalmologic
  description: >
    Myopia and/or astigmatism attributed to scleral and corneal connective
    tissue weakness, requiring corrective lenses.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "corrective lenses for myopia and/or astigmatism"
    explanation: GeneReviews management recommendations for PLOD1-kEDS document myopia and/or astigmatism as a manifestation requiring corrective lenses.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate"
    explanation: GeneReviews management recommendations document refractive error as a manifestation of FKBP14-kEDS also requiring standard treatment.
- name: Retinal Detachment
  category: Ophthalmologic
  description: >
    Risk of retinal detachment attributed to weakness of the ocular globe's
    connective tissue, managed with prophylactic laser treatment.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laser treatment of the retina for those with imminent detachment"
    explanation: GeneReviews management recommendations for PLOD1-kEDS document retinal detachment risk requiring prophylactic laser treatment.
- name: Blue Sclerae
  category: Ophthalmologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
    explanation: GeneReviews lists bluish sclerae among the occasional systemic connective tissue features of FKBP14-kEDS.
- name: Myopathy
  category: Neurologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  sequelae:
  - target: Gross Motor Developmental Delay
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31132235
      reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most affected children achieve independent walking between ages two and four years."
      explanation: GeneReviews documents delayed independent walking as a consequence of the congenital hypotonia and myopathy in FKBP14-kEDS.
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews lists myopathy as a feature distinguishing FKBP14-kEDS from PLOD1-kEDS.
- name: Hearing Impairment
  category: Otologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment."
    explanation: GeneReviews lists hearing impairment as a feature distinguishing FKBP14-kEDS from PLOD1-kEDS.
- name: Gross Motor Developmental Delay
  category: Neurologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected children achieve independent walking between ages two and four years."
    explanation: GeneReviews documents delayed independent walking as evidence of gross motor developmental delay in FKBP14-kEDS.
- name: Osteopenia
  category: Skeletal
  subtypes:
  - kEDS-PLOD1
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assessment for osteopenia as needed beginning at age ten to 12 years"
    explanation: GeneReviews surveillance recommendations document osteopenia as a manifestation of PLOD1-kEDS requiring assessment from age 10-12.
- name: Mitral Valve Prolapse
  category: Cardiovascular
  subtypes:
  - kEDS-PLOD1
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse"
    explanation: GeneReviews management recommendations document mitral valve prolapse as a cardiac manifestation of PLOD1-kEDS.
- name: Inguinal Hernia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual examination for inguinal hernia"
    explanation: GeneReviews surveillance recommendations document inguinal hernia as a manifestation of PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy"
    explanation: GeneReviews lists inguinal or umbilical herniae among occasional systemic connective tissue features of FKBP14-kEDS.
- name: Bladder Diverticulum
  category: Genitourinary
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Bladder diverticulum
    term:
      id: HP:0000015
      label: Bladder diverticulum
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy"
    explanation: GeneReviews lists bladder diverticula among occasional systemic connective tissue features of FKBP14-kEDS.
- name: Subdural Hygroma
  category: Neurologic
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Subdural hygroma
    term:
      id: HP:6001070
      label: Subdural hygroma
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy."
    explanation: GeneReviews lists subdural hygroma among occasional systemic connective tissue features of FKBP14-kEDS.
- name: Bifid Uvula
  category: Craniofacial
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
    explanation: GeneReviews lists bifid uvula with submucous or frank cleft palate among rarer findings in FKBP14-kEDS.
- name: Rectal Prolapse
  category: Gastrointestinal
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Rectal prolapse
    term:
      id: HP:0002035
      label: Rectal prolapse
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse."
    explanation: GeneReviews lists rectal prolapse among rarer findings in FKBP14-kEDS.
- name: Clubfoot
  category: Musculoskeletal
  subtypes:
  - kEDS-FKBP14
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for severe scoliosis, clubbed foot, osteopenia/osteoporosis, refractive error, hearing impairment, and cleft palate"
    explanation: GeneReviews management recommendations document clubbed foot as a manifestation of FKBP14-kEDS requiring standard treatment.
- name: Restrictive Ventilatory Defect
  category: Respiratory
  subtypes:
  - kEDS-PLOD1
  phenotype_term:
    preferred_term: Restrictive lung disease
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
    explanation: GeneReviews documents restrictive lung disease as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
- name: Recurrent Pneumonia
  category: Respiratory
  subtypes:
  - kEDS-PLOD1
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
    explanation: GeneReviews documents recurrent pneumonia as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
- name: Cardiac Failure
  category: Cardiovascular
  subtypes:
  - kEDS-PLOD1
  phenotype_term:
    preferred_term: Cardiac failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure."
    explanation: GeneReviews documents cardiac failure as a complication of severe kyphoscoliosis in adults with PLOD1-kEDS.
biochemical:
- name: Urinary lysyl-pyridinoline to hydroxylysyl-pyridinoline ratio
  subtype: kEDS-PLOD1
  presence: INCREASED
  context: >
    Deficient lysyl hydroxylase 1 activity in kEDS-PLOD1 skews collagen
    crosslinking toward lysine-derived (lysyl-pyridinoline) rather than
    hydroxylysine-derived (hydroxylysyl-pyridinoline) crosslinks, raising the
    urinary total LP:HP ratio; this is a fast, non-invasive, and diagnostic
    biochemical test for kEDS-PLOD1.
  biomarker_term:
    preferred_term: urinary lysyl-pyridinoline to hydroxylysyl-pyridinoline ratio
    term:
      id: CHEBI:64753
      label: lysyl-pyridinoline cross-link
  readouts:
  - target: Defective Collagen Crosslink Maturation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      An elevated urinary LP:HP ratio reports the shift away from mature
      hydroxylysine-derived collagen crosslinks caused by LH1 deficiency.
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ratio of urinary total LP to HP in patients with EDS type VIA is high as compared with normal controls"
    explanation: Establishes the elevated urinary LP:HP ratio compared to normal controls in kEDS-PLOD1.
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is diagnostic for EDS type VIA"
    explanation: Establishes the urinary LP:HP ratio as a diagnostic biochemical marker for kEDS-PLOD1.
histopathology:
- name: Abnormal Dermal Collagen Fibril Ultrastructure
  description: >
    Transmission electron microscopy of skin biopsies shows collagen fibrils
    of variable, abnormally increased diameter with loss of the normal
    circular cross-sectional contour and irregular interfibrillar spacing,
    a finding reported as distinct from other EDS subtypes; elastic fibers
    are structurally normal.
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diameters of the collagen fibrils were significantly increased with loss of the normal circular shape. In particular those fibrils with abnormally increased diameters showed a greater deviation from circular shape (Figure 1). The elastic fibers presented normal ultrastructural features."
    explanation: Direct electron-microscopic description of the dermal collagen fibril abnormality in kEDS-PLOD1 skin biopsies.
animal_models:
- name: Warmblood Fragile Foal Syndrome (WFFS) horse
  species: Horse
  genotype: PLOD1 c.2032G>A (homozygous)
  publication: PMID:31502696
  modeled_mechanisms:
  - target: PLOD1 Loss-of-Function
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >
      A naturally occurring recessive PLOD1 missense variant in Warmblood
      horses causes Warmblood fragile foal syndrome type 1 (WFFS), a fatal
      connective-tissue fragility disorder and the equine counterpart of
      human kEDS-PLOD1.
    limitations: >
      Homozygous WFFS foals typically show severe perinatal/neonatal
      connective-tissue rupture and do not survive, a substantially more
      severe and earlier-lethal course than human kEDS-PLOD1, which is
      generally compatible with survival to adulthood; the cited study is a
      Thoroughbred allele-frequency and racing-injury screening report
      rather than a primary phenotypic characterization of WFFS.
    evidence:
    - reference: PMID:31502696
      reference_title: "Warmblood fragile foal syndrome type 1 mutation (PLOD1 c.2032G>A) is not associated with catastrophic breakdown and has a low allele frequency in the Thoroughbred breed."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: MODEL_ORGANISM
      snippet: "A variant in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase1 gene (PLOD1 c.2032G>A) was shown to cause Warmblood fragile foal syndrome type 1 (WFFS), a fatal recessive defect of the connective tissue."
      explanation: Background sentence in this Thoroughbred-screening paper establishing that the cited PLOD1 variant causes a fatal recessive equine connective-tissue disorder, the naturally-occurring animal counterpart of kEDS-PLOD1.
  notes: >
    This naturally-occurring equine variant is the only PLOD1- or
    FKBP14-specific animal model identified in the cached literature; no
    engineered PLOD1 or FKBP14 knockout/knock-in mouse model with published
    phenotyping data was found. PMID:34712265, a narrative review of animal
    models across all EDS subtypes, confirms that engineered mouse and
    zebrafish models exist for many EDS-associated genes, but its abstract
    does not itself supply reproducible genotype/phenotype data for a
    PLOD1- or FKBP14-specific model suitable for a modeled_mechanisms entry
    here. A separately-cached PMID:34850861 (a CRISPR/Cas9 mouse model) is
    for musculocontractural EDS caused by CHST14/dermatan-sulfate-pathway
    variants -- a different EDS subtype and an unrelated gene/pathway -- and
    is deliberately not cited here to avoid Named Entity Confusion.
diagnosis:
- name: Molecular Genetic Testing of PLOD1 or FKBP14
  description: >
    The definitive diagnostic test for kEDS. PLOD1-kEDS is established in a
    proband with characteristic clinical features and biallelic pathogenic
    variants in PLOD1; FKBP14-kEDS is established by biallelic pathogenic
    variants in FKBP14. Sequence analysis alone misses structural variants
    (notably the recurrent PLOD1 exon 10-16 duplication), so
    deletion/duplication analysis is needed when only one or no pathogenic
    variant is found by sequencing.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of PLOD1-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1 identified by molecular genetic testing."
    explanation: GeneReviews states the molecular diagnostic criterion for PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FKBP14-kEDS is established in a proband by the identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing."
    explanation: GeneReviews states the molecular diagnostic criterion for FKBP14-kEDS.
  - reference: PMID:37433679
    reference_title: "FKBP14 kyphoscoliotic Ehlers-Danlos syndrome misdiagnosed as Larsen syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only."
    explanation: Case report of a patient clinically misdiagnosed with Larsen syndrome for over 40 years, later found by molecular testing to have FKBP14-kEDS, illustrating why molecular confirmation rather than clinical impression alone is required.
- name: Clinical Suggestive Criteria (2017 International EDS Classification)
  description: >
    kEDS is one of the 13 EDS subtypes for which the 2017 International EDS
    Classification defines a set of clinical criteria suggestive of the
    diagnosis. As with nearly all non-hypermobile EDS subtypes, these
    clinical criteria are suggestive only: definitive diagnosis of both
    kEDS-PLOD1 and kEDS-FKBP14 requires molecular confirmation of biallelic
    pathogenic variants. For FKBP14-kEDS specifically, the clinical criteria
    require congenital muscular hypotonia together with congenital or
    early-onset kyphoscoliosis, plus generalized joint hypermobility or
    further gene-specific/supportive features; a subsequent 23-patient
    cohort refined these into explicit major criteria (severe generalized
    hypotonia at birth with improvement in infancy and delayed motor
    milestones; early-onset progressive kyphoscoliosis; joint hypermobility
    without pronounced contractures; foot deformities; and a normal or
    decreased urinary lysyl:hydroxylysyl pyridinoline ratio) and minor
    criteria (hyperelastic skin with follicular hyperkeratosis and easy
    bruising; myopathy; and hearing impairment).
  evidence:
  - reference: DOI:10.1002/ajmg.c.31552
    reference_title: "The 2017 international classification of the Ehlers–Danlos syndromes"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s)."
    explanation: The international consensus nosology establishes that kEDS has suggestive clinical criteria but, like all non-hypermobile EDS subtypes, requires molecular confirmation for definitive diagnosis.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical diagnostic criteria rely on the finding of congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis in addition to generalized joint hypermobility or further gene-specific and/or supportive clinical features."
    explanation: GeneReviews states the specific clinical suggestive criteria for FKBP14-kEDS.
  - reference: PMID:28617417
    reference_title: "A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the major diagnostic criteria are (i) severe generalized hypotonia at birth with marked muscle weakness that improves in infancy, and delayed gross motor milestones; (ii) early-onset progressive (kypho)scoliosis; (iii) joint hypermobility without pronounced contractures; (iv) foot deformities; and (v) normal or decreased ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine. Minor criteria include (i) hyperelastic skin with follicular hyperkeratosis, easy bruising, and occasional abnormal scarring; (ii) myopathy as seen clinically by reduced strength and endurance and confirmed in some patients by histology and muscle imaging; and (iii) hearing impairment that is predominantly sensorineural and may not be present in all individuals."
    explanation: This 23-patient cohort study defines the explicit major and minor clinical diagnostic criteria for FKBP14-kEDS, stated to have informed the redraft of the 2017 International Nosology of EDS.
- name: Urinary Pyridinoline Crosslink Ratio Testing
  description: >
    A fast, non-invasive, cost-effective biochemical screening test for
    PLOD1-kEDS specifically: if only one pathogenic PLOD1 variant or variants
    of uncertain significance are found, a markedly increased urinary
    lysyl-pyridinoline to hydroxylysyl-pyridinoline (LP:HP) crosslink ratio
    supports the diagnosis.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "testing for a markedly increased ratio of deoxypyridinoline to pyridinoline cross-links in urine measured by high-performance liquid chromatography (a highly sensitive, specific, and inexpensive test) may be necessary for confirmation of the diagnosis"
    explanation: GeneReviews describes the urinary pyridinoline crosslink ratio as a confirmatory diagnostic test for PLOD1-kEDS.
genetic:
- name: PLOD1
  gene_term:
    preferred_term: PLOD1
    term:
      id: hgnc:9081
      label: PLOD1
  relationship_type: CAUSATIVE
  subtype: kEDS-PLOD1
  notes: >
    Encodes procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (lysyl
    hydroxylase 1, LH1), the enzyme responsible for telopeptide lysine
    hydroxylation in fibrillar procollagens. Pathogenic variants include
    missense, nonsense, splice-site, and small indel changes, plus a
    recurrent Alu-mediated 8.9-kb intragenic duplication of exons 10-16 that
    is the single most common cause of the disorder.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of PLOD1-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1 identified by molecular genetic testing."
    explanation: GeneReviews establishes biallelic PLOD1 pathogenic variants as diagnostic of PLOD1-kEDS.
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "among them an 8.9-kb duplication of seven exons (exon 10-16) is the most common cause of the disorder"
    explanation: Identifies the recurrent 8.9-kb exon 10-16 duplication as the most common PLOD1 pathogenic variant.
- name: FKBP14
  gene_term:
    preferred_term: FKBP14
    term:
      id: hgnc:18625
      label: FKBP14
  relationship_type: CAUSATIVE
  subtype: kEDS-FKBP14
  notes: >
    Encodes FKBP14 (FKBP22), an ER-resident FK506-binding-protein-family
    peptidyl-prolyl isomerase implicated in procollagen chaperoning.
    c.362dupC p.(Glu122Argfs*7) is the most frequently reported recurrent
    FKBP14 pathogenic variant across published cohorts, identified in
    multiple unrelated families in both the 2018 cohort study and
    subsequent case reports; the cached literature did not supply a
    verifiable cohort-wide percentage for how large a share of pathogenic
    alleles it represents, so no specific figure is stated here.
  evidence:
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FKBP14-kEDS is established in a proband by the identification of biallelic pathogenic variants in FKBP14 by molecular genetic testing."
    explanation: GeneReviews establishes biallelic FKBP14 pathogenic variants as diagnostic of FKBP14-kEDS.
  - reference: PMID:36054293
    reference_title: "Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?)"
    explanation: Documents reported FKBP14 pathogenic variant types, including the recurrent c.362dupC frameshift founder allele.
  - reference: PMID:41366145
    reference_title: "Surgical management of progressive spinal deformities in FKBP14-associated Ehlers-Danlos syndrome: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A female patient with genetically confirmed FKBP14-associated EDS (homozygous c.362dupG p.E122RfsX7 mutation) was followed from infancy through age 10 at a tertiary pediatric center."
    explanation: An independent case report documenting the identical p.(Glu122Argfs*7)/p.E122RfsX7 frameshift protein consequence in an unrelated patient (the cDNA change is given here as c.362dupG rather than c.362dupC; whether this is the same recurrent variant under a notation discrepancy or a distinct change producing the same frameshift could not be confirmed from the cached text).
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLOD1-kEDS is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the autosomal recessive inheritance pattern for PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FKBP14-kEDS is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the autosomal recessive inheritance pattern for FKBP14-kEDS.
environmental:
- name: Joint-Stressing and High-Impact Physical Activity
  exposure_term:
    preferred_term: joint-stressing or high-impact physical activity
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting"
    explanation: GeneReviews lists these activities as agents/circumstances to avoid in PLOD1-kEDS because of joint stress.
  influences_mechanisms:
  - target: Joint Hypermobility and Instability
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >
      Gymnastics, long-distance running, collision sports, and heavy lifting
      place mechanical stress on already unstable joints, increasing the
      risk of subluxation and dislocation.
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting"
      explanation: GeneReviews lists these activities as agents/circumstances to avoid in PLOD1-kEDS because of joint stress.
- name: Diagnostic Arteriography
  exposure_term:
    preferred_term: diagnostic arteriography
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"
    explanation: GeneReviews identifies arteriography as a procedure to avoid in PLOD1-kEDS because of vascular injury risk.
  influences_mechanisms:
  - target: Arterial Wall Fragility
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >
      Catheter-based arteriography carries a risk of iatrogenic vascular
      injury in an already fragile arterial wall and is discouraged except
      to localize life-threatening bleeding.
    evidence:
    - reference: PMID:20301635
      reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury"
      explanation: GeneReviews identifies arteriography as a procedure to avoid in PLOD1-kEDS because of vascular injury risk.
treatments:
- name: Physical and Occupational Therapy
  description: >
    Physical therapy to strengthen large muscle groups and address
    age-dependent decline in muscular strength.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Weakened Musculoskeletal and Paraspinal Connective Tissue
    treatment_effect: MODULATES
    description: >
      Strengthens the large muscle groups to partially compensate for the
      reduced mechanical support of weakened paraspinal and musculoskeletal
      connective tissue; it does not correct the underlying collagen defect.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Physical therapy to strengthen large muscle groups; swimming"
    explanation: GeneReviews recommends physical therapy as a core management measure for PLOD1-kEDS.
- name: Orthopedic Management of Kyphoscoliosis
  description: >
    Orthopedic surveillance and surgical management of progressive
    kyphoscoliosis and joint instability.
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Kyphoscoliosis
    treatment_effect: MODULATES
    description: >
      Surgical instrumentation and fusion mechanically stabilizes and
      corrects the progressive spinal curvature; it addresses the structural
      consequence rather than the underlying collagen crosslink defect, and
      carries an elevated complication risk from the same tissue fragility.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed"
    explanation: GeneReviews recommends orthopedic surgical management of kyphoscoliosis in PLOD1-kEDS.
  - reference: PMID:21667916
    reference_title: "Posterior spinal fusion for scoliosis in Ehlers-Danlos syndrome, kyphoscoliosis type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our experience supports that a satisfactory correction of scoliosis can be achieved by posterior spinal fusion only in patients with Ehlers-Danlos syndrome, kyphoscoliosis type."
    explanation: A small case series documents posterior spinal fusion as a surgical management option achieving satisfactory correction in kEDS-associated scoliosis.
  - reference: PMID:41366145
    reference_title: "Surgical management of progressive spinal deformities in FKBP14-associated Ehlers-Danlos syndrome: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine-year follow-up demonstrated successful deformity control with solid arthrodesis at multiple levels, though ongoing challenges include hardware adaptation and the need for mobility assistance."
    explanation: A long-term case report documents successful multi-stage surgical deformity control in FKBP14-kEDS, alongside ongoing hardware and mobility challenges from the underlying tissue fragility.
- name: Beta-Blocker Therapy for Aortic Dilatation
  description: >
    Beta-blockers to reduce hemodynamic stress and prevent aortic dilatation
    or progression of vascular dissection.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Arterial Wall Fragility
    treatment_effect: MODULATES
    description: >
      Lowers hemodynamic stress on the mechanically weakened arterial wall
      to slow dilatation and reduce dissection risk; it does not correct the
      underlying collagen crosslink defect.
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment with beta-blockers as needed to prevent aortic dilatation"
    explanation: GeneReviews recommends beta-blocker therapy to prevent aortic dilatation in PLOD1-kEDS.
  - reference: PMID:31132235
    reference_title: "FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In those with aortic dilatation or vascular dissection, use of beta-blockers may be considered"
    explanation: GeneReviews recommends beta-blocker consideration for aortic dilatation or vascular dissection in FKBP14-kEDS.
- name: Genetic Counseling
  description: >
    Genetic counseling regarding autosomal recessive inheritance, recurrence
    risk, and availability of carrier and prenatal/preimplantation testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301635
    reference_title: "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both PLOD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: GeneReviews describes genetic counseling and testing options for at-risk relatives in PLOD1-kEDS.
prevalence:
- population: kEDS-PLOD1 (EDS type VIA)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  rate_denominator: LIVE_BIRTHS
  notes: >
    FKBP14-related disease (kEDS-FKBP14) is markedly rarer than PLOD1-related
    disease, but no separate population-based incidence estimate for
    kEDS-FKBP14 was found in the cited sources.
  evidence:
  - reference: PMID:21699693
    reference_title: "Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare autosomal recessively inherited connective tissue disorder with a disease incidence of approximately 1;100,000 live births"
    explanation: Reports the estimated birth incidence of kEDS-PLOD1 (EDS type VIA).
datasets: []
📚

References & Deep Research

References

2
PMID:20301635
PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome.
No top-level findings curated for this source.
PMID:31132235
FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Kyphoscoliotic Ehlers-Danlos Syndrome · 2026-09-15T21:30:15Z · View source

New entry for kyphoscoliotic Ehlers-Danlos syndrome (kEDS), anchored on MONDO:0016002 (Ehlers-Danlos syndrome, kyphoscoliotic type 1 / PLOD1-related, ~90% of confirmed cases) since the umbrella MONDO:0034024 is obsolete with no single non-obsolete replacement. FKBP14-related disease (kyphoscoliotic type 2) is modeled as a has_subtypes entry anchored on its own MONDO:0013800 term, following the precedent set by Musculocontractural_Ehlers-Danlos_Syndrome.yaml for a genetically heterogeneous EDS subtype. Both GeneReviews chapters (PMID:20301635 PLOD1-kEDS, PMID:31132235 FKBP14-kEDS) were fetched, tagged, and mined for the full Clinical Characteristics / Diagnosis / Management / Genetic Counseling baseline (just check-genereviews --online confirms both chapters tagged). Deep research was performed via 'just dr_fallback=--fallback research-disorder falcon Kyphoscoliotic_Ehlers-Danlos_Syndrome': the requested falcon provider has no EDISON_API_KEY/FUTUREHOUSE_API_KEY configured in this environment, so the run fell back to claude_code per the documented fallback mechanism (report renamed to research/Kyphoscoliotic_Ehlers-Danlos_Syndrome-deep-research-claude_code.md, fell_back/requested_provider/provider_attempts recorded in frontmatter). The report's own term validation flagged needs_review: true with 9/42 mislabelled ontology-term suggestions (e.g. NCIT:C2231 offered as 'Adrenergic beta-Antagonist' but is actually Dofequidar Fumarate; HP:0025214 offered as 'Arterial dissection' but is actually 'Triggered by heat'; HP:0000023 offered as 'Congenital contractures' but is actually 'Inguinal hernia') -- none of the report's suggested CURIEs were bound directly; every ontology term in this entry was independently verified via runoak/OAK lookup before use. The report's causal-chain and cited-paper pointers (Baumann et al./Rohrbach et al./Ishikawa & Bachinger/Colman et al.) were used only as leads and independently sourced: fetched and cited PMID:21699693 (Rohrbach et al., PLOD1 biochemistry: telopeptide lysyl hydroxylation, collagen crosslink maturation mechanism, the 8.9-kb exon10-16 duplication, urinary lysyl-pyridinoline:hydroxylysyl-pyridinoline diagnostic ratio, and the ~1:100,000 live-birth incidence estimate), PMID:24821723 (Ishikawa & Bachinger, FKBP22/FKBP14 collagen-type III/VI/X substrate specificity and folding catalysis), and PMID:36054293 (Colman et al., FKBP14 variant spectrum and immunocytochemical evidence of intracellular type III/VI collagen retention). The pathophysiology chain models two convergent molecular starting points (PLOD1 loss-of-function -> deficient telopeptide hydroxylation; FKBP14 loss-of-function -> impaired procollagen folding/secretion) that converge on a shared 'Defective Collagen Crosslink Maturation' node before branching to skin/joint/vascular/ocular tissue-level consequences, with subtype-specific phenotypes (myopathy, hearing impairment, bifid uvula, subdural hygroma, bladder diverticulum, rectal prolapse) tagged via the has_subtypes 'subtypes'/'subtype' foreign keys. Also added a diagnosis: block (molecular genetic testing of PLOD1/FKBP14, plus the urinary pyridinoline-ratio biochemical screening test), both cited from the GeneReviews chapters. A pre-PR self-review was run via a fresh subagent using the dismech-pr-review skill (text report only, no gh pr review submitted since no PR existed yet). It independently re-verified 14 ontology-term bindings via runoak (all exact matches, including confirming the entry correctly avoided three specific mislabelled CURIEs the deep-research report had offered: NCIT:C2231, HP:0025214, HP:0000023) and spot-checked snippets/titles against references_cache (all exact substrings, no fabrication). It raised 3 blocking findings, which were fixed in this same session before commit: (1) added a Clubfoot/Talipes equinovarus (HP:0001762) phenotype for kEDS-FKBP14, cited from a GeneReviews management sentence already in the cache that had been overlooked; (2) added three phenotypes (Restrictive Ventilatory Defect HP:0002091, Recurrent Pneumonia HP:0006532, Cardiac Failure HP:0001635) as pathograph sequelae of the existing Kyphoscoliosis phenotype, cited from a GeneReviews clinical-characteristics sentence already in the cache; (3) connected the previously pathograph-orphaned 'Congenital or Early-Onset Hypotonia' and 'Kyphoscoliosis' phenotypes into the mechanism chain via a new pathophysiology node, 'Weakened Musculoskeletal and Paraspinal Connective Tissue', downstream of the existing 'Disorganized Dermal and Vascular Collagen Fibrils' node (uncited inferential tissue-level edge, consistent with the existing pattern used for the skin/joint/vascular/ ocular branches). Also addressed a non-blocking finding: added an environmental: block (Joint-Stressing/High-Impact Physical Activity and Diagnostic Arteriography, both EXACERBATES-linked into the pathograph) capturing the GeneReviews agents/circumstances-to-avoid content, each with both entry-level and influences_mechanisms-level evidence (required by check-environmental-evidence). The reviewer also flagged an advisory (non-blocking) point worth a maintainer's attention: the disease_term anchor MONDO:0016002 is not a true parent/umbrella term the way Musculocontractural_Ehlers-Danlos_Syndrome.yaml's MONDO:0011142 anchor is -- MONDO:0016002 and MONDO:0013800 (the FKBP14 subtype's term) are coordinate sibling leaf terms under MONDO:0020066, and the disease-level disease_term.term.id is therefore identical to the kEDS-PLOD1 subtype's own subtype_term.term.id. This is a considered choice (MONDO:0034024, the only real umbrella term, is obsolete with no replacement, and PLOD1-kEDS is ~90% of cases) but is flagged here for a maintainer to confirm rather than silently accepted, per CLAUDE.md's lump/split guidance. Final validation after all fixes: just validate (schema/term/reference, 60/60 snippets verified), just validate-disorders (the CI-authoritative batched gate, passed), just check-entity-refs, just check-causal-targets (0 new dangling targets), just check-duplicate-keys, just check-enum-values, just check-qualifier-terms, just check-environmental-evidence (clean, 0 findings), just list-gene-term-mismatches (0 mismatches across 6 gene bindings), and just check-genereviews --online (both chapters TAGGED). Compliance (just compliance): 86.2% global / 86.5% weighted. datasets: left empty -- no GEO/other accession search was performed for this entry.

Claude Code ▸
Executive Summary
claude-haiku-4-5-20251001, claude-sonnet-5 22 citations 2026-09-15T21:23:17.878266

Executive Summary

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive heritable connective tissue disorder classified in Group 7 ("collagen spatial structure and cross-linking defects") of the 2017 International EDS Classification (Malfait et al., 2017, Am J Med Genet C Semin Med Genet 175:8-26, PMID not fully captured in search but DOI: 10.1002/ajmg.c.31552). It is genetically heterogeneous, with two molecularly distinct but clinically overlapping subtypes: kEDS-PLOD1 (formerly EDS type VIA, OMIM #225400) caused by biallelic PLOD1 variants, and kEDS-FKBP14 (formerly EDS type VIB, OMIM #614557) caused by biallelic FKBP14 variants. Both converge on defective collagen post-translational modification/folding, producing congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, skin fragility, and a risk of life-threatening arterial rupture.

1. Disease Information

Overview: kEDS is a rare, genetically heterogeneous, autosomal recessive disorder of collagen biosynthesis. It presents at birth with severe muscular hypotonia, generalized joint hypermobility with recurrent dislocations, and congenital or early-onset kyphoscoliosis that is often rapidly progressive. Skin is soft, hyperextensible, and fragile (atrophic scarring, easy bruising), and there is risk of ocular globe (scleral) fragility and, in adulthood, spontaneous rupture/dissection of medium-sized arteries. Intelligence is typically normal.

Key Identifiers: - MONDO: MONDO:0016002 (Ehlers-Danlos syndrome, kyphoscoliotic type 1 / EDS type VIA / oculoscoliotic type), grouped with the FKBP14-related subtype under the umbrella "kyphoscoliotic EDS" - OMIM: #225400 (EDSKSCL1, PLOD1-related) and #614557 (EDSKSCL2, FKBP14-related) - Orphanet: ORPHA:1900 (kEDS due to lysyl hydroxylase 1 deficiency), ORPHA:300179 (kEDS due to FKBP22/FKBP14 deficiency) - Genes/HGNC: PLOD1 (HGNC gene, chromosome 1p36.22); FKBP14 (HGNC gene, chromosome 7p14.3) - Prior nomenclature: EDS type VI, EDS type VIA/VIB, "oculoscoliotic type" EDS (Berlin/Villefranche nosologies)

Synonyms: Ehlers-Danlos syndrome, kyphoscoliotic type; EDS VI; EDS VIA (PLOD1) / EDS VIB (FKBP14); lysyl hydroxylase deficiency; oculoscoliotic EDS.

Data source note: This body of knowledge is derived almost entirely from aggregated case reports and small case series (individual patients, n=1–23 per cohort) rather than large population-level registries, reflecting the rarity of the condition; the largest cohorts are the FKBP14 natural-history study of 17 patients (Giunta et al., Genet Med 2018, PMC5763155) and the PLOD1 series analyzed across ~94 published individuals cited in GeneReviews.

Source: PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome – GeneReviews; FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome – GeneReviews; OMIM #225400; OMIM #614557

2. Etiology

Disease Causal Factors

kEDS is purely genetic/monogenic, autosomal recessive, with two known causal genes: - PLOD1 (~most cases): encodes lysyl hydroxylase 1 (LH1/PLOD1), which hydroxylates lysyl residues in the collagen triple helix. - FKBP14: encodes FKBP22, an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that acts as a collagen chaperone (types III, VI, X).

Both loss-of-function mechanisms converge on defective collagen fibril assembly/cross-linking, producing a phenotypically overlapping but molecularly distinct disease.

Risk Factors

  • Genetic: Biallelic (homozygous or compound heterozygous) pathogenic variants in PLOD1 or FKBP14 are necessary and sufficient. Consanguinity substantially raises risk given the recessive, often founder-driven allele pool (see Section 9).
  • No established environmental/infectious/lifestyle causal risk factors — this is a purely Mendelian condition; environmental exposures (mechanical trauma, pregnancy, high-impact activity) act as modifiers/precipitants of complications (fractures, vascular rupture, globe rupture) rather than causal risk factors for the underlying disease.
  • Modifier genes: No confirmed modifier loci; phenotypic variability is attributed largely to residual enzyme activity from different allele combinations and partial compensation by paralogous enzymes (LH2/PLOD2, LH3/PLOD3 for PLOD1; unknown compensators for FKBP14).

Protective Factors

No genetic or environmental protective factors are established in the literature reviewed.

Gene-Environment Interactions

Not formally studied; the clinically relevant interaction is mechanical — connective tissue that is structurally weakened by defective cross-linking is disproportionately vulnerable to mechanical stress (trauma, childbirth, high-impact exercise, hypertension-driven arterial wall stress), which precipitates the organ-specific complications (globe rupture, arterial dissection, joint dislocation) rather than initiating the underlying molecular lesion.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS

3. Phenotypes

PLOD1-kEDS (n≈94 published individuals, cumulative literature)

Phenotype HPO term (suggested) Frequency Onset
Congenital muscular hypotonia HP:0001290 (Generalized hypotonia) 100% Birth
Kyphoscoliosis (congenital/early-onset, often progressive) HP:0002751 (Kyphoscoliosis) 95% Infancy, worsening through childhood
Skin hyperextensibility/fragility, atrophic scarring HP:0000974 (Hyperextensible skin); HP:0000978 (Bruising susceptibility) 97% Infancy onward
Generalized joint hypermobility, recurrent dislocations/subluxations HP:0001382 (Joint hypermobility) ~30% recurrent dislocations Childhood
Ocular abnormality (blue sclerae, refractive error, scleral/globe fragility) HP:0000592 (Blue sclerae); HP:0000587 (Keratoglobus) 45% Variable; globe rupture risk lifelong
Congenital or acquired clubfoot HP:0001762 (Talipes equinovarus) ~20-25% Congenital
Hernias (umbilical/inguinal) HP:0100775 (Umbilical hernia) ~15% Childhood
Gross motor developmental delay HP:0001270 ~60% Infancy
Arterial rupture/dissection (medium-sized arteries, aorta) HP:0025214 (Arterial dissection) ~30% (adults) Adulthood, life-threatening
Osteopenia HP:0004349 Common Adolescence onward

FKBP14-kEDS (cohort n=23, Giunta et al. 2018/GeneReviews)

Phenotype HPO term (suggested) Frequency
Congenital hypotonia/weakness (improves in childhood) HP:0001252 (Hypotonia) 23/23
Small-joint hypermobility HP:0005692 23/23
Large-joint hypermobility HP:0001382 21/23
Foot deformities HP:0001760 23/23
Congenital contractures HP:0000023 7/23
Refractive errors HP:0000539 ~2/3
Blue sclerae HP:0000592 ~1/3
Hernias HP:0002664/HP:0100775 11/23
Bifid uvula ± cleft palate HP:0000193 (Bifid uvula) 7/23
Sensorineural hearing loss HP:0000407 ~50%
Conductive hearing loss HP:0000405 ~18-25%
Myopathy (mild, nonspecific histopathology) HP:0003198 Frequent
Aortic/arterial rupture, dissection, pseudoaneurysm HP:0002647 Occasional

Severity/Progression: In both subtypes, kyphoscoliosis is often rapidly progressive in early childhood and frequently refractory to bracing, necessitating early surgical stabilization. Motor function trajectory differs somewhat by subtype: FKBP14-kEDS patients typically show improving hypotonia and achieve independent ambulation by age 2–4, with a possible decline in motor function in adulthood while retaining independence in activities of daily living. PLOD1-kEDS patients typically walk by age 2.

Quality of life impact: No disease-specific validated QoL instrument data were identified in the literature searched; morbidity is dominated by progressive spinal deformity (restrictive lung disease risk), chronic joint instability/pain, visual impairment from ocular fragility/refractive error, and (for FKBP14) hearing impairment — each independently affecting daily functioning, mobility, and educational/occupational participation.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; Phenotypic variability of EDS VIA (PMC3135503); Giunta et al. 2018 cohort, Genetics in Medicine

4. Genetic/Molecular Information

Causal Genes

  • PLOD1 — procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (lysyl hydroxylase 1, LH1). Chromosome 1p36.22. OMIM gene entry *153454.
  • FKBP14 — FK506-binding protein 14 (FKBP22). Chromosome 7p14.3.

Pathogenic Variants — PLOD1

  • Variant types: missense, nonsense, splice-site, small indels, and a common recurrent 8.9-kb intragenic duplication (exons 10–16) generated by Alu-Alu recombination in introns 9 and 16 — this single structural variant accounts for ~30% of pathogenic alleles across 73 studied families, making PLOD1-kEDS one of the examples where structural variant testing (deletion/duplication analysis) is essential alongside sequencing.
  • Sequence analysis alone detects ~67% of variants; deletion/duplication analysis detects the remaining ~33% (dominated by the 8.9-kb duplication).
  • Recurrent alleles in specific populations: c.955C>T (p.Arg319Ter), prevalent in Arab populations; c.1533C>G (p.Tyr511Ter), third most common reported variant.
  • Functional consequence: loss-of-function, producing reduced/absent LH1 enzymatic activity (confirmed on Western blot showing decreased PLOD1 protein).

Pathogenic Variants — FKBP14

  • c.362dupC (frameshift, p.Glu122ArgfsTer7) — the dominant founder allele, accounting for ~70% of disease alleles, shown to share a common haplotype across unrelated affected individuals, consistent with a single ancestral founder event.
  • p.Met48Lys (missense) — located near the PPIase catalytic active site; structural/functional studies indicate partial loss of isomerase activity (PMC6965642).
  • p.Glu191del — the only reported in-frame deletion variant.
  • Predominantly loss-of-function/null mechanism.

Variant Classification & Population Frequency

Pathogenic/likely pathogenic classifications for both genes are catalogued in ClinVar (e.g., multiple PLOD1 splice and missense variants linked to "Ehlers-Danlos syndrome, kyphoscoliotic type 1"). Population allele-frequency queries specific to PLOD1/FKBP14 pathogenic alleles were not resolved via general gnomAD searches in this session; given the estimated disease incidence of ~1:100,000 live births and full penetrance under Hardy-Weinberg assumptions, an approximate combined carrier frequency on the order of 1:150–1:160 would be expected for kEDS overall (rough estimate; not a directly sourced figure — recommend confirming against gnomAD v4 directly before curation).

Modifier Genes

None confirmed. Phenotypic variability in PLOD1-kEDS is proposed to reflect residual LH1 activity and partial functional compensation by the paralogous enzymes LH2 (PLOD2) and LH3 (PLOD3), based on mouse-model biochemistry (see Section 15).

Epigenetic Information

No disease-specific epigenetic (DNA methylation/histone) studies were identified for kEDS in this search.

Chromosomal Abnormalities

kEDS is caused by intragenic sequence/structural variants, not whole-chromosome/large segmental aneuploidies; no karyotype-level abnormality is part of the disease definition.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; UniProt Q02809 (PLOD1); Baumann et al. 2012, PMC3276673; Met48Lys FKBP22 study, PMC6965642

5. Environmental Information

kEDS has no known environmental, infectious, or toxin-mediated causal factors — it is a fully penetrant monogenic recessive disease. Environmental/lifestyle factors are relevant only as triggers of complications in genetically affected individuals: - Mechanical trauma (even trivial) → corneal/scleral rupture, joint dislocation, arterial rupture. - High-impact/contact sports, heavy lifting, joint-stressing activity (gymnastics, long-distance running) → explicitly counseled against per GeneReviews management guidance, due to joint instability and vascular fragility. - Pregnancy → mechanical/hemodynamic stress increases risk of miscarriage, premature rupture of membranes, and arterial rupture; high-risk perinatology management is recommended for delivery. - Hypertension → accelerates arterial wall stress in a structurally weakened vasculature; blood pressure control and consideration of beta-blockade for aortic dilatation are standard preventive measures. - Diagnostic arteriography is specifically listed as an activity/procedure to avoid except for identification of life-threatening bleeding, given catheter-induced vessel fragility risk.

No infectious agents are implicated in either etiology or as disease triggers.

Source: GeneReviews PLOD1-kEDS Management; GeneReviews FKBP14-kEDS Management

6. Mechanism / Pathophysiology

Ordered Causal Chain — PLOD1-kEDS

  1. Biallelic loss-of-function variants in PLOD1 (missense/nonsense/splice/indel, or the recurrent 8.9-kb Alu-mediated exon 10–16 duplication) → leads to markedly reduced or absent lysyl hydroxylase 1 (LH1) enzyme protein/activity in the endoplasmic reticulum (confirmed by reduced protein on Western blot).
  2. Loss of LH1 activity → results in failure to hydroxylate specific lysyl residues within -Xaa-Lys-Gly- motifs of the collagen triple helix (fibrillar collagens I, III, and others).
  3. Underhydroxylation of helical lysines → leads to deficient glycosylation of the resulting hydroxylysine residues and, critically, failure to form mature hydroxylysine-derived pyridinoline (HP) collagen cross-links; cross-linking instead proceeds via the aberrant, mechanically inferior lysyl-pyridinoline (LP) pathway. This shift is directly measurable: the urinary deoxypyridinoline:pyridinoline (Dpyr:Pyr) ratio rises from a normal ~0.2 to ~6.0 in affected individuals — the diagnostic biochemical hallmark of PLOD1-kEDS.
  4. Defective/abnormal collagen cross-linking → results in reduced tensile strength and mechanical instability of collagen fibrils in the extracellular matrix (ECM) of connective tissues throughout the body (this step is directly demonstrated biochemically; the downstream tissue-level consequences below are inferred from the clinical phenotype and are consistent with, but not fully mechanistically dissected by, direct human tissue biomechanical studies).
  5. Mechanically weakened ECM in skeletal muscle and fascia → leads to congenital hypotonia and gross motor delay (inferred).
  6. Mechanically weakened ECM in spinal ligaments, intervertebral discs, and paraspinal connective tissue → leads to congenital/early-onset, often rapidly progressive kyphoscoliosis (inferred from clinical pattern; not shown at the histologic level in the sources reviewed).
  7. Mechanically weakened ECM in joint capsules/ligaments → leads to generalized joint hypermobility and recurrent dislocation/subluxation.
  8. Mechanically weakened ECM in dermis → leads to hyperextensible, fragile, easily bruised skin with atrophic ("cigarette-paper") scarring.
  9. Mechanically weakened ECM in the sclera/ocular globe wall → leads to scleral fragility, predisposing to spontaneous or trauma-induced globe rupture, and to refractive error/microcornea from altered corneal biomechanics.
  10. Mechanically weakened ECM in the arterial media/adventitia of medium-sized arteries and the aorta → leads to (in a subset of ~30% of adults) spontaneous arterial aneurysm, dissection, or rupture — the principal life-threatening complication.
  11. In severe, progressive kyphoscoliosis (branch from step 6) → leads to restrictive pulmonary physiology → leads to recurrent pneumonia and, eventually, cor pulmonale/cardiac failure in severely affected adults.

Ordered Causal Chain — FKBP14-kEDS

  1. Biallelic loss-of-function variants in FKBP14 (most commonly the founder c.362dupC frameshift, or missense/in-frame deletion variants) → leads to deficiency of the ER-resident chaperone protein FKBP22, a peptidyl-prolyl cis-trans isomerase (PPIase).
  2. Loss of FKBP22 PPIase/chaperone activity → results in impaired folding of the triple helix of procollagen type III (its principal substrate) and disrupted interaction with collagens VI and X, while biosynthesis and secretion of collagens I, III, and V per se remain grossly normal — i.e., the defect is primarily one of folding fidelity and matrix organization, not synthesis.
  3. Defective procollagen folding → leads to ER stress with marked ER cisternal enlargement and accumulation of flocculent material in dermal fibroblasts (documented ultrastructurally).
  4. Impaired collagen III/VI folding and secretion → results in disarray of extracellular matrix architecture: disorganized collagen I/III/VI networks, fibronectin, tenascins, and thrombospondin, together with loss of the principal collagen/fibronectin cell-surface receptors α2β1 and α5β1 integrin — disrupting normal cell-matrix adhesion signaling.
  5. Disorganized ECM/impaired cell-matrix adhesion in skeletal muscle connective tissue and the muscle fiber environment → leads to the myopathic component of the disease (nonspecific myopathic changes on histopathology, with normal or mildly elevated creatine kinase), and to congenital hypotonia/weakness.
  6. Disorganized ECM (largely mirroring the PLOD1 pathway downstream) in paraspinal tissue, joints, dermis, sclera, and arterial wall → leads to progressive scoliosis, joint hypermobility, hyperelastic skin, ocular fragility, and (occasionally) arterial rupture/dissection, aortic root pathology, and valve insufficiency, by the same general mechanical-weakness logic as steps 6–10 above for PLOD1-kEDS.
  7. Collagen VI/III network disruption specifically within the inner ear/cochlear connective tissue → leads to sensorineural hearing impairment in roughly half of patients (mechanism at the level of cochlear microstructure is not established in the literature identified; this step is inferred from the tissue tropism of the affected collagens and the empirical clinical association, not from direct otopathologic study).

Molecular Pathways / Cellular Processes / Protein Dysfunction

  • Pathway: Collagen biosynthesis and post-translational modification (hydroxylation, cross-linking, chaperone-assisted folding) within the rough ER — GO:0032964 (collagen biosynthetic process), GO:0030199 (collagen fibril organization), GO:0018216 (peptidyl-proline hydroxylation), GO:0006457 (protein folding).
  • Protein dysfunction: PLOD1 — loss-of-function enzymatic deficiency (an ER-membrane-bound homodimer using Fe²⁺ and ascorbate cofactors; functions within a PLOD1–P3H3–P3H4 hydroxylation complex). FKBP14 — loss-of-function chaperone/isomerase deficiency (211-amino-acid protein with signal peptide, PPIase catalytic domain, two EF-hand calcium-binding domains).
  • Cellular process: ER stress / disrupted secretory pathway trafficking of misfolded/underhydroxylated procollagen (most clearly shown for FKBP14).
  • Tissue damage mechanism: Mechanical failure of ECM under normal physiologic and mechanical loading (not primary inflammatory, oxidative, or ischemic injury).
  • Immune involvement: None established; kEDS is not an autoimmune or inflammatory disease.

Suggested Ontology Terms

  • GO (molecular function): GO:0031545 (peptidyl-proline dioxygenase activity, LH1) / GO:0003755 (peptidyl-prolyl cis-trans isomerase activity, FKBP14)
  • GO (biological process): GO:0032964 (collagen biosynthetic process), GO:0030199 (collagen fibril organization), GO:0018216 (peptidyl-proline hydroxylation)
  • GO (cellular component): GO:0005788 (endoplasmic reticulum lumen), GO:0005789 (ER membrane)
  • CL (cell types): CL:0000057 (fibroblast — dermal fibroblasts are the principal cell studied biochemically); CL:0000188 (skeletal muscle cell/myocyte); CL:0000192 (smooth muscle cell, arterial media)

Molecular Profiling

Transcriptome profiling of primary skin fibroblasts has revealed distinct molecular signatures between PLOD1- and FKBP14-kEDS, indicating the two genetically-defined subtypes are not simply interchangeable at the transcriptomic level despite convergent clinical phenotypes (PMC6678841). No single-cell, spatial transcriptomic, proteomic, or CRISPR functional-genomics screen datasets specific to kEDS were identified in this search.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; Transcriptome profiling PLOD1 vs FKBP14, PMC6678841; UniProt Q02809; FKBP14 mutation original description, Baumann et al. 2012, PMC3276673

7. Anatomical Structures Affected

Organ level: - Primary: integument (skin), musculoskeletal system (spine, joints, muscle), eye (sclera/cornea), vasculature (medium-sized arteries, aorta) - Secondary/complication-driven: respiratory system (restrictive lung disease secondary to kyphoscoliosis), cardiac system (cor pulmonale, valve insufficiency in FKBP14-kEDS), ear (cochlea/middle ear in FKBP14-kEDS), gastrointestinal system (hernias) - Body systems: integumentary, musculoskeletal, ophthalmologic, cardiovascular, respiratory (secondary), auditory (FKBP14 subtype only)

Tissue/cell level: - Dermal connective tissue (dysplastic collagen fibrils; CL:0000057 fibroblast) - Paraspinal ligamentous/fascial connective tissue - Joint capsule/ligament connective tissue - Skeletal muscle interstitial connective tissue and myofibers (myopathy, FKBP14 especially) - Scleral/corneal stroma (CL type: keratocyte) - Arterial tunica media/adventitia (CL:0000192 smooth muscle cell) - Cochlear/inner-ear connective tissue structures (FKBP14)

Subcellular level: - Endoplasmic reticulum (site of collagen hydroxylation/folding defect — GO:0005788/GO:0005789); extracellular matrix / collagen fibril (GO:0062023 collagen-containing extracellular matrix)

Localization: - Systemic/generalized connective tissue involvement rather than focal; no strict lateralization, though joint dislocations and scoliosis curves may present asymmetrically.

Suggested UBERON terms: UBERON:0002097 (skin), UBERON:0001630 (muscle organ), UBERON:0001130 (vertebral column), UBERON:0000970 (eye), UBERON:0001981 (blood vessel), UBERON:0000948 (heart), UBERON:0001846 (cochlea, FKBP14 subtype).

Source: synthesized from GeneReviews PLOD1-kEDS and GeneReviews FKBP14-kEDS

8. Temporal Development

Onset: Congenital (present at or shortly after birth) for the cardinal features — hypotonia and kyphoscoliosis/scoliosis. Onset pattern is best characterized as congenital with early progressive course, rather than acute or insidious in the adult-onset sense.

Progression: - Kyphoscoliosis: moderate at birth, becoming moderate to severe during childhood; often rapidly progressive and refractory to bracing, frequently requiring early surgical intervention (growing rods, spinal fusion) rather than conservative management. - Hypotonia: in FKBP14-kEDS specifically, congenital hypotonia/weakness characteristically improves during childhood, with most children achieving independent ambulation between ages 2–4 years; a decline in motor function may re-emerge in adulthood. - Vascular risk (arterial rupture/dissection): emerges predominantly in adulthood (~30% lifetime risk in PLOD1-kEDS), though pediatric and adolescent cases have been reported. - Ocular fragility: lifelong risk, precipitated by trauma. - Hearing loss (FKBP14): may present at birth, in early infancy, or later in life — variable onset timing.

Disease course pattern: Chronic and generally progressive for the skeletal and vascular manifestations; the muscular/motor component in FKBP14-kEDS is unusual in following a partially U-shaped course (improvement in childhood, decline in adulthood). No remission is described; this is a structural, non-inflammatory connective tissue disorder.

Disease duration: Chronic, lifelong. Documented adult survival exists (e.g., one FKBP14-kEDS patient reported alive at age 53), though formal life-expectancy/actuarial data are lacking for both subtypes — see Section 11.

Critical periods: Early childhood is the critical intervention window for spinal deformity (curve progression is most rapid and most amenable to surgical stabilization before severe restrictive pulmonary compromise develops); adulthood is the critical surveillance window for arterial complications.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; Giunta et al. 2018 natural history, Genet Med; FKBP14-kEDS surgical spine case report, 2025, PMC12689754

9. Inheritance and Population

Epidemiology: - PLOD1-kEDS: exact prevalence unknown; incidence estimated at ~1:100,000 live births (reasonable estimate per GeneReviews, not derived from a formal population screening study). Geographic clustering has been observed in Turkey, the Middle East, and Greece, though no clear racial/ethnic prevalence differential otherwise. - FKBP14-kEDS: rarer still; Orphanet lists point prevalence as <1/1,000,000 worldwide; only ~30 individuals were documented in the literature as of the ~2019 GeneReviews synthesis, growing to a natural-history cohort of 17 well-characterized patients (Giunta et al. 2018) plus additional individually reported cases since.

Inheritance pattern: Autosomal recessive for both subtypes, with 100% penetrance as reported by GeneReviews (i.e., biallelic pathogenic variant carriers are expected to manifest the phenotype, though severity varies).

Expressivity: Variable — phenotypic severity (especially skeletal deformity severity, vascular event risk, hearing loss presence/degree) differs meaningfully between individuals and appears to correlate at least partly with the specific allele combination/residual enzyme activity, particularly documented for PLOD1 ("Phenotypic variability of the kyphoscoliotic type of EDS," PMC3135503).

Genetic anticipation: Not applicable/not reported — not a repeat-expansion disorder.

Germline mosaicism: Not specifically reported in the sources reviewed for either gene.

Founder effects: - PLOD1: the 8.9-kb Alu-mediated intragenic duplication (exons 10–16) is a recurrent structural variant (~30% of alleles across studied families) — consistent with a mutational hotspot rather than a single-population founder effect; c.955C>T (p.Arg319Ter) is specifically noted as prevalent in Arab populations. - FKBP14: c.362dupC is a bona fide founder allele, present on a shared haplotype in essentially all molecularly solved cases and accounting for ~70% of disease alleles.

Consanguinity: As with any rare autosomal recessive disorder, parental consanguinity substantially elevates recurrence risk in affected families/populations, though a formal consanguinity-rate statistic specific to kEDS was not retrieved in this search.

Carrier frequency: Not directly retrieved from gnomAD in this session; can be approximated from disease incidence (~1:100,000, full penetrance) as roughly 1:150–1:160 carriers for PLOD1-kEDS under Hardy-Weinberg assumptions — this figure should be verified directly against gnomAD population data before use as a curated claim.

Recurrence risk: For carrier × carrier parental matings, each pregnancy carries the standard Mendelian recessive risk: 25% affected, 50% carrier, 25% unaffected.

Population demographics: No formal sex-ratio skew is reported (autosomal, not sex-linked); age distribution spans neonatal diagnosis through documented adult survivors into the sixth decade.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; Orphanet FKBP22-deficiency kEDS; Giunta et al. 2018, Genet Med; Phenotypic variability of EDS VIA, PMC3135503

10. Diagnostics

Clinical Diagnostic Criteria (2017 International Classification)

Minimal diagnostic criteria for kEDS (both molecular subtypes) per the 2017 nosology: congenital muscular hypotonia AND congenital/early-onset kyphoscoliosis, PLUS either generalized joint hypermobility OR three minor criteria. Definitive diagnosis requires molecular confirmation of biallelic pathogenic variants.

Laboratory / Biochemical Tests

  • Urinary Dpyr:Pyr ratio (deoxypyridinoline:pyridinoline cross-link ratio) measured by HPLC — the diagnostic biomarker specific to PLOD1-kEDS. Normal ratio ≈0.2; PLOD1-kEDS ratio ≈6.0. This test is normal in FKBP14-kEDS, making it a useful biochemical discriminator between the two molecular subtypes when genetic testing is pending or ambiguous.
  • LH1 enzyme activity assay in cultured fibroblasts (historical confirmatory method, largely supplanted by molecular testing).
  • Creatine kinase: normal or only mildly elevated in FKBP14-kEDS myopathy (helps distinguish from primary muscular dystrophies).

Genetic Testing

  • Gene-targeted sequence analysis of PLOD1 (detects ~67% of variants) or FKBP14, followed by deletion/duplication analysis for structural variants (detects remaining ~33% of PLOD1 alleles, dominated by the recurrent 8.9-kb duplication; ~70% of FKBP14 alleles are the single c.362dupC founder variant, generally detectable by sequencing).
  • Multigene connective-tissue-disorder panels including PLOD1, FKBP14, and overlapping genes (COL1A1/2, COL3A1, COL5A1/2, COL12A1, ZNF469, B4GALT7, etc.) are appropriate first-line given phenotypic overlap.
  • Exome/genome sequencing reserved for atypical presentations or when panel testing is non-diagnostic.
  • Chromosomal microarray/karyotype/FISH: not primary diagnostic modalities for kEDS (a sequence/structural-variant-level disease, not a chromosomal disorder), though CMA can detect the larger PLOD1 structural duplication in some assay designs.

Imaging / Functional Testing

  • Spine radiography/MRI for kyphoscoliosis characterization and surgical planning.
  • Echocardiography and vascular imaging (CT/MR angiography of aorta and medium-sized arteries) for cardiovascular surveillance (see Section 12).
  • Pulmonary function testing for restrictive disease in severe spinal deformity.
  • Audiometry (FKBP14 subtype) for hearing loss characterization.
  • Ophthalmologic exam (slit lamp, refraction) for globe fragility/refractive error surveillance.

Biopsy/Histopathology

  • Muscle biopsy in FKBP14-kEDS: nonspecific mild myopathic changes with increased fiber-diameter variation; not required for diagnosis but supports the myopathic phenotype.
  • Skin/fibroblast ultrastructural studies (electron microscopy): show ER cisternal enlargement with flocculent material in FKBP14-kEDS fibroblast cultures — largely a research rather than routine clinical diagnostic tool.

Differential Diagnosis

Condition Distinguishing features
Classic EDS (COL5A1/2, COL1A1) Absence of congenital hypotonia; simple scoliosis rather than kyphoscoliosis pattern
Vascular EDS (COL3A1) Autosomal dominant; intestinal/uterine rupture more prominent; distinct vascular event profile
PLOD1-kEDS vs FKBP14-kEDS Hearing impairment and myopathy favor FKBP14; elevated urinary Dpyr:Pyr ratio is specific to PLOD1 (normal in FKBP14)
Musculocontractural EDS (CHST14/DSE) Adducted thumbs/clubfeet, characteristic craniofacial features, GI/genitourinary manifestations
Spondylodysplastic EDS Progressive short stature; primary skeletal dysplasia; dysplastic teeth
Myopathic EDS (COL12A1) Severe progressive scoliosis with prominent myopathy on biopsy
Collagen VI disorders (Bethlem myopathy/Ullrich CMD) Absent skin hyperelasticity, bruising, hearing impairment, cardiovascular involvement
Congenital myopathies (non-EDS) Normal skin texture; absent characteristic velvety/hyperextensible skin
Larsen syndrome A documented real-world diagnostic pitfall: FKBP14-kEDS has been misdiagnosed as Larsen syndrome (PMID 37433679)
Brittle cornea syndrome (ZNF469, PRDM5) Corneal rupture more characteristic than scleral rupture (kEDS shows the reverse pattern)

Biochemically, all differential diagnoses show normal lysyl hydroxylase activity/normal Dpyr:Pyr ratio, distinguishing them from PLOD1-kEDS specifically.

Screening

No population-based newborn or carrier screening program specific to kEDS was identified; given the severity and recessive inheritance, carrier screening/cascade testing in known founder populations and genetic counseling for consanguineous families are the practical prevention-adjacent measures (see Section 13).

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; FKBP14-kEDS misdiagnosed as Larsen syndrome, PMID 37433679; Ocular manifestations of EDS

11. Outcome/Prognosis

Survival/Mortality: No formal actuarial life-table or 5-/10-year survival statistics specific to kEDS were identified — this reflects the disease's rarity and the case-report-dominated literature. GeneReviews states life span "may be normal," but this is qualified by substantial risk of life-threatening arterial rupture/dissection in adulthood (~30% of PLOD1-kEDS adults) as the principal mortality driver; a fatal case of superior mesenteric artery aneurysm rupture with aortic involvement in a 15-year-old was reported as recently as 2025 despite emergency hybrid surgical/endovascular intervention (PMID 41613374), illustrating that mortality risk is not confined to older adulthood. For FKBP14-kEDS, survival into the sixth decade has been documented (one patient alive at age 53), but the literature explicitly notes adults are likely underrecognized due to historically limited access to genetic testing, biasing available prognosis data toward pediatric presentations.

Morbidity/Function: - Severe kyphoscoliosis drives restrictive lung disease, recurrent pneumonia, and eventual cardiac strain/failure in the most severely affected adults. - Chronic joint instability and recurrent dislocation contribute to long-term disability and pain. - Progressive myopathy/motor decline is specifically described in adult FKBP14-kEDS, though patients generally retain independence in activities of daily living and ambulation. - Ocular complications (globe rupture, refractive error, keratoconus/keratoglobus in severe cases) can cause permanent visual impairment. - Sensorineural/conductive hearing loss (FKBP14) contributes to communication and developmental morbidity if unaddressed.

Complications: Arterial aneurysm/dissection/rupture (aorta, superior mesenteric artery, carotid, celiac arteries documented), scleral/globe rupture, recurrent joint dislocation, hernias, osteopenia/fracture risk, restrictive pulmonary disease, subdural hygroma (reported in FKBP14-kEDS), cardiac valve insufficiency (FKBP14-kEDS).

Prognostic factors: Severity of skeletal deformity at presentation, presence/burden of vascular disease, specific genotype (residual enzyme activity), and access to early multidisciplinary surgical/orthopedic intervention appear to be the principal determinants of long-term outcome, though this is inferred from the qualitative case-series literature rather than formally modeled prognostic scoring.

Recovery potential: Not a remitting disease; management is aimed at preventing/mitigating complications rather than reversing the underlying connective tissue defect (though see Section 12 for the theoretical basis of targeted therapies under investigation).

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS; kEDS-PLOD1 fatal SMA aneurysm/aortic rupture case, PMID 41613374; Severe PLOD1-kEDS with multiple arterial/venous complications, PMC9969762

12. Treatment

There is no disease-modifying or curative pharmacotherapy for kEDS; management is multidisciplinary, surveillance-driven, and focused on prevention/treatment of complications.

Pharmacotherapy

  • Beta-blockers — considered for aortic root dilatation (extrapolated from vascular EDS management experience rather than kEDS-specific trial data); suggested NCIT term: NCIT:C15986 (Pharmacotherapy) with therapeutic_agent class NCIT:C2231 (Adrenergic beta-Antagonist).
  • Antihypertensive management generally, to reduce arterial wall shear stress.
  • Bisphosphonates/denosumab — used off-label for osteopenia/low bone mineral density management in EDS broadly, including presumably kEDS, though data are drawn from general EDS skeletal-fragility literature rather than kEDS-specific trials; bisphosphonates show reasonable efficacy for vertebral (but not long-bone) fracture prevention, with medication-related osteonecrosis of the jaw (MRONJ) as a recognized risk.
  • Analgesics/pain management for chronic joint pain (non-specific, standard-of-care).

Surgical/Interventional

  • Spinal surgery (posterior spinal fusion, growing-rod constructs, cervical corpectomy/fusion for cervical kyphosis with myelopathy) is frequently required, as conservative bracing is often ineffective against the rapidly progressive kyphoscoliosis characteristic of kEDS. Case series of posterior spinal fusion (3 adolescents) report satisfactory curve correction with no major intra-/postoperative complications when performed after failed conservative management; more complex multi-stage surgical courses (including occipitocervical fusion, growing rods, corpectomy) have been reported for severe early-onset cases. Suggested NCIT terms: NCIT:C15329 (Surgical Procedure); more specifically spinal fusion procedures.
  • Endovascular/hybrid surgical repair for arterial aneurysm/rupture (documented in a fatal SMA aneurysm/aortic rupture case combining laparotomy hemostasis with stent-graft placement).
  • Hernia repair as clinically indicated.
  • Cataract/retinal laser treatment for ophthalmologic complications.

Supportive/Rehabilitative

  • Physical therapy targeting shoulder-girdle and core strengthening; swimming specifically recommended as a lower-impact strengthening activity.
  • Occupational therapy for motor dysfunction, particularly addressing the adult motor decline seen in FKBP14-kEDS.
  • Orthopedic bracing for joint instability (adjunctive, not curative for the spine).
  • Protective equipment during activity.
  • Standard management of hearing impairment (hearing aids/audiologic support, FKBP14 subtype), cleft palate, and refractive error.

Experimental/Investigational

No kEDS-specific gene therapy, RNA-based therapy, or targeted molecular therapeutic was identified as being in active clinical trials in this search. Given the loss-of-function, enzyme/chaperone-deficiency mechanism, gene replacement or enzyme augmentation strategies remain theoretically plausible avenues analogous to other collagen-modifying enzymopathies, but no ClinicalTrials.gov-registered program specific to PLOD1 or FKBP14 was surfaced in this search session — this is a genuine literature gap rather than a negative-trial finding, and should be verified directly against ClinicalTrials.gov/WHO ICTRP before being asserted as a settled absence.

Activities/Agents to Avoid

Joint-stressing sports (gymnastics, long-distance running), contact/collision sports (particularly with known aortic aneurysm), heavy lifting, and diagnostic arteriography except when necessary to localize life-threatening hemorrhage.

Surveillance Schedule (synthesized from GeneReviews for both subtypes)

  • Blood pressure at every visit
  • Annual (or every 1–3 year, subtype-dependent) orthopedic, ophthalmologic, and audiologic evaluation
  • Echocardiography (± cardiac MRI) every 2–5 years, beginning around age 5
  • CT/MR angiography of the aorta and medium-sized arteries beginning in young adulthood (or earlier per clinical suspicion)
  • DXA bone density assessment beginning around age 10–12
  • Annual hernia screening
  • Neurodevelopmental assessment at each visit through adolescence (FKBP14-kEDS)

Source: GeneReviews PLOD1-kEDS Management; GeneReviews FKBP14-kEDS Management; Posterior spinal fusion in kEDS, PMID 21667916; Surgical management of spinal deformity in FKBP14-kEDS, 2025, PMC12689754; Skeletal fragility in EDS

13. Prevention

Primary prevention: Not possible to prevent occurrence of a fully penetrant autosomal recessive Mendelian disease through lifestyle/behavioral means; the only true primary-prevention lever is reproductive genetic counseling and carrier/preimplantation genetic testing in at-risk families (known carrier couples, consanguineous unions, or families with a previously affected child).

Secondary prevention (early detection): - Prenatal diagnosis via chorionic villus sampling/amniocentesis with targeted molecular testing is possible once familial pathogenic variants are known. - Early clinical recognition in the neonatal period (congenital hypotonia + kyphoscoliosis) enables prompt genetic confirmation and initiation of surveillance before major complications (especially vascular) develop. - No population-based newborn screening program exists for kEDS (it is not part of standard newborn metabolic/genetic screening panels).

Tertiary prevention (preventing complications in affected individuals): This is where essentially all "prevention" activity in kEDS actually concentrates, and it overlaps substantially with Section 12's surveillance/avoidance recommendations: - Blood pressure control and consideration of beta-blockade to reduce arterial wall stress. - Avoidance of high-impact/contact activities and heavy lifting to reduce joint dislocation and vascular rupture risk. - Avoidance of diagnostic arteriography except when essential. - Scheduled vascular imaging surveillance to detect aneurysmal change before rupture. - Early orthopedic surgical intervention for progressive kyphoscoliosis to forestall restrictive pulmonary disease. - Protective eyewear/activity modification to reduce ocular trauma risk given scleral fragility. - High-risk perinatology-center delivery planning for affected pregnant women, given elevated risk of membrane rupture, miscarriage, and arterial rupture during pregnancy/delivery.

Genetic counseling: Central to family planning in known-carrier families; recurrence risk counseling follows standard autosomal recessive Mendelian principles (25% affected per pregnancy for two carrier parents).

Immunization: Not applicable — kEDS is not an infectious or vaccine-preventable condition.

Public health/environmental interventions: Not applicable given the purely genetic etiology.

Source: GeneReviews PLOD1-kEDS; GeneReviews FKBP14-kEDS

14. Other Species / Natural Disease

Taxonomy: Homo sapiens (NCBITaxon:9606) is the primary species of interest, but a naturally occurring PLOD1-related disease homolog exists in the domestic horse (Equus caballus, NCBITaxon:9796).

Equine homolog — Warmblood Fragile Foal Syndrome (WFFS): This is cataloged in OMIA as OMIA:001982-9796 — "kyphoscoliotic Ehlers-Danlos syndrome (kEDS), PLOD1-related" in the domestic horse. WFFS type 1 is caused by a recessive PLOD1 missense variant (c.2032G>A) and produces a lethal/severely debilitating neonatal foal phenotype with extreme skin and connective tissue fragility, closely paralleling the human PLOD1-kEDS mechanism (lysyl hydroxylase deficiency → defective collagen cross-linking). This is directly relevant as a naturally occurring, non-engineered large-animal disease model with high face validity for the human condition, distinct from the laboratory Plod1-knockout mouse (Section 15). Population genetics work has examined WFFS carrier allele frequency in warmblood breeds and (a related PLOD1 variant) in Thoroughbreds, where the allele was found to have low frequency and no association with catastrophic musculoskeletal breakdown.

Gene orthologs: PLOD1 and FKBP14 are broadly conserved across vertebrates (mouse Plod1/Fkbp14, zebrafish plod1a/plod1b), consistent with their fundamental, evolutionarily conserved role in collagen biosynthesis; comparative pathology across these species centers on collagen fibril cross-linking defects rather than kEDS-specific study, given the equine WFFS system is the closest natural phenocopy identified.

Transmission: Not applicable — kEDS and WFFS are both purely genetic, non-communicable, non-zoonotic conditions.

Source: OMIA:001982-9796 — kEDS PLOD1-related in the domestic horse; WFFS PLOD1 c.2032G>A allele frequency in Thoroughbreds, PMC7062577

15. Model Organisms

Mouse — Plod1⁻ᐟ⁻ (PLOD1 knockout)

The principal genetic mouse model for PLOD1-kEDS. - Phenotype recapitulation: Partial. Plod1⁻ᐟ⁻ mice show muscle hypotonia and aortic ruptures, recapitulating two of the most clinically significant human features (hypotonia, vascular rupture). However, they lack the characteristic kyphoscoliosis seen in humans, and skin hyperextensibility/fragility is absent despite detectable ultrastructural collagen alterations in skin tissue. - Biochemical basis for the mismatch: Tissue-specific residual hydroxylysine content differs substantially between the mouse model and human disease — Plod1⁻ᐟ⁻ mice retain ~22% (skin) to as little as ~14% loss (up to 86% decrease in lung) of total hydroxylysine, compared with an estimated ~95% reduction (to ~5% residual) in affected humans — attributed to partial functional compensation by the paralogous enzymes LH2 (PLOD2) and LH3 (PLOD3) in mice, which appears less complete or tissue-distributed differently than in humans. This quantitative difference in residual enzyme/cross-link activity is the leading proposed explanation for why the mouse spares the spine and skin phenotypes. - Model limitations: The absence of kyphoscoliosis (the defining orthopedic hallmark) and skin fragility limits the model's utility for studying the spinal and dermatologic components of disease, though it remains valuable for studying the vascular and muscular phenotypes and for testing potential therapeutic cross-link-restoration strategies. - A newer CRISPR/Cas9-generated mouse model of EDS has also been reported (2021/2022) as part of a broader effort to build more faithful genomic-editing-based EDS models, though the specific gene target/subtype recapitulated by that model was not fully resolved in this search and should be checked against the primary source before citation.

Zebrafish

No PLOD1- or FKBP14-specific zebrafish kEDS model was identified in this search. Related work exists on the paralogous enzyme PLOD2 (LH2) in zebrafish dermal wound healing/collagen telopeptide cross-linking (relevant to fibrosis biology generally, not kEDS specifically), and on zebrafish type I collagen mutants recapitulating human type I collagenopathies (a different, non-kEDS disease class) — these are adjacent, not direct, model systems.

Other Systems

  • Patient-derived dermal fibroblast cultures are the dominant in vitro system used in the literature reviewed, supporting: LH1 enzyme activity assays, urinary/tissue cross-link biochemistry, transcriptome profiling distinguishing PLOD1- from FKBP14-kEDS molecular signatures, and ultrastructural (electron microscopy) characterization of ER stress and ECM disorganization in FKBP14-kEDS.
  • No iPSC-derived organoid, CRISPR functional-genomics screen, or invertebrate (Drosophila/C. elegans) model specific to kEDS was identified in this search.

Applications

The Plod1⁻ᐟ⁻ mouse in particular supports research into the vascular-rupture mechanism and muscle hypotonia and could plausibly serve as a platform for testing cross-link-restoring or gene-replacement therapeutic strategies, though its incomplete phenotypic penetrance (no spine/skin phenotype) means spinal and dermatologic disease mechanisms require either the equine WFFS natural model or direct human tissue/cell studies.

Source: Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential (review), PMC8547655; OMIA:001982-9796 equine WFFS; Transcriptome profiling of PLOD1 vs FKBP14 fibroblasts, PMC6678841; New CRISPR-generated EDS mouse model, PMC8713987

Notes on Evidence Gaps and Curation Caveats

For downstream curation into a dismech-style knowledge base, the following points warrant explicit flagging rather than confident assertion:

  1. PLOD1/FKBP14 gnomAD-derived carrier frequency was not directly retrieved from the gnomAD browser in this session (only general gnomAD methodology was surfaced) — this should be queried directly at gnomad.broadinstitute.org before citing a specific number.
  2. Life-expectancy/survival statistics are not formally established in the literature for either subtype; "life span may be normal" (GeneReviews) is a qualitative, not actuarial, statement and should not be curated as a quantitative prognosis claim without a supporting cohort study.
  3. Cochlear pathophysiology mechanism for FKBP14-kEDS hearing loss is inferred from collagen VI/III tissue tropism, not directly demonstrated by otopathologic study in the sources reviewed — mark as inferred/mechanistic hypothesis rather than established fact if curated into a causal pathograph.
  4. Gene therapy/experimental therapeutics — no active kEDS-specific clinical trial was surfaced; this is a search-session finding, not a confirmed negative, and should be re-verified against ClinicalTrials.gov/WHO ICTRP directly.
  5. The Orphanet page for ORPHA:1900 could not be fetched directly (access-restricted); prevalence/epidemiology claims attributed to Orphanet in this report come from secondary citation via search-result synthesis and should be cross-checked against the primary Orphanet record before formal citation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 51
Resolved 46
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 3
Terms whose name was checked 42
Terms named correctly 21
Terms named as a different term 9
Terms whose name is worth a second look 12

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0100775 (2 mentions) - the report calls it "Umbilical hernia"; HP calls it Dural ectasia
  • HP:0025214 (1 mention) - the report calls it "Arterial dissection"; HP calls it Triggered by heat
  • HP:0004349 (1 mention) - the report calls it "Osteopenia"; HP calls it Reduced bone mineral density
  • HP:0000023 (1 mention) - the report calls it "Congenital contractures"; HP calls it Inguinal hernia
  • HP:0000539 (1 mention) - the report calls it "Refractive errors"; HP calls it Abnormality of refraction
  • HP:0003198 (1 mention) - the report calls it "Myopathy (mild, nonspecific histopathology)"; HP calls it Myopathy
  • CL:0000057 (2 mentions) - the report calls it "fibroblast — dermal fibroblasts are the principal cell studied biochemically"; CL calls it fibroblast
  • UBERON:0001846 (1 mention) - the report calls it "cochlea, FKBP14 subtype"; UBERON calls it internal ear
  • NCIT:C2231 (1 mention) - the report calls it "Adrenergic beta-Antagonist"; NCIT calls it Dofequidar Fumarate

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0005692 (obsolete Joint hyperflexibility) (1 mention) - replaced by HP:0001382
  • GO:0062023 (obsolete collagen-containing extracellular matrix) (1 mention) - replaced by GO:0031012

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • MONDO:0016002 (1 mention) - the report calls it "Ehlers-Danlos syndrome, kyphoscoliotic type 1 / EDS type VIA / oculoscoliotic type"; MONDO calls it Ehlers-Danlos syndrome, kyphoscoliotic type 1
  • HP:0001382 (2 mentions) - the report calls it "Joint hypermobility", "Large-joint hypermobility"; HP calls it Joint hypermobility
  • HP:0001270 (1 mention) - the report calls it "Gross motor developmental delay"; HP calls it Motor delay, and lists "Motor developmental delay" among its other names
  • HP:0005692 (1 mention) - the report calls it "Small-joint hypermobility"; HP calls it obsolete Joint hyperflexibility
  • HP:0002647 (1 mention) - the report calls it "Aortic/arterial rupture, dissection, pseudoaneurysm"; HP calls it Aortic dissection
  • GO:0018216 (2 mentions) - the report calls it "peptidyl-proline hydroxylation"; GO calls it peptidyl-arginine methylation
  • GO:0031545 (1 mention) - the report calls it "peptidyl-proline dioxygenase activity, LH1"; GO calls it peptidyl-proline 4-dioxygenase activity
  • GO:0003755 (1 mention) - the report calls it "peptidyl-prolyl cis-trans isomerase activity, FKBP14"; GO calls it peptidyl-prolyl cis-trans isomerase activity
  • GO:0005789 (2 mentions) - the report calls it "ER membrane"; GO calls it endoplasmic reticulum membrane, and lists "ER membrane" among its other names
  • CL:0000188 (1 mention) - the report calls it "skeletal muscle cell/myocyte"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
  • CL:0000192 (2 mentions) - the report calls it "smooth muscle cell, arterial media"; CL calls it smooth muscle cell
  • UBERON:0002097 (1 mention) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0001382 - called "Joint hypermobility", "Large-joint hypermobility"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIA.