Osteogenesis Imperfecta Type IX — Comprehensive Research Report

1. Disease Information

Overview

Osteogenesis Imperfecta Type IX (OI9; OI type 9) is a rare, autosomal recessive form of brittle bone disease caused by loss-of-function variants in the PPIB gene (peptidylprolyl isomerase B), which encodes cyclophilin B (CyPB), an endoplasmic reticulum–resident peptidyl-prolyl cis-trans isomerase. OI type IX was formally delineated as a molecular subtype when Van Dijk et al. (2009) demonstrated that homozygous null mutations in PPIB cause severe-to-lethal bone fragility (PMID: 19781681). It is distinguished from other recessive OI types affecting the prolyl 3-hydroxylation complex (types VII and VIII, caused by CRTAP and LEPRE1/P3H1 mutations, respectively) primarily by the absence of rhizomelia (proximal limb shortening) and by a relatively broader phenotypic spectrum ranging from perinatal lethality to moderate deforming disease.

Key Identifiers

Synonyms and Alternative Names

• Osteogenesis imperfecta, type 9
• OI9
• Osteogenesis imperfecta due to cyclophilin B deficiency
• PPIB-related osteogenesis imperfecta
• Cyclophilin B-deficient osteogenesis imperfecta
• Recessive OI type IX

Evidence Base

Information is derived from aggregated disease-level resources (OMIM, Orphanet), published molecular genetics studies, individual patient case reports, and animal model data from the Ppib-null mouse. Because OI type IX is extremely rare, the clinical literature consists primarily of small case series and individual family reports rather than large epidemiological cohorts.

2. Etiology

Disease Causal Factors

OI type IX is a monogenic disorder. It is caused exclusively by biallelic (homozygous or compound heterozygous) loss-of-function variants in PPIB (chromosome 15q22.31), the gene encoding cyclophilin B (CyPB). There are no established non-genetic causes. The disorder arises from deficiency of CyPB, which impairs post-translational modification of type I procollagen in the endoplasmic reticulum.

Genetic Risk Factors

• Causal gene: PPIB (HGNC:9239), chromosome 15q22.31
• Inheritance: Autosomal recessive — both copies of PPIB must be non-functional for disease to occur
• Carrier status: Heterozygous carriers are phenotypically unaffected
• Founder variants: A homozygous missense variant c.509G>A / p.Gly170Asp is specific to East Asian (predominantly Chinese) populations, with an allele frequency of ~0.000924 in gnomAD East Asian populations; estimated variant age ~65,160 years (PMID: 34659339)
• Consanguinity: Described in multiple consanguineous families given the rarity of null alleles

Pathogenic Variants Reported

Functional consequences: All reported variants result in absence or severe reduction of CyPB protein. Critically, CyPB loss is independent of its complex partners: in patient fibroblasts, P3H1 levels are substantially reduced (indicating P3H1 stability depends partially on CyPB), but CRTAP remains unaffected (PMID: 19781681).

Environmental Risk Factors

No environmental risk factors specifically modulate risk of OI type IX. As a Mendelian autosomal recessive disorder, risk is determined entirely by carrier status of parents. Advanced parental age is not a significant risk factor. Consanguinity increases the probability of biallelic inheritance in rare-allele families.

Protective Factors

No genetic protective factors have been identified that prevent disease expression once biallelic PPIB mutations are inherited. Modifier alleles affecting collagen processing could theoretically modulate severity but have not been systematically identified.

3. Phenotypes

OI type IX spans a spectrum from perinatal lethality to moderate deforming disease (PMID: 21282188). The majority of reported patients have severe-to-lethal phenotypes, but at least one molecularly confirmed patient without rhizomelia has had a moderate disease course.

Core Skeletal Phenotypes

Extraskeletal Phenotypes

Clinical Distinctive Features Vs. Other Recessive OI Types

A key distinguishing phenotypic feature is the absence of rhizomelia (proximal limb shortening) in OI type IX, contrasting with OI types VII (CRTAP) and VIII (LEPRE1/P3H1), which typically show rhizomelic shortening of upper extremities. As noted for the Native American patient: "There appears to be a trend toward rhizomelic shortening and less severe bowing of the extremities, as compared to patients with comparably severe OI caused by COL1A1 or COL1A2 mutation" (PMID: 27625864)—though one case did show prenatal rhizomelia, indicating phenotypic overlap.

Hearing Loss

Hearing loss management recommendations: "Patients with OI caused by PPIB mutation should have appropriate early and regular management of their hearing" (PMID: 27625864). Whether congenital sensorineural hearing loss is a true recurrent feature of OI type IX or represents a co-incidental finding remains uncertain given limited case numbers.

Onset and Severity

• Onset: Prenatal in severe/lethal cases (fractures visible on ultrasound in 2nd trimester); perinatal in lethal form; early postnatal in survivors
• Severity spectrum: Perinatal lethality (Sillence type II equivalent) to severe deforming (Sillence type III equivalent) to moderate
• Progression: Progressive deformity with growth; multiple fractures throughout childhood and potentially adulthood

4. Genetic / Molecular Information

Causal Gene

• Gene symbol: PPIB
• Gene full name: Peptidylprolyl isomerase B (cyclophilin B)
• HGNC ID: hgnc:9239
• OMIM Gene: #123841
• Chromosome location: 15q22.31
• Protein: Cyclophilin B (CyPB), 21 kDa
• Alternative gene names: CYP-S1, CYPB, HEL-S-39, SCYLP

Variant Classification

All reported disease-causing variants are classified pathogenic or likely pathogenic (ACMG/AMP criteria). The founder variant p.Gly170Asp received PM3, PM1 (change at pro-isomerase domain), and PP3 (REVEL score 0.94) evidence codes (PMID: 34659339).

Variant types reported: - Nonsense (PTC) - Frameshift (deletion) - Splice-site - Missense (affecting pro-isomerase domain)

All result in loss of function. Biochemical studies consistently reveal undetectable CyPB protein in patient fibroblasts from families with frameshift/nonsense mutations (PMID: 19781681).

Allele Frequency

• The c.509G>A / p.Gly170Asp Chinese founder allele frequency in gnomAD: 0.000924 in East Asian populations; absent in non-East Asian populations (PMID: 34659339)
• Other pathogenic alleles are extremely rare, below gnomAD detection thresholds or absent

Somatic vs. Germline

OI type IX is exclusively a germline disorder. Somatic mosaicism is theoretically possible but has not been documented in published literature.

Modifier Genes

No confirmed modifier genes have been described for OI type IX specifically. In the broader OI context, variants in BMP1, PLOD2, IFITM5, and other collagen-modifying genes have been considered modifiers, but these have not been specifically studied in PPIB-null disease.

Chromosomal Abnormalities

Not applicable; OI type IX is a point mutation / small insertion-deletion disorder without large-scale chromosomal changes.

5. Environmental Information

Environmental Factors

No specific environmental toxins, radiation, or occupational exposures are known to cause or exacerbate the molecular defect in OI type IX. As with all OI, secondary fracture risk may be modulated by environmental factors including fall risk, activity level, and calcium/vitamin D nutrition, but these do not alter the underlying genetic defect.

Lifestyle Factors

• Calcium and vitamin D supplementation are standard supportive measures for all OI patients
• Exercise programs (especially swimming, low-impact activities) are recommended to build muscle strength and improve mobility
• Contact sports are generally contraindicated

Infectious Agents

Respiratory infections are a significant complication (not cause) in patients with severe thoracic involvement. The Native American patient with lethal OI IX died at age 16 months from pneumonia (PMID: 27625864). Recurrent respiratory infections are a major source of morbidity in the severe phenotype.

6. Mechanism / Pathophysiology

The Prolyl 3-Hydroxylation Complex

The central pathophysiological mechanism in OI type IX is deficiency of cyclophilin B (CyPB), disrupting multiple post-translational modification steps of type I collagen in the endoplasmic reticulum.

CyPB (PPIB) functions as a component of a heterotrimeric complex with: 1. P3H1 (prolyl 3-hydroxylase 1, encoded by LEPRE1/P3H1) — the enzymatic hydroxylase 2. CRTAP (cartilage-associated protein) — structural scaffolding

This complex performs the 3-hydroxylation of proline at position 986 (P986) in the α1(I) chain of type I collagen — a modification essential for normal collagen fibril structure and bone mechanical properties.

Molecular functions of CyPB: - Peptidyl-prolyl cis-trans isomerase (PPIase) activity: CyPB is proposed to be the major PPIase catalyzing the rate-limiting step in collagen triple-helix formation, catalyzing cis-to-trans isomerization of proline imidic peptide bonds (proline constitutes ~20% of collagen residues) - Chaperone function: CyPB participates in ER chaperone complexes with BiP, GRP94, PDI, and calreticulin - Complex stabilization: CyPB is required for proper P3H1 retention/stability in cells; loss of CyPB leads to substantial reduction of P3H1 levels in patient fibroblasts

Collagen Modification Defects

Prolyl-3 hydroxylation: In PPIB-null patient fibroblasts, P986 3-hydroxylation is severely reduced (to ~33% of controls in OI IX, compared to 93–100% in controls). Paradoxically, this is less severe than in OI VII (CRTAP null, ~16%) and OI VIII (P3H1 null, ~22%), suggesting CyPB influences complex function but P3H1 retains partial activity without CyPB (PMID: 19781681). In the Ppib-KO mouse, only 5–11% of α1(I) P986 residues were hydroxylated in osteoblasts and fibroblasts, and 1–2% in tissue (PMID: 24968150).

Collagen folding delay: "Collagen folds more slowly in the absence of CyPB," with 5–8 minute delays in triple helix formation documented in Ppib-KO osteoblasts. This implicates CyPB as the predominant collagen PPIase, though residual CsA-sensitive activity (possibly FKBPs) provides partial redundancy (PMID: 24968150).

Lysyl hydroxylation defects — a distinctive biochemical signature: Beyond the prolyl-3 hydroxylation defect, CyPB deficiency creates tissue-specific dysregulation of helical lysyl hydroxylation and glycosylation by disrupting lysyl hydroxylase (LH) chaperone complexes: - In bone: site-specific underhydroxylation at crosslinking residues α1(I) K87 (57% vs. 98% in wild-type) and α2(I) K87 (45% vs. 77%), leading to an altered collagen crosslink profile - In skin: >80% decrease in total hydroxylysine; positive regulatory LH chaperones (FKBP65/Sc65/P3H3) drop to <11% of wild-type while negative regulator HSP47 increases - "CyPB deficiency profoundly affects Lys post-translational modifications of collagen likely by modulating LH chaperone complexes" (PMID: 30562343)

Crosslink abnormalities: In Ppib-KO bone: - Nearly 3-fold increase in the helical lysine-involved crosslink hydroxylysinonorleucine (HLNL) - Lysylpyridinoline (LP) increased 4–5-fold - HP/LP (hydroxylysylpyridinoline/lysylpyridinoline) ratio decreased 4.25- to 5.6-fold - Deoxy-HHMD and LNL (non-hydroxylysine crosslinks) form exclusively in KO tissue (PMID: 24968150)

These crosslink alterations reduce bone mechanical competence independently of the prolyl-3 hydroxylation defect.

ER trafficking defect: In CyPB-deficient fibroblasts, "a significant amount of collagen remained in the ER" rather than trafficking properly to the Golgi after ascorbic acid stimulation (PMID: 19997487), indicating disrupted intracellular collagen transport.

Reduced collagen deposition: Collagen deposited into insoluble extracellular matrix by Ppib-KO osteoblasts was decreased ~80%, linked to altered fibrillogenesis and abnormal fibril structure (PMID: 24968150).

Collagen Fibril Morphology

Transmission electron microscopy of Ppib-KO mice shows collagen fibrils are abnormally enlarged — on average 1.45 times wider than controls (114.6 ± 22.4 nm vs. 78.6 ± 12.4 nm diameter) (PMID: 19997487), indicating disrupted fibril assembly.

Causal Chain Summary

Biallelic PPIB loss-of-function mutation
    ↓
Absence of cyclophilin B (CyPB) in ER
    ↓
[Branch 1] Reduced P3H1 stability → decreased Pro-986 3-hydroxylation
[Branch 2] Disrupted PPIase activity → delayed collagen triple-helix folding
[Branch 3] Disrupted LH chaperone complexes → abnormal helical lysyl hydroxylation
    ↓
Altered collagen crosslink chemistry (LP↑, HP/LP ratio↓)
Abnormal fibril morphology (enlarged fibrils)
Reduced collagen matrix deposition
    ↓
Defective bone matrix organization and mechanical incompetence
    ↓
Severe osteoporosis, bone fragility, susceptibility to fractures

Cell Types and Biological Processes Involved

Primary cell types: - Osteoblasts (CL:0000062): Primary producers of type I collagen; most severely affected by CyPB deficiency - Chondrocytes (CL:0000138): Type II collagen also lacks Pro3-hydroxylation in KO mice - Fibroblasts (CL:0000057): Show ER retention of collagen and reduced P3H1 levels - Odontoblasts (CL:0000060): Involved in dentinogenesis imperfecta

GO Biological Processes: - Collagen fibril organization (GO:0030199) - Peptidyl-proline modification (GO:0018208) - Post-translational protein modification (GO:0043687) - Collagen biosynthetic process (GO:0032964) - Bone mineralization (GO:0030282) - Protein folding (GO:0006457) - Endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888)

GO Cellular Components: - Endoplasmic reticulum lumen (GO:0005788) - Collagen-containing extracellular matrix (GO:0062023) - Extracellular matrix (GO:0031012)

7. Anatomical Structures Affected

Skeletal System (Primary)

• Long bones (UBERON:0002492): Femur, tibia, humerus, radius, ulna — cortical thinning, bowing, fractures
• Spine (UBERON:0001617): Platyspondyly, kyphoscoliosis
• Skull (UBERON:0003129): Decreased calvarial ossification, wormian bones (sutural ossification)
• Ribs (UBERON:0002228): Fractures, narrow thorax
• Teeth (UBERON:0007759): Dentinogenesis imperfecta

Secondary Organ Involvement

• Lung / respiratory system (UBERON:0001004): Restrictive lung disease secondary to narrow chest; recurrent pneumonias in severe cases
• Ear (UBERON:0001690): Sensorineural hearing loss (cochlea); possibly also conductive component
• Eye / sclera (UBERON:0001827): Blue sclerae from abnormal scleral collagen
• Skin (UBERON:0002097): Documented loose/lax skin; abnormal collagen crosslinking

Tissue and Cell Level

• Bone tissue (UBERON:0002481): Primary affected tissue — osteoporotic cortical and trabecular bone
• Connective tissue (UBERON:0002384): Broadly affected given ubiquitous type I collagen
• Cartilage (UBERON:0002418): Type II collagen also affected in KO model

Subcellular Level

• Endoplasmic reticulum (GO:0005783): Site of CyPB action; collagen retained here in CyPB deficiency
• Golgi apparatus (GO:0005794): Impaired collagen trafficking
• Extracellular matrix (GO:0031012): Reduced collagen deposition, abnormal fibril assembly

8. Temporal Development

Onset

• Perinatal lethal form: Fractures present in utero (detectable by ultrasound at 2nd trimester); bowed long bones at birth; respiratory failure common
• Severe deforming (non-lethal) form: Fractures at birth or early infancy; wheelchair dependence by age 7 documented (PMID: 19781681)
• Moderate form: Onset with fractures in early childhood; slower progression

Progression

• Disease course: Chronic, progressive
• Fracture accumulation: Multiple fractures through childhood and adolescence, often with minimal trauma
• Deformity progression: Progressive kyphoscoliosis and long-bone deformity from repeated fracture-healing cycles
• Lifespan: Variable — perinatal lethality in severe cases; the Ppib-KO mouse has a lifespan of 40–50 weeks with progressive kyphosis (PMID: 19997487)

Critical Periods

• Prenatal period: Fracture accumulation in utero in severe cases
• Early childhood: Most critical for fracture management and mobility preservation; "The age at onset of long bone fractures is a critical predictor of future ambulatory ability"
• Puberty: BMD typically improves relative to childhood during growth but deformity may worsen

9. Inheritance and Population

Epidemiology

• Overall OI prevalence: ~1 in 15,000–20,000 births across all types
• OI type IX specifically: Extremely rare; estimated incidence in Chinese population ~1/1,000,000 (PMID: 34659339); worldwide frequency not established due to rarity
• Fraction of all OI: OI types caused by CRTAP, LEPRE1, and PPIB mutations collectively account for a small minority of OI cases (~5% of total OI); PPIB variants are the least common of the three

Inheritance Pattern

• Autosomal recessive (AR)
• Penetrance: Complete — biallelic loss-of-function results in disease
• Expressivity: Variable (perinatal lethal to moderate)
• Consanguinity: Multiple reported families involve parental consanguinity, consistent with AR inheritance of rare alleles

Founder Effect

• East Asian (Chinese) populations have a specific founder variant c.509G>A/p.Gly170Asp with estimated mutation age 65,160 years (~3,258 generations), implying spread from a single common ancestral haplotype. This provides the basis for targeted carrier screening in Chinese populations (PMID: 34659339).

Carrier Frequency

• Based on gnomAD data for the Chinese founder allele (AF ~0.000924), carrier frequency is approximately 1/540 in East Asian populations for this single variant
• No reliable carrier frequency data for global PPIB pathogenic variants

Sex Ratio

No sex predilection — autosomal recessive, affects males and females equally.

Geographic Distribution

OI type IX cases have been reported in multiple ethnic and geographic contexts: - North America (consanguineous families; one Native American family) - China/Taiwan (multiple families with founder variant) - Middle Eastern consanguineous families (not specifically OI IX, but recessive OI broadly)

10. Diagnostics

Clinical Criteria

No OI-type-IX-specific diagnostic criteria exist. Diagnosis follows the general OI diagnostic approach combined with molecular confirmation:

1. Clinical recognition of bone fragility with multiple fractures, ± blue sclerae, ± DI, ± hearing loss
2. Exclusion of non-accidental injury
3. Radiographic assessment (wormian bones, osteopenia, long-bone bowing, platyspondyly)
4. DXA bone mineral density (reduced Z-score for age/height)
5. Molecular genetic confirmation (PPIB sequencing)

Laboratory Tests

• Routine labs are typically normal in OI (including calcium, phosphate, alkaline phosphatase); ALP may be mildly elevated
• Collagen biochemical analysis: Electrophoretic analysis of type I collagen from fibroblast culture can show slightly delayed migration (from altered PTMs); may reveal reduced P3H1 complex function
• Pro-986 hydroxylation assay: Mass spectrometric analysis can demonstrate reduced Pro-986 3-hydroxylation in collagen from patient fibroblasts (33% vs. controls 93–100%) (PMID: 19781681)

Imaging

• Radiographs (X-ray): Primary modality — reveals osteopenia, long-bone bowing, fractures, platyspondyly, wormian bones
• Prenatal ultrasound: Short/bowed long bones in severe cases detectable in 2nd trimester
• DXA: Quantitative BMD measurement; height-adjusted Z-scores used in children; reveals severely reduced BMD
• CT: For assessment of scoliosis, basilar invagination

Genetic Testing

• Preferred approach: Next-generation sequencing (NGS) gene panel for OI-related genes (includes COL1A1, COL1A2, PPIB, CRTAP, LEPRE1/P3H1, and others)
• Whole exome sequencing (WES): Highly effective; identified novel PPIB variants in multiple families (PMID: 34659339: average WES coverage 242×)
• Sanger sequencing: Targeted confirmation of variants and parental carrier testing
• ACMG/AMP classification: All reported PPIB variants are pathogenic or likely pathogenic
• Carrier testing: Targeted Sanger sequencing of familial variant for parental/sibling testing
• Prenatal diagnosis: Chorionic villus sampling or amniocentesis with targeted PPIB analysis is feasible once familial variant is known

Available genetic tests: NIH GTR lists 34 clinical tests for OI type IX conditions, including sequence analysis (31 tests), deletion/duplication analysis (18), and targeted variant analysis (7).

Differential Diagnosis

11. Outcome / Prognosis

Survival and Mortality

• Perinatal lethal form (Type II-equivalent): Death in utero or within days of birth from respiratory failure secondary to rib fractures and pulmonary hypoplasia
• Severe deforming form (Type III-equivalent): Variable survival; one reported patient died at 16 months from pneumonia (PMID: 27625864); survival into adulthood possible with intensive support
• Life expectancy: Not established for OI IX specifically; severe OI overall has significantly reduced life expectancy, primarily from pulmonary and neurological complications (basilar invagination)

Morbidity

• Mobility: Progressive loss of ambulatory ability in severe cases; wheelchair dependence may occur by mid-childhood
• Respiratory: Restrictive lung disease is a major cause of morbidity and death in severe cases
• Hearing: Early-onset bilateral sensorineural hearing loss documented; requires audiological follow-up
• Chronic pain: From recurrent fractures and skeletal deformity

Prognostic Factors

• Severity of skeletal phenotype at birth — most important prognostic indicator
• Achievement of motor milestones — children achieving independent sitting/standing by age 12 have better ambulatory prognosis
• Spinal deformity — severe kyphoscoliosis worsens pulmonary and cardiovascular prognosis
• Response to bisphosphonate treatment — improves BMD and may reduce fracture rate

12. Treatment

Bisphosphonate Therapy (Standard of Care)

Bisphosphonates are the most established pharmacological treatment across all OI types, including recessive forms:

• Intravenous pamidronate: Most widely used in children; typical regimen 1–3 mg/kg every 3–4 months; reduces fracture rate and improves lumbar spine BMD (~25% annual increase in young children); PMID: 25054949
• Intravenous zoledronic acid: 0.05 mg/kg/dose; comparable efficacy to pamidronate with fewer infusions; both increase lumbar spine BMD (51.8% vs. 67.6% respectively)
• Oral alendronate: Alternative for milder cases
• Duration: Typically continued through childhood growth; drug holiday considered after reaching final height

No PPIB-specific pharmacological trials exist; bisphosphonate data for OI IX is extrapolated from broader OI studies.

MAXO term: MAXO:0000647 (chemotherapy) — not applicable; pharmacotherapy with bisphosphonates: NCIT:C15986 (Pharmacotherapy); specific agents: CHEBI:60753 (pamidronate), CHEBI:74699 (zoledronic acid)

Emerging Pharmacological Treatments

• Setrusumab (UX143): Anti-sclerostin monoclonal antibody promoting bone formation; Phase 2b ASTEROID trial showed BMD improvement in adult OI; Phase 3 ORBIT and COSMIC trials missed primary endpoint (fracture rate reduction) but achieved secondary endpoints (BMD increase); FDA Breakthrough Therapy designation granted. No specific data for OI IX.
• Anti-TGF-β antibodies (fresolimumab): Preclinical studies showing promise in OI mouse models
• 4-Phenylbutyrate (4-PBA): Chemical chaperone shown to rescue ER stress in recessive OI zebrafish models; targets the cellular stress from impaired prolyl hydroxylation complex
• Denosumab: Anti-RANKL antibody; small studies in severe pediatric OI; not standard

MAXO term: MAXO:0000950 (supportive care) for symptom management

Surgical Management

• Intramedullary rodding (telescoping rods — Fassier-Duval, Bailey-Dubow): Prophylactic stabilization of femora/tibiae prone to bowing and fracture; telescoping rods accommodate growth; telescopic nailing significantly reduces fracture rates (33.3% vs. 75%) and deformity rates (23.3% vs. 50%) vs. traditional nails
• Osteotomy with internal fixation: For correction of severe long-bone deformity
• Spinal surgery: For severe progressive scoliosis (>40–50°); high complication risk given osteoporotic bone

MAXO term: MAXO:0000004 (surgical procedure)

Supportive Care

• Physiotherapy: Aquatic therapy, low-impact exercise; improves muscle strength and mobility; MAXO:0000011 (physical therapy)
• Occupational therapy: Adaptive equipment, fall prevention
• Calcium and Vitamin D supplementation: Standard nutritional support
• Hearing aids / audiological management: For sensorineural hearing loss; recommended for all PPIB-OI patients (PMID: 27625864)
• Respiratory support: Supplemental oxygen, ventilatory assistance in severe cases

Gene Therapy (Preclinical)

• AAV-based gene editing for collagen mutations is in preclinical development; no specific PPIB-targeted gene therapy trials
• CRISPR/Cas9 and gene addition approaches are in animal model testing
• Stem cell therapy (mesenchymal stem cell transplantation — BOOSTB4 trial) is under investigation for severe OI, potentially applicable to recessive forms

13. Prevention

Primary Prevention

• Genetic counseling for families with a known PPIB mutation — essential before further pregnancies (MAXO:0000079 genetic counseling)
• Cascade screening of siblings and relatives of affected individuals and known carriers
• Preimplantation genetic diagnosis (PGD): Available for couples where both are identified carriers

Secondary Prevention (Early Detection)

• Prenatal diagnosis: Molecular analysis of CVS or amniocentesis for known familial PPIB variants; prenatal ultrasound for skeletal dysplasia signs in at-risk pregnancies
• Newborn screening: Not currently part of national newborn screening programs; no metabolite-based test exists; diagnosis requires clinical suspicion + genetic testing
• Founder variant carrier screening: In East Asian (Chinese) populations, screening for the c.509G>A/p.Gly170Asp founder allele may be considered in preconception or prenatal settings given carrier frequency ~1/540

Tertiary Prevention (Preventing Complications)

• Fracture prevention: Bisphosphonate therapy, intramedullary rodding, avoidance of contact sports
• Hearing loss monitoring: Audiological testing at diagnosis and regular follow-up
• Respiratory monitoring: Pulmonary function tests; prompt treatment of respiratory infections
• Scoliosis surveillance: Regular spinal imaging; early intervention when curvature progresses
• Nutritional optimization: Calcium, Vitamin D, protein intake

14. Other Species / Natural Disease

Animal Models

OI type IX is not documented as a naturally occurring disease in veterinary species. The PPIB orthologue is highly conserved across mammals.

NCBI Taxon: Mus musculus (10090) — primary model

15. Model Organisms

Ppib Knockout Mouse Model

The Ppib-null (cyclophilin B-deficient) mouse is the principal model organism for OI type IX and was characterized by Choi et al. (PMID: 19997487):

Phenotype: - Severe osteopenia with dramatically reduced trabecular bone volume - Increased trabecular separation, reduced trabecular number - Progressive kyphosis, evident by 8 weeks, progressively worsening - Reduced body size and weight - Lifespan 40–50 weeks - Loose, lax skin (Ehlers-Danlos-like properties) - Normal femur-to-tibia ratios (no rhizomelia) - Normal fertility and birth appearance

Collagen findings: - Abnormally enlarged collagen fibrils (114.6 ± 22.4 nm vs. 78.6 ± 12.4 nm in controls) — "on average 1.45 times wider than similar samples from littermate control mice" (PMID: 19997487) - Near-total loss of Pro-986 3-hydroxylation (1–5% vs. near-100% in controls) - Severely disrupted helical lysyl hydroxylation and crosslink pattern (PMID: 24968150) - 80% reduction in collagen matrix deposition by osteoblasts - Reduced total skin collagen content; reduced skin tensile strength

Molecular findings: - P3H1 levels substantially reduced; CRTAP levels unaffected — demonstrating CyPB-dependent P3H1 stabilization - Collagen retained in ER rather than trafficking to Golgi - Residual collagen PPIase activity attributable to cyclosporine A-sensitive enzymes (suggesting FKBP redundancy)

Model limitations (Human-Model Mismatch considerations): - Mice do not show rhizomelia observed in some human cases - Mouse lifespan (40–50 weeks) and the degree of phenotypic severity may not fully recapitulate the human perinatal lethal form - Mice show pronounced skin laxity; this is less well-documented in human patients - Mouse bone biology differs from human (faster remodeling, different cortical organization)

Genetic model type: Constitutive knockout (whole-body Ppib deletion)

Available resources: - MGI: Available through IMPC and KOMP2 programs - JAX: Ppib-null alleles available for research

Summary of Key Evidence Citations

Suggested MONDO ID: MONDO:0012978 (Osteogenesis imperfecta type IX)

Key HPO terms: - HP:0002757 (Recurrent fractures) - HP:0000939 (Osteoporosis) - HP:0002645 (Wormian bones) - HP:0002808 (Kyphosis) - HP:0002650 (Scoliosis) - HP:0000592 (Blue sclerae) - HP:0000703 (Dentinogenesis imperfecta) - HP:0000407 (Sensorineural hearing impairment) - HP:0004322 (Short stature) - HP:0001382 (Joint hypermobility) - HP:0000926 (Platyspondyly)

Key GO terms (Biological Process): - GO:0030199 (Collagen fibril organization) - GO:0018208 (Peptidyl-proline modification) - GO:0032964 (Collagen biosynthetic process) - GO:0006457 (Protein folding)

Key CL terms: - CL:0000062 (Osteoblast) - CL:0000057 (Fibroblast) - CL:0000138 (Chondrocyte)

Sources: - PPIB Mutations Cause Severe Osteogenesis Imperfecta (PMC2756556) - Severe Osteogenesis Imperfecta in Cyclophilin B–Deficient Mice (PMC2777385) - Abnormal Type I Collagen PTM and Crosslinking in Cyclophilin B KO Mouse (PMC4072593) - Osteogenesis imperfecta caused by PPIB mutation with congenital hearing loss (PMC5020983) - A Founder Pathogenic Variant of PPIB Unique to Chinese Population (PMC8511635) - Cyclophilin B control of lysine PTMs of skin type I collagen (PMC6602281) - Osteogenesis Imperfecta - StatPearls (NBK536957) - OMIM #259440 — Osteogenesis Imperfecta, Type IX - NIH GTR — Osteogenesis imperfecta type 9 - Setrusumab for OI — Phase 2b ASTEROID Study (PMC11371902) - Mutations in PPIB delay procollagen chain association (HMG, PMID:21282188) - Bisphosphonate therapy for osteogenesis imperfecta (PMC6611487)

1. Disease Information

Overview

Osteogenesis Imperfecta Type IX (OI type IX) is an autosomal recessive form of osteogenesis imperfecta, a heritable skeletal dysplasia characterized by bone fragility, skeletal deformity, and growth deficiency (jovanovic2024updateonthe pages 8-9). OI type IX is caused by biallelic mutations in the PPIB gene (MIM 123841), which encodes cyclophilin B (CyPB), a 21-kDa endoplasmic reticulum (ER)-resident peptidyl-prolyl cis-trans isomerase (PPIase) (dijk2009ppibmutationscause pages 1-2). The disease was first described in 2009 when van Dijk et al. reported the initial two families with PPIB mutations causing severe OI (dijk2009ppibmutationscause pages 1-2).

The following table summarizes the key disease characteristics:

Table: This table summarizes the core disease characteristics of Osteogenesis Imperfecta Type IX, including genetics, clinical presentation, mechanism, rarity, model systems, and current management. It is useful as a compact knowledge-base style overview anchored to cited evidence from the retrieved literature.

Key Identifiers

• OMIM Phenotype: 259440 (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, pyott2011mutationsinppib pages 1-2)
• OMIM Gene: PPIB, 123841
• ICD-10: Q78.0 (Osteogenesis imperfecta, general)
• MONDO: MONDO:0013329 (osteogenesis imperfecta type 9)
• Orphanet: ORPHA:2769 (classified under rare OI forms)

Synonyms

• Osteogenesis Imperfecta Type 9
• OI Type IX
• PPIB-related Osteogenesis Imperfecta
• Cyclophilin B-deficient OI

Information Source

The information is derived from aggregated disease-level resources including landmark genetic studies, reviews, and animal model characterization, rather than individual patient electronic health records.

2. Etiology

Disease Causal Factors

OI type IX is a monogenic disorder caused exclusively by homozygous or compound heterozygous loss-of-function mutations in the PPIB gene (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, pyott2011mutationsinppib pages 2-3). There are no known environmental or infectious etiological components. The disease is purely genetic in origin, arising from defects in the collagen biosynthetic machinery (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4).

Genetic Risk Factors

• Causal gene: PPIB (peptidyl-prolyl cis-trans isomerase B), located on chromosome 15q22.31 (pyott2011mutationsinppib pages 2-3)
• Causal variants: Frameshift deletions, nonsense mutations, splice-site mutations, and start-codon substitutions in PPIB (pyott2011mutationsinppib pages 4-5, pyott2011mutationsinppib pages 3-4, cotti2025moleculardriversof pages 9-10)
• Inheritance: Autosomal recessive; both parents must be heterozygous carriers (pyott2011mutationsinppib pages 3-4)
• Consanguinity role: At least one of the originally reported families (van Dijk family 2) involved consanguineous Pakistani parents (first cousins), consistent with the autosomal recessive inheritance pattern (dijk2009ppibmutationscause pages 2-3)

Environmental Risk Factors

No specific environmental risk factors have been identified for OI type IX. As a congenital genetic disorder, the disease manifests independently of environmental exposures. However, environmental factors such as trauma, inadequate nutrition (particularly calcium and vitamin D deficiency), and immobilization may exacerbate fracture risk in affected individuals.

Protective Factors

No genetic or environmental protective factors specific to OI type IX have been identified. General bone health measures (adequate nutrition, weight-bearing activity when possible) may offer modest benefit as in all forms of OI.

Gene-Environment Interactions

No specific gene-environment interactions have been described for OI type IX.

3. Phenotypes

Clinical Features

OI type IX presents with a phenotypic spectrum ranging from moderate to perinatal lethal disease, clinically compatible with Sillence type II-B/III OI (dijk2009ppibmutationscause pages 1-2). The condition is generally described as less severe than OI types VII (CRTAP) and VIII (P3H1), and notably occurs without rhizomelia (cotti2025moleculardriversof pages 9-10).

Skeletal phenotype (HP:0000924 – Abnormality of the skeletal system): - Bone fragility / recurrent fractures (HP:0002757): Multiple long-bone fractures, often with prenatal or neonatal onset. Fractures of humeri, radii, ulna, femora, tibiae, and fibula with callus formation have been reported (dijk2009ppibmutationscause pages 2-3, dijk2009ppibmutationscause pages 1-2). Frequency: virtually 100% of affected individuals. - Bowed long bones (HP:0002982): Bowing of femora, tibiae, ulnae, and anterior bowing of tibiae are consistent findings (dijk2009ppibmutationscause pages 2-3, cotti2025moleculardriversof pages 9-10). Frequency: high, >90%. - Short stature (HP:0004322): Severe growth deficiency. One patient at age 8 years had a height of 79.9 cm (SDS −8.4), corresponding to the 50th percentile for a 17-month-old child. Another patient at 6 months measured 47.4 cm (SDS −8.8) (dijk2009ppibmutationscause pages 2-3). - Scoliosis / Kyphoscoliosis (HP:0002650, HP:0002751): Kyphoscoliosis of thoracic and lumbar spine was evident in reported patients (dijk2009ppibmutationscause pages 2-3, cotti2025moleculardriversof pages 9-10). - Abnormal rib morphology (HP:0000772): Discontinuously beaded ribs, slender ribs, and small bell-shaped thorax have been described (dijk2009ppibmutationscause pages 2-3, dijk2009ppibmutationscause pages 1-2). - Platyspondyly (HP:0000926): Described in some patients (pyott2011mutationsinppib pages 3-4). - Decreased calvarial mineralization (HP:0100252): Near-absence of calvarial mineralization described in severe cases (pyott2011mutationsinppib pages 3-4). - Large anterior fontanelle (HP:0000260): Noted in affected neonates (dijk2009ppibmutationscause pages 2-3).

Non-skeletal features: - Gray sclerae (HP:0000592): Gray-colored sclerae typical of severe OI were noted in at least one patient, not the distinctly blue sclerae of OI type I (dijk2009ppibmutationscause pages 2-3). - No dentinogenesis imperfecta: Absence of dentinogenesis imperfecta was specifically noted in at least one patient (dijk2009ppibmutationscause pages 2-3). - Joint hypermobility (HP:0001382): Hypermobility of joints, especially hip and finger joints, was observed (dijk2009ppibmutationscause pages 2-3, cotti2025moleculardriversof pages 9-10). - Motor developmental delay (HP:0001270): Gross motor development was delayed; one patient achieved unsupported sitting at age 2.5 years and standing with support at age 4.5 years, and never walked independently (dijk2009ppibmutationscause pages 2-3). - Skin laxity: Loose, thin skin similar to OI patients has been observed in animal models (choi2009severeosteogenesisimperfecta pages 2-3, choi2009severeosteogenesisimperfecta pages 3-5).

HPO Terms

• HP:0002757 – Recurrent fractures
• HP:0002982 – Bowed long bones
• HP:0004322 – Short stature
• HP:0002650 – Scoliosis
• HP:0002751 – Kyphosis
• HP:0000772 – Abnormal rib morphology
• HP:0001382 – Joint hypermobility
• HP:0000592 – Blue/gray sclerae
• HP:0001270 – Motor delay
• HP:0000926 – Platyspondyly
• HP:0100252 – Decreased calvarial mineralization
• HP:0000260 – Wide anterior fontanelle

Quality of Life Impact

Patients with OI type IX experience severe impairment in mobility and activities of daily living. The most severely affected children are wheelchair-dependent and unable to ambulate independently (dijk2009ppibmutationscause pages 2-3). Chronic fractures, skeletal deformity, and short stature profoundly affect quality of life. Perinatal lethal forms preclude survival.

4. Genetic/Molecular Information

Causal Gene

PPIB (Peptidyl-Prolyl Isomerase B; HGNC:9255; OMIM 123841), located on chromosome 15q22.31, comprises 5 exons and encodes a 216-amino acid protein (pyott2011mutationsinppib pages 2-3, pyott2011mutationsinppib pages 3-4). The gene product, cyclophilin B (CyPB), is an ER-resident PPIase belonging to the cyclophilin family, with roles in collagen folding, prolyl 3-hydroxylation, inflammation, viral infection, and cancer (dijk2009ppibmutationscause pages 1-2, jovanovic2024updateonthe pages 8-9).

Pathogenic Variants

The following table details the specific PPIB mutations reported in OI type IX patients:

Table: This table summarizes the reported PPIB variants associated with osteogenesis imperfecta type IX, including their molecular class, predicted effect on cyclophilin B, and associated clinical severity. It is useful for linking genotype to mechanism and phenotype across the key early case series and later review evidence.

Key variant types include: - Frameshift deletions: c.556_559delAAGA (p.Lys186GlnfsX8), c.414_423del (p.Ser139ThrfsX21), c.120delC (dijk2009ppibmutationscause pages 2-3, pyott2011mutationsinppib pages 4-5, pyott2011mutationsinppib pages 3-4) - Nonsense: c.451C>T (p.Gln151X) (dijk2009ppibmutationscause pages 3-6) - Splice-site: c.343+1G>A (IVS3+1G>A) (pyott2011mutationsinppib pages 4-5) - Missense (compound heterozygous): c.313G>A (p.Gly105Arg) (pyott2011mutationsinppib pages 5-6) - Start codon substitution: Arg-to-Met substitution affecting translation initiation (cotti2025moleculardriversof pages 9-10)

All reported variants are classified as pathogenic and result in absent or severely reduced CyPB protein levels (dijk2009ppibmutationscause pages 3-6, pyott2011mutationsinppib pages 5-6). The variants are germline in origin. Population allele frequencies in gnomAD are expected to be extremely low or absent, consistent with ultra-rare recessive disease.

Functional Consequences

PPIB mutations predominantly cause loss of function through: 1. Nonsense-mediated mRNA decay (NMD) leading to absent protein (pyott2011mutationsinppib pages 4-5, pyott2011mutationsinppib pages 3-4) 2. Protein truncation/instability with undetectable CyPB on western blot (dijk2009ppibmutationscause pages 3-6, pyott2011mutationsinppib pages 4-5) 3. Marked reduction of CyPB protein with residual partial function in compound heterozygotes (pyott2011mutationsinppib pages 5-6)

Notably, PPIB mutations do not destabilize the other complex members CRTAP and P3H1; immunohistochemistry of bone tissue from PPIB-mutant patients showed positive staining for both CRTAP and P3H1, despite absent CyPB signal (dijk2009ppibmutationscause pages 3-6). This contrasts with CRTAP or LEPRE1 (P3H1) mutations, where the partner proteins are also destabilized.

Modifier Genes

No specific modifier genes have been identified for OI type IX.

Epigenetic Information

No disease-specific epigenetic modifications have been described for OI type IX.

5. Environmental Information

OI type IX is a purely genetic disorder with no identified environmental causal factors, lifestyle contributors, or infectious agents. General bone health optimization (nutrition, vitamin D, calcium, and avoidance of high-impact trauma) is recommended as supportive management.

6. Mechanism / Pathophysiology

Molecular Pathways

CyPB participates in multiple interconnected pathways relevant to collagen biosynthesis:

1. Prolyl 3-Hydroxylation Complex (GO:0030867 – rough endoplasmic reticulum membrane): CyPB forms a 1:1:1 complex with P3H1 (encoded by LEPRE1) and CRTAP in the ER, responsible for 3-hydroxylation of proline at position 986 (Pro986) in the α1 chains of type I collagen (dijk2009ppibmutationscause pages 1-2, cabral2014abnormaltypei pages 1-2). In PPIB-deficient patients, Pro986 3-hydroxylation is reduced to approximately 30% of control levels (compared to 16% in CRTAP-deficient and 22% in P3H1-deficient patients) (dijk2009ppibmutationscause pages 3-6). In Ppib knockout mice, 3-hydroxylation is essentially absent (2–11% residual activity) (cabral2014abnormaltypei pages 1-2).

2. Peptidyl-Prolyl Cis-Trans Isomerization (GO:0003755): CyPB catalyzes the cis-trans isomerization of prolyl-peptide bonds, which is the rate-limiting step in collagen triple helix folding (cabral2014abnormaltypei pages 1-2). Loss of CyPB delays collagen folding, leading to extended exposure of unfolded procollagen chains to modifying enzymes (hydroxylases and glycosyltransferases), resulting in overmodification of the collagen triple helix (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, cotti2025moleculardriversof pages 7-9).

3. Procollagen Chain Association and C-Propeptide Folding: CyPB facilitates folding of the proline-rich C-terminal propeptide regions required for procollagen chain association. Loss of CyPB causes slow incorporation of proα1(I) chains into trimers (pyott2011mutationsinppib pages 1-2).

4. Lysyl Hydroxylation and Collagen Crosslinking: CyPB indirectly regulates lysyl hydroxylase 1 (LH1/PLOD1) activity. In CyPB-deficient mice and cells, site-specific helical lysine hydroxylation is altered, particularly at the critical crosslinking residue K87, which shows significantly reduced hydroxylation (~20% unhydroxylated vs. <1% in wild-type) (cabral2014abnormaltypei pages 12-13, cabral2014abnormaltypei pages 6-8). This leads to increased underhydroxylated crosslinks, altered HP/LP (hydroxylysyl pyridinoline/lysyl pyridinoline) crosslink ratios, and ultimately compromised collagen fiber integrity and bone strength (cabral2014abnormaltypei pages 12-13, cabral2014abnormaltypei pages 1-2).

Cellular Processes

ER Stress and Unfolded Protein Response (UPR): Overmodified procollagen accumulates in the ER, where it binds to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1), triggering ER stress and UPR activation (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, jovanovic2024updateonthe pages 15-16). Application of the chaperone 4-phenylbutyrate (4-PBA) has been shown to decrease UPR and ameliorate cellular homeostasis in OI patient fibroblasts with prolyl 3-hydroxylation complex defects (jovanovic2024updateonthe pages 15-16).

Impaired Procollagen Trafficking: In CyPB-deficient cells, procollagen fails to properly localize to the Golgi apparatus and instead accumulates in the ER (choi2009severeosteogenesisimperfecta pages 1-2, choi2009severeosteogenesisimperfecta pages 2-3). CyPB normally traverses the ER with procollagen into pre-Golgi intermediate vesicles, facilitating procollagen export (jovanovic2024updateonthe pages 19-20).

Abnormal Collagen Fibrillogenesis: Collagen fibrils in CyPB-deficient tissues exhibit abnormal morphology, with fibrils approximately 1.45 times wider than normal (114.6 nm vs. 78.6 nm diameter) (choi2009severeosteogenesisimperfecta pages 2-3). Collagen deposition into the extracellular matrix is decreased in CyPB-deficient cells (cabral2014abnormaltypei pages 1-2).

GO Terms for Biological Processes

• GO:0032502 – developmental process
• GO:0001503 – ossification
• GO:0006457 – protein folding
• GO:0003755 – peptidyl-prolyl cis-trans isomerase activity
• GO:0030867 – rough endoplasmic reticulum membrane
• GO:0030199 – collagen fibril organization
• GO:0018401 – peptidyl-proline hydroxylation to 4-hydroxy-L-proline

CL Terms for Cell Types

• CL:0000062 – osteoblast
• CL:0000138 – fibroblast
• CL:0000092 – osteocyte
• CL:0000137 – osteoclast (involved in bone remodeling response)

7. Anatomical Structures Affected

Organ Level

• Primary organs: Skeletal system (bones), including long bones, vertebrae, ribs, skull (UBERON:0001474 – bone element)
• Secondary involvement: Connective tissues broadly, including skin (loose/thin skin observed) (choi2009severeosteogenesisimperfecta pages 2-3, choi2009severeosteogenesisimperfecta pages 3-5); potential respiratory compromise due to thoracic deformity
• Body systems: Musculoskeletal system primarily; potential cardiovascular and respiratory involvement as secondary complications in severe OI generally (jovanovic2024updateonthe pages 16-17)

Tissue and Cell Level

• Tissue types: Bone (UBERON:0002481), cartilage, connective tissue (dermis)
• Cell populations: Osteoblasts (CL:0000062 – primary bone-forming cells affected), fibroblasts (CL:0000138), chondrocytes

Subcellular Level

• Endoplasmic reticulum (GO:0005783): Primary site of CyPB function; procollagen accumulation and ER stress occur here (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, choi2009severeosteogenesisimperfecta pages 1-2)
• Golgi apparatus (GO:0005794): Impaired procollagen trafficking to Golgi (choi2009severeosteogenesisimperfecta pages 1-2)
• Extracellular matrix (GO:0031012): Abnormal collagen deposition, fibril formation, and crosslinking (cabral2014abnormaltypei pages 1-2)

UBERON Terms

• UBERON:0002481 – bone tissue
• UBERON:0001474 – bone element
• UBERON:0000004 – nose (craniofacial)
• UBERON:0001137 – dorsum (spine/kyphosis)
• UBERON:0002229 – femur
• UBERON:0004247 – rib

8. Temporal Development

Onset

• Age of onset: Congenital; fractures are typically detected prenatally (by 20 weeks gestation on ultrasound) or at birth (dijk2009ppibmutationscause pages 2-3). In the most severe cases, pregnancy termination occurred at 16–22 weeks after prenatal diagnosis (dijk2009ppibmutationscause pages 2-3).
• Onset pattern: Congenital with chronic progressive course

Progression

• Disease course: Chronic, lifelong, progressive skeletal deformity with ongoing fracture risk (cotti2025moleculardriversof pages 9-10)
• Progression rate: Variable; some patients survive infancy and childhood with progressive deformity (scoliosis, bowing), while others die perinatally (dijk2009ppibmutationscause pages 2-3, pyott2011mutationsinppib pages 1-2)
• Milestones in reported patients: One patient (P2-1, van Dijk family 2) had no new fractures between birth and age 3 years while on pamidronate therapy, achieved unsupported sitting at age 2.5 years, standing with support at 4.5 years, and remained wheelchair-dependent at age 7 years (dijk2009ppibmutationscause pages 2-3)

Critical Periods

• Prenatal period is critical for diagnosis (ultrasound detection of fractures/bowing)
• Growth periods in childhood represent windows for maximal bisphosphonate benefit (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8)

9. Inheritance and Population

Epidemiology

• Overall OI prevalence: Approximately 1 in 15,000–20,000 births worldwide (chetty2021theevolutionof pages 5-6)
• OI type IX prevalence: Ultra-rare; only a handful of families have been reported since the initial description in 2009. The initial reports included 2 families (4 affected individuals) by van Dijk et al. (2009) and 3 additional families by Pyott et al. (2011) (dijk2009ppibmutationscause pages 1-2, pyott2011mutationsinppib pages 3-4). Additional cases have been reported subsequently, including a Chinese pedigree (Jiang et al. 2017, not fully available in current search).
• Proportion of OI: Recessive forms collectively account for approximately 10% of all OI cases, with PPIB mutations representing an extremely small fraction of these (chetty2021theevolutionof pages 5-6)

Inheritance Pattern

• Autosomal recessive (AR) (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4, pyott2011mutationsinppib pages 3-4)
• Penetrance: Complete in homozygotes/compound heterozygotes for pathogenic variants
• Expressivity: Variable; phenotype ranges from moderate OI to perinatal lethal (jovanovic2024updateonthe pages 8-9, pyott2011mutationsinppib pages 1-2)
• Carrier frequency: Unknown but expected to be extremely low
• Consanguinity: Consanguinity has been documented in at least one family (first-cousin Pakistani parents) (dijk2009ppibmutationscause pages 2-3)
• Geographic distribution: Cases reported from diverse ethnic backgrounds including North European and Pakistani families (dijk2009ppibmutationscause pages 2-3), and Chinese families
• Sex ratio: No sex predilection; males and females equally affected (autosomal inheritance)

10. Diagnostics

Clinical Tests

• Radiographic findings (imaging): Skeletal surveys reveal shortened/bowed long bones, fractures with callus formation, discontinuously beaded ribs, bell-shaped thorax, platyspondyly, irregular metaphyses, decreased calvarial mineralization, and osteopenia (dijk2009ppibmutationscause pages 2-3, pyott2011mutationsinppib pages 3-4, dijk2009ppibmutationscause pages 1-2)
• Bone densitometry (DXA): Decreased bone mineral density (BMD) Z-scores (dijk2014osteogenesisimperfectaclinical pages 5-7)
• Collagen electrophoresis: Overmodification of type I collagen (slower electrophoretic migration) on SDS-PAGE analysis of fibroblast-produced collagen, with normal thermal stability—distinguishing it from dominant collagen mutations (pyott2011mutationsinppib pages 2-3, pyott2011mutationsinppib pages 1-2)
• Prenatal ultrasound: Advanced ultrasound at 20 weeks gestation can detect long-bone fractures and bowing (dijk2009ppibmutationscause pages 2-3)

Genetic Testing

• Recommended approach: Next-generation sequencing (NGS) gene panels for OI-related genes including COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, IFITM5, and other known OI genes (dinulescu2024newperspectivesof pages 2-4)
• Whole exome sequencing (WES): Useful for identifying PPIB mutations, particularly in cases where standard collagen gene testing is negative
• Single gene testing: Sanger sequencing of PPIB (5 exons and adjacent intronic sequences) can confirm suspected mutations (dijk2009ppibmutationscause pages 2-3)
• Confirmation: Western blot analysis using anti-CyPB antibodies can confirm absence or reduction of CyPB protein (dijk2009ppibmutationscause pages 3-6, pyott2011mutationsinppib pages 5-6)

Differential Diagnosis

• OI type VII (CRTAP mutations): Similar phenotype but typically more severe, with rhizomelia
• OI type VIII (P3H1/LEPRE1 mutations): Similar phenotype, generally more severe
• OI types I–IV (COL1A1/COL1A2 mutations): Dominant inheritance pattern
• OI type X (SERPINH1/HSP47 mutations): Autosomal recessive, severe
• Bruck syndrome (FKBP10/PLOD2 mutations): OI with congenital contractures

Key distinguishing features of OI type IX include: autosomal recessive inheritance, absence of rhizomelia, generally milder than types VII/VIII, partial preservation of Pro986 3-hydroxylation in some patients, and CRTAP/P3H1 proteins remaining stable despite CyPB deficiency (dijk2009ppibmutationscause pages 3-6, cotti2025moleculardriversof pages 9-10).

11. Outcome/Prognosis

Survival and Mortality

• Severity spectrum: Ranges from perinatal lethal (pregnancies terminated at 16–22 weeks, or neonatal death) to long-term survival with severe disability (dijk2009ppibmutationscause pages 2-3, pyott2011mutationsinppib pages 1-2)
• Surviving patients: Some patients survive into childhood and beyond with moderate to severe OI. One patient was alive and wheelchair-dependent at age 8 years (dijk2009ppibmutationscause pages 2-3); another (Pyott P3) had stable scoliosis at age 16 years (pyott2011mutationsinppib pages 3-4)
• Mouse model lifespan: Ppib−/− mice have a typical lifespan of 40–50 weeks, compared to normal mouse lifespan, indicating significant life-shortening effect of CyPB deficiency (choi2009severeosteogenesisimperfecta pages 2-3)

Morbidity and Function

• Wheelchair dependence in surviving severely affected patients (dijk2009ppibmutationscause pages 2-3)
• Progressive skeletal deformity limiting mobility
• Chronic bone pain requiring management
• Respiratory compromise potential from thoracic deformity

Complications

• Progressive kyphoscoliosis
• Respiratory insufficiency (major cause of mortality in severe OI generally) (jovanovic2024updateonthe pages 16-17)
• Potential cardiovascular complications as in other severe OI types (jovanovic2024updateonthe pages 16-17)

12. Treatment

Pharmacotherapy

Bisphosphonates (MAXO:0001298 – bisphosphonate administration): - Intravenous pamidronate has been directly used in reported OI type IX patients. One patient (P2-1) received 0.5 mg/kg/day IV pamidronate for 3 consecutive days every 6 weeks, starting at age 2 weeks; another (P2-2) commenced pamidronate shortly after birth (dijk2009ppibmutationscause pages 2-3) - Bisphosphonates bind to hydroxyapatite crystals and induce osteoclast apoptosis, reducing bone resorption and increasing bone mass (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8) - IV bisphosphonate therapy has positive effects on skeletal pain, bone mass, and mobility in OI generally, though reduction in fracture rate has not been conclusively demonstrated in controlled trials (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, dwan2016bisphosphonatetherapyfor pages 5-6) - It is not clear whether patients with recessive OI respond identically to those with dominant OI (alharbi2016asystematicoverview pages 5-6)

Denosumab: - A monoclonal antibody against RANKL showing promise in OI, particularly types III, IV, and VI, by increasing BMD and reducing fracture risk (kresnadi2024theroleof pages 8-9) - No specific data on denosumab use in OI type IX have been reported

Other agents under investigation: - Sclerostin inhibitors (anti-sclerostin antibodies) have shown increases in bone formation rate and bone mass in murine models (dinulescu2024newperspectivesof pages 2-4) - Teriparatide (recombinant PTH) and TGF-β antibodies are being explored (dinulescu2024newperspectivesof pages 2-4) - 4-Phenylbutyrate (4-PBA) has shown amelioration of ER stress/UPR in OI fibroblasts in vitro (jovanovic2024updateonthe pages 15-16)

Surgical and Interventional (MAXO:0000004 – surgical procedure)

• Intramedullary rodding with telescopic rods for severe long-bone bowing and fracture stabilization (dinulescu2024newperspectivesof pages 2-4, kresnadi2024theroleof pages 5-7)
• Orthopedic management of fractures

Supportive and Rehabilitative (MAXO:0000950 – physical therapy)

• Physical therapy and occupational therapy for mobility optimization (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8, kresnadi2024theroleof pages 5-7)
• Muscle strengthening provides osteoanabolic stimulus (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8)
• Wheelchair and assistive device provision
• Pain management

Experimental Therapies

• Gene therapy approaches using viral vectors and CRISPR are being explored for OI generally but are at preclinical stages (dinulescu2024newperspectivesof pages 2-4, alharbi2016asystematicoverview pages 5-6)
• Bone marrow/mesenchymal stem cell transplantation shows promise in animal models (dinulescu2024newperspectivesof pages 2-4)
• No OI type IX-specific clinical trials were identified in the current search

13. Prevention

Primary Prevention

• No primary prevention is available for this genetic disorder

Genetic Counseling (MAXO:0000079 – genetic counseling)

• Genetic counseling is essential for families with affected individuals
• Carrier testing can identify heterozygous parents for recurrence risk assessment (25% per pregnancy for carrier couples) (pyott2011mutationsinppib pages 3-4)
• Preimplantation genetic diagnosis (PGD) and prenatal diagnosis via chorionic villus sampling or amniocentesis are available for families with known mutations (dijk2009ppibmutationscause pages 2-3)

Prenatal Screening

• Prenatal ultrasound at 20 weeks gestation can detect skeletal abnormalities including fractures and bowing (dijk2009ppibmutationscause pages 2-3)
• Molecular testing of chorionic villus cells can confirm diagnosis when family mutations are known; overmodification of collagen type I in chorionic villi cells was used for prenatal diagnosis in one family (dijk2009ppibmutationscause pages 2-3)

Tertiary Prevention

• Regular bisphosphonate therapy during growth to maximize bone mass
• Fracture prevention strategies including safe environments and activity modification
• Regular monitoring of bone density, growth, and spinal alignment

14. Other Species / Natural Disease

No naturally occurring PPIB-mutation OI has been documented in companion animals or wildlife. The orthologous gene Ppib in mouse (Mus musculus, NCBI Taxon: 10090) has been studied extensively through knockout models.

15. Model Organisms

Ppib Knockout Mouse (Ppib−/−)

Two independent Ppib knockout mouse models have been generated and characterized:

Choi et al. (2009) model (choi2009severeosteogenesisimperfecta pages 1-2, choi2009severeosteogenesisimperfecta pages 2-3): - Generated using Cre/lox system targeting exon 3 of Ppib - Phenotype: kyphosis appearing at 8 weeks of age and progressing with age; severe osteoporosis; reduced bone density on DXA; abnormal collagen fibril morphology (fibrils ~1.45× wider than normal, 114.6 nm vs. 78.6 nm); absence of rhizomelia; loose/thin skin; reduced body mass; lifespan approximately 40–50 weeks - Molecular findings: essentially absent Pro986 3-hydroxylation; substantially reduced P3H1 levels (while CRTAP unaffected); impaired procollagen localization to Golgi; procollagen accumulation in ER

Cabral/Marini et al. (2014) model (cabral2014abnormaltypei pages 1-2, cabral2014abnormaltypei pages 2-3, cabral2014abnormaltypei pages 3-6): - Phenotype: small body size (~25% less body weight); reduced femoral aBMD and BV/TV; reduced mechanical properties with 48% less energy required to fracture, 37% reduced stiffness; dramatically increased brittleness (77% reduced post-yield displacement, 89% reduced plastic energy); deformed rib cage; kyphosis - Molecular findings: only 2–11% residual prolyl 3-hydroxylation; slower collagen folding but treatment with cyclosporine A (CsA) caused further delay, suggesting existence of another collagen PPIase; site-specific underhydroxylation at K87 (~20% unhydroxylated vs. <1% wild-type) and K933; increased underhydroxylated crosslinks; altered HP/LP crosslink ratio; decreased collagen deposition into matrix; abnormal fibril structure

Phenotype Recapitulation

Both models faithfully recapitulate the human OI type IX phenotype, including bone fragility, osteoporosis, kyphosis, growth deficiency, abnormal collagen fibrils, and absence of rhizomelia (choi2009severeosteogenesisimperfecta pages 1-2). The models have been essential for understanding the molecular pathophysiology, particularly the dual role of CyPB in both prolyl 3-hydroxylation and collagen crosslinking regulation.

Model Limitations

• Mouse lifespan does not fully model the chronic decades-long disease course in humans
• Some molecular findings differ between human patients and mice (e.g., complete absence of Pro986 3-hydroxylation in mice vs. partial preservation in some human patients) (cotti2025moleculardriversof pages 9-10)
• No zebrafish or other non-mammalian models for OI type IX have been reported

Resources

• International Mouse Phenotyping Consortium (IMPC) for Ppib mutant mice
• Model organism databases: MGI (Mouse Genome Informatics), IMSR (International Mouse Strain Resource)

Summary

Osteogenesis Imperfecta Type IX is an ultra-rare autosomal recessive bone fragility disorder caused by loss-of-function mutations in PPIB, encoding cyclophilin B (CyPB). The disease was first described in 2009 and fewer than 10 families have been reported in the literature (dijk2009ppibmutationscause pages 1-2, pyott2011mutationsinppib pages 3-4). CyPB is a multifunctional ER-resident protein that serves as a peptidyl-prolyl cis-trans isomerase, molecular chaperone, and component of the P3H1/CRTAP/CyPB prolyl 3-hydroxylation complex (jovanovic2024updateonthe pages 8-9, dijk2009ppibmutationscause pages 1-2). Its deficiency leads to delayed collagen folding, overmodification, impaired crosslinking, ER stress, and ultimately fragile bone with diminished mechanical properties (cabral2014abnormaltypei pages 1-2, etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4). The clinical phenotype spans moderate to perinatal lethal severity, with features including multiple fractures, severe short stature, bowed long bones, kyphoscoliosis, and gray sclerae (dijk2009ppibmutationscause pages 2-3, cotti2025moleculardriversof pages 9-10). Current management relies on bisphosphonate therapy, orthopedic intervention, and supportive care, with novel therapeutic approaches including gene therapy and anti-sclerostin antibodies under investigation for OI broadly (dinulescu2024newperspectivesof pages 2-4, etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8). Ppib knockout mice provide valuable preclinical models that faithfully recapitulate the human disease phenotype (cabral2014abnormaltypei pages 2-3, choi2009severeosteogenesisimperfecta pages 1-2).

References

1. (jovanovic2024updateonthe pages 8-9): Milena Jovanovic and Joan C. Marini. Update on the genetics of osteogenesis imperfecta. Calcified Tissue International, 115:891-914, Aug 2024. URL: https://doi.org/10.1007/s00223-024-01266-5, doi:10.1007/s00223-024-01266-5. This article has 76 citations and is from a peer-reviewed journal.

2. (dijk2009ppibmutationscause pages 1-2): Fleur S. van Dijk, Isabel M. Nesbitt, Eline H. Zwikstra, Peter G.J. Nikkels, Sander R. Piersma, Silvina A. Fratantoni, Connie R. Jimenez, Margriet Huizer, Alice C. Morsman, Jan M. Cobben, Mirjam H.H. van Roij, Mariet W. Elting, Jonathan I.M.L. Verbeke, Liliane C.D. Wijnaendts, Nick J. Shaw, Wolfgang Högler, Carole McKeown, Erik A. Sistermans, Ann Dalton, Hanne Meijers-Heijboer, and Gerard Pals. Ppib mutations cause severe osteogenesis imperfecta. American journal of human genetics, 85 4:521-7, Oct 2009. URL: https://doi.org/10.1016/j.ajhg.2009.09.001, doi:10.1016/j.ajhg.2009.09.001. This article has 354 citations and is from a highest quality peer-reviewed journal.

3. (etich2020osteogenesisimperfecta—pathophysiologyand pages 2-4): Julia Etich, Lennart Leßmeier, Mirko Rehberg, Helge Sill, Frank Zaucke, Christian Netzer, and Oliver Semler. Osteogenesis imperfecta—pathophysiology and therapeutic options. Molecular and Cellular Pediatrics, Aug 2020. URL: https://doi.org/10.1186/s40348-020-00101-9, doi:10.1186/s40348-020-00101-9. This article has 113 citations.

4. (pyott2011mutationsinppib pages 1-2): Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human molecular genetics, 20 8:1595-609, Apr 2011. URL: https://doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 164 citations and is from a domain leading peer-reviewed journal.

5. (pyott2011mutationsinppib pages 2-3): Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human molecular genetics, 20 8:1595-609, Apr 2011. URL: https://doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 164 citations and is from a domain leading peer-reviewed journal.

6. (pyott2011mutationsinppib pages 3-4): Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human molecular genetics, 20 8:1595-609, Apr 2011. URL: https://doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 164 citations and is from a domain leading peer-reviewed journal.

7. (dijk2009ppibmutationscause pages 2-3): Fleur S. van Dijk, Isabel M. Nesbitt, Eline H. Zwikstra, Peter G.J. Nikkels, Sander R. Piersma, Silvina A. Fratantoni, Connie R. Jimenez, Margriet Huizer, Alice C. Morsman, Jan M. Cobben, Mirjam H.H. van Roij, Mariet W. Elting, Jonathan I.M.L. Verbeke, Liliane C.D. Wijnaendts, Nick J. Shaw, Wolfgang Högler, Carole McKeown, Erik A. Sistermans, Ann Dalton, Hanne Meijers-Heijboer, and Gerard Pals. Ppib mutations cause severe osteogenesis imperfecta. American journal of human genetics, 85 4:521-7, Oct 2009. URL: https://doi.org/10.1016/j.ajhg.2009.09.001, doi:10.1016/j.ajhg.2009.09.001. This article has 354 citations and is from a highest quality peer-reviewed journal.

8. (cotti2025moleculardriversof pages 9-10): Silvia Cotti, Wendy Pérez Franco, and Antonella Forlino. Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease. Clinical Science, 139(24):1733-1768, Dec 2025. URL: https://doi.org/10.1042/cs20255642, doi:10.1042/cs20255642. This article has 3 citations and is from a peer-reviewed journal.

9. (cabral2014abnormaltypei pages 1-2): Wayne A. Cabral, Irina Perdivara, MaryAnn Weis, Masahiko Terajima, Angela R. Blissett, Weizhong Chang, Joseph E. Perosky, Elena N. Makareeva, Edward L. Mertz, Sergey Leikin, Kenneth B. Tomer, Kenneth M. Kozloff, David R. Eyre, Mitsuo Yamauchi, and Joan C. Marini. Abnormal type i collagen post-translational modification and crosslinking in a cyclophilin b ko mouse model of recessive osteogenesis imperfecta. PLoS Genetics, 10:e1004465, Jun 2014. URL: https://doi.org/10.1371/journal.pgen.1004465, doi:10.1371/journal.pgen.1004465. This article has 143 citations and is from a domain leading peer-reviewed journal.

10. (cabral2014abnormaltypei pages 2-3): Wayne A. Cabral, Irina Perdivara, MaryAnn Weis, Masahiko Terajima, Angela R. Blissett, Weizhong Chang, Joseph E. Perosky, Elena N. Makareeva, Edward L. Mertz, Sergey Leikin, Kenneth B. Tomer, Kenneth M. Kozloff, David R. Eyre, Mitsuo Yamauchi, and Joan C. Marini. Abnormal type i collagen post-translational modification and crosslinking in a cyclophilin b ko mouse model of recessive osteogenesis imperfecta. PLoS Genetics, 10:e1004465, Jun 2014. URL: https://doi.org/10.1371/journal.pgen.1004465, doi:10.1371/journal.pgen.1004465. This article has 143 citations and is from a domain leading peer-reviewed journal.

11. (choi2009severeosteogenesisimperfecta pages 1-2): Jae Won Choi, Shari L. Sutor, Lonn Lindquist, Glenda L. Evans, Benjamin J. Madden, H. Robert Bergen, Theresa E. Hefferan, Michael J. Yaszemski, and Richard J. Bram. Severe osteogenesis imperfecta in cyclophilin b–deficient mice. PLoS Genetics, 5:e1000750, Dec 2009. URL: https://doi.org/10.1371/journal.pgen.1000750, doi:10.1371/journal.pgen.1000750. This article has 123 citations and is from a domain leading peer-reviewed journal.

12. (etich2020osteogenesisimperfecta—pathophysiologyand pages 7-8): Julia Etich, Lennart Leßmeier, Mirko Rehberg, Helge Sill, Frank Zaucke, Christian Netzer, and Oliver Semler. Osteogenesis imperfecta—pathophysiology and therapeutic options. Molecular and Cellular Pediatrics, Aug 2020. URL: https://doi.org/10.1186/s40348-020-00101-9, doi:10.1186/s40348-020-00101-9. This article has 113 citations.

13. (kresnadi2024theroleof pages 5-7): Agus Kresnadi, Tri Wahyu Martanto, Arif Zulkarnain, and Hizbillah Yazid. The role of denosumab and bisphosphonate in osteogenesis imperfecta: a literature review. Salud, Ciencia y Tecnología, 4:894, Apr 2024. URL: https://doi.org/10.56294/saludcyt2024894, doi:10.56294/saludcyt2024894. This article has 1 citations.

14. (pyott2011mutationsinppib pages 4-5): Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human molecular genetics, 20 8:1595-609, Apr 2011. URL: https://doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 164 citations and is from a domain leading peer-reviewed journal.

15. (choi2009severeosteogenesisimperfecta pages 2-3): Jae Won Choi, Shari L. Sutor, Lonn Lindquist, Glenda L. Evans, Benjamin J. Madden, H. Robert Bergen, Theresa E. Hefferan, Michael J. Yaszemski, and Richard J. Bram. Severe osteogenesis imperfecta in cyclophilin b–deficient mice. PLoS Genetics, 5:e1000750, Dec 2009. URL: https://doi.org/10.1371/journal.pgen.1000750, doi:10.1371/journal.pgen.1000750. This article has 123 citations and is from a domain leading peer-reviewed journal.

16. (choi2009severeosteogenesisimperfecta pages 3-5): Jae Won Choi, Shari L. Sutor, Lonn Lindquist, Glenda L. Evans, Benjamin J. Madden, H. Robert Bergen, Theresa E. Hefferan, Michael J. Yaszemski, and Richard J. Bram. Severe osteogenesis imperfecta in cyclophilin b–deficient mice. PLoS Genetics, 5:e1000750, Dec 2009. URL: https://doi.org/10.1371/journal.pgen.1000750, doi:10.1371/journal.pgen.1000750. This article has 123 citations and is from a domain leading peer-reviewed journal.

17. (dijk2009ppibmutationscause pages 3-6): Fleur S. van Dijk, Isabel M. Nesbitt, Eline H. Zwikstra, Peter G.J. Nikkels, Sander R. Piersma, Silvina A. Fratantoni, Connie R. Jimenez, Margriet Huizer, Alice C. Morsman, Jan M. Cobben, Mirjam H.H. van Roij, Mariet W. Elting, Jonathan I.M.L. Verbeke, Liliane C.D. Wijnaendts, Nick J. Shaw, Wolfgang Högler, Carole McKeown, Erik A. Sistermans, Ann Dalton, Hanne Meijers-Heijboer, and Gerard Pals. Ppib mutations cause severe osteogenesis imperfecta. American journal of human genetics, 85 4:521-7, Oct 2009. URL: https://doi.org/10.1016/j.ajhg.2009.09.001, doi:10.1016/j.ajhg.2009.09.001. This article has 354 citations and is from a highest quality peer-reviewed journal.

18. (pyott2011mutationsinppib pages 5-6): Shawna M. Pyott, Ulrike Schwarze, Helena E. Christiansen, Melanie G. Pepin, Dru F. Leistritz, Richard Dineen, Catharine Harris, Barbara K. Burton, Brad Angle, Katherine Kim, Michael D. Sussman, MaryAnn Weis, David R. Eyre, David W. Russell, Kevin J. McCarthy, Robert D. Steiner, and Peter H. Byers. Mutations in ppib (cyclophilin b) delay type i procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Human molecular genetics, 20 8:1595-609, Apr 2011. URL: https://doi.org/10.1093/hmg/ddr037, doi:10.1093/hmg/ddr037. This article has 164 citations and is from a domain leading peer-reviewed journal.

19. (cotti2025moleculardriversof pages 7-9): Silvia Cotti, Wendy Pérez Franco, and Antonella Forlino. Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease. Clinical Science, 139(24):1733-1768, Dec 2025. URL: https://doi.org/10.1042/cs20255642, doi:10.1042/cs20255642. This article has 3 citations and is from a peer-reviewed journal.

20. (cabral2014abnormaltypei pages 12-13): Wayne A. Cabral, Irina Perdivara, MaryAnn Weis, Masahiko Terajima, Angela R. Blissett, Weizhong Chang, Joseph E. Perosky, Elena N. Makareeva, Edward L. Mertz, Sergey Leikin, Kenneth B. Tomer, Kenneth M. Kozloff, David R. Eyre, Mitsuo Yamauchi, and Joan C. Marini. Abnormal type i collagen post-translational modification and crosslinking in a cyclophilin b ko mouse model of recessive osteogenesis imperfecta. PLoS Genetics, 10:e1004465, Jun 2014. URL: https://doi.org/10.1371/journal.pgen.1004465, doi:10.1371/journal.pgen.1004465. This article has 143 citations and is from a domain leading peer-reviewed journal.

21. (cabral2014abnormaltypei pages 6-8): Wayne A. Cabral, Irina Perdivara, MaryAnn Weis, Masahiko Terajima, Angela R. Blissett, Weizhong Chang, Joseph E. Perosky, Elena N. Makareeva, Edward L. Mertz, Sergey Leikin, Kenneth B. Tomer, Kenneth M. Kozloff, David R. Eyre, Mitsuo Yamauchi, and Joan C. Marini. Abnormal type i collagen post-translational modification and crosslinking in a cyclophilin b ko mouse model of recessive osteogenesis imperfecta. PLoS Genetics, 10:e1004465, Jun 2014. URL: https://doi.org/10.1371/journal.pgen.1004465, doi:10.1371/journal.pgen.1004465. This article has 143 citations and is from a domain leading peer-reviewed journal.

22. (jovanovic2024updateonthe pages 15-16): Milena Jovanovic and Joan C. Marini. Update on the genetics of osteogenesis imperfecta. Calcified Tissue International, 115:891-914, Aug 2024. URL: https://doi.org/10.1007/s00223-024-01266-5, doi:10.1007/s00223-024-01266-5. This article has 76 citations and is from a peer-reviewed journal.

23. (jovanovic2024updateonthe pages 19-20): Milena Jovanovic and Joan C. Marini. Update on the genetics of osteogenesis imperfecta. Calcified Tissue International, 115:891-914, Aug 2024. URL: https://doi.org/10.1007/s00223-024-01266-5, doi:10.1007/s00223-024-01266-5. This article has 76 citations and is from a peer-reviewed journal.

24. (jovanovic2024updateonthe pages 16-17): Milena Jovanovic and Joan C. Marini. Update on the genetics of osteogenesis imperfecta. Calcified Tissue International, 115:891-914, Aug 2024. URL: https://doi.org/10.1007/s00223-024-01266-5, doi:10.1007/s00223-024-01266-5. This article has 76 citations and is from a peer-reviewed journal.

25. (chetty2021theevolutionof pages 5-6): Manogari Chetty, Imaan Amina Roomaney, and Peter Beighton. The evolution of the nosology of osteogenesis imperfecta. Clinical Genetics, 99:42-52, Nov 2021. URL: https://doi.org/10.1111/cge.13846, doi:10.1111/cge.13846. This article has 48 citations and is from a peer-reviewed journal.

26. (dijk2014osteogenesisimperfectaclinical pages 5-7): F.S. Van Dijk and D.O. Sillence. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. American Journal of Medical Genetics. Part a, 164:1470-1481, Apr 2014. URL: https://doi.org/10.1002/ajmg.a.36545, doi:10.1002/ajmg.a.36545. This article has 1005 citations and is from a peer-reviewed journal.

27. (dinulescu2024newperspectivesof pages 2-4): Alexandru Dinulescu, Alexandru-Sorin Păsărică, Mădălina Carp, Andrei Dușcă, Irina Dijmărescu, Mirela Luminița Pavelescu, Daniela Păcurar, and Alexandru Ulici. New perspectives of therapies in osteogenesis imperfecta—a literature review. Journal of Clinical Medicine, 13:1065, Feb 2024. URL: https://doi.org/10.3390/jcm13041065, doi:10.3390/jcm13041065. This article has 25 citations.

28. (dwan2016bisphosphonatetherapyfor pages 5-6): Kerry Dwan, Carrie A Phillipi, Robert D Steiner, and Donald Basel. Bisphosphonate therapy for osteogenesis imperfecta. The Cochrane database of systematic reviews, 10:CD005088, Oct 2016. URL: https://doi.org/10.1002/14651858.cd005088.pub4, doi:10.1002/14651858.cd005088.pub4. This article has 559 citations.

29. (alharbi2016asystematicoverview pages 5-6): Samir Abdulkarim Alharbi. A systematic overview of osteogenesis imperfecta. ArXiv, 5:1-9, Jan 2016. URL: https://doi.org/10.4172/2168-9547.1000150, doi:10.4172/2168-9547.1000150. This article has 44 citations.

30. (kresnadi2024theroleof pages 8-9): Agus Kresnadi, Tri Wahyu Martanto, Arif Zulkarnain, and Hizbillah Yazid. The role of denosumab and bisphosphonate in osteogenesis imperfecta: a literature review. Salud, Ciencia y Tecnología, 4:894, Apr 2024. URL: https://doi.org/10.56294/saludcyt2024894, doi:10.56294/saludcyt2024894. This article has 1 citations.

31. (cabral2014abnormaltypei pages 3-6): Wayne A. Cabral, Irina Perdivara, MaryAnn Weis, Masahiko Terajima, Angela R. Blissett, Weizhong Chang, Joseph E. Perosky, Elena N. Makareeva, Edward L. Mertz, Sergey Leikin, Kenneth B. Tomer, Kenneth M. Kozloff, David R. Eyre, Mitsuo Yamauchi, and Joan C. Marini. Abnormal type i collagen post-translational modification and crosslinking in a cyclophilin b ko mouse model of recessive osteogenesis imperfecta. PLoS Genetics, 10:e1004465, Jun 2014. URL: https://doi.org/10.1371/journal.pgen.1004465, doi:10.1371/journal.pgen.1004465. This article has 143 citations and is from a domain leading peer-reviewed journal.

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