Hajdu-Cheney Syndrome

Mendelian MONDO:0007057 Pathograph 6 Show in embeddings browser hereditary disease bone development disease

Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant connective-tissue and skeletal disorder caused by heterozygous truncating mutations in the terminal coding exon (exon 34) of NOTCH2. Because these mutations cluster in the last exon, the mutant transcripts escape nonsense-mediated decay and produce a truncated, stabilized NOTCH2 protein lacking the C-terminal PEST degradation domain, yielding enhanced (gain-of-function) NOTCH2 signaling. The disorder is characterized by progressive acro-osteolysis of the distal phalanges, severe generalized osteoporosis with fractures, short stature, distinctive craniofacial features, wormian bones, platybasia/basilar invagination, premature tooth loss, joint laxity, and variable cardiovascular, renal, and neurologic involvement.

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1
Inheritance
3
Pathophys.
11
Phenotypes
6
Pathograph
1
Genes
5
Medical Actions
2
Models
8
References
1
Deep Research
🏷

Classifications

ISDS Skeletal Nosology
osteolysis
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
HCS is inherited in an autosomal dominant manner, although many affected individuals represent sporadic (de novo) cases.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:32854429 SUPPORT Human Clinical
"It has an autosomal dominant inheritance, although there are several sporadic non-hereditary cases."
The systematic review directly establishes autosomal dominant inheritance with sporadic de novo cases.
PMID:25491639 SUPPORT Human Clinical
"HCS is rare and is inherited as autosomal dominant although many sporadic cases have been reported."
An authoritative review corroborates autosomal dominant inheritance with frequent sporadic cases.
⚙

Pathophysiology

3
NOTCH2 terminal-exon truncation escapes nonsense-mediated decay
Heterozygous nonsense and frameshift mutations cluster in the last coding exon (exon 34) of NOTCH2. Because they lie in the terminal exon, the mutant mRNAs escape nonsense-mediated decay and encode a truncated NOTCH2 protein that has lost the C-terminal PEST proteolytic-recognition (degradation) sequence.
NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Enhanced NOTCH2 signaling with increased osteoclastogenesis The stabilized truncated NOTCH2 protein produces enhanced NOTCH2 signaling activity.
Show evidence (2 references)
PMID:21378989 SUPPORT Human Clinical
"All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner."
This directly supports terminal-exon clustering, escape from nonsense-mediated decay, and a gain-of-function mechanism.
PMID:21378985 SUPPORT Human Clinical
"The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling."
This establishes loss of the C-terminal PEST proteolytic-recognition sequence as the molecular lesion that increases Notch signaling.
Enhanced NOTCH2 signaling with increased osteoclastogenesis
The truncated, stable NOTCH2 protein has enhanced signaling activity that shifts bone remodeling toward high-turnover bone loss, increasing osteoclastogenesis and bone resorption without a compensatory decrease in osteoblast number or bone formation.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↑ INCREASED bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Acroosteolysis High-turnover resorption of the terminal phalanges produces acro-osteolysis.
Osteoporosis Generalized excess osteoclastic resorption produces severe osteoporosis.
Show evidence (2 references)
PMID:25491639 SUPPORT Human Clinical
"HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity."
This links the exon 34 / PEST-domain lesion to a stable NOTCH2 protein with enhanced signaling activity.
PMID:26627824 SUPPORT Model Organism
"In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption."
A knock-in mouse reproducing an HCS NOTCH2 truncation shows osteopenia with enhanced osteoclastogenesis and increased bone resorption.
High-turnover osteoclastic bone resorption
Histomorphometry in the HCS mouse model shows an increased number of osteoclasts and increased bone resorption, without a decrease in osteoblast number or bone formation, and the enhanced osteoclastogenesis is RANKL-dependent and Notch-dependent (suppressed by a gamma-secretase inhibitor).
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology. osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:26627824 SUPPORT Model Organism
"Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation."
This defines the high-turnover, resorption-dominant mechanism with preserved osteoblast number/formation.
PMID:26627824 SUPPORT Model Organism
"The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor κB ligand in vitro were increased in Notch2(Q2319X) mutants."
This supports RANKL-dependent enhancement of osteoclast differentiation and resorption downstream of mutant NOTCH2.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Acroosteolysis' (from 'Enhanced NOTCH2 signaling with increased osteoclastogenesis') not found in named elements
Pathograph: causal mechanism network for Hajdu-Cheney 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

11
Cardiovascular 1
Cardiovascular defects OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys."
The review lists cardiovascular defects among the features of HCS.
Genitourinary 1
Polycystic kidneys OCCASIONAL Renal cyst HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys."
The review lists polycystic kidneys among the features of HCS.
Head and Neck 3
Wormian bones FREQUENT HP:0002645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wormian bones (HP:0002645). HP:0002645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys."
The review explicitly lists wormian bones as a characteristic feature.
Specific craniofacial features FREQUENT Coarse facial features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys."
The review lists specific craniofacial features as a defining manifestation.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36079132 SUPPORT Human Clinical
"A case report of an 11-year-old boy with a de novo variant in NOTCH2 and clinical features characteristic of Hajdu-Cheney syndrome is reported, with acroosteolysis of the distal phalanges of the feet and hands, generalized osteoporosis, musculoskeletal and craniofacial alterations, short..."
Micrognathia is documented among the craniofacial features in this genetically confirmed case.
Musculoskeletal 2
Osteoporosis VERY_FREQUENT HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32854429 SUPPORT Human Clinical
"Hajdu-Cheney syndrome (HCS) is a rare genetic disease that causes acroosteolysis and generalized osteoporosis, accompanied by a series of developmental skeletal disorders and multiple clinical and radiological manifestations."
The systematic review lists generalized osteoporosis as a defining manifestation.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36079132 SUPPORT Human Clinical
"A case report of an 11-year-old boy with a de novo variant in NOTCH2 and clinical features characteristic of Hajdu-Cheney syndrome is reported, with acroosteolysis of the distal phalanges of the feet and hands, generalized osteoporosis, musculoskeletal and craniofacial alterations, short..."
Joint (and skin) hyperlaxity is documented, supporting a joint hypermobility annotation.
Growth 1
Short stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys."
The review lists short stature among the defining features of HCS.
Other 3
Acroosteolysis of distal phalanges VERY_FREQUENT Acroosteolysis of distal phalanges (feet) HP:0001870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acroosteolysis of distal phalanges (feet) (HP:0001870). HP:0001870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36079132 SUPPORT Human Clinical
"A case report of an 11-year-old boy with a de novo variant in NOTCH2 and clinical features characteristic of Hajdu-Cheney syndrome is reported, with acroosteolysis of the distal phalanges of the feet and hands, generalized osteoporosis, musculoskeletal and craniofacial alterations, short..."
This documents acroosteolysis of the distal phalanges of the feet and hands as a characteristic feature.
Basilar invagination FREQUENT Basilar impression HP:0005758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basilar impression (HP:0005758). HP:0005758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32854429 SUPPORT Human Clinical
"The most frequent clinical complications in this syndrome are basilar invagination, and consequently, brain damage, hydrocephalus"
The systematic review identifies basilar invagination as among the most frequent, and most dangerous, clinical complications of HCS.
Premature loss of teeth FREQUENT HP:0006480 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature loss of teeth (HP:0006480). HP:0006480 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32854429 SUPPORT Human Clinical
"all patients show a case of osteolysis of the distal phalanges and generalized osteoporosis, accompanied by other disorders, such as craniofacial and skeletal dysmorphia, developmental skeletal disorders, premature loss of teeth, and a short stature"
The systematic review lists premature loss of teeth among the disorders accompanying the cardinal osteolysis and osteoporosis of HCS.
🧬

Genetic Associations

1
NOTCH2 (Gain-of-function terminal-exon truncating mutation)
Gene: NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:21378985 SUPPORT Human Clinical
"We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss."
This identifies NOTCH2 as the causative gene in an allelic series for HCS.
PMID:21378989 SUPPORT Human Clinical
"We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them."
An independent exome study confirms heterozygous NOTCH2 truncating mutations as the cause of HCS.
💊

Medical Actions

5
Bisphosphonate antiresorptive therapy
Action: bisphosphonate agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bisphosphonate agent therapy, annotated with Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. Ontology label: Bisphosphonate Therapy NCIT:C198585
Bisphosphonates are the most commonly reported antiresorptive treatment for the osteoporosis of HCS, aimed at improving bone density; however, controlled benefit at the syndrome level has not been established.
Target Phenotypes: Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36079132 SUPPORT Human Clinical
"Treatment is with bisphosphonates in the framework of bone density improvement and with focal vibration therapy for rehabilitation of the musculoskeletal system and gait improvement."
This documents bisphosphonate use for bone-density improvement in a genetically confirmed HCS patient.
PMID:25491639 SUPPORT Human Clinical
"Bone antiresorptive and anabolic agents have been tried to treat the osteoporosis, but their benefit has not been established."
The review notes antiresorptive/anabolic agents are used but with unproven benefit, tempering the strength of this recommendation.
Denosumab (off-label RANKL inhibitor) with MRONJ precautions
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. Ontology label: Pharmacotherapy NCIT:C15986
Denosumab, a monoclonal antibody against RANKL that suppresses osteoclast activity, has been used off-label. It carries a risk of delayed oral wound healing and medication-related osteonecrosis of the jaw (MRONJ), so invasive dental procedures require careful planning.
Show evidence (2 references)
PMID:34501688 SUPPORT Human Clinical
"Denosumab is a monoclonal antibody against RANKL."
This identifies denosumab's mechanism as an anti-RANKL monoclonal antibody used in an HCS patient.
PMID:34501688 SUPPORT Human Clinical
"In patients receiving denosumab, a delayed wound healing in the oral cavity and osteonecrosis may occur."
This documents the delayed oral wound healing / osteonecrosis safety concern that motivates dental precautions.
Focal vibration therapy and physical rehabilitation
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. Ontology label: Physical Therapy NCIT:C15302
Focal vibration therapy and physical rehabilitation are used to support the musculoskeletal system and improve gait.
Show evidence (1 reference)
PMID:36079132 SUPPORT Human Clinical
"Treatment is with bisphosphonates in the framework of bone density improvement and with focal vibration therapy for rehabilitation of the musculoskeletal system and gait improvement."
This documents focal vibration therapy for musculoskeletal rehabilitation and gait improvement.
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. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling and cascade testing are relevant because HCS is an autosomal dominant, NOTCH2-defined disorder.
Show evidence (1 reference)
PMID:32854429 SUPPORT Human Clinical
"It has an autosomal dominant inheritance, although there are several sporadic non-hereditary cases."
Autosomal dominant inheritance supports genetic counseling and cascade testing in families with an identified variant.
Multidisciplinary supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
There is no curative treatment; management is multidisciplinary and complication-directed across orthopedics, neurosurgery, dentistry, nephrology, cardiology, and rehabilitation.
Show evidence (1 reference)
PMID:32854429 SUPPORT Human Clinical
"As few as 50 cases of this disease, for which there is currently no curative treatment, have been reported to date."
The review states there is no curative treatment, supporting supportive, complication-directed management.
🔬

Diagnosis

1
NOTCH2 sequencing (exon 34)
Molecular diagnosis is established by sequence analysis of exon 34 of NOTCH2 to identify the causative truncating variant.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A pathogenic terminal-exon NOTCH2 truncating variant confirms the diagnosis of HCS.
Show evidence (1 reference)
PMID:25491639 SUPPORT Human Clinical
"Although the number of cases with NOTCH2 mutations reported are limited, it would seem that the diagnosis of HCS can be established by sequence analysis of exon 34 of NOTCH2."
The review supports establishing diagnosis by sequence analysis of exon 34 of NOTCH2.
🐁

Animal Models

2
Notch2 Q2319X knock-in (6955C>T) Mus musculus
A heterozygous Notch2(Q2319X) knock-in mouse, reproducing an HCS-like terminal NOTCH2 truncation, exhibits cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption, with RANKL-driven osteoclast differentiation suppressed by a gamma-secretase inhibitor.
Species
Mus musculus
Genotype
Notch2 Q2319X knock-in (6955C>T)
Show evidence (1 reference)
PMID:26627824 SUPPORT Model Organism
"In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption."
This establishes the knock-in mouse and its recapitulation of the HCS high-turnover bone phenotype.
Notch2 HCS knock-in (fracture-healing model) Mus musculus
In an HCS mouse fracture-healing model with high-turnover osteopenia, structural indices of bone regeneration were near-normal, but the callus showed increased osteoclast parameters and osteoclast/osteoblast marker expression, and healed femora had inferior biomechanical stability.
Species
Mus musculus
Genotype
Notch2 HCS knock-in (fracture-healing model)
Show evidence (2 references)
PMID:37452111 SUPPORT Model Organism
"Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures."
This supports impaired biomechanical stability of healed fractures despite near-normal structural healing in the HCS mouse model.
PMID:37452111 SUPPORT Model Organism
"Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers."
This documents increased osteoclast activity in fracture callus, consistent with the high-turnover mechanism.
{ }

Source YAML

click to show 
name: Hajdu-Cheney Syndrome
creation_date: '2026-07-24T12:00:00Z'
category: Mendelian
synonyms:
- acroosteolysis dominant type
- acro-osteolysis with osteoporosis and changes in skull and mandible
- acro-dento-osteo dysplasia
- arthrodentoosteodysplasia
- Cheney syndrome
- serpentine fibula-polycystic kidney syndrome
- Hajdu-Cheney syndrome, NOTCH2-related
description: >-
  Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant connective-tissue and
  skeletal disorder caused by heterozygous truncating mutations in the terminal
  coding exon (exon 34) of NOTCH2. Because these mutations cluster in the last exon,
  the mutant transcripts escape nonsense-mediated decay and produce a truncated,
  stabilized NOTCH2 protein lacking the C-terminal PEST degradation domain, yielding
  enhanced (gain-of-function) NOTCH2 signaling. The disorder is characterized by
  progressive acro-osteolysis of the distal phalanges, severe generalized
  osteoporosis with fractures, short stature, distinctive craniofacial features,
  wormian bones, platybasia/basilar invagination, premature tooth loss, joint
  laxity, and variable cardiovascular, renal, and neurologic involvement.
disease_term:
  preferred_term: Hajdu-Cheney syndrome
  term:
    id: MONDO:0007057
    label: acroosteolysis dominant type
parents:
- hereditary disease
- bone development disease
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    HCS is inherited in an autosomal dominant manner, although many affected
    individuals represent sporadic (de novo) cases.
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has an autosomal dominant inheritance, although there are several sporadic
      non-hereditary cases.
    explanation: >-
      The systematic review directly establishes autosomal dominant inheritance
      with sporadic de novo cases.
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCS is rare and is inherited as autosomal dominant although many sporadic
      cases have been reported.
    explanation: >-
      An authoritative review corroborates autosomal dominant inheritance with
      frequent sporadic cases.
classifications:
  isds_skeletal_category:
  - classification_value: osteolysis
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 28 "Osteolysis
      group"; listed as "Hajdu-Cheney syndrome".
pathophysiology:
- name: NOTCH2 terminal-exon truncation escapes nonsense-mediated decay
  description: >-
    Heterozygous nonsense and frameshift mutations cluster in the last coding exon
    (exon 34) of NOTCH2. Because they lie in the terminal exon, the mutant mRNAs
    escape nonsense-mediated decay and encode a truncated NOTCH2 protein that has
    lost the C-terminal PEST proteolytic-recognition (degradation) sequence.
  genes:
  - preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:21378989
    reference_title: Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations cluster to the last coding exon of the gene, suggesting that the
      mutant mRNA products escape nonsense-mediated decay and that the resulting
      truncated NOTCH2 proteins act in a gain-of-function manner.
    explanation: >-
      This directly supports terminal-exon clustering, escape from
      nonsense-mediated decay, and a gain-of-function mechanism.
  - reference: PMID:21378985
    reference_title: Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Hajdu-Cheney syndrome mutations are predicted to lead to the premature
      truncation of NOTCH2 with either disruption or loss of the C-terminal
      proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the
      absence of which has previously been shown to increase Notch signaling.
    explanation: >-
      This establishes loss of the C-terminal PEST proteolytic-recognition sequence
      as the molecular lesion that increases Notch signaling.
  downstream:
  - target: Enhanced NOTCH2 signaling with increased osteoclastogenesis
    description: The stabilized truncated NOTCH2 protein produces enhanced NOTCH2 signaling activity.
    causal_link_type: DIRECT
- name: Enhanced NOTCH2 signaling with increased osteoclastogenesis
  description: >-
    The truncated, stable NOTCH2 protein has enhanced signaling activity that shifts
    bone remodeling toward high-turnover bone loss, increasing osteoclastogenesis
    and bone resorption without a compensatory decrease in osteoblast number or bone
    formation.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: INCREASED
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain
      that lead to the creation of a truncated and stable NOTCH2 protein with
      enhanced NOTCH2 signaling activity.
    explanation: >-
      This links the exon 34 / PEST-domain lesion to a stable NOTCH2 protein with
      enhanced signaling activity.
  - reference: PMID:26627824
    reference_title: "Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone
      osteopenia, enhanced osteoclastogenesis, and increased bone resorption.
    explanation: >-
      A knock-in mouse reproducing an HCS NOTCH2 truncation shows osteopenia with
      enhanced osteoclastogenesis and increased bone resorption.
  downstream:
  - target: Acroosteolysis
    description: High-turnover resorption of the terminal phalanges produces acro-osteolysis.
    causal_link_type: DIRECT
  - target: Osteoporosis
    description: Generalized excess osteoclastic resorption produces severe osteoporosis.
    causal_link_type: DIRECT
- name: High-turnover osteoclastic bone resorption
  description: >-
    Histomorphometry in the HCS mouse model shows an increased number of osteoclasts
    and increased bone resorption, without a decrease in osteoblast number or bone
    formation, and the enhanced osteoclastogenesis is RANKL-dependent and
    Notch-dependent (suppressed by a gamma-secretase inhibitor).
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:26627824
    reference_title: "Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cancellous bone histomorphometry revealed an increased number of osteoclasts
      and bone resorption, without a decrease in osteoblast number or bone
      formation.
    explanation: >-
      This defines the high-turnover, resorption-dominant mechanism with preserved
      osteoblast number/formation.
  - reference: PMID:26627824
    reference_title: "Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption
      in response to receptor activator of nuclear factor κB ligand in vitro were
      increased in Notch2(Q2319X) mutants.
    explanation: >-
      This supports RANKL-dependent enhancement of osteoclast differentiation and
      resorption downstream of mutant NOTCH2.
phenotypes:
- name: Acroosteolysis of distal phalanges
  category: Skeletal
  frequency: VERY_FREQUENT
  description: >-
    Progressive acro-osteolysis (resorption) of the distal phalanges of the hands
    and feet is a cardinal, defining feature.
  phenotype_term:
    preferred_term: Acroosteolysis of distal phalanges (feet)
    term:
      id: HP:0001870
      label: Acroosteolysis of distal phalanges (feet)
  evidence:
  - reference: PMID:36079132
    reference_title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A case report of an 11-year-old boy with a de novo variant in NOTCH2 and
      clinical features characteristic of Hajdu-Cheney syndrome is reported, with
      acroosteolysis of the distal phalanges of the feet and hands, generalized
      osteoporosis, musculoskeletal and craniofacial alterations, short stature,
      bowing of long bones, vertebral anomalies, genu recurvatum, hypertrichosis,
      joint and skin hyperlaxity, atopic dermatitis, megalocorneas, micrognathia and
      frequent respiratory infections, among others.
    explanation: >-
      This documents acroosteolysis of the distal phalanges of the feet and hands as
      a characteristic feature.
- name: Osteoporosis
  category: Skeletal
  frequency: VERY_FREQUENT
  description: >-
    Severe, generalized osteoporosis leads to recurrent fragility fractures.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu-Cheney syndrome (HCS) is a rare genetic disease that causes
      acroosteolysis and generalized osteoporosis, accompanied by a series of
      developmental skeletal disorders and multiple clinical and radiological
      manifestations.
    explanation: >-
      The systematic review lists generalized osteoporosis as a defining
      manifestation.
- name: Short stature
  category: Growth
  frequency: FREQUENT
  description: >-
    Short stature is a common feature and may worsen with vertebral collapse.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by
      acroosteolysis, severe osteoporosis, short stature, specific craniofacial
      features, wormian bones, neurological symptoms, cardiovascular defects and
      polycystic kidneys.
    explanation: >-
      The review lists short stature among the defining features of HCS.
- name: Wormian bones
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Multiple wormian bones in the cranial sutures are a characteristic radiographic
    finding.
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by
      acroosteolysis, severe osteoporosis, short stature, specific craniofacial
      features, wormian bones, neurological symptoms, cardiovascular defects and
      polycystic kidneys.
    explanation: >-
      The review explicitly lists wormian bones as a characteristic feature.
- name: Specific craniofacial features
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Distinctive coarse/dysmorphic craniofacial features are part of the recognizable
    HCS phenotype.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by
      acroosteolysis, severe osteoporosis, short stature, specific craniofacial
      features, wormian bones, neurological symptoms, cardiovascular defects and
      polycystic kidneys.
    explanation: >-
      The review lists specific craniofacial features as a defining manifestation.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia is part of the craniofacial dysmorphism reported in HCS.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:36079132
    reference_title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A case report of an 11-year-old boy with a de novo variant in NOTCH2 and
      clinical features characteristic of Hajdu-Cheney syndrome is reported, with
      acroosteolysis of the distal phalanges of the feet and hands, generalized
      osteoporosis, musculoskeletal and craniofacial alterations, short stature,
      bowing of long bones, vertebral anomalies, genu recurvatum, hypertrichosis,
      joint and skin hyperlaxity, atopic dermatitis, megalocorneas, micrognathia and
      frequent respiratory infections, among others.
    explanation: >-
      Micrognathia is documented among the craniofacial features in this genetically
      confirmed case.
- name: Joint hypermobility
  category: Musculoskeletal
  description: >-
    Joint and skin hyperlaxity is reported as part of the connective-tissue
    involvement.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:36079132
    reference_title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A case report of an 11-year-old boy with a de novo variant in NOTCH2 and
      clinical features characteristic of Hajdu-Cheney syndrome is reported, with
      acroosteolysis of the distal phalanges of the feet and hands, generalized
      osteoporosis, musculoskeletal and craniofacial alterations, short stature,
      bowing of long bones, vertebral anomalies, genu recurvatum, hypertrichosis,
      joint and skin hyperlaxity, atopic dermatitis, megalocorneas, micrognathia and
      frequent respiratory infections, among others.
    explanation: >-
      Joint (and skin) hyperlaxity is documented, supporting a joint hypermobility
      annotation.
- name: Polycystic kidneys
  category: Renal
  frequency: OCCASIONAL
  description: >-
    Renal cysts / polycystic kidneys are part of the multisystem HCS spectrum.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by
      acroosteolysis, severe osteoporosis, short stature, specific craniofacial
      features, wormian bones, neurological symptoms, cardiovascular defects and
      polycystic kidneys.
    explanation: >-
      The review lists polycystic kidneys among the features of HCS.
- name: Cardiovascular defects
  category: Cardiovascular
  frequency: OCCASIONAL
  description: >-
    Congenital cardiovascular defects are part of the multisystem involvement.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by
      acroosteolysis, severe osteoporosis, short stature, specific craniofacial
      features, wormian bones, neurological symptoms, cardiovascular defects and
      polycystic kidneys.
    explanation: >-
      The review lists cardiovascular defects among the features of HCS.
- name: Basilar invagination
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Basilar invagination is among the most frequent clinical complications and can
    cause brainstem compression, hydrocephalus, and syringomyelia.
  phenotype_term:
    preferred_term: Basilar impression
    term:
      id: HP:0005758
      label: Basilar impression
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent clinical complications in this syndrome are basilar
      invagination, and consequently, brain damage, hydrocephalus
    explanation: >-
      The systematic review identifies basilar invagination as among the most
      frequent, and most dangerous, clinical complications of HCS.
- name: Premature loss of teeth
  category: Dental
  frequency: FREQUENT
  description: >-
    Premature loss of teeth is a recognized dental manifestation of HCS.
  phenotype_term:
    preferred_term: Premature loss of teeth
    term:
      id: HP:0006480
      label: Premature loss of teeth
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all patients show a case of osteolysis of the distal phalanges and generalized
      osteoporosis, accompanied by other disorders, such as craniofacial and
      skeletal dysmorphia, developmental skeletal disorders, premature loss of teeth,
      and a short stature
    explanation: >-
      The systematic review lists premature loss of teeth among the disorders
      accompanying the cardinal osteolysis and osteoporosis of HCS.
genetic:
- name: NOTCH2
  association: Gain-of-function terminal-exon truncating mutation
  gene_term:
    preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  notes: >-
    Heterozygous nonsense/frameshift mutations in the last coding exon (exon 34) of
    NOTCH2, upstream of the PEST domain, cause HCS by producing a stabilized,
    gain-of-function NOTCH2 protein.
  evidence:
  - reference: PMID:21378985
    reference_title: Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used an exome-sequencing strategy and identified an allelic series of NOTCH2
      mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder
      characterized by severe and progressive bone loss.
    explanation: >-
      This identifies NOTCH2 as the causative gene in an allelic series for HCS.
  - reference: PMID:21378989
    reference_title: Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the exomes of six unrelated individuals with this syndrome and
      identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of
      them.
    explanation: >-
      An independent exome study confirms heterozygous NOTCH2 truncating mutations as
      the cause of HCS.
treatments:
- name: Bisphosphonate antiresorptive therapy
  description: >-
    Bisphosphonates are the most commonly reported antiresorptive treatment for the
    osteoporosis of HCS, aimed at improving bone density; however, controlled benefit
    at the syndrome level has not been established.
  treatment_term:
    preferred_term: bisphosphonate agent therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  target_phenotypes:
  - preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:36079132
    reference_title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is with bisphosphonates in the framework of bone density improvement
      and with focal vibration therapy for rehabilitation of the musculoskeletal
      system and gait improvement.
    explanation: >-
      This documents bisphosphonate use for bone-density improvement in a
      genetically confirmed HCS patient.
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone antiresorptive and anabolic agents have been tried to treat the
      osteoporosis, but their benefit has not been established.
    explanation: >-
      The review notes antiresorptive/anabolic agents are used but with unproven
      benefit, tempering the strength of this recommendation.
- name: Denosumab (off-label RANKL inhibitor) with MRONJ precautions
  description: >-
    Denosumab, a monoclonal antibody against RANKL that suppresses osteoclast
    activity, has been used off-label. It carries a risk of delayed oral wound
    healing and medication-related osteonecrosis of the jaw (MRONJ), so invasive
    dental procedures require careful planning.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:34501688
    reference_title: "Oral Surgery Procedures in a Patient with Hajdu-Cheney Syndrome Treated with Denosumab-A Rare Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Denosumab is a monoclonal antibody against RANKL.
    explanation: >-
      This identifies denosumab's mechanism as an anti-RANKL monoclonal antibody used
      in an HCS patient.
  - reference: PMID:34501688
    reference_title: "Oral Surgery Procedures in a Patient with Hajdu-Cheney Syndrome Treated with Denosumab-A Rare Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients receiving denosumab, a delayed wound healing in the oral cavity and
      osteonecrosis may occur.
    explanation: >-
      This documents the delayed oral wound healing / osteonecrosis safety concern
      that motivates dental precautions.
- name: Focal vibration therapy and physical rehabilitation
  description: >-
    Focal vibration therapy and physical rehabilitation are used to support the
    musculoskeletal system and improve gait.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:36079132
    reference_title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is with bisphosphonates in the framework of bone density improvement
      and with focal vibration therapy for rehabilitation of the musculoskeletal
      system and gait improvement.
    explanation: >-
      This documents focal vibration therapy for musculoskeletal rehabilitation and
      gait improvement.
- name: Genetic counseling
  description: >-
    Genetic counseling and cascade testing are relevant because HCS is an autosomal
    dominant, NOTCH2-defined disorder.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has an autosomal dominant inheritance, although there are several sporadic
      non-hereditary cases.
    explanation: >-
      Autosomal dominant inheritance supports genetic counseling and cascade testing
      in families with an identified variant.
- name: Multidisciplinary supportive care
  description: >-
    There is no curative treatment; management is multidisciplinary and
    complication-directed across orthopedics, neurosurgery, dentistry, nephrology,
    cardiology, and rehabilitation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32854429
    reference_title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As few as 50 cases of this disease, for which there is currently no curative
      treatment, have been reported to date.
    explanation: >-
      The review states there is no curative treatment, supporting supportive,
      complication-directed management.
diagnosis:
- name: NOTCH2 sequencing (exon 34)
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular diagnosis is established by sequence analysis of exon 34 of NOTCH2 to
    identify the causative truncating variant.
  results: A pathogenic terminal-exon NOTCH2 truncating variant confirms the diagnosis of HCS.
  evidence:
  - reference: PMID:25491639
    reference_title: "Hajdu-Cheney syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the number of cases with NOTCH2 mutations reported are limited, it
      would seem that the diagnosis of HCS can be established by sequence analysis of
      exon 34 of NOTCH2.
    explanation: >-
      The review supports establishing diagnosis by sequence analysis of exon 34 of
      NOTCH2.
animal_models:
- species: Mus musculus
  genotype: Notch2 Q2319X knock-in (6955C>T)
  description: >-
    A heterozygous Notch2(Q2319X) knock-in mouse, reproducing an HCS-like terminal
    NOTCH2 truncation, exhibits cancellous and cortical bone osteopenia, enhanced
    osteoclastogenesis, and increased bone resorption, with RANKL-driven osteoclast
    differentiation suppressed by a gamma-secretase inhibitor.
  evidence:
  - reference: PMID:26627824
    reference_title: "Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone
      osteopenia, enhanced osteoclastogenesis, and increased bone resorption.
    explanation: >-
      This establishes the knock-in mouse and its recapitulation of the HCS
      high-turnover bone phenotype.
- species: Mus musculus
  genotype: Notch2 HCS knock-in (fracture-healing model)
  description: >-
    In an HCS mouse fracture-healing model with high-turnover osteopenia, structural
    indices of bone regeneration were near-normal, but the callus showed increased
    osteoclast parameters and osteoclast/osteoblast marker expression, and healed
    femora had inferior biomechanical stability.
  evidence:
  - reference: PMID:37452111
    reference_title: "Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, our data demonstrate that structural indices of bone regeneration are
      normal in HCS mice, which, however, exhibit signs of increased callus turnover
      and display impaired biomechanical stability of healed fractures.
    explanation: >-
      This supports impaired biomechanical stability of healed fractures despite
      near-normal structural healing in the HCS mouse model.
  - reference: PMID:37452111
    reference_title: "Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histomorphometry showed increased osteoclast parameters in the callus of HCS
      mice, which was accompanied by an increased expression of osteoclast and
      osteoblast markers.
    explanation: >-
      This documents increased osteoclast activity in fracture callus, consistent
      with the high-turnover mechanism.
datasets: []
references:
- reference: PMID:21378985
  title: "Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: An allelic series of NOTCH2 truncating mutations causes HCS by removing the C-terminal PEST proteolytic-recognition sequence, increasing Notch signaling.
    supporting_text: >-
      The Hajdu-Cheney syndrome mutations are predicted to lead to the premature
      truncation of NOTCH2 with either disruption or loss of the C-terminal
      proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the
      absence of which has previously been shown to increase Notch signaling.
- reference: PMID:21378989
  title: Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: Heterozygous NOTCH2 truncating mutations cluster in the last coding exon, escape nonsense-mediated decay, and act in a gain-of-function manner.
    supporting_text: >-
      All mutations cluster to the last coding exon of the gene, suggesting that the
      mutant mRNA products escape nonsense-mediated decay and that the resulting
      truncated NOTCH2 proteins act in a gain-of-function manner.
- reference: PMID:25491639
  title: "Hajdu-Cheney syndrome: a review."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: HCS is an autosomal dominant disorder caused by exon 34 NOTCH2 mutations producing a truncated stable protein with enhanced signaling; antiresorptive/anabolic benefit is unproven.
    supporting_text: >-
      HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain
      that lead to the creation of a truncated and stable NOTCH2 protein with
      enhanced NOTCH2 signaling activity.
- reference: PMID:26627824
  title: "Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: A Notch2(Q2319X) knock-in mouse recapitulates HCS bone disease with osteopenia, enhanced osteoclastogenesis, and increased RANKL-dependent bone resorption.
    supporting_text: >-
      In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone
      osteopenia, enhanced osteoclastogenesis, and increased bone resorption.
- reference: PMID:32854429
  title: "Hajdu-Cheney Syndrome: A Systematic Review of the Literature."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: HCS causes acroosteolysis and generalized osteoporosis, is autosomal dominant with sporadic cases, is associated with NOTCH2, and has no curative treatment.
    supporting_text: >-
      Hajdu-Cheney syndrome (HCS) is a rare genetic disease that causes acroosteolysis
      and generalized osteoporosis, accompanied by a series of developmental skeletal
      disorders and multiple clinical and radiological manifestations.
- reference: PMID:36079132
  title: "Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: A genetically confirmed HCS case shows distal-phalangeal acroosteolysis of feet and hands and is treated with bisphosphonates and focal vibration therapy.
    supporting_text: >-
      Treatment is with bisphosphonates in the framework of bone density improvement
      and with focal vibration therapy for rehabilitation of the musculoskeletal
      system and gait improvement.
- reference: PMID:37452111
  title: "Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: In HCS mice, fracture structural healing is near-normal but callus turnover is increased and healed-bone biomechanical stability is impaired.
    supporting_text: >-
      Together, our data demonstrate that structural indices of bone regeneration are
      normal in HCS mice, which, however, exhibit signs of increased callus turnover
      and display impaired biomechanical stability of healed fractures.
- reference: PMID:34501688
  title: "Oral Surgery Procedures in a Patient with Hajdu-Cheney Syndrome Treated with Denosumab-A Rare Case Report."
  found_in:
  - Hajdu-Cheney_Syndrome-deep-research-falcon.md
  findings:
  - statement: Denosumab (anti-RANKL) is used off-label in HCS but carries MRONJ and delayed oral-healing risk relevant to dental surgery planning.
    supporting_text: >-
      In patients receiving denosumab, a delayed wound healing in the oral cavity and
      osteonecrosis may occur.
📚

References & Deep Research

References

8
PMID:21378985
Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.
1 finding
An allelic series of NOTCH2 truncating mutations causes HCS by removing the C-terminal PEST proteolytic-recognition sequence, increasing Notch signaling.
"The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling."
PMID:21378989
Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
1 finding
Heterozygous NOTCH2 truncating mutations cluster in the last coding exon, escape nonsense-mediated decay, and act in a gain-of-function manner.
"All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner."
PMID:25491639
Hajdu-Cheney syndrome: a review.
1 finding
HCS is an autosomal dominant disorder caused by exon 34 NOTCH2 mutations producing a truncated stable protein with enhanced signaling; antiresorptive/anabolic benefit is unproven.
"HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity."
PMID:26627824
Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption.
1 finding
A Notch2(Q2319X) knock-in mouse recapitulates HCS bone disease with osteopenia, enhanced osteoclastogenesis, and increased RANKL-dependent bone resorption.
"In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption."
PMID:32854429
Hajdu-Cheney Syndrome: A Systematic Review of the Literature.
1 finding
HCS causes acroosteolysis and generalized osteoporosis, is autosomal dominant with sporadic cases, is associated with NOTCH2, and has no curative treatment.
"Hajdu-Cheney syndrome (HCS) is a rare genetic disease that causes acroosteolysis and generalized osteoporosis, accompanied by a series of developmental skeletal disorders and multiple clinical and radiological manifestations."
PMID:36079132
Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy: A Case Report.
1 finding
A genetically confirmed HCS case shows distal-phalangeal acroosteolysis of feet and hands and is treated with bisphosphonates and focal vibration therapy.
"Treatment is with bisphosphonates in the framework of bone density improvement and with focal vibration therapy for rehabilitation of the musculoskeletal system and gait improvement."
PMID:37452111
Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability.
1 finding
In HCS mice, fracture structural healing is near-normal but callus turnover is increased and healed-bone biomechanical stability is impaired.
"Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures."
PMID:34501688
Oral Surgery Procedures in a Patient with Hajdu-Cheney Syndrome Treated with Denosumab-A Rare Case Report.
1 finding
Denosumab (anti-RANKL) is used off-label in HCS but carries MRONJ and delayed oral-healing risk relevant to dental surgery planning.
"In patients receiving denosumab, a delayed wound healing in the oral cavity and osteonecrosis may occur."

Deep Research

1
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Disease Characteristics Research Template
Edison Scientific Literature 25 citations 2026-07-24T11:59:52.639824

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hajdu-Cheney Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hajdu-Cheney Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hajdu–Cheney syndrome: comprehensive disease-characteristics report

Executive summary

Hajdu–Cheney syndrome (HCS) is an ultra-rare, progressive, autosomal-dominant skeletal dysplasia caused by heterozygous gain-of-function variants in NOTCH2. Its defining manifestations are distal phalangeal acro-osteolysis and generalized osteoporosis, accompanied variably by short stature, craniofacial dysmorphism, wormian bones, dental disease, vertebral deformity, skull-base abnormalities, renal cysts, congenital cardiac defects, and respiratory or neurologic complications. Published prevalence is <1 per 1,000,000, but this estimate is uncertain because only approximately 50–100 patients had been described in historical reviews. Evidence is therefore dominated by case reports, small family series, reviews, and engineered mice—not registries or large prospective cohorts. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2)

The causal variants are predominantly nonsense or small deletion/frameshift variants in exon 34, the terminal exon of NOTCH2. They truncate the receptor before its PEST degradation domain, stabilize the NOTCH2 intracellular domain (NICD2), and prolong canonical signaling. Experimental evidence supports increased osteoclastogenesis and high-turnover bone loss, although reduced or dysregulated bone formation may also contribute. There is no curative or approved disease-specific treatment; surveillance, rehabilitation, fracture prevention, dental care, and complication-directed surgery are central. Antiresorptive or anabolic drugs have only low-level, case-based evidence. (canalis2014hajducheneysyndromea pages 1-2, canalis2014hajducheneysyndromea pages 5-6, cortesmartin2020hajdu–cheneysyndromea pages 9-13, canalis2016hajducheneymouse pages 1-2)

The following table provides a curation-oriented synopsis.

Domain Knowledge-base statement Evidence type/strength Suggested ontology terms
Identity / epidemiology Hajdu-Cheney syndrome (HCS) is an ultra-rare Mendelian connective-tissue/skeletal disorder characterized by acro-osteolysis and generalized osteoporosis; commonly cited identifiers include ORPHA:955, OMIM #102500, and MONDO:0007057 (acroosteolysis dominant type / Hajdu-Cheney syndrome groupings). Reported prevalence is <1/1,000,000 and historical literature reviews estimate roughly 50-100 described cases, indicating that most current knowledge comes from aggregated case reports/reviews rather than EHR-scale cohorts. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 3-6, OpenTargets Search: Hajdu-Cheney syndrome-NOTCH2) Human clinical aggregated review evidence; moderate for definition/rarity, low for exact prevalence because of ascertainment and historical undercount. MONDO:0007057; MeSH: use disease name if mapping required; HCS synonyms: acroosteolysis dominant type, serpentine fibula-polycystic kidney syndrome
Genetics / inheritance HCS is usually autosomal dominant and caused by heterozygous germline NOTCH2 pathogenic variants, typically nonsense or small deletion/frameshift variants in exon 34. Many cases are de novo/sporadic, but familial transmission is established. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, canalis2016hajducheneymouse pages 1-2) Human genetics + review evidence; strong for causal gene/inheritance. HGNC:7882 NOTCH2; inheritance: autosomal dominant
Variant mechanism Pathogenic variants truncate NOTCH2 upstream of the PEST domain, preserving signaling machinery but impairing NICD2 degradation, producing a stabilized gain-of-function receptor with excessive NOTCH2 signaling. (canalis2014hajducheneysyndromea pages 1-2, canalis2014hajducheneysyndromea pages 5-6, cortesmartin2020hajdu–cheneysyndromea pages 9-13, canalis2016hajducheneymouse pages 1-2, canalis2016hajducheneymouse pages 18-19) Human molecular genetics + engineered mouse knock-in; strong for gain-of-function mechanism. GO:0007219 Notch signaling pathway; protein region: PEST domain
Pathophysiology / mechanism Current disease model supports high-turnover bone loss with increased osteoclastogenesis/bone resorption and relative dysregulation of bone formation. NOTCH2 activation is linked to pro-osteoclastogenic mediators such as NFATC1, RANKL, and IL6; mouse studies show osteopenia, increased osteoclast number, and increased bone resorption. (canalis2014hajducheneysyndromea pages 1-2, canalis2014hajducheneysyndromea pages 5-6, cortesmartin2020hajdu–cheneysyndromea pages 9-13, ballhause2023fracturehealingin pages 7-8, canalis2016hajducheneymouse pages 1-2) Mechanistic review + knock-in mouse functional evidence; moderate-strong. GO:0045453 bone resorption; GO:0030316 osteoclast differentiation; GO:0001649 osteoblast differentiation; CL:0000090 osteoclast; CL:0000062 osteoblast
Cardinal skeletal phenotypes Core manifestations are acro-osteolysis of distal phalanges, osteoporosis/osteopenia, short stature, fractures, wormian bones, kyphoscoliosis, vertebral anomalies/collapse, serpentine fibula, joint laxity, and progressive distal bone resorption. These features are variable but progressive over time. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13) Human case-series/review evidence; strong for recurrent phenotype set, low for precise frequency percentages. HP:0001841 Acroosteolysis; HP:0000939 Osteoporosis; HP:0004322 Short stature; HP:0000928 Scoliosis; HP:0008466 Wormian bones
Craniofacial / dental / neurologic / renal / cardiovascular phenotypes Frequent extra-appendicular features include coarse/dysmorphic facies, micrognathia, hypertelorism/telecanthus, high-arched palate, delayed/premature tooth loss, malocclusion, basilar invagination/platybasia, hydrocephalus, hearing issues, renal cysts/polcystic kidneys, congenital heart disease/patent ductus arteriosus, and recurrent respiratory infections from thoracic deformity. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13, cortesmartin2022hajducheneysyndromea pages 8-11) Human review + case evidence; moderate. HP:0000347 Micrognathia; HP:0000235 Hydrocephalus; HP:0000107 Renal cyst; HP:0001643 Patent ductus arteriosus; UBERON:0002101 skull; UBERON:0001134 kidney
Temporal course Onset is often congenital or early childhood, with early craniofacial/hand findings and later progressive skeletal fragility. The course is chronic, age-dependent, and progressive, with increasing disability risk from fractures, vertebral collapse, and skull-base complications. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 12-14, cortesmartin2020hajdu–cheneysyndromea pages 9-13, cortesmartin2022hajducheneysyndromea pages 8-11) Human longitudinal case/review evidence; moderate. HPO onset terms: congenital onset, childhood onset; course descriptors: progressive
Diagnostics Diagnosis is primarily clinical-radiologic plus molecular. Imaging may show distal phalangeal acro-osteolysis, wormian bones, platybasia/basilar invagination, vertebral deformities, serpentine fibula, and renal cysts. Genetic confirmation is typically by sequencing NOTCH2, especially exon 34; broad exome/panel testing is useful when phenotype is unclear or syndromic short stature is present. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13, cortesmartin2022hajducheneysyndromea pages 8-11) Human clinical/review evidence; strong for gene testing utility, moderate for formal criteria. MAXO: genetic testing; imaging terms: radiography, MRI, ultrasound; NOTCH2 single-gene testing / exome sequencing
Differential diagnosis Important differentials for acro-osteolysis and overlapping syndromic features include systemic sclerosis/scleroderma, sarcoidosis, hyperparathyroidism, local trauma/thermal injury, neuropathic causes, progeria, and Alagille syndrome or other NOTCH-related disorders. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13) Review evidence; moderate. HPO anchor feature: Acroosteolysis; related disease names as differential set
Treatment / management There is no curative therapy. Management is multidisciplinary and complication-directed: bone health surveillance, fracture prevention, orthopedic/neurosurgical management, respiratory and renal monitoring, dental care, and rehabilitation. Bisphosphonates are the most commonly reported pharmacologic intervention; denosumab, pamidronate, zoledronic acid, teriparatide, and romosozumab have only case-level/off-label evidence with variable benefit. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, cortesmartin2020hajdu–cheneysyndromea pages 7-9, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 12-14, cortesmartin2022hajducheneysyndromea pages 1-2, kaczorukwieremczuk2021oralsurgeryprocedures pages 3-10) Human case reports/reviews; low-moderate for drug efficacy, strong that no standard curative therapy exists. MAXO: bisphosphonate therapy; denosumab therapy; physical therapy / rehabilitation; surgical management
Real-world implementation / safety Real-world care issues include rehabilitation approaches (e.g., gait-focused vibrotherapy/physiotherapy), dental extraction/implant planning, and antiresorptive safety concerns such as delayed oral healing and medication-related osteonecrosis of the jaw risk in denosumab-treated patients. (cortesmartin2022hajducheneysyndromea pages 12-14, kaczorukwieremczuk2021oralsurgeryprocedures pages 3-10, cortesmartin2022hajducheneysyndromea pages 8-11) Human case evidence; low but clinically actionable. MAXO: dental procedure management; physical therapy; supportive care
Prognosis Life expectancy is not well quantified, but morbidity can be substantial due to fractures, vertebral compression/collapse, ventilatory restriction, basilar invagination, hydrocephalus, and rare sudden death/central respiratory complications. Prognosis depends on severity of skeletal and skull-base disease and adequacy of surveillance/intervention. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13) Review evidence; low-moderate because no registry-scale survival data. Prognostic features: basilar invagination, fractures, ventilatory restriction
Research gaps / omics No disease-specific single-cell, spatial transcriptomic, proteomic, metabolomic, or large natural-history registry dataset was identified in the retrieved evidence; current knowledge remains dominated by case reports, reviews, and mouse models. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, cortesmartin2020hajdu–cheneysyndromea pages 3-6) Absence-of-evidence statement from available literature set; low but important for KB completeness. Evidence gap annotation; omics not available / not established
Experimental models Engineered heterozygous Notch2 knock-in mice recapitulate major bone features of HCS, including short femora, cortical/cancellous osteopenia, increased osteoclastogenesis and bone resorption. In a 2023 fracture-healing model, overall structural healing appeared near-normal, but callus turnover was increased and biomechanical stability of healed femora was impaired. (ballhause2023fracturehealingin pages 1-2, ballhause2023fracturehealingin pages 10-11, canalis2016hajducheneymouse pages 1-2, canalis2016hajducheneymouse pages 18-19) Primary in vivo model evidence; strong for skeletal mechanism/model utility. Mouse model; CL:0000090 osteoclast; GO:0042060 wound healing; GO:0060348 bone development
Other species / natural disease No convincing naturally occurring veterinary counterpart or zoonotic relevance was identified in the retrieved evidence; current comparative biology relies mainly on engineered murine models. (canalis2016hajducheneymouse pages 1-2, canalis2016hajducheneymouse pages 18-19) Evidence gap / comparative inference; low. NCBI Taxon: Mus musculus (model organism)

Table: This table condenses the most actionable disease-characterization points for Hajdu-Cheney syndrome into a knowledge-base format, with evidence strength and ontology suggestions. It is useful for rapid curation across clinical, molecular, and translational domains.

1. Disease information

Definition and identifiers

HCS is a Mendelian connective-tissue and skeletal disorder characterized by progressive acro-osteolysis, severe low bone mass, skeletal dysplasia, and multisystem developmental abnormalities. The disorder’s phenotype evolves with age, so absence of classic acro-osteolysis early in childhood does not exclude it. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13)

Resource Identifier / designation
MONDO MONDO:0007057, acroosteolysis, dominant type
OMIM #102500, Hajdu–Cheney syndrome
Orphanet ORPHA:955
Open Targets NOTCH2–MONDO:0007057 association; target ENSG00000134250
ICD-10/ICD-11 No highly specific HCS code was established in the retrieved evidence; coding generally falls under an appropriate congenital osteochondrodysplasia/other specified skeletal disorder category
MeSH No uniquely disease-specific MeSH identifier was confirmed in the retrieved evidence; use “Hajdu-Cheney Syndrome” as a supplementary concept/search term where supported

Open Targets reports five genetic/curation evidence items linking NOTCH2 to MONDO:0007057, including literature evidence associated with PMID 21378985, the landmark causal-gene report. (OpenTargets Search: Hajdu-Cheney syndrome-NOTCH2)

Synonyms: acro-osteolysis, dominant type; acroosteolysis with osteoporosis; acro-dento-osteo-dysplasia; arthro-dento-osteo dysplasia; Cheney syndrome; and serpentine fibula–polycystic kidney syndrome. The latter is now regarded as part of the HCS phenotypic spectrum, not a separate disorder. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 3-6, cortesmartin2020hajdu–cheneysyndromea pages 9-13)

Data provenance: almost all available information is aggregated disease-level evidence derived from published individual patients/families and model organisms. No EHR-scale cohort or population registry was identified.

2. Etiology and risk factors

Causal factor

The primary cause is a heterozygous germline pathogenic variant in NOTCH2, usually a truncating variant in exon 34. Familial autosomal-dominant transmission and de novo cases both occur. This is not an environmentally caused, infectious, autoimmune, or lifestyle-mediated disorder. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2, canalis2016hajducheneymouse pages 1-2)

The landmark human genetic study is Simpson et al., Nature Genetics, published April 2011, “Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss,” PMID 21378985, DOI: https://doi.org/10.1038/ng.779. Open Targets independently links this PMID to the NOTCH2–HCS association. (OpenTargets Search: Hajdu-Cheney syndrome-NOTCH2)

Risk and protective factors

  • Genetic risk: inheriting a causal allele from an affected parent confers an a priori 50% transmission probability per pregnancy. De novo pathogenic variants explain many sporadic patients.
  • Modifiers: no reproducible modifier gene, susceptibility locus, founder allele, or protective NOTCH2 allele has been established. Marked intrafamilial variability implies modifiers, stochastic developmental effects, age, or exposures, but these remain unproven.
  • Environment/lifestyle: no exposure causes HCS. Falls, immobilization, low mechanical loading, poor nutrition, vitamin-D deficiency, and medications harmful to bone could plausibly amplify fragility, but disease-specific interaction estimates are unavailable.
  • Protective factors: no genetic protection is known. Adequate calcium/vitamin-D status, safe weight-bearing activity, physiotherapy, healthy weight, and fall avoidance support skeletal health but do not prevent the genotype or reverse acro-osteolysis.
  • Gene–environment interaction: no formal HCS G×E study was identified. A 2023 fracture study noted lifestyle factors as general determinants of non-union but did not establish an HCS-specific interaction. (ballhause2023fracturehealingin pages 1-2)

3. Phenotypes

Reliable percentages are generally unavailable: published samples are tiny, age-heterogeneous, and affected by reporting bias. “Cardinal,” “common,” or “variable” is therefore more defensible than numerical frequency except where noted.

Phenotype/type Onset, course, severity and impact Suggested HPO term
Distal phalangeal acro-osteolysis; radiographic sign Usually emerges/progresses in childhood; progressive and cardinal; causes shortening, pseudoclubbing, deformity, impaired grip/gait HP:0001841 Acroosteolysis
Generalized osteoporosis/osteopenia; imaging/laboratory phenotype Early-onset, progressive or persistently severe; fractures, pain, deformity and reduced mobility HP:0000939 Osteoporosis
Recurrent/fragility fractures Childhood onward; variable; non-union has been reported HP:0002757 Recurrent fractures
Short stature Childhood, variable, may worsen with vertebral collapse HP:0004322 Short stature
Wormian bones/delayed cranial-suture closure Congenital or early childhood; stable structural sign HP:0002645 Wormian bones; curator should verify the artifact’s alternative ID before ingestion
Coarse/dysmorphic facies, micrognathia, hypertelorism/telecanthus, low-set ears, long philtrum Features change with age; early synophrys/hypotelorism may give way to coarser childhood/adolescent facies HP:0000347 Micrognathia, HP:0000316 Hypertelorism
Kyphosis/scoliosis, biconcave vertebrae and vertebral collapse Progressive; moderate to severe; pain, height loss, restrictive ventilation HP:0002808 Kyphosis; HP:0002650 Scoliosis; HP:0002953 Vertebral compression fracture
Joint laxity and long-bone deformity Childhood onward; gait impairment and dislocation risk HP:0001382 Joint hypermobility
Basilar invagination/platybasia Variable but potentially life-threatening; may compress brainstem or cause syringomyelia/hydrocephalus HP:0005758 Basilar invagination; HP:0002691 Platybasia
Dental eruption abnormalities, malocclusion, periodontitis, premature tooth loss/root or alveolar resorption Childhood/adulthood; substantial feeding, speech and quality-of-life effects HP:0006480 Premature loss of teeth; HP:0000689 Dental malocclusion
Renal cysts/polcystic kidneys Variable; congenital to adult; occasionally renal impairment HP:0000107 Renal cyst
Congenital heart disease/PDA/septal defects Congenital, variably severe HP:0001643 Patent ductus arteriosus
Recurrent respiratory infections/restrictive ventilation Secondary to thoracic deformity and airway/ENT problems; episodic infections with potentially progressive restriction HP:0002205 Recurrent respiratory infections; HP:0002091 Restrictive ventilatory defect
Hydrocephalus/syringomyelia Variable neurologic complication, potentially severe HP:0000238 Hydrocephalus; HP:0003396 Syringomyelia
Hearing loss, hypotonia, delayed motor or expressive-language development Variable, often mild-to-moderate but can affect education and independence HP:0000365 Hearing impairment; HP:0001252 Hypotonia

The broad reported phenotype also includes serpentine fibula, dolichocephaly/bathrocephaly, absent or hypoplastic frontal sinuses, high-arched palate, hypertrichosis, short nails, hypospadias, cryptorchidism, intestinal malrotation, hernia, plantar ulcers, and deep voice. (cortesmartin2020hajdu–cheneysyndromea pages 9-13)

A detailed 2022 pediatric case documented delayed lambdoid closure, short broad phalanges, hypotonia, expressive-language delay, megalocornea/blue sclerae, delayed tooth eruption, bilateral foot valgus and Trendelenburg gait. Focal vibration plus aquatic/hippotherapy was followed by longer steps, faster cadence, and disappearance of the observed Trendelenburg pattern, but this uncontrolled observation cannot establish efficacy. (cortesmartin2022hajducheneysyndromea pages 8-11)

4. Genetic and molecular information

Gene and variant class

  • Gene: NOTCH2, notch receptor 2; chromosome 1p12 region; Ensembl ENSG00000134250; HGNC HGNC:7882.
  • Typical variants: heterozygous nonsense or small deletion/frameshift variants in terminal exon 34, creating a premature stop upstream of the PEST domain.
  • Origin: germline; either inherited or de novo. HCS is not a somatic neoplasm-associated phenotype.
  • ACMG interpretation: a terminal-exon truncation requires phenotype, segregation/de novo status, database evidence, and the established gain-of-function mechanism. Ordinary “loss-of-function” rules must be applied carefully because HCS truncations escape conventional nonsense-mediated decay and act through protein stabilization.
  • Population frequency: pathogenic HCS variants are expected to be absent or extremely rare in gnomAD/1000 Genomes. Variant-specific frequencies should be queried at curation time; no defensible pooled carrier frequency exists.

The mechanistic distinction from NOTCH2-related Alagille syndrome is important: HCS terminal-exon variants stabilize NICD2, whereas Alagille syndrome generally reflects NOTCH-pathway haploinsufficiency/reduced signaling. (cortesmartin2020hajdu–cheneysyndromea pages 9-13)

Functional consequence

Normal ligand engagement triggers proteolysis and release of NICD2, which enters the nucleus and complexes with RBPJ and Mastermind-like proteins. The PEST domain normally permits ubiquitination and degradation. HCS truncation removes that degron while retaining RAM/ankyrin and nuclear-signaling elements, producing prolonged gain-of-function signaling. (cortesmartin2020hajdu–cheneysyndromea pages 9-13, canalis2016hajducheneymouse pages 1-2, canalis2016hajducheneymouse pages 18-19)

Exact primary-study abstract quote: “Hajdu Cheney Syndrome…is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function.” Canalis et al., published online December 1, 2015/final 2016, DOI: https://doi.org/10.1074/jbc.M115.685453. (canalis2016hajducheneymouse pages 1-2)

No established modifier gene, disease-specific methylation episignature, recurrent chromosomal rearrangement, or pathogenic aneuploidy was identified. CMA/karyotype findings therefore are not defining features.

5. Environmental information

No toxin, radiation, pollution, occupation, infectious agent, smoking behavior, alcohol exposure, or diet has been shown to cause HCS. Such factors can modify general bone health, surgical risk, or fracture healing but are secondary rather than etiologic. HCS has no infectious transmission and no zoonotic potential.

Practical lifestyle considerations are individualized safe activity, avoidance of high-impact trauma and falls, maintenance of muscle strength, healthy weight, adequate nutrition, and avoidance of smoking/excess alcohol in adults. A 2022 case report recommended continued physical/intellectual activity and avoidance of overweight, but this is expert supportive advice rather than trial evidence. (cortesmartin2022hajducheneysyndromea pages 12-14)

6. Mechanism and pathophysiology

Causal chain

  1. Upstream trigger: germline terminal-exon NOTCH2 truncation.
  2. Protein defect: loss of the PEST degron impairs NICD2 ubiquitination/degradation.
  3. Signaling: persistent canonical NOTCH2–RBPJ/MAML transcriptional activity, including HES/HEY programs.
  4. Cellular response: altered skeletal progenitor/osteoblast-lineage signaling and a pro-osteoclastogenic marrow environment; NOTCH2 can promote NFATC1-dependent osteoclast differentiation. Mouse marrow shows increased Rankl/Tnfsf11 and Il6 expression.
  5. Tissue process: excessive osteoclastogenesis/resorption and high bone turnover, with possible concurrent dysregulation of formation and developmental ossification.
  6. Clinical result: generalized osteopenia/osteoporosis, fractures, deformity and focal distal phalangeal osteolysis. Skull-base and vertebral changes can secondarily cause neurologic or respiratory injury. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13, ballhause2023fracturehealingin pages 7-8, canalis2016hajducheneymouse pages 1-2)

Suggested GO annotations: GO:0007219 Notch signaling pathway; GO:0030316 osteoclast differentiation; GO:0045453 bone resorption; GO:0001649 osteoblast differentiation; GO:0060348 bone development; GO:0042060 wound healing. Cell Ontology: CL:0000090 osteoclast; CL:0000062 osteoblast; bone-marrow stromal/mesenchymal progenitor and chondrocyte terms should be added after identifier validation.

The mechanism of sharply localized acro-osteolysis remains less certain than generalized high-turnover osteopenia. Inflammatory/local mechanical mechanisms have been proposed but not demonstrated conclusively. (canalis2014hajducheneysyndromea pages 5-6)

Molecular profiling and advanced technologies

Disease-specific large-scale transcriptomics, proteomics, metabolomics, lipidomics, single-cell RNA sequencing, spatial transcriptomics, multi-omics integration, or CRISPR-screen datasets were not identified through 2024. Existing expression measurements are mostly targeted qRT-PCR in mice. This is a major research gap—not evidence that these layers are normal.

7. Anatomical structures affected

  • Primary organs/tissues: appendicular and axial skeleton—distal phalanges, hands/feet, long bones, vertebrae, skull, cranial sutures, skull base, jaw and alveolar bone.
  • Secondary systems: kidneys, heart/great vessels, respiratory thorax/airways, CNS/craniovertebral junction, ear/hearing apparatus, dentition/periodontium, and connective tissues/joints. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13)
  • Cells: osteoclasts and precursors are the best-supported effector population; osteoblasts, stromal progenitors, chondrocytes and osteocytes participate in development/remodeling.
  • Subcellular compartments: plasma membrane NOTCH2; cleaved NICD2 in cytoplasm/nucleus; nuclear RBPJ/MAML transcriptional complex; ubiquitin-proteasome degradation machinery.
  • Localization: usually bilateral/generalized rather than lateralized, although severity can be asymmetric.

Suggested UBERON mappings include skeleton (UBERON:0004288), bone tissue (UBERON:0002481), skull (UBERON:0003129), vertebral column (UBERON:0001130), kidney (UBERON:0002113), heart (UBERON:0000948), and distal phalanx/hand/foot terms after curator validation.

8. Temporal development

HCS is congenital/genetic, but clinical recognition ranges from infancy to adulthood. Early findings can include craniofacial differences, wormian bones, delayed suture closure, short stature or hand/foot abnormalities. Acro-osteolysis, osteoporosis, vertebral collapse and coarse facial features often become more apparent with age. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13, cortesmartin2022hajducheneysyndromea pages 8-11)

The course is lifelong, chronic, progressive and highly variable—not relapsing-remitting. There is no spontaneous remission. Critical intervention windows include early recognition of osteoporosis/fractures, serial evaluation of the craniovertebral junction before irreversible neurologic injury, and early dental/rehabilitation support. Formal disease stages and validated progression rates do not exist.

9. Inheritance and population

  • Inheritance: autosomal dominant.
  • Penetrance: apparently high for some phenotype, but age-dependent and incompletely quantified.
  • Expressivity: markedly variable, including within families.
  • Anticipation: not established; HCS is not a repeat-expansion disorder.
  • Mosaicism: parental/germline mosaicism is biologically possible but no frequency estimate is available.
  • Founder effects/consanguinity: none established; consanguinity is not etiologically relevant to a dominant disorder.
  • Carrier frequency: unknown and likely extremely low.
  • Prevalence: <1/1,000,000; approximately 50 cases in the 2020 systematic review and roughly 100 described in some later summaries. Differences reflect search dates and case definitions, not a documented incidence increase. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, cortesmartin2022hajducheneysyndromea pages 12-14, cortesmartin2022hajducheneysyndromea pages 1-2)
  • Incidence, sex ratio, ethnicity and geography: no robust estimates or population enrichment. Cases occur worldwide and both sexes are affected.

10. Diagnostics

Clinical-radiologic approach

Suspect HCS when progressive distal phalangeal acro-osteolysis occurs with generalized osteoporosis, short stature, wormian bones, craniofacial dysmorphism, dental loss, vertebral abnormalities, basilar invagination, serpentine fibula or renal cysts. A historical Brennan–Pauli clinical tool incorporates acro-osteolysis, wormian bones, platybasia, premature tooth loss, micrognathia, coarse facies and short stature, but molecular confirmation is preferred. (cortesmartin2020hajdu–cheneysyndromea pages 7-9)

Recommended evaluation:

  1. Hand/foot radiographs and skeletal survey where appropriate.
  2. Spine radiographs/vertebral-fracture assessment and DXA, corrected for age, sex, height and pediatric body size.
  3. CT or MRI of the craniovertebral junction when platybasia, basilar invagination, Chiari-type crowding or neurologic symptoms are suspected.
  4. Renal ultrasound, echocardiography, dental/periodontal examination, hearing assessment, respiratory evaluation and developmental assessment according to phenotype.
  5. Serum calcium, phosphate, alkaline phosphatase, creatinine/eGFR, 25-hydroxyvitamin D, PTH and selected turnover markers—mainly to assess bone health and exclude acquired mimics; no diagnostic biochemical biomarker exists.

Characteristic imaging includes transverse osteolysis of terminal phalanges, reduced bone density, wormian bones, hypoplastic frontal sinuses, serpentine fibula, biconcave “fish” vertebrae, scoliosis, renal cysts and craniovertebral abnormalities. (cortesmartin2020hajdu–cheneysyndromea pages 9-13)

Genetic testing

Use NOTCH2 sequencing with adequate exon-34 coverage and deletion/duplication analysis. A skeletal-dysplasia/acro-osteolysis panel or WES is appropriate for an uncertain phenotype; targeted exome sequencing diagnosed rare syndromic short-stature disorders including HCS in a 2021 cohort. WGS can detect difficult coding, structural or mosaic variants when panel/WES results are negative. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2022hajducheneysyndromea pages 1-2)

CMA, karyotyping, FISH, mitochondrial sequencing and repeat-expansion assays are not first-line unless another diagnosis is suspected. RNA-seq may help resolve a splice VUS but is not routine. Cascade testing should follow identification of a familial variant.

Differential diagnosis

Major alternatives include systemic sclerosis/scleroderma, psoriatic arthritis, primary hypertrophic osteoarthropathy, multicentric carpotarsal osteolysis, Winchester syndrome/MMP2-related osteolysis, progeroid disorders, hyperparathyroidism, sarcoidosis, neuropathy, thermal injury/trauma, spinal dysraphism, osteogenesis imperfecta, idiopathic juvenile osteoporosis, pycnodysostosis and Alagille syndrome. Acro-osteolysis itself is a radiographic sign that should trigger etiologic investigation. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, cortesmartin2022hajducheneysyndromea pages 1-2)

11. Outcome and prognosis

No reliable 5-year survival, mortality rate, or life-expectancy estimate exists. Many affected individuals survive into adulthood, but morbidity may be considerable: recurrent fractures, impaired healing, pain, progressive short stature, deformity, reduced mobility, dental loss and cardiopulmonary or renal complications. No validated HCS-specific EQ-5D, SF-36 or PROMIS dataset was found.

The most dangerous complications are basilar invagination with brainstem injury, hydrocephalus, syringomyelia, vertebral collapse, restrictive ventilation and—rarely—central respiratory arrest or sudden death. (canalis2014hajducheneysyndromea pages 1-2, cortesmartin2020hajdu–cheneysyndromea pages 9-13)

Likely prognostic factors are fracture burden, bone density/architecture, spinal deformity, craniovertebral-junction severity, respiratory restriction, renal/cardiac involvement and access to multidisciplinary management. No validated molecular prognostic biomarker or genotype-based outcome model exists.

12. Treatment

There is no approved, curative, genotype-directed HCS therapy. Management should be coordinated by a metabolic-bone specialist with genetics, orthopedics, neurosurgery, dentistry, nephrology, cardiology, pulmonology, ENT/audiology and rehabilitation as indicated.

Pharmacotherapy

  • Bisphosphonates—alendronate, pamidronate and zoledronic acid—are most often reported. Some patients gain BMD or experience fewer fractures; others show limited or nonpersistent benefit, and convincing control of acro-osteolysis has not been demonstrated. A referenced pediatric report described increased BMD and no fractures during two years of cyclic pamidronate, but this remains uncontrolled evidence. (cortesmartin2020hajdu–cheneysyndromea pages 7-9, cortesmartin2022hajducheneysyndromea pages 15-17)
  • Denosumab suppresses RANKL-dependent osteoclast activity and has been used off label. Risks include hypocalcemia, rebound high turnover/vertebral fractures after discontinuation, delayed oral healing and medication-related osteonecrosis of the jaw. Dental planning is essential. (kaczorukwieremczuk2021oralsurgeryprocedures pages 3-10)
  • Teriparatide has anecdotal use; disease-specific fracture-efficacy and safety are not established, particularly in growing children.
  • Romosozumab: a 2023 single-patient exploratory report exists (DOI: https://doi.org/10.1007/s00198-023-06668-z), but one case cannot define benefit/risk or establish standard care.
  • Calcium or vitamin D should correct deficiency, not be represented as disease-modifying therapy. No HCS-specific pharmacogenomic guidance exists.

Suggested MAXO concepts: genetic counseling; bone-density surveillance; bisphosphonate therapy; denosumab therapy; calcium/vitamin-D supplementation when deficient; physical therapy; occupational therapy; dental surveillance; orthopedic surgery; spinal fusion/decompression; renal ultrasonography; echocardiography.

Surgery and supportive care

Treat fractures using careful fixation and prolonged follow-up where healing is uncertain. Severe scoliosis, cervical instability, basilar invagination, hydrocephalus and syringomyelia may require specialized orthopedic/neurosurgical intervention. Dental management includes intensive periodontal prevention, conservative restoration where possible and carefully planned extraction/prosthodontics.

A real-world dental series reported successful osseointegration and five-year follow-up of multiple implants with extended healing and three-month maintenance intervals, illustrating feasibility in selected patients rather than general efficacy. (kaczorukwieremczuk2021oralsurgeryprocedures pages 3-10)

Physical/occupational therapy, muscle strengthening, aquatic therapy, gait aids, fall prevention, pain management, hearing/speech support and educational accommodations address function and quality of life. (cortesmartin2022hajducheneysyndromea pages 12-14, cortesmartin2022hajducheneysyndromea pages 8-11)

Experimental approaches and trials

No disease-specific interventional HCS trial was identified in the retrieved ClinicalTrials.gov search. The returned NCT02823925 study concerns MONA spectrum disorder, not HCS, and must not be misclassified. Proposed molecular approaches—NOTCH2-selective antibodies, disruption of the NICD transcriptional complex, or allele-specific RNA/gene editing—remain preclinical concepts. Broad systemic Notch inhibition could produce substantial on-target toxicity because Notch regulates many tissues. (canalis2014hajducheneysyndromea pages 5-6)

13. Prevention

Primary prevention: no lifestyle or vaccine prevents a de novo/inherited NOTCH2 variant. Reproductive genetic counseling, prenatal diagnosis and preimplantation genetic testing are options once a familial pathogenic variant is known.

Secondary prevention: cascade testing of relatives, early skeletal/radiologic assessment, DXA and vertebral screening, craniovertebral-junction surveillance, renal ultrasound, echocardiography and dental evaluation can detect complications before irreversible injury.

Tertiary prevention: optimize bone nutrition, use safe individualized weight-bearing activity, prevent falls/trauma, avoid smoking and excess alcohol, minimize immobilization, maintain dental hygiene before antiresorptives, monitor spinal/respiratory function, and intervene promptly for neurologic warning signs. Routine vaccination follows standard recommendations; no HCS-specific immunization exists.

14. Other species and natural disease

No convincing naturally occurring HCS counterpart was identified in companion animals, livestock or wildlife. No breed association or VBO term is established. The disease is noninfectious and nonzoonotic.

NOTCH2 is evolutionarily conserved across vertebrates, enabling engineered Mus musculus models (NCBI Taxonomy 10090). Ortholog identifiers should be obtained directly from NCBI Gene/Alliance at ingestion because database records can change.

15. Model organisms

The principal model is a heterozygous knock-in mouse carrying a human HCS-like terminal Notch2 truncation. In the Canalis model, a 6955C>T, p.Gln2319Ter (Q2319X) allele produced smaller mice, shorter femora, early cancellous and cortical osteopenia, increased osteoclast numbers/resorption, and increased RANKL-driven osteoclast differentiation. A γ-secretase inhibitor suppressed the enhanced in-vitro osteoclast phenotype, demonstrating Notch dependence. (canalis2016hajducheneymouse pages 1-2, canalis2016hajducheneymouse pages 18-19)

Exact abstract quote: “Notch2Q2319X mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis and increased bone resorption.” (canalis2016hajducheneymouse pages 1-2)

A 2023 study used 88 operated male Notch2+/HCS mice carrying 6272delT, created standardized femoral osteotomies, and examined healing on days 3, 7, 14, 21 and 28. Static radiology/histology showed only minor morphologic changes, but HCS callus had increased osteoclast parameters and osteoblast/osteoclast marker expression, and healed femora had inferior biomechanical stability. (ballhause2023fracturehealingin pages 1-2, ballhause2023fracturehealingin pages 10-11)

Exact 2023 abstract quote: “structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.” Ballhause et al., Scientific Reports, July 2023, DOI: https://doi.org/10.1038/s41598-023-38638-0. (ballhause2023fracturehealingin pages 1-2)

These models are valuable for osteoclast biology, high-turnover osteopenia, fracture healing and preclinical antiresorptive/Notch-directed studies. Limitations include incomplete reproduction of human acro-osteolysis and multisystem disease, species-specific skeletal remodeling, engineered alleles, and controlled laboratory environments. The 2023 study used only male 12–14-week-old mice, limiting sex- and age-generalization. (ballhause2023fracturehealingin pages 10-11)

Recent developments, evidence appraisal and priorities

The most consequential 2023–2024 development was the 2023 demonstration that apparently normal structural fracture repair in HCS mice can conceal increased turnover and reduced mechanical competence. This argues that radiographic union alone may be an inadequate endpoint and supports biomechanical/functional follow-up in future human natural-history studies. (ballhause2023fracturehealingin pages 1-2, ballhause2023fracturehealingin pages 7-8)

Recent human literature remains predominantly case reports: exploratory romosozumab treatment in 2023, new NOTCH2 variants and phenotype expansions in 2023–2024, dental/orofacial reports, and perioperative descriptions. These improve recognition but do not establish frequencies or treatment efficacy. The expert consensus across authoritative reviews remains that HCS has no curative therapy and that antiresorptive/anabolic benefits are unproven at syndrome level. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, canalis2014hajducheneysyndromea pages 1-2)

Priority research needs are: an international prospective registry; standardized HPO-based phenotyping; longitudinal DXA, HR-pQCT, fracture and craniovertebral outcomes; patient-reported quality-of-life measures; systematic ClinVar/gnomAD variant curation; patient-derived iPSC osteoclast/osteoblast studies; single-cell and spatial profiling of bone; and multicenter treatment protocols with prespecified fracture, function and safety endpoints.

Selected primary and authoritative references

  1. Simpson MA et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nature Genetics. Published April 2011. PMID: 21378985. DOI: https://doi.org/10.1038/ng.779. (OpenTargets Search: Hajdu-Cheney syndrome-NOTCH2)
  2. Canalis E, Zanotti S. Hajdu-Cheney syndrome: a review. Orphanet Journal of Rare Diseases. Published December 2014. DOI: https://doi.org/10.1186/s13023-014-0200-y. (canalis2014hajducheneysyndromea pages 1-2)
  3. Canalis E et al. Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption. Journal of Biological Chemistry. Published 2016. DOI: https://doi.org/10.1074/jbc.M115.685453. (canalis2016hajducheneymouse pages 1-2)
  4. Cortés-Martín J et al. Hajdu–Cheney Syndrome: A Systematic Review of the Literature. International Journal of Environmental Research and Public Health. Published August 2020. DOI: https://doi.org/10.3390/ijerph17176174. (cortesmartin2020hajdu–cheneysyndromea pages 6-7, cortesmartin2020hajdu–cheneysyndromea pages 3-6)
  5. Cortés-Martín J et al. Hajdu-Cheney Syndrome: A Novel NOTCH2 Mutation in a Spanish Child in Treatment with Vibrotherapy. Journal of Clinical Medicine. Published September 2022. DOI: https://doi.org/10.3390/jcm11175205. (cortesmartin2022hajducheneysyndromea pages 12-14, cortesmartin2022hajducheneysyndromea pages 8-11)
  6. Ballhause TM et al. Fracture healing in a mouse model of Hajdu–Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability. Scientific Reports. Published July 2023. DOI: https://doi.org/10.1038/s41598-023-38638-0. (ballhause2023fracturehealingin pages 1-2)

Overall evidence judgment: causal gene and gain-of-function mechanism are strong; cardinal phenotype evidence is moderate-to-strong but frequency estimates are weak; treatment evidence is very low because it consists mainly of uncontrolled individual cases; epidemiology, survival, quality of life, modifiers and advanced omics remain major evidence gaps.

References

  1. (cortesmartin2020hajdu–cheneysyndromea pages 7-9): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Raquel Rodríguez-Blanque, Antonio Bermejo-Fernández, and Juan Carlos Sánchez-García. Hajdu–cheney syndrome: a systematic review of the literature. International Journal of Environmental Research and Public Health, 17:6174, Aug 2020. URL: https://doi.org/10.3390/ijerph17176174, doi:10.3390/ijerph17176174. This article has 33 citations.

  2. (canalis2014hajducheneysyndromea pages 1-2): Ernesto Canalis and Stefano Zanotti. Hajdu-cheney syndrome: a review. Orphanet Journal of Rare Diseases, Dec 2014. URL: https://doi.org/10.1186/s13023-014-0200-y, doi:10.1186/s13023-014-0200-y. This article has 109 citations and is from a peer-reviewed journal.

  3. (cortesmartin2022hajducheneysyndromea pages 1-2): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Juan Carlos Sánchez-García, Antonio Liñán González, and Raquel Rodríguez-Blanque. Hajdu-cheney syndrome: a novel notch2 mutation in a spanish child in treatment with vibrotherapy: a case report. Sep 2022. URL: https://doi.org/10.3390/jcm11175205, doi:10.3390/jcm11175205. This article has 4 citations.

  4. (canalis2014hajducheneysyndromea pages 5-6): Ernesto Canalis and Stefano Zanotti. Hajdu-cheney syndrome: a review. Orphanet Journal of Rare Diseases, Dec 2014. URL: https://doi.org/10.1186/s13023-014-0200-y, doi:10.1186/s13023-014-0200-y. This article has 109 citations and is from a peer-reviewed journal.

  5. (cortesmartin2020hajdu–cheneysyndromea pages 9-13): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Raquel Rodríguez-Blanque, Antonio Bermejo-Fernández, and Juan Carlos Sánchez-García. Hajdu–cheney syndrome: a systematic review of the literature. International Journal of Environmental Research and Public Health, 17:6174, Aug 2020. URL: https://doi.org/10.3390/ijerph17176174, doi:10.3390/ijerph17176174. This article has 33 citations.

  6. (canalis2016hajducheneymouse pages 1-2): Ernesto Canalis, Lauren Schilling, Siu-Pok Yee, Sun-Kyeong Lee, and Stefano Zanotti. Hajdu cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption. Journal of Biological Chemistry, 291:1538-1551, Jan 2016. URL: https://doi.org/10.1074/jbc.m115.685453, doi:10.1074/jbc.m115.685453. This article has 96 citations and is from a domain leading peer-reviewed journal.

  7. (cortesmartin2020hajdu–cheneysyndromea pages 3-6): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Raquel Rodríguez-Blanque, Antonio Bermejo-Fernández, and Juan Carlos Sánchez-García. Hajdu–cheney syndrome: a systematic review of the literature. International Journal of Environmental Research and Public Health, 17:6174, Aug 2020. URL: https://doi.org/10.3390/ijerph17176174, doi:10.3390/ijerph17176174. This article has 33 citations.

  8. (OpenTargets Search: Hajdu-Cheney syndrome-NOTCH2): Open Targets Query (Hajdu-Cheney syndrome-NOTCH2, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  9. (canalis2016hajducheneymouse pages 18-19): Ernesto Canalis, Lauren Schilling, Siu-Pok Yee, Sun-Kyeong Lee, and Stefano Zanotti. Hajdu cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption. Journal of Biological Chemistry, 291:1538-1551, Jan 2016. URL: https://doi.org/10.1074/jbc.m115.685453, doi:10.1074/jbc.m115.685453. This article has 96 citations and is from a domain leading peer-reviewed journal.

  10. (ballhause2023fracturehealingin pages 7-8): Tobias Malte Ballhause, Shan Jiang, Weixin Xie, Jan Sevecke, Christine Dowling, Tobias Dust, Sabine Brandt, Peter R. Mertens, Timur Alexander Yorgan, Thorsten Schinke, Karl-Heinz Frosch, Anke Baranowsky, and Johannes Keller. Fracture healing in a mouse model of hajdu–cheney-syndrome with high turnover osteopenia results in decreased biomechanical stability. Scientific Reports, Jul 2023. URL: https://doi.org/10.1038/s41598-023-38638-0, doi:10.1038/s41598-023-38638-0. This article has 4 citations and is from a peer-reviewed journal.

  11. (cortesmartin2020hajdu–cheneysyndromea pages 6-7): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Raquel Rodríguez-Blanque, Antonio Bermejo-Fernández, and Juan Carlos Sánchez-García. Hajdu–cheney syndrome: a systematic review of the literature. International Journal of Environmental Research and Public Health, 17:6174, Aug 2020. URL: https://doi.org/10.3390/ijerph17176174, doi:10.3390/ijerph17176174. This article has 33 citations.

  12. (cortesmartin2022hajducheneysyndromea pages 8-11): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Juan Carlos Sánchez-García, Antonio Liñán González, and Raquel Rodríguez-Blanque. Hajdu-cheney syndrome: a novel notch2 mutation in a spanish child in treatment with vibrotherapy: a case report. Sep 2022. URL: https://doi.org/10.3390/jcm11175205, doi:10.3390/jcm11175205. This article has 4 citations.

  13. (cortesmartin2022hajducheneysyndromea pages 12-14): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Juan Carlos Sánchez-García, Antonio Liñán González, and Raquel Rodríguez-Blanque. Hajdu-cheney syndrome: a novel notch2 mutation in a spanish child in treatment with vibrotherapy: a case report. Sep 2022. URL: https://doi.org/10.3390/jcm11175205, doi:10.3390/jcm11175205. This article has 4 citations.

  14. (kaczorukwieremczuk2021oralsurgeryprocedures pages 3-10): Magdalena Kaczoruk-Wieremczuk, Paulina Adamska, Łukasz Jan Adamski, Piotr Wychowański, Barbara Alicja Jereczek-Fossa, and Anna Starzyńska. Oral surgery procedures in a patient with hajdu-cheney syndrome treated with denosumab—a rare case report. International Journal of Environmental Research and Public Health, 18:9099, Aug 2021. URL: https://doi.org/10.3390/ijerph18179099, doi:10.3390/ijerph18179099. This article has 9 citations.

  15. (ballhause2023fracturehealingin pages 1-2): Tobias Malte Ballhause, Shan Jiang, Weixin Xie, Jan Sevecke, Christine Dowling, Tobias Dust, Sabine Brandt, Peter R. Mertens, Timur Alexander Yorgan, Thorsten Schinke, Karl-Heinz Frosch, Anke Baranowsky, and Johannes Keller. Fracture healing in a mouse model of hajdu–cheney-syndrome with high turnover osteopenia results in decreased biomechanical stability. Scientific Reports, Jul 2023. URL: https://doi.org/10.1038/s41598-023-38638-0, doi:10.1038/s41598-023-38638-0. This article has 4 citations and is from a peer-reviewed journal.

  16. (ballhause2023fracturehealingin pages 10-11): Tobias Malte Ballhause, Shan Jiang, Weixin Xie, Jan Sevecke, Christine Dowling, Tobias Dust, Sabine Brandt, Peter R. Mertens, Timur Alexander Yorgan, Thorsten Schinke, Karl-Heinz Frosch, Anke Baranowsky, and Johannes Keller. Fracture healing in a mouse model of hajdu–cheney-syndrome with high turnover osteopenia results in decreased biomechanical stability. Scientific Reports, Jul 2023. URL: https://doi.org/10.1038/s41598-023-38638-0, doi:10.1038/s41598-023-38638-0. This article has 4 citations and is from a peer-reviewed journal.

  17. (cortesmartin2022hajducheneysyndromea pages 15-17): Jonathan Cortés-Martín, Lourdes Díaz-Rodríguez, Beatriz Piqueras-Sola, Juan Carlos Sánchez-García, Antonio Liñán González, and Raquel Rodríguez-Blanque. Hajdu-cheney syndrome: a novel notch2 mutation in a spanish child in treatment with vibrotherapy: a case report. Sep 2022. URL: https://doi.org/10.3390/jcm11175205, doi:10.3390/jcm11175205. This article has 4 citations.

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