Sclerosteosis

🏷

Classifications

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal Recessive

Autosomal recessive inheritance. High incidence in the South African Afrikaner population due to a founder effect. Two nonsense mutations and one splice site mutation identified.

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance"

Confirms autosomal recessive inheritance of sclerosteosis.

◆

Subtypes

2

Van Buchem Disease

SOST-related endosteal hyperostosis, van Buchem type, is caused by a biallelic 52-kb regulatory deletion downstream of SOST. It is generally milder than SOST-related sclerosteosis, lacks syndactyly or other digit deformities, and has apparently normal life span.

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Pathophysiology

3

Loss of Sclerostin (SOST Loss-of-Function)

SOST encodes sclerostin, a secreted glycoprotein with a cysteine-knot motif that functions as an antagonist of the Wnt/beta-catenin signaling pathway by binding to LRP5/LRP6 coreceptors on osteoblasts. Loss-of- function mutations abolish sclerostin production, removing the physiological brake on bone formation.

Show evidence (3 references)

PMID:11181578 SUPPORT

"the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation"

Establishes that SOST loss causes massive bone formation and that sclerostin normally suppresses bone formation.

PMID:11181578 SUPPORT

"This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif"

Characterizes sclerostin as a secreted cysteine-knot protein.

PMID:11179006 SUPPORT

"The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte"

Places sclerostin in the DAN family of BMP/Wnt antagonists.

Unopposed Wnt/Beta-Catenin Osteoblast Activation

Loss of sclerostin removes the physiological brake on Wnt/beta-catenin signaling in osteoblasts, leading to continuous, unopposed osteoblast activity and massive accumulation of structurally normal bone throughout life. SOST is an important therapeutic target for osteoporosis (anti-sclerostin antibody romosozumab).

Osteoblast CL:0000062

Wnt Signaling Pathway GO:0016055 Ossification GO:0001503

Show evidence (1 reference)

PMID:11179006 SUPPORT

"the SOST gene encodes an important new regulator of bone homeostasis"

Confirms SOST as a key regulator of bone metabolism.

Progressive Cranial Hyperostosis and Nerve Compression

Massive bone accumulation preferentially affects the skull and mandible, progressively narrowing cranial nerve foramina. This causes facial nerve palsy, hearing loss, and optic atrophy.

Bone Development GO:0060348

Cranium UBERON:0003128

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur"

Cranial nerve foramen narrowing from progressive bone overgrowth causes neurological complications.

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Pathograph

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

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Phenotypes

10

Ear 1

Hearing Impairment HP:0000365

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur."

Directly supports hearing loss caused by cranial nerve foraminal narrowing.

Context-specific annotations (1)

Onset: CHILDHOOD

Childhood onset was reported in the South African natural history cohort.

Show evidence (1 reference)

PMID:12694228 SUPPORT

"Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons."

Supports childhood onset of deafness/hearing impairment due to cranial nerve entrapment.

Eye 1

Optic Atrophy HP:0000648

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur."

Supports compressive optic neuropathy manifesting as optic atrophy.

Head and Neck 1

Cranial Hyperostosis HP:0004437

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull"

Supports cranial hyperostosis as a hallmark radiographic phenotype.

Integument 1

Nail Dysplasia HP:0002164

Show evidence (1 reference)

PMID:11385236 SUPPORT

"In many cases this syndactyly is associated with nail dysplasia"

Supports nail dysplasia as a recurring hand phenotype associated with sclerosteosis syndactyly.

Limbs 1

Finger Syndactyly FREQUENT HP:0006101

Show evidence (3 references)

PMID:223247 SUPPORT

"Early presenting features are syndactyly and facial palsy"

Establishes syndactyly as an early presenting manifestation.

PMID:12694228 SUPPORT

"Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%)."

Syndactyly occurred in 48 of 63 affected individuals (76%), which falls in the FREQUENT band.

PMID:11385236 SUPPORT

"Besides generalized bone changes the presence of asymmetric cutaneous syndactyly of the index and middle fingers is characteristic."

Specifies the characteristic morphology as asymmetric index-middle finger cutaneous syndactyly.

Nervous System 1

Increased Intracranial Pressure HP:0002516

Show evidence (2 references)

PMID:12694228 SUPPORT

"24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth."

The natural history cohort links calvarial overgrowth directly to elevated intracranial pressure.

PMID:8433139 SUPPORT

"Sclerosteosis is a craniotubular bone modeling disorder and presents with cranial nerve palsies and raised intracranial pressure"

Neurosurgical series independently confirms raised intracranial pressure as a presenting manifestation.

Growth 1

Tall Stature HP:0000098

Show evidence (1 reference)

PMID:11181578 SUPPORT

"Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients."

Supports tall stature as a distinguishing phenotype of sclerosteosis.

Other 3

Generalized Osteosclerosis HP:0005789

Show evidence (2 references)

PMID:11181578 SUPPORT

"with mandible, ribs, clavicles and all long bones also being affected"

Shows that the diffuse sclerosing process involves the axial and appendicular skeleton beyond the skull.

PMID:7891385 SUPPORT

"the typical radiological features, including generalised bone sclerosis and cortical widening of the tubular bones"

Independent case report corroborates generalized bone sclerosis with long-bone cortical widening.

Mandibular Prognathia FREQUENT HP:0000303

Show evidence (2 references)

PMID:12694228 SUPPORT

"Mandibular overgrowth was present in 46 (73%) adults"

The natural history abstract reports mandibular overgrowth in 73% of affected adults, which falls in the FREQUENT band.

PMID:11570544 SUPPORT

"Gross asymmetrical hypertrophy of the mandible was present in all eight patients"

Dedicated oral evaluation confirms severe mandibular enlargement as a consistent orofacial manifestation.

Facial Palsy Facial palsy secondary to cranial hyperostosis HP:0007285

Show evidence (2 references)

PMID:11181578 SUPPORT

"Due to narrowing of the foramina of the cranial nerves, facial nerve palsy"

Directly supports facial palsy as a consequence of skull-base hyperostosis.

PMID:223247 SUPPORT

"Early presenting features are syndactyly and facial palsy"

Shows that facial palsy is an early recognized clinical manifestation.

Context-specific annotations (1)

Onset: CHILDHOOD

Childhood onset was reported in the South African natural history cohort.

Show evidence (1 reference)

PMID:12694228 SUPPORT

"Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons."

Supports childhood onset of facial palsy due to cranial nerve entrapment.

🧬

Genetic Associations

2

SOST Mutations (Causative)

Show evidence (2 references)

PMID:11181578 SUPPORT

"Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients"

Identifies the three types of SOST mutations in sclerosteosis.

PMID:11179006 SUPPORT

"Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene"

Details the specific mutations in Afrikaner and Senegalese patients.

💊

Medical Actions

7

Cranial Decompression and Intracranial Pressure Management

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Located in: cranium UBERON:0003128

Cranial hyperostosis requires close monitoring for raised intracranial pressure, brainstem-herniation risk, facial nerve entrapment, hearing loss, optic neuropathy, and regrowth after surgery. Management may include decompressive craniotomy, posterior fossa decompression, craniectomy, and ventriculoperitoneal drainage when clinically indicated.

Target Phenotypes: Increased intracranial pressure HP:0002516 Facial palsy secondary to cranial hyperostosis HP:0007285 Optic atrophy HP:0000648

Show evidence (2 references)

PMID:8433139 SUPPORT Human Clinical

"Sclerosteosis is a craniotubular bone modeling disorder and presents with cranial nerve palsies and raised intracranial pressure; sudden death may occur without neurosurgical intervention."

Supports neurosurgical surveillance and intervention for raised intracranial pressure and cranial nerve compromise.

PMID:8433139 SUPPORT Human Clinical

"Patients should be followed closely since the regrowth of bone may necessitate repeated decompressive procedures."

Supports ongoing post-decompression monitoring because bone regrowth can require repeat procedures.

Audiologic Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Hearing loss from cranial nerve or middle-ear involvement should be followed with audiology and managed with hearing aids, middle-ear surgery, or cochlear implantation according to the hearing-loss mechanism and severity.

Target Phenotypes: Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:36508511 SUPPORT Other

"Hearing aids with middle ear surgery or cochlear implant depending on the nature of the hearing loss"

GeneReviews directly supports hearing aids, middle-ear surgery, or cochlear implantation according to hearing-loss type.

Ophthalmologic and Optic Nerve Surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Ophthalmology follow-up should monitor proptosis, intraocular pressure, and optic nerve papilla/optic atrophy because cranial hyperostosis can compress the optic nerve and threaten vision.

Target Phenotypes: Optic atrophy HP:0000648

Show evidence (1 reference)

PMID:36508511 SUPPORT Other

"annual ophthalmology examination to assess for proptosis, intraocular pressure, and evaluation of the optic nerve papilla"

GeneReviews supports routine ophthalmologic surveillance for vision-risk complications.

Dental, Orthodontic, and Mandibular Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Dental and craniofacial care should assess mandibular overgrowth, malocclusion, tooth alignment, delayed eruption or anodontia, difficult extraction risk, drooling, and mastication problems. Selected patients may need orthodontic care, craniofacial-team management, or surgical reduction of mandibular overgrowth.

Target Phenotypes: Mandibular prognathia HP:0000303

Show evidence (2 references)

PMID:36508511 SUPPORT Other

"surgical reduction of mandibular overgrowth; orbital decompression for proptosis; treatment of dental manifestations per orthodontist and/or craniofacial team"

GeneReviews supports mandibular reduction and dental/craniofacial team management.

PMID:11570544 SUPPORT Human Clinical

"Accurate differentiation of sclerosteosis from the other sclerosing bone dysplasias is crucial for effective dental prognostication and management."

Dedicated oral/dental evaluation supports diagnosis-specific dental prognostication and management.

Syndactyly Correction

Action: surgical repair Ontology label: Surgical Procedure NCIT:C15329

Syndactyly should be assessed in infancy or childhood, with surgical correction considered when the anatomy limits hand function or care.

Target Phenotypes: Finger syndactyly HP:0006101

Show evidence (1 reference)

PMID:36508511 SUPPORT Other

"surgical correction of syndactyly."

GeneReviews lists surgical correction of syndactyly as treatment of a manifestation.

Avoid Bone-Overgrowth-Exacerbating Agents

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Avoid antiresorptive and bone-anabolic agents that could worsen the high bone-mass state, including bisphosphonates, denosumab, selective estrogen receptor modulators, teriparatide, abaloparatide, and romosozumab.

Show evidence (1 reference)

PMID:36508511 SUPPORT Other

"Agents known to suppress bone resorption (e.g., bisphosphonates, denosumab, selective estrogen receptor modulators) and agents known to stimulate bone formation (e.g., teriparatide, abaloparatide, romozosumab)."

GeneReviews explicitly lists these antiresorptive and bone-anabolic agents as agents to avoid because they can exacerbate bone overgrowth.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected families should cover autosomal recessive inheritance, carrier testing of relatives and reproductive partners, prenatal/preimplantation testing once familial variants are known, and founder variants in high-risk ancestries such as the South African Afrikaner population.

Show evidence (2 references)

PMID:36508511 SUPPORT Other

"SOST-related sclerosing bone dysplasias are inherited in an autosomal recessive manner."

GeneReviews supports autosomal recessive counseling for the SOST-related sclerosing bone dysplasia spectrum.

PMID:36508511 SUPPORT Other

"Once the pathogenic variants associated with a SOST-related sclerosing bone dysplasia have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible."

Supports carrier testing and reproductive counseling once familial SOST variants are known.

🔬

Diagnosis

1

Clinical, Radiographic, and Molecular Diagnosis

Sclerosteosis is diagnosed from generalized progressive bone overgrowth with tall stature, facial features of cranial sclerosis, syndactyly, and raised intracranial pressure or cranial nerve palsies from skull thickening. Molecular testing confirms SOST-related sclerosteosis by identifying biallelic loss-of-function SOST variants and distinguishes van Buchem disease caused by a biallelic 52-kb deletion downstream of SOST.

molecular genetic testing NCIT:C19770

Show evidence (3 references)

PMID:11181578 SUPPORT Human Clinical

"Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance"

Defines sclerosteosis as a recessive progressive sclerosing bone dysplasia, the clinical/radiographic basis of diagnosis.

PMID:11181578 SUPPORT Human Clinical

"the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation"

Supports SOST loss-of-function molecular testing as the basis of confirmation.

PMID:36508511 SUPPORT Other

"The diagnosis of a SOST-related sclerosing bone dysplasia is established in a proband with typical clinical and radiographic findings and biallelic pathogenic variants in SOST (in individuals with SOST-related sclerosteosis) or a biallelic 52-kb deletion downstream of SOST (in individuals with..."

GeneReviews provides the diagnostic boundary between SOST-related sclerosteosis and van Buchem disease.

📊

Prevalence

1

South African Afrikaner founder population

Point Prevalence 1.333333 per 100,000 1–9 per 100,000

A nationwide South African investigation reported a minimum prevalence of 1 in 75,000 in the Afrikaner community, reflecting the well-known founder effect in this population.

Show evidence (2 references)

PMID:187366 SUPPORT Human Clinical

"The minimum prevalence of the contition in this community is 1 in 75,000."

This nationwide study provides a direct minimum prevalence estimate for sclerosteosis in the South African Afrikaner population.

PMID:11179006 SUPPORT Human Clinical

"The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect."

This later molecular study corroborates the strong Afrikaner founder effect underlying the reported prevalence.

{ }

Source YAML

click to show

name: Sclerosteosis
creation_date: '2026-02-13T00:31:42Z'
category: Mendelian
description: >
  Sclerosteosis is an autosomal recessive progressive sclerosing bone dysplasia
  caused by loss-of-function mutations in the SOST gene, which encodes sclerostin,
  a secreted Wnt signaling antagonist. This entry focuses on SOST-related
  sclerosteosis within the broader SOST-related sclerosing bone dysplasia
  spectrum. Loss of sclerostin leads to unopposed Wnt-mediated osteoblast
  activation and massive progressive bone formation throughout life. The
  condition is characterized by generalized hyperostosis and sclerosis of the
  skull, mandible, ribs, clavicles, and long bones, leading to cranial nerve
  compression and potentially lethal intracranial-pressure complications. Hand
  malformations (syndactyly) and tall stature distinguish sclerosteosis from the
  related SOST-regulatory deletion disorder van Buchem disease. LRP4-related
  sclerosteosis-like disease is a separate genetic boundary condition affecting
  sclerostin signaling rather than SOST itself. The majority of affected
  individuals have been reported in the South African Afrikaner population due
  to a founder effect. Discovery of SOST led to development of anti-sclerostin
  antibodies (romosozumab) for osteoporosis.
disease_term:
  preferred_term: sclerosteosis
  term:
    id: MONDO:0017838
    label: sclerosteosis
parents:
- Sclerosing Bone Dysplasias
has_subtypes:
- name: SOST-related Sclerosteosis
  subtype_term:
    preferred_term: sclerosteosis 1
    term:
      id: MONDO:0010016
      label: sclerosteosis 1
  description: >
    Classic sclerosteosis caused by biallelic SOST loss-of-function variants,
    with progressive skull and mandibular overgrowth, syndactyly, tall stature,
    cranial nerve entrapment, and increased intracranial-pressure risk.
- name: Van Buchem Disease
  description: >
    SOST-related endosteal hyperostosis, van Buchem type, is caused by a
    biallelic 52-kb regulatory deletion downstream of SOST. It is generally
    milder than SOST-related sclerosteosis, lacks syndactyly or other digit
    deformities, and has apparently normal life span.
inheritance:
- name: Autosomal Recessive
  description: >
    Autosomal recessive inheritance. High incidence in the South African
    Afrikaner population due to a founder effect. Two nonsense mutations
    and one splice site mutation identified.
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance"
    explanation: "Confirms autosomal recessive inheritance of sclerosteosis."
classifications:
  isds_skeletal_category:
  - classification_value: osteosclerotic_disorders
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders. Assigned from the 2019 revision
      (Mortier et al., PMID:31633310), Table 1 group 24 "Other sclerosing bone
      disorders"; listed as "Sclerosteosis". The 2023 revision (Unger et al.,
      PMID:36779427) dissolved that group into group 25 "Osteosclerotic disorders",
      fusing the neonatal osteosclerotic dysplasias with the other sclerosing bone
      disorders, so the value is carried forward here. Membership has not been
      re-verified against the 2023 table.
prevalence:
- population: South African Afrikaner founder population
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.333333
  percentage: 1 in 75,000
  notes: >-
    A nationwide South African investigation reported a minimum prevalence of
    1 in 75,000 in the Afrikaner community, reflecting the well-known founder
    effect in this population.
  evidence:
  - reference: PMID:187366
    reference_title: "Sclerosteosis - an autosomal recessive disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The minimum prevalence of the contition in this community is 1 in 75,000."  # codespell:ignore-line
    explanation: This nationwide study provides a direct minimum prevalence estimate for sclerosteosis in the South African Afrikaner population.
  - reference: PMID:11179006
    reference_title: "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect."
    explanation: This later molecular study corroborates the strong Afrikaner founder effect underlying the reported prevalence.
pathophysiology:
- name: Loss of Sclerostin (SOST Loss-of-Function)
  description: >
    SOST encodes sclerostin, a secreted glycoprotein with a cysteine-knot
    motif that functions as an antagonist of the Wnt/beta-catenin signaling
    pathway by binding to LRP5/LRP6 coreceptors on osteoblasts. Loss-of-
    function mutations abolish sclerostin production, removing the
    physiological brake on bone formation.
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation"
    explanation: "Establishes that SOST loss causes massive bone formation and that sclerostin normally suppresses bone formation."
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif"
    explanation: "Characterizes sclerostin as a secreted cysteine-knot protein."
  - reference: PMID:11179006
    reference_title: "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein."
    supports: SUPPORT
    snippet: "The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte"
    explanation: "Places sclerostin in the DAN family of BMP/Wnt antagonists."
- name: Unopposed Wnt/Beta-Catenin Osteoblast Activation
  description: >
    Loss of sclerostin removes the physiological brake on Wnt/beta-catenin
    signaling in osteoblasts, leading to continuous, unopposed osteoblast
    activity and massive accumulation of structurally normal bone throughout
    life. SOST is an important therapeutic target for osteoporosis
    (anti-sclerostin antibody romosozumab).
  biological_processes:
  - preferred_term: Wnt Signaling Pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:11179006
    reference_title: "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein."
    supports: SUPPORT
    snippet: "the SOST gene encodes an important new regulator of bone homeostasis"
    explanation: "Confirms SOST as a key regulator of bone metabolism."
- name: Progressive Cranial Hyperostosis and Nerve Compression
  description: >
    Massive bone accumulation preferentially affects the skull and mandible,
    progressively narrowing cranial nerve foramina. This causes facial nerve
    palsy, hearing loss, and optic atrophy.
  biological_processes:
  - preferred_term: Bone Development
    term:
      id: GO:0060348
      label: bone development
  locations:
  - preferred_term: Cranium
    term:
      id: UBERON:0003128
      label: cranium
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur"
    explanation: "Cranial nerve foramen narrowing from progressive bone overgrowth causes neurological complications."
phenotypes:
- name: Cranial Hyperostosis
  description: >
    Progressive calvarial thickening causes marked skull sclerosis and
    narrowing of cranial nerve foramina.
  phenotype_term:
    preferred_term: Cranial hyperostosis
    term:
      id: HP:0004437
      label: Cranial hyperostosis
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull"
    explanation: "Supports cranial hyperostosis as a hallmark radiographic phenotype."
- name: Generalized Osteosclerosis
  description: >
    Diffuse skeletal sclerosis extends beyond the skull to the mandible, ribs,
    clavicles, and long bones, with cortical widening of tubular bones.
  phenotype_term:
    preferred_term: Generalized osteosclerosis
    term:
      id: HP:0005789
      label: Generalized osteosclerosis
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "with mandible, ribs, clavicles and all long bones also being affected"
    explanation: "Shows that the diffuse sclerosing process involves the axial and appendicular skeleton beyond the skull."
  - reference: PMID:7891385
    reference_title: "Sclerosteosis in a Spanish male: first report in a person of Mediterranean origin."
    supports: SUPPORT
    snippet: "the typical radiological features, including generalised bone sclerosis and cortical widening of the tubular bones"
    explanation: "Independent case report corroborates generalized bone sclerosis with long-bone cortical widening."
- name: Finger Syndactyly
  description: >
    Syndactyly is a common early manifestation and often involves asymmetric
    cutaneous fusion of the index and middle fingers.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Finger syndactyly
    term:
      id: HP:0006101
      label: Finger syndactyly
  evidence:
  - reference: PMID:223247
    reference_title: "Sclerosteosis in South Africa."
    supports: SUPPORT
    snippet: "Early presenting features are syndactyly and facial palsy"
    explanation: "Establishes syndactyly as an early presenting manifestation."
  - reference: PMID:12694228
    reference_title: "The natural history of sclerosteosis."
    supports: SUPPORT
    snippet: "Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%)."
    explanation: "Syndactyly occurred in 48 of 63 affected individuals (76%), which falls in the FREQUENT band."
  - reference: PMID:11385236
    reference_title: "Syndactyly/brachyphalangy and nail dysplasias as marker lesions for sclerosteosis."
    supports: SUPPORT
    snippet: "Besides generalized bone changes the presence of asymmetric cutaneous syndactyly of the index and middle fingers is characteristic."
    explanation: "Specifies the characteristic morphology as asymmetric index-middle finger cutaneous syndactyly."
- name: Nail Dysplasia
  description: >
    Nail dysplasia may accompany the hand malformation, especially involving
    the index fingers.
  phenotype_term:
    preferred_term: Nail dysplasia
    term:
      id: HP:0002164
      label: Nail dysplasia
  evidence:
  - reference: PMID:11385236
    reference_title: "Syndactyly/brachyphalangy and nail dysplasias as marker lesions for sclerosteosis."
    supports: SUPPORT
    snippet: "In many cases this syndactyly is associated with nail dysplasia"
    explanation: "Supports nail dysplasia as a recurring hand phenotype associated with sclerosteosis syndactyly."
- name: Tall Stature
  description: >
    Large stature is a distinguishing clinical feature relative to van Buchem
    disease.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients."
    explanation: "Supports tall stature as a distinguishing phenotype of sclerosteosis."
- name: Mandibular Prognathia
  description: >
    Mandibular overgrowth is common in adults and contributes to chin
    protrusion and striking orofacial enlargement.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: PMID:12694228
    reference_title: "The natural history of sclerosteosis."
    supports: SUPPORT
    snippet: "Mandibular overgrowth was present in 46 (73%) adults"
    explanation: "The natural history abstract reports mandibular overgrowth in 73% of affected adults, which falls in the FREQUENT band."
  - reference: PMID:11570544
    reference_title: "Dental and oral manifestations of sclerosteosis."
    supports: SUPPORT
    snippet: "Gross asymmetrical hypertrophy of the mandible was present in all eight patients"
    explanation: "Dedicated oral evaluation confirms severe mandibular enlargement as a consistent orofacial manifestation."
- name: Facial Palsy
  description: >
    Facial palsy results from compression of the facial nerve as progressive
    skull overgrowth narrows cranial foramina.
  phenotype_term:
    preferred_term: Facial palsy secondary to cranial hyperostosis
    term:
      id: HP:0007285
      label: Facial palsy secondary to cranial hyperostosis
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Due to narrowing of the foramina of the cranial nerves, facial nerve palsy"
    explanation: "Directly supports facial palsy as a consequence of skull-base hyperostosis."
  - reference: PMID:223247
    reference_title: "Sclerosteosis in South Africa."
    supports: SUPPORT
    snippet: "Early presenting features are syndactyly and facial palsy"
    explanation: "Shows that facial palsy is an early recognized clinical manifestation."
  phenotype_contexts:
  - onset:
      onset_category: CHILDHOOD
    notes: Childhood onset was reported in the South African natural history cohort.
    evidence:
    - reference: PMID:12694228
      reference_title: "The natural history of sclerosteosis."
      supports: SUPPORT
      snippet: "Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons."
      explanation: "Supports childhood onset of facial palsy due to cranial nerve entrapment."
- name: Hearing Impairment
  description: >
    Hearing loss results from cranial nerve entrapment caused by progressive
    skull-base hyperostosis.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur."
    explanation: "Directly supports hearing loss caused by cranial nerve foraminal narrowing."
  phenotype_contexts:
  - onset:
      onset_category: CHILDHOOD
    notes: Childhood onset was reported in the South African natural history cohort.
    evidence:
    - reference: PMID:12694228
      reference_title: "The natural history of sclerosteosis."
      supports: SUPPORT
      snippet: "Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons."
      explanation: "Supports childhood onset of deafness/hearing impairment due to cranial nerve entrapment."
- name: Optic Atrophy
  description: >
    Optic nerve compromise can develop when skull overgrowth narrows the optic
    canals.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur."
    explanation: "Supports compressive optic neuropathy manifesting as optic atrophy."
- name: Increased Intracranial Pressure
  description: >
    Calvarial overgrowth can elevate intracranial pressure and drive
    life-threatening neurologic complications.
  phenotype_term:
    preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  evidence:
  - reference: PMID:12694228
    reference_title: "The natural history of sclerosteosis."
    supports: SUPPORT
    snippet: "24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth."
    explanation: "The natural history cohort links calvarial overgrowth directly to elevated intracranial pressure."
  - reference: PMID:8433139
    reference_title: "Sclerosteosis: neurosurgical experience with 14 cases."
    supports: SUPPORT
    snippet: "Sclerosteosis is a craniotubular bone modeling disorder and presents with cranial nerve palsies and raised intracranial pressure"
    explanation: "Neurosurgical series independently confirms raised intracranial pressure as a presenting manifestation."
genetic:
- name: SOST Mutations
  association: Causative
  notes: >
    Homozygous loss-of-function mutations in SOST on chromosome 17q12-q21.
    Two nonsense mutations and one splice site mutation identified. Affected
    Afrikaners carry a nonsense mutation near the amino terminus; an unrelated
    person of Senegalese origin carries a splicing mutation in the single
    intron. No SOST mutations found in Van Buchem disease patients, who
    instead have a 52-kb regulatory deletion downstream.
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    snippet: "Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients"
    explanation: "Identifies the three types of SOST mutations in sclerosteosis."
  - reference: PMID:11179006
    reference_title: "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein."
    supports: SUPPORT
    snippet: "Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene"
    explanation: "Details the specific mutations in Afrikaner and Senegalese patients."
- name: LRP4-related Sclerosteosis-like Disease
  association: Differential diagnosis
  gene_term:
    preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  notes: >
    LRP4-related sclerosteosis is a separate genetic condition that overlaps
    clinically through impaired sclerostin signaling. Unlike SOST-related
    sclerosteosis, LRP4-related disease can show increased circulating
    sclerostin because mutant LRP4 fails to retain/facilitate sclerostin action
    in bone.
  evidence:
  - reference: PMID:21471202
    reference_title: "Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that these mutations impair LRP4 interaction with sclerostin and
      its concomitant sclerostin facilitator effect.
    explanation: >-
      Supports LRP4-related bone overgrowth as a mechanistically distinct
      sclerostin-signaling disorder.
  - reference: PMID:26751728
    reference_title: "A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that impaired sclerostin binding to the mutated LRP4
      protein leads to dramatic increase in circulating sclerostin in this
      patient.
    explanation: >-
      Elevated circulating sclerostin helps distinguish LRP4-related
      sclerosteosis-like disease from SOST loss-of-function disease.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    Sclerosteosis is diagnosed from generalized progressive bone overgrowth
    with tall stature, facial features of cranial sclerosis, syndactyly, and
    raised intracranial pressure or cranial nerve palsies from skull thickening.
    Molecular testing confirms SOST-related sclerosteosis by identifying
    biallelic loss-of-function SOST variants and distinguishes van Buchem
    disease caused by a biallelic 52-kb deletion downstream of SOST.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance"
    explanation: >-
      Defines sclerosteosis as a recessive progressive sclerosing bone dysplasia, the clinical/radiographic basis of diagnosis.
  - reference: PMID:11181578
    reference_title: "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation"
    explanation: >-
      Supports SOST loss-of-function molecular testing as the basis of confirmation.
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of a SOST-related sclerosing bone dysplasia is established
      in a proband with typical clinical and radiographic findings and biallelic
      pathogenic variants in SOST (in individuals with SOST-related
      sclerosteosis) or a biallelic 52-kb deletion downstream of SOST (in
      individuals with van Buchem disease) identified on molecular genetic
      testing.
    explanation: >-
      GeneReviews provides the diagnostic boundary between SOST-related
      sclerosteosis and van Buchem disease.
treatments:
- name: Cranial Decompression and Intracranial Pressure Management
  description: >
    Cranial hyperostosis requires close monitoring for raised intracranial
    pressure, brainstem-herniation risk, facial nerve entrapment, hearing loss,
    optic neuropathy, and regrowth after surgery. Management may include
    decompressive craniotomy, posterior fossa decompression, craniectomy, and
    ventriculoperitoneal drainage when clinically indicated.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    located_in:
      preferred_term: cranium
      term:
        id: UBERON:0003128
        label: cranium
  target_phenotypes:
  - preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  - preferred_term: Facial palsy secondary to cranial hyperostosis
    term:
      id: HP:0007285
      label: Facial palsy secondary to cranial hyperostosis
  - preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:8433139
    reference_title: "Sclerosteosis: neurosurgical experience with 14 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sclerosteosis is a craniotubular bone modeling disorder and presents with
      cranial nerve palsies and raised intracranial pressure; sudden death may
      occur without neurosurgical intervention.
    explanation: >-
      Supports neurosurgical surveillance and intervention for raised
      intracranial pressure and cranial nerve compromise.
  - reference: PMID:8433139
    reference_title: "Sclerosteosis: neurosurgical experience with 14 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients should be followed closely since the regrowth of bone may
      necessitate repeated decompressive procedures.
    explanation: >-
      Supports ongoing post-decompression monitoring because bone regrowth can
      require repeat procedures.
- name: Audiologic Management
  description: >
    Hearing loss from cranial nerve or middle-ear involvement should be followed
    with audiology and managed with hearing aids, middle-ear surgery, or
    cochlear implantation according to the hearing-loss mechanism and severity.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hearing aids with middle ear surgery or cochlear implant depending on the
      nature of the hearing loss
    explanation: >-
      GeneReviews directly supports hearing aids, middle-ear surgery, or
      cochlear implantation according to hearing-loss type.
- name: Ophthalmologic and Optic Nerve Surveillance
  description: >
    Ophthalmology follow-up should monitor proptosis, intraocular pressure, and
    optic nerve papilla/optic atrophy because cranial hyperostosis can compress
    the optic nerve and threaten vision.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      annual ophthalmology examination to assess for proptosis, intraocular
      pressure, and evaluation of the optic nerve papilla
    explanation: >-
      GeneReviews supports routine ophthalmologic surveillance for vision-risk
      complications.
- name: Dental, Orthodontic, and Mandibular Management
  description: >
    Dental and craniofacial care should assess mandibular overgrowth,
    malocclusion, tooth alignment, delayed eruption or anodontia, difficult
    extraction risk, drooling, and mastication problems. Selected patients may
    need orthodontic care, craniofacial-team management, or surgical reduction
    of mandibular overgrowth.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      surgical reduction of mandibular overgrowth; orbital decompression for
      proptosis; treatment of dental manifestations per orthodontist and/or
      craniofacial team
    explanation: >-
      GeneReviews supports mandibular reduction and dental/craniofacial team
      management.
  - reference: PMID:11570544
    reference_title: "Dental and oral manifestations of sclerosteosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Accurate differentiation of sclerosteosis from the other sclerosing bone
      dysplasias is crucial for effective dental prognostication and management.
    explanation: >-
      Dedicated oral/dental evaluation supports diagnosis-specific dental
      prognostication and management.
- name: Syndactyly Correction
  description: >
    Syndactyly should be assessed in infancy or childhood, with surgical
    correction considered when the anatomy limits hand function or care.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Finger syndactyly
    term:
      id: HP:0006101
      label: Finger syndactyly
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "surgical correction of syndactyly."
    explanation: >-
      GeneReviews lists surgical correction of syndactyly as treatment of a
      manifestation.
- name: Avoid Bone-Overgrowth-Exacerbating Agents
  description: >
    Avoid antiresorptive and bone-anabolic agents that could worsen the high
    bone-mass state, including bisphosphonates, denosumab, selective estrogen
    receptor modulators, teriparatide, abaloparatide, and romosozumab.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents known to suppress bone resorption (e.g., bisphosphonates,
      denosumab, selective estrogen receptor modulators) and agents known to
      stimulate bone formation (e.g., teriparatide, abaloparatide, romozosumab).
    explanation: >-
      GeneReviews explicitly lists these antiresorptive and bone-anabolic
      agents as agents to avoid because they can exacerbate bone overgrowth.
- name: Genetic Counseling
  description: >
    Genetic counseling for affected families should cover autosomal recessive
    inheritance, carrier testing of relatives and reproductive partners,
    prenatal/preimplantation testing once familial variants are known, and
    founder variants in high-risk ancestries such as the South African
    Afrikaner population.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SOST-related sclerosing bone dysplasias are inherited in an autosomal
      recessive manner.
    explanation: >-
      GeneReviews supports autosomal recessive counseling for the SOST-related
      sclerosing bone dysplasia spectrum.
  - reference: PMID:36508511
    reference_title: "SOST-Related Sclerosing Bone Dysplasias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once the pathogenic variants associated with a SOST-related sclerosing
      bone dysplasia have been identified in an affected family member, carrier
      testing for at-risk family members and prenatal/preimplantation genetic
      testing are possible.
    explanation: >-
      Supports carrier testing and reproductive counseling once familial SOST
      variants are known.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK587318/
  title: "SOST-Related Sclerosing Bone Dysplasias - GeneReviews® - NCBI Bookshelf"
  findings: []
  tags:
  - GeneReviews

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url:https://www.ncbi.nlm.nih.gov/books/NBK587318/

SOST-Related Sclerosing Bone Dysplasias - GeneReviews® - NCBI Bookshelf

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