Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis or Touraine-Solente-Gole syndrome, is a rare genetic disorder characterized by digital clubbing, periostosis of tubular bones, and pachydermia (skin thickening). It results from defective prostaglandin E2 (PGE2) metabolism caused by pathogenic variants in HPGD (encoding 15-hydroxyprostaglandin dehydrogenase) or SLCO2A1 (encoding the prostaglandin transporter). Excess circulating PGE2 drives periosteal new bone formation, connective tissue proliferation, and the characteristic clinical triad. Three subtypes are recognized: PHOAR1 (HPGD, autosomal recessive), PHOAR2 (SLCO2A1, autosomal recessive, most common), and PHOAD (SLCO2A1, autosomal dominant, milder). Onset is typically in childhood for PHOAR1 and puberty for PHOAR2/PHOAD. Males are more frequently and severely affected.
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name: Primary Hypertrophic Osteoarthropathy
creation_date: "2026-04-22T00:00:00Z"
updated_date: "2026-04-26T22:37:52Z"
description: >-
Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis
or Touraine-Solente-Gole syndrome, is a rare genetic disorder characterized by
digital clubbing, periostosis of tubular bones, and pachydermia (skin thickening).
It results from defective prostaglandin E2 (PGE2) metabolism caused by pathogenic
variants in HPGD (encoding 15-hydroxyprostaglandin dehydrogenase) or SLCO2A1
(encoding the prostaglandin transporter). Excess circulating PGE2 drives periosteal
new bone formation, connective tissue proliferation, and the characteristic clinical
triad. Three subtypes are recognized: PHOAR1 (HPGD, autosomal recessive), PHOAR2
(SLCO2A1, autosomal recessive, most common), and PHOAD (SLCO2A1, autosomal dominant,
milder). Onset is typically in childhood for PHOAR1 and puberty for PHOAR2/PHOAD.
Males are more frequently and severely affected.
category: Genetic
disease_term:
preferred_term: primary hypertrophic osteoarthropathy
term:
id: MONDO:0016620
label: primary hypertrophic osteoarthropathy
parents:
- Bone Disease
- Connective Tissue Disorder
prevalence:
- population: Global
percentage: Rare
evidence:
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Primary hypertrophic osteoarthropathy (PHO), also known as
pachydermoperiostosis, is a rare congenital disease.
explanation: Clinical trial introduction describes PHO as a rare
congenital disease, supporting the rare prevalence category.
inheritance:
- name: Autosomal Recessive
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic mutations in HPGD and SLCO2A1, disturbing prostaglandin E2
(PGE2 ) catabolism and leading to increased circulating PGE2 level,
cause PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive
2 (PHOAR2), respectively.
explanation: Supports autosomal recessive PHO through biallelic HPGD
and SLCO2A1 mutations.
- name: Autosomal Dominant
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
our findings confirm that SLCO2A1 monoallelic mutations are the cause
of PHOAD and broaden phenotypic spectrum of PHO.
explanation: Establishes autosomal dominant PHO via monoallelic SLCO2A1
mutations.
has_subtypes:
- name: PHOAR1
display_name: PHO Autosomal Recessive Type 1 (HPGD)
subtype_term:
preferred_term: hypertrophic osteoarthropathy, primary, autosomal recessive, 1
term:
id: MONDO:0024546
label: hypertrophic osteoarthropathy, primary, autosomal recessive, 1
description: >-
Caused by biallelic loss-of-function variants in HPGD encoding
15-hydroxyprostaglandin dehydrogenase, leading to failure of PGE2
degradation. Earlier onset (childhood) and elevated urinary PGE2
with decreased PGE-M.
evidence:
- reference: PMID:18500342
reference_title: "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified mutations in HPGD, encoding 15-hydroxyprostaglandin
dehydrogenase, the main enzyme of prostaglandin degradation.
explanation: Original gene-discovery paper for PHOAR1 (HPGD-associated
PHO).
- name: PHOAR2
display_name: PHO Autosomal Recessive Type 2 (SLCO2A1)
subtype_term:
preferred_term: hypertrophic osteoarthropathy, primary, autosomal recessive, 2
term:
id: MONDO:0013756
label: hypertrophic osteoarthropathy, primary, autosomal recessive, 2
description: >-
Caused by biallelic loss-of-function variants in SLCO2A1 encoding the
prostaglandin transporter (PGT), impairing cellular uptake of PGE2 for
degradation. Most common form worldwide. Later onset (puberty), all-male
predominance, and associated with peptic ulcers and myelofibrosis.
evidence:
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic SLCO2A1 mutations were identified in 12 of the 13 families.
explanation: Original gene-discovery paper for PHOAR2 (SLCO2A1-associated
recessive PHO with myelofibrosis association).
- name: PHOAD
display_name: PHO Autosomal Dominant (SLCO2A1)
subtype_term:
preferred_term: hypertrophic osteoarthropathy, primary, autosomal dominant
term:
id: MONDO:0008172
label: hypertrophic osteoarthropathy, primary, autosomal dominant
description: >-
Caused by monoallelic mutations in SLCO2A1. Milder phenotype with less
severe pachydermia and periostosis compared to PHOAR2. Onset in puberty.
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
our findings confirm that SLCO2A1 monoallelic mutations are the cause
of PHOAD and broaden phenotypic spectrum of PHO.
explanation: Original report establishing PHOAD as a monoallelic
SLCO2A1 form of PHO.
pathophysiology:
- name: Defective PGE2 Degradation (HPGD)
description: >-
Loss-of-function mutations in HPGD impair 15-hydroxyprostaglandin
dehydrogenase activity, the main enzyme of prostaglandin degradation.
This leads to chronically elevated prostaglandin E2 levels and failure
of the two-step PGE2 catabolic pathway.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: Prostaglandin catabolic process
term:
id: GO:1905344
label: prostaglandin catabolic process
modifier: DECREASED
evidence:
- reference: PMID:18500342
reference_title: "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD,
encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of
prostaglandin degradation. Homozygous individuals develop PHO secondary
to chronically elevated prostaglandin E(2) levels.
explanation: >-
Seminal paper identifying HPGD mutations as the cause of PHO type 1,
establishing the prostaglandin degradation defect.
downstream:
- target: Periosteal New Bone Formation
description: Excess PGE2 stimulates osteoblast-mediated periosteal bone formation.
- target: Connective Tissue Proliferation
description: PGE2 excess drives dermal fibroblast proliferation and collagen deposition.
- name: Impaired PGE2 Transport (SLCO2A1)
description: >-
Loss-of-function mutations in SLCO2A1 impair the prostaglandin
transporter, which is required for cellular uptake of PGE2 prior to
intracellular degradation by HPGD. Both biallelic (PHOAR2) and
monoallelic (PHOAD) mutations cause disease. SLCO2A1-deficient
individuals have elevated urinary PGE2 and also excrete considerable
quantities of the PGE2 metabolite PGE-M.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: Prostaglandin transport
term:
id: GO:0015732
label: prostaglandin transport
modifier: DECREASED
evidence:
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we use whole-exome sequencing to identify recessive mutations of the
prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations.
explanation: >-
Key paper identifying SLCO2A1 mutations as the second genetic cause
of PHO, establishing the prostaglandin transport defect.
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals had elevated urinary PGE(2), but unlike
HPGD-deficient patients, also excreted considerable quantities of
the PGE(2) metabolite, PGE-M.
explanation: >-
Distinguishes biochemical profile of SLCO2A1 deficiency from HPGD
deficiency.
downstream:
- target: Periosteal New Bone Formation
description: Impaired PGE2 clearance leads to sustained osteoblast stimulation.
- target: Connective Tissue Proliferation
description: Extracellular PGE2 accumulation drives dermal changes.
- target: Myelofibrosis (SLCO2A1)
description: Impaired prostaglandin transporter activity disrupts hematopoietic stem cell maintenance, leading to myelofibrosis.
- name: Periosteal New Bone Formation
description: >-
Excess PGE2 stimulates osteoblast activity and periosteal new bone
formation in tubular bones, leading to periostosis, arthralgia,
and digital clubbing.
cell_types:
- preferred_term: osteoblast
term:
id: CL:0000062
label: osteoblast
biological_processes:
- preferred_term: Bone formation
term:
id: GO:0001503
label: ossification
modifier: INCREASED
evidence:
- reference: PMID:37705574
reference_title: "Primary hypertrophic osteoarthropathy: genetics, clinical features and management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly
characterized by clubbing fingers, pachydermia and periostosis. Mutations
in the HPGD or SLCO2A1 gene lead to impaired prostaglandin E2 (PGE2)
degradation, thus elevating PGE2 levels.
explanation: >-
Comprehensive review confirming elevated PGE2 as the driver of the
skeletal and dermatologic manifestations of PHO.
- name: Connective Tissue Proliferation
description: >-
PGE2 excess drives dermal fibroblast proliferation and collagen
deposition, resulting in pachydermia (skin thickening), cutis
verticis gyrata, and sebaceous gland hyperplasia.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: Collagen biosynthetic process
term:
id: GO:0032964
label: collagen biosynthetic process
modifier: INCREASED
evidence:
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This disease is characterized by the triad of digital clubbing, periostosis and pachydermia, as well as additional features including arthritis, hyperhidrosis and congenital heart disease"
explanation: >-
Pachydermia (skin thickening from connective tissue proliferation)
is one of the three defining features of PHO.
- name: Myelofibrosis (SLCO2A1)
description: >-
SLCO2A1-deficient individuals have a high frequency of severe anemia
due to myelofibrosis. This may reflect prostaglandin-dependent effects
on hematopoietic stem cell maintenance.
cell_types:
- preferred_term: hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
biological_processes:
- preferred_term: Hematopoiesis
term:
id: GO:0030097
label: hemopoiesis
modifier: DYSREGULATED
evidence:
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLCO2A1-deficient individuals have a high frequency of severe anemia
due to myelofibrosis. These findings reinforce the key role of
systemic or local prostaglandin excess as the stimulus to HO. They
also suggest that the induction or maintenance of hematopoietic stem
cells by prostaglandin may depend upon transporter activity.
explanation: >-
Myelofibrosis is a distinctive complication of PHOAR2 not seen in PHOAR1,
suggesting a specific role for the prostaglandin transporter in
hematopoiesis.
phenotypes:
- name: Digital Clubbing
category: Musculoskeletal
frequency: VERY_FREQUENT
description: >-
Enlargement of the distal phalanges with increased nail curvature,
the hallmark finding of PHO. Present in virtually all patients.
phenotype_term:
preferred_term: Digital clubbing
term:
id: HP:0001217
label: Clubbing
evidence:
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Primary hypertrophic osteoarthropathy (PHO) is an inherited disease
characterized by digital clubbing, periostosis, and pachydermia.
explanation: >-
Digital clubbing is one of the three cardinal features of PHO.
- reference: PMID:35813463
reference_title: "Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Digital clubbing and periostosis came out to be the most common
features, which always occur in the early childhood.
explanation: >-
In PHOAR1, digital clubbing is the most common and earliest
presenting feature.
- name: Periostosis
category: Musculoskeletal
frequency: VERY_FREQUENT
description: >-
Subperiosteal new bone formation along the diaphyses of long bones,
visible on radiographs.
phenotype_term:
preferred_term: Periostosis
term:
id: HP:0030314
label: Periostosis
evidence:
- reference: PMID:35813463
reference_title: "Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Digital clubbing and periostosis came out to be the most common
features, which always occur in the early childhood.
explanation: >-
Periostosis is one of the most common and earliest features in PHOAR1.
- name: Pachydermia
category: Dermatologic
frequency: FREQUENT
description: >-
Thickening and coarsening of the skin, particularly on the face
and scalp.
phenotype_term:
preferred_term: Pachydermia
term:
id: HP:0001072
label: Thickened skin
evidence:
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
18 patients displayed complete phenotypes of PHO with digital
clubbing, periostosis, and pachydermia.
explanation: >-
Pachydermia is part of the complete PHO triad, present in most
but not all patients.
- name: Cutis Verticis Gyrata
category: Dermatologic
description: >-
Deep furrows and folds of the scalp skin resembling cerebral gyri.
Less frequent in PHOAD than PHOAR2.
phenotype_term:
preferred_term: Cutis verticis gyrata
term:
id: HP:0010541
label: Cutis gyrata of scalp
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "symptoms and signs of PHOAD were milder, including less severe pachydermia (p = .027) and periostosis (p = .005), and less frequent cutis verticis gyrata (p = .011)"
explanation: >-
Cutis verticis gyrata is a recognized feature that differs in
frequency between PHOAD and PHOAR2.
- name: Arthralgia
category: Musculoskeletal
description: >-
Joint pain, particularly affecting the knees, ankles, and wrists.
phenotype_term:
preferred_term: Arthralgia
term:
id: HP:0002829
label: Arthralgia
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "less frequent cutis verticis gyrata (p = .011), acne (p = .005), arthralgia (p = .037), and anemia (p = .023)"
explanation: >-
Arthralgia is a feature of PHO that varies in frequency between
subtypes.
- name: Hyperhidrosis
category: Dermatologic
description: >-
Excessive sweating, especially of the palms and soles.
phenotype_term:
preferred_term: Hyperhidrosis
term:
id: HP:0000975
label: Hyperhidrosis
evidence:
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the majority of patients experienced resolution of symptoms including
pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%)
and hyperhidrosis (55.0%).
explanation: >-
Hyperhidrosis is a recognized symptom of PHO that responded to
COX-2 inhibitor treatment.
- name: Acne
category: Dermatologic
description: >-
Acne is reported among cutaneous manifestations of PHO and varies between
PHO subtypes.
phenotype_term:
preferred_term: Acne
term:
id: HP:0001061
label: Acne
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "less frequent cutis verticis gyrata (p = .011), acne (p = .005), arthralgia (p = .037)"
explanation: >-
Acne is a feature of PHO that varies between PHOAD and PHOAR2
subtypes.
- name: Joint Swelling
category: Musculoskeletal
description: >-
Joint swelling is a prominent feature of PHO, particularly affecting
the knees. All patients in one treatment trial had joint swelling.
phenotype_term:
preferred_term: Joint swelling
term:
id: HP:0001386
label: Joint swelling
evidence:
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the majority of patients experienced resolution of symptoms including
pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%)
and hyperhidrosis (55.0%).
explanation: >-
Joint swelling was present in all patients and showed 100% response
to COX-2 inhibitor treatment.
- name: Delayed Cranial Suture Closure
category: Musculoskeletal
description: >-
Delayed closure of fontanels and cranial sutures, reported in
approximately 16.9% of HPGD-related PHO cases.
phenotype_term:
preferred_term: Delayed cranial suture closure
term:
id: HP:0000270
label: Delayed cranial suture closure
evidence:
- reference: PMID:40140750
reference_title: "Two cases of primary hypertrophic osteoarthropathy caused by HPGD variants: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 1 displayed gait abnormalities and delayed cranial suture closure"
explanation: >-
Delayed cranial suture closure is a documented feature in
HPGD-related PHO cases.
- name: Anemia
category: Hematologic
subtype: PHOAR2
description: >-
Severe anemia due to myelofibrosis, occurring specifically in
SLCO2A1-deficient patients.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLCO2A1-deficient individuals have a high frequency of severe
anemia due to myelofibrosis.
explanation: >-
Anemia from myelofibrosis is a distinguishing complication of
PHOAR2, not seen in PHOAR1.
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients.
explanation: >-
Confirms myelofibrosis (and consequent anemia) is specific to PHOAR2.
- name: Peptic Ulcer
category: Gastrointestinal
subtype: PHOAR2
description: >-
Peptic ulcers occur specifically in SLCO2A1-deficient patients,
likely related to dysregulated prostaglandin metabolism in the
gastric mucosa.
phenotype_term:
preferred_term: Peptic ulcer
term:
id: HP:0004398
label: Peptic ulcer
evidence:
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients.
explanation: >-
Peptic ulcers are a subtype-specific complication of PHOAR2.
- name: Patent Ductus Arteriosus
category: Cardiovascular
description: >-
Patent ductus arteriosus is reported in a subset of PHO patients.
PGE2 is known to maintain ductus arteriosus patency in fetal life,
and elevated PGE2 may prevent normal postnatal closure.
phenotype_term:
preferred_term: Patent ductus arteriosus
term:
id: HP:0001643
label: Patent ductus arteriosus
evidence:
- reference: PMID:40140750
reference_title: "Two cases of primary hypertrophic osteoarthropathy caused by HPGD variants: a case report and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients exhibited congenital digital clubbing and patent ductus arteriosus from birth."
explanation: >-
PDA documented from birth in two HPGD-related PHO cases,
consistent with the role of PGE2 in maintaining ductus
arteriosus patency.
genetic:
- name: HPGD
association: Pathogenic Variants
subtype: PHOAR1
notes: >-
Biallelic loss-of-function variants in HPGD encoding
15-hydroxyprostaglandin dehydrogenase. The recurrent mutation
c.310_311delCT is a hotspot in Chinese patients.
features: hgnc:5154
evidence:
- reference: PMID:18500342
reference_title: "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we mapped PHO to chromosome 4q33-q34 and identified mutations
in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the
main enzyme of prostaglandin degradation.
explanation: >-
Original discovery of HPGD as the causative gene for PHOAR1.
- reference: PMID:35813463
reference_title: "Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The recurrent mutation c.310_311delCT were found in all eleven
patients, suggesting it is a hotspot mutation.
explanation: >-
Identifies the most common HPGD mutation in Chinese PHOAR1 patients.
- name: SLCO2A1
association: Pathogenic Variants
subtype: PHOAR2
notes: >-
Biallelic loss-of-function variants in SLCO2A1 encoding the
prostaglandin transporter. The most common genetic cause of PHO.
All affected patients in the largest cohort were male.
features: hgnc:10955
evidence:
- reference: PMID:22553128
reference_title: "Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic SLCO2A1 mutations were identified in 12 of the 13 families.
explanation: >-
Establishes SLCO2A1 as a major cause of PHO in HPGD-negative families.
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PHO patients with SLCO2A1 mutations were all male and presented
with a later onset age.
explanation: >-
Confirms male predominance and later onset in PHOAR2 compared to PHOAR1.
- name: SLCO2A1 (Dominant)
association: Pathogenic Variants
subtype: PHOAD
notes: >-
Monoallelic mutations in SLCO2A1 cause autosomal dominant PHO
with milder phenotype than biallelic PHOAR2.
features: hgnc:10955
evidence:
- reference: PMID:33852188
reference_title: "Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "our findings confirm that SLCO2A1 monoallelic mutations are the cause of PHOAD and broaden phenotypic spectrum of PHO."
explanation: >-
First identification of monoallelic SLCO2A1 mutations as the cause
of autosomal dominant PHO.
biochemical:
- name: Urinary PGE2
presence: Elevated
notes: >-
Markedly elevated urinary prostaglandin E2 levels are a diagnostic
biomarker for PHO in both subtypes.
evidence:
- reference: PMID:35813463
reference_title: "Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
our PHOAR1 patients have elevated urinary prostaglandin E2 (PGE2)
levels (P<0.001)
explanation: >-
Confirms elevated urinary PGE2 as a biomarker in PHOAR1.
- reference: PMID:18500342
reference_title: "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homozygous individuals develop PHO secondary to chronically elevated
prostaglandin E(2) levels. Heterozygous relatives also show milder
biochemical and clinical manifestations.
explanation: >-
Establishes the dose-dependent effect of PGE2 elevation in HPGD
deficiency.
- name: Urinary PGE-M
presence: Elevated
subtype: PHOAR2
notes: >-
Urinary PGE2 metabolite (PGE-M) is significantly higher in PHOAR2
than PHOAR1, serving as a differential diagnostic biomarker.
evidence:
- reference: PMID:28963081
reference_title: "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The urinary level of prostaglandin E2 metabolite (PGEM) is
significantly higher in PHOAR2 patients than that in PHOAR1 group.
explanation: >-
PGE-M levels distinguish PHOAR2 from PHOAR1 and can guide
differential diagnosis.
- name: Urinary PGE-M (decreased in PHOAR1)
presence: Decreased
subtype: PHOAR1
notes: >-
In PHOAR1, urinary PGE-M is decreased compared to controls, reflecting
impaired PGE2 catabolism by HPGD.
evidence:
- reference: PMID:35813463
reference_title: "Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
decreased urinary prostaglandin E metabolite (PGE-M) levels (P=0.04)
compared with healthy controls.
explanation: >-
Decreased PGE-M in PHOAR1 reflects the enzymatic block in PGE2
degradation.
treatments:
- name: COX-2 Inhibitor (Etoricoxib)
description: >-
Selective COX-2 inhibitor etoricoxib (60 mg daily) reduces PGE2
synthesis and is the most studied targeted treatment for PHO. Shown
to improve pachydermia, joint swelling, digital clubbing, and
hyperhidrosis.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: etoricoxib
term:
id: CHEBI:6339
label: etoricoxib
evidence:
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the majority of patients experienced resolution of symptoms including
pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%)
and hyperhidrosis (55.0%).
explanation: >-
Single-arm trial of 27 PHO patients showing etoricoxib efficacy
across multiple symptom domains.
- reference: PMID:31508314
reference_title: "Safety and efficacy of cyclooxygenase-2 inhibition for treatment of primary hypertrophic osteoarthropathy: A single-arm intervention trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In both the PHO subtypes, serum and urinary levels of PGE2 were
elevated at baseline and declined sharply upon treatment.
explanation: >-
Confirms biochemical efficacy of COX-2 inhibition in reducing
PGE2 levels in both PHO subtypes.
- reference: PMID:37705574
reference_title: "Primary hypertrophic osteoarthropathy: genetics, clinical features and management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cyclooxygenase-2 (COX-2) is the key enzyme that acts as the rate-limiting
step for prostaglandin production, thus COX-2 inhibitors have been used to
treat this disease. Although this treatment showed effective results, it has
side effects that restrain its use.
explanation: >-
Review confirms COX-2 inhibitors as the main targeted therapy
but notes side effect concerns limiting long-term use.
- name: NSAIDs
description: >-
Non-steroidal anti-inflammatory drugs provide symptomatic relief
of arthralgia and were the mainstay of treatment before discovery
of the underlying genetic cause.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Genetic Counseling
description: >-
Genetic counseling is recommended for affected families given the
autosomal recessive and dominant inheritance patterns and the
availability of molecular diagnosis.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
datasets:
Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis (PDP) or Touraine–Solente–Golé syndrome, is a rare inherited disorder with a characteristic triad of digital clubbing, pachydermia, and periostosis, driven by impaired prostaglandin E2 (PGE2) clearance due to pathogenic variants in HPGD and/or SLCO2A1. The most actionable current therapeutic axis is suppression of prostaglandin synthesis (notably COX-2 inhibition), with evidence of improvement in soft-tissue/joint manifestations and biochemical markers but limited effect on established periostosis. (lu2023primaryhypertrophicosteoarthropathy pages 1-2, li2025twocasesof pages 1-2, lu2023primaryhypertrophicosteoarthropathy pages 7-8)
| Domain | Summary |
|---|---|
| Disease names / synonyms | Primary hypertrophic osteoarthropathy (PHO); also pachydermoperiostosis (PDP) and Touraine–Solente–Golé syndrome. Clinical forms: complete, incomplete, and forme fruste/fruste (lu2023primaryhypertrophicosteoarthropathy pages 1-2, nicolau2023tourainesolentegolesyndromepathogenic pages 1-2, joshi2019pachydermoperiostosis(touraine–solente–golesyndrome) pages 1-2, cai2025distinctfeaturesof pages 1-2) |
| Key identifiers | Genetic subtypes: PHOAR1 MIM 259100, PHOAR2 MIM 614441, PHOAD MIM 167100. Causal gene IDs: HPGD MIM 601688, SLCO2A1 MIM 601460. MeSH from ClinicalTrials.gov: Osteoarthropathy, Primary Hypertrophic (D010004) (lu2023primaryhypertrophicosteoarthropathy pages 1-2, xu2021monoallelicmutationsin pages 1-2, NCT02438709 chunk 1) |
| Causal genes & inheritance | HPGD loss-of-function causes PHOAR1, classically autosomal recessive; SLCO2A1 biallelic variants cause PHOAR2 (autosomal recessive), and monoallelic SLCO2A1 variants can cause PHOAD (autosomal dominant) with generally milder phenotype and incomplete/sex-skewed penetrance (lu2023primaryhypertrophicosteoarthropathy pages 1-2, xu2021monoallelicmutationsin pages 1-2, li2025twocasesof pages 1-2) |
| Core mechanism | Disease results from impaired PGE2 catabolism: SLCO2A1/OATP2A1 (PGT) mediates cellular uptake of prostaglandins, and 15-PGDH (HPGD) oxidizes PGE2 to PGE-M. Deficiency of either step elevates PGE2, promoting angiogenesis, fibroblast activity, endothelial changes, and abnormal bone remodeling/periostosis (lu2023primaryhypertrophicosteoarthropathy pages 2-4, lu2023primaryhypertrophicosteoarthropathy pages 4-6, li2025twocasesof pages 1-2) |
| Key biomarkers | Urinary PGE2 is elevated across PHO subtypes. In HPGD deficiency (PHOAR1), urinary PGE-M usually decreases and the PGE2/PGE-M ratio rises; in SLCO2A1 deficiency (PHOAR2), urinary PGE-M usually increases and the PGE2/PGE-M ratio is near normal. Reported median urinary PGE2:creatinine in HPGD-related literature review: 627.1 ng/mmol versus 61.49 ng/mmol normal. In one comparison, urinary PGE2 median was 277.58 ng/mmol creatinine in PHOAD vs 473.19 ng/mmol in PHOAR2 (p=0.038) (lu2023primaryhypertrophicosteoarthropathy pages 4-6, li2025twocasesof pages 1-2, xu2021monoallelicmutationsin pages 1-2) |
| Hallmark clinical triad | Digital clubbing + pachydermia + periostosis are the hallmark triad. Clubbing occurs in almost all PHO patients and is often the initial symptom. Periostosis is typically symmetric and often affects long bones (radius, ulna, tibia, metacarpals, metatarsals) (lu2023primaryhypertrophicosteoarthropathy pages 4-6, lu2023primaryhypertrophicosteoarthropathy pages 1-2, nicolau2023tourainesolentegolesyndromepathogenic pages 1-2) |
| Common additional features | Frequent additional manifestations include hyperhidrosis, seborrhea/acne, cutis verticis gyrata, joint swelling/stiffness/arthralgia, acro-osteolysis, anemia, and occasional gastrointestinal involvement. Quantitative data from an HPGD review/case series: hyperhidrosis 60.1%, joint pain 46.1%, joint swelling 37.1%, osteolysis 30.3%, delayed cranial suture closure 16.9%, patent ductus arteriosus 15.7%; median symptom onset 5.1 years, median diagnosis 22.1 years, male:female 2.2:1 (li2025twocasesof pages 4-7, li2025twocasesof pages 1-2, lu2023primaryhypertrophicosteoarthropathy pages 4-6) |
| GI / systemic complications | GI disease is especially linked to SLCO2A1-related PHO. In a Chinese review of 158 patients, 17.2% had gastrointestinal involvement; among those with GI disease, anemia 40.0% vs 4.5%, hypoalbuminemia 16.7% vs 0.9%, myelofibrosis 19.0% vs 0.9% compared with PHO patients without GI involvement; 86.7% (13/15) with GI complications had SLCO2A1 variants (rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4) |
| Epidemiologic notes | PHO is rare; secondary hypertrophic osteoarthropathy accounts for the large majority of HOA overall (~95%), so exclusion of secondary causes is essential. Sex skew varies by subtype: PHOAR1 ~1:1 male:female, whereas PHOAR2/PHOAD are predominantly male; some older reports cite male predominance around 7:1 or 9:1 in clinically defined PDP/PHO cohorts (nicolau2023tourainesolentegolesyndromepathogenic pages 2-5, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4, lu2023primaryhypertrophicosteoarthropathy pages 4-6, nicolau2023tourainesolentegolesyndromepathogenic pages 1-2, joshi2019pachydermoperiostosis(touraine–solente–golesyndrome) pages 1-2) |
| Etoricoxib / COX-2 inhibitors | Best-supported targeted symptomatic therapy because COX-2 is rate-limiting for prostaglandin synthesis. A 6-month intervention in 41 PHO patients showed significant reduction in urinary PGE2 and clinical remission/improvement of digital clubbing, pachydermia, and arthritic symptoms, but periostosis and anemia did not improve; GI ulcer/bleeding may persist or worsen. A ClinicalTrials.gov study (NCT02438709) evaluated etoricoxib 60 mg daily, enrollment 30, with outcomes including PGE2 at 3 and 6 months, pain VAS, finger volume, and knee circumference (lu2023primaryhypertrophicosteoarthropathy pages 7-8, NCT02438709 chunk 1) |
| NSAIDs (nonselective) | Commonly used for pain and arthritis-related symptoms; can improve joint pain/swelling, morning stiffness, and inflammatory markers, but are palliative and limited by gastrointestinal toxicity, especially problematic in PHO with GI involvement. Some reports note poor response in individual cases (nicolau2023tourainesolentegolesyndromepathogenic pages 2-5, almalki2024pachydermoperiostosisdueto pages 1-2, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4) |
| Bisphosphonates | Reported as adjunctive treatment for musculoskeletal pain and high bone turnover; evidence is limited to case reports/small series (e.g., pamidronate mentioned in review literature), with rationale to reduce increased bone remodeling rather than correct the upstream prostaglandin defect (li2025twocasesof pages 4-7, li2025twocasesof pages 8-9, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4) |
| Lanreotide | Evidence limited to a 2024 HPGD splice-variant case report initially mistaken for acromegaly: symptoms responded poorly to NSAIDs but showed excellent response to lanreotide autogel used for ~1 year. This is anecdotal and not established standard therapy (almalki2024pachydermoperiostosisdueto pages 1-2) |
| Other reported therapies | Refractory or supportive options reported in case literature include hydroxychloroquine, tamoxifen, octreotide, colchicine, botulinum toxin A, intra-articular steroids, synovectomy/radiosynoviorthesis, and plastic surgery for severe ptosis/skin changes. Evidence remains low-level and case-based (nicolau2023tourainesolentegolesyndromepathogenic pages 2-5, li2025twocasesof pages 8-9, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4) |
Table: This table condenses the main identifiers, genetics, biomarkers, phenotype spectrum, and treatment evidence for primary hypertrophic osteoarthropathy/pachydermoperiostosis. It is designed for quick knowledge-base population using only the cited context IDs.
PHO is an inherited disorder of skeletal and skin abnormalities, classically presenting with digital clubbing, pachydermia, and periostosis. (lu2023primaryhypertrophicosteoarthropathy pages 1-2, li2025twocasesof pages 1-2)
Recent authoritative definition (2023 review, Frontiers in Endocrinology; published 29 Aug 2023; URL: https://doi.org/10.3389/fendo.2023.1235040): The abstract states: “Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly characterized by clubbing fingers, pachydermia and periostosis.” (lu2023primaryhypertrophicosteoarthropathy pages 1-2)
Not available in retrieved evidence: MONDO ID, ICD-10/ICD-11 codes, and a verified Orphanet ORPHA code were not explicitly present in the retrieved full-text evidence; they therefore cannot be asserted here without external database verification. (shahin2025theroleof pages 5-5)
The information synthesized here is derived from aggregated disease-level review literature (notably a 2023 review) plus primary patient-level evidence (case reports/series and a 2025 systematic review of HPGD-related cases), and a trial registry record (ClinicalTrials.gov). (lu2023primaryhypertrophicosteoarthropathy pages 1-2, li2025twocasesof pages 1-2, almalki2024pachydermoperiostosisdueto pages 1-2, NCT02438709 chunk 1)
PHO is primarily genetic, caused by impaired PGE2 degradation/transport: * HPGD encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme that oxidizes (inactivates) PGE2. (lu2023primaryhypertrophicosteoarthropathy pages 2-4) * SLCO2A1 encodes OATP2A1 / prostaglandin transporter (PGT), which mediates cellular prostaglandin uptake needed for intracellular degradation. (lu2023primaryhypertrophicosteoarthropathy pages 1-2, lu2023primaryhypertrophicosteoarthropathy pages 2-4)
A two-step clearance model is described: (1) selective uptake across the plasma membrane and (2) oxidation in the cell; deficiency of either elevates prostaglandins. (lu2023primaryhypertrophicosteoarthropathy pages 2-4)
Genetic subtypes/inheritance: * PHOAR1 (AR): caused by HPGD mutation. (lu2023primaryhypertrophicosteoarthropathy pages 1-2) * PHOAR2 (AR): caused by SLCO2A1 biallelic mutation. (lu2023primaryhypertrophicosteoarthropathy pages 1-2) * PHOAD (AD): caused by SLCO2A1 monoallelic pathogenic variants. (lu2023primaryhypertrophicosteoarthropathy pages 1-2, xu2021monoallelicmutationsin pages 1-2)
Authoritative 2021 primary genetics paper (Journal of Bone and Mineral Research; Apr 2021; URL: https://doi.org/10.1002/jbmr.4310): abstract states: “Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy.” (xu2021monoallelicmutationsin pages 1-2)
No robust, disease-specific environmental risk or protective factors were identified in the retrieved evidence; PHO is primarily a monogenic prostaglandin-metabolism disorder. Secondary hypertrophic osteoarthropathy (not PHO) is associated with underlying systemic disease (e.g., malignancy, infections, lung disease), which must be excluded diagnostically. (lu2023primaryhypertrophicosteoarthropathy pages 7-8, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
No explicit gene–environment interaction evidence was present in the retrieved texts.
A 2025 systematic literature review of 89 HPGD-related PHO cases reported frequencies including: hyperhidrosis 60.1%, joint pain 46.1%, joint swelling 37.1%, osteolysis 30.3%, delayed cranial suture closure 16.9%, and patent ductus arteriosus 15.7%. (li2025twocasesof pages 4-7)
Other commonly described manifestations include seborrhea/acne, cutis verticis gyrata, arthropathy, acro-osteolysis, anemia and GI abnormalities. (lu2023primaryhypertrophicosteoarthropathy pages 4-6, xu2021monoallelicmutationsin pages 1-2)
Direct quality-of-life instrument data (e.g., SF-36, EQ-5D) were not found in the retrieved evidence. Functional impact is inferred from pain, joint swelling/stiffness, and disfiguring skin changes (including ptosis/cutis verticis gyrata), and from delays in correct diagnosis. (lu2023primaryhypertrophicosteoarthropathy pages 4-6, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
Based on described manifestations: * Digital clubbing — HP:0100759 * Pachydermia / skin thickening — HP:0001067 (general) / HP:0008066 (thickened skin; depends on exact mapping) * Periostosis — HP:0002758 * Hyperhidrosis — HP:0000975 * Acne — HP:0001061 * Cutis verticis gyrata — HP:0007539 * Acro-osteolysis — HP:0006046 * Arthralgia — HP:0002829 * Joint swelling — HP:0001386 * Anemia — HP:0001903 * Patent ductus arteriosus — HP:0001643
(li2025twocasesof pages 4-7, lu2023primaryhypertrophicosteoarthropathy pages 4-6, xu2021monoallelicmutationsin pages 1-2)
Upstream defect: impaired prostaglandin clearance due to loss of PGT-mediated uptake (SLCO2A1) and/or 15-PGDH-mediated oxidation (HPGD). (lu2023primaryhypertrophicosteoarthropathy pages 2-4)
Biochemical consequence: elevated PGE2; 2023 review states it is “generally accepted” that PGE2 plays important roles in PHO development, and that mutations in either gene impair degradation and elevate PGE2. (lu2023primaryhypertrophicosteoarthropathy pages 4-6)
Downstream signaling: PGE2 signals via EP1–EP4 receptors (GPCRs). The 2023 review highlights EP receptor biology and notes EP4 signaling in particular in skeletal biology (including a proposed sensory nerve EP4 axis). (lu2023primaryhypertrophicosteoarthropathy pages 2-4, lu2023primaryhypertrophicosteoarthropathy pages 4-6)
Cell/tissue-level effects: PGE2 is linked to cell proliferation and angiogenesis seen in histology of clubbing/skin; VEGF is discussed as a mediator whose expression can be stimulated by PGE2. (lu2023primaryhypertrophicosteoarthropathy pages 2-4, lu2023primaryhypertrophicosteoarthropathy pages 4-6)
No modifier genes, epigenetic mechanisms, or chromosomal abnormalities were identified in the retrieved evidence.
(lu2023primaryhypertrophicosteoarthropathy pages 2-4, lu2023primaryhypertrophicosteoarthropathy pages 4-6)
Based on described receptor/pathology targets: * Osteoblast — CL:0000062 * Osteoclast — CL:0000092 * Endothelial cell — CL:0000115 * Fibroblast — CL:0000057
(lu2023primaryhypertrophicosteoarthropathy pages 4-6, lu2023primaryhypertrophicosteoarthropathy pages 2-4)
PHO is a primary genetic disorder; the retrieved evidence did not identify specific toxins, lifestyle risks, or infectious triggers. Key “environmental” considerations are iatrogenic—e.g., NSAID-related GI risk is clinically relevant, particularly when GI involvement exists. (rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4, lu2023primaryhypertrophicosteoarthropathy pages 7-8)
The 2023 review notes COX-2 as the rate-limiting enzyme for prostaglandin production and discusses future possibilities including targeting PGES or blocking prostaglandin action (e.g., EP4 antagonists). (lu2023primaryhypertrophicosteoarthropathy pages 7-8, lu2023primaryhypertrophicosteoarthropathy pages 2-4)
(lu2023primaryhypertrophicosteoarthropathy pages 4-6, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
The condition generally progresses slowly, with symptoms often evolving over years and diagnosis frequently delayed into adulthood; substantial diagnostic delay is quantified in the 2025 review (median diagnosis 22.1 years vs onset 5.1 years). (li2025twocasesof pages 4-7)
Robust population prevalence/incidence is not established in the retrieved evidence base. A case report cites “estimated prevalence ~0.16%” and male:female ~7:1, but this estimate is not corroborated by an epidemiologic study in the retrieved set and should be treated cautiously. (joshi2019pachydermoperiostosis(touraine–solente–golesyndrome) pages 1-2)
Subtype-specific sex patterns are emphasized: * PHOAR1: male:female ~1:1 (lu2023primaryhypertrophicosteoarthropathy pages 4-6) * PHOAR2/PHOAD: predominantly male in reported series (lu2023primaryhypertrophicosteoarthropathy pages 4-6)
In the HPGD-focused systematic review of 89 cases, male predominance was quantified as male:female 2.2:1. (li2025twocasesof pages 4-7)
PHO shows variable expressivity and can follow recessive or irregular dominant patterns; autosomal dominant familial transmission in 54.4% of families (historical review) is referenced in both the 2023 review and 2021 genetics paper. (lu2023primaryhypertrophicosteoarthropathy pages 2-4, xu2021monoallelicmutationsin pages 1-2)
A specific diagnostic rule (attributed to Borochowitz et al. in a case report) states that PHO/PDP diagnosis should be made when ≥2 of the following are present: (i) family history, (ii) clubbing, (iii) hypertrophic skin changes, (iv) bone pain/radiographic changes. (joshi2019pachydermoperiostosis(touraine–solente–golesyndrome) pages 1-2)
Key biomarkers (urine): * Urinary PGE2 is a key biological indicator and is elevated across subtypes. (lu2023primaryhypertrophicosteoarthropathy pages 4-6) * PGE-M patterns help subtype discrimination: typically decreased in HPGD deficiency and increased in SLCO2A1 deficiency; the urinary PGE2/PGE-M ratio differs by genetic subtype. (lu2023primaryhypertrophicosteoarthropathy pages 4-6)
A 2025 HPGD-case systematic review reported a median urinary PGE2-to-creatinine ratio 627.1 ng/mmol vs 61.49 ng/mmol normal. (li2025twocasesof pages 1-2)
Plain radiographs show periosteal ossification/cortical thickening and may show acro-osteolysis. (nicolau2023tourainesolentegolesyndromepathogenic pages 1-2, lu2023primaryhypertrophicosteoarthropathy pages 4-6)
Secondary hypertrophic osteoarthropathy is more common (~95% of HOA overall) and must be excluded; additional differentials include acromegaly, thyroid acropachy, rheumatoid/psoriatic arthritis, and juvenile idiopathic arthritis. (rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4, nicolau2023tourainesolentegolesyndromepathogenic pages 1-2)
Mortality and life expectancy data were not identified in the retrieved evidence. Morbidity is driven by chronic pain, joint symptoms, disfigurement, anemia, and GI complications in subsets. Anemia is described as a major complication, potentially related to GI hemorrhage or myelofibrosis. (lu2023primaryhypertrophicosteoarthropathy pages 4-6, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
COX-2 inhibition (etoricoxib; highest-quality evidence in retrieved set): * The 2023 review reports that in a 6-month clinical intervention in 41 PHO patients, urinary PGE2 significantly decreased and patients experienced clinical remission of clubbing, pachydermia, and arthritic symptoms, but periostosis was not relieved; anemia and GI issues may not improve. (lu2023primaryhypertrophicosteoarthropathy pages 7-8)
Clinical trial registry evidence (real-world implementation): * ClinicalTrials.gov NCT02438709 (“Application of COX-2 Inhibitor for Treatment of Primary Hypertrophic Osteoarthropathy”; first posted 08 May 2015; sponsor Peking Union Medical College Hospital) describes etoricoxib 60 mg daily with primary outcomes measuring serum PGE2 change at 3 and 6 months, and secondary outcomes including pain VAS and distal finger volume. (NCT02438709 chunk 1)
NSAIDs: commonly used for symptomatic relief; however GI toxicity is an important limitation, especially in those with GI involvement. (nicolau2023tourainesolentegolesyndromepathogenic pages 2-5, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
Bisphosphonates: reported for musculoskeletal pain/high bone turnover, but evidence is largely case-based and not definitive. (li2025twocasesof pages 4-7, rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4)
(lu2023primaryhypertrophicosteoarthropathy pages 7-8, NCT02438709 chunk 1, li2025twocasesof pages 4-7)
No primary prevention (in the sense of preventing disease occurrence) is established for monogenic PHO in the retrieved evidence. Practical prevention focuses on: * Genetic counseling, cascade testing in families, and reproductive counseling given recessive/dominant forms. (xu2021monoallelicmutationsin pages 2-3, lu2023primaryhypertrophicosteoarthropathy pages 1-2) * Tertiary prevention: mitigating complications (e.g., monitoring/avoiding GI harms from NSAIDs/COX-2 inhibitors in patients with GI disease; multidisciplinary management to reduce diagnostic delays). (rodriguez2009primaryhypertrophicosteoarthropathy pages 3-4, li2025twocasesof pages 4-7)
No naturally occurring veterinary analogs or cross-species susceptibility data were identified in the retrieved evidence.
The 2023 review notes major limitations of animal models: HPGD−/− and SLCO2A1−/− mice are not viable postnatally, and pharmacologic modulation of 15-PGDH affects bone/muscle but does not reproduce PHO skeletal phenotype; better models are needed. (lu2023primaryhypertrophicosteoarthropathy pages 7-8)
References
(lu2023primaryhypertrophicosteoarthropathy pages 1-2): Q. Lu, Yang Xu, Zeng Zhang, Shan-shan Li, and Zhenlin Zhang. Primary hypertrophic osteoarthropathy: genetics, clinical features and management. Frontiers in Endocrinology, Aug 2023. URL: https://doi.org/10.3389/fendo.2023.1235040, doi:10.3389/fendo.2023.1235040. This article has 51 citations.
(li2025twocasesof pages 1-2): Jun Li, Shilei Jia, Jianqun Guo, Wenhui Xie, Yijiao Ma, Xiaojie Gao, and Meihao Gao. Two cases of primary hypertrophic osteoarthropathy caused by hpgd variants: a case report and literature review. BMC Pediatrics, Mar 2025. URL: https://doi.org/10.1186/s12887-025-05590-z, doi:10.1186/s12887-025-05590-z. This article has 1 citations and is from a peer-reviewed journal.
(lu2023primaryhypertrophicosteoarthropathy pages 7-8): Q. Lu, Yang Xu, Zeng Zhang, Shan-shan Li, and Zhenlin Zhang. Primary hypertrophic osteoarthropathy: genetics, clinical features and management. Frontiers in Endocrinology, Aug 2023. URL: https://doi.org/10.3389/fendo.2023.1235040, doi:10.3389/fendo.2023.1235040. This article has 51 citations.
(nicolau2023tourainesolentegolesyndromepathogenic pages 1-2): Rafaela Nicolau, Tiago Beirão, Francisca Guimarães, Francisca Aguiar, Sara Ganhão, Mariana Rodrigues, Ana Grangeia, and Iva Brito. Touraine-solente-gole syndrome: pathogenic variant in slco2a1 presented with polyarthralgia and digital clubbing. Pediatric Rheumatology Online Journal, May 2023. URL: https://doi.org/10.1186/s12969-023-00831-w, doi:10.1186/s12969-023-00831-w. This article has 6 citations.
(joshi2019pachydermoperiostosis(touraine–solente–golesyndrome) pages 1-2): Amir Joshi, Gaurav Nepal, Yow Ka Shing, Hari Prasad Panthi, and Suman Baral. Pachydermoperiostosis (touraine–solente–gole syndrome): a case report. Journal of Medical Case Reports, Feb 2019. URL: https://doi.org/10.1186/s13256-018-1961-z, doi:10.1186/s13256-018-1961-z. This article has 24 citations and is from a peer-reviewed journal.
(cai2025distinctfeaturesof pages 1-2): Xilei Cai, Xiujuan Yang, Pengyue Zhang, Ziyue Dou, Zilian Chen, Chongzhi Zhu, Weiwei Xu, Xinchen Wang, Xiaodan Hong, and Zhenhua Zhang. Distinct features of three clinical subtypes in 533 patients with primary hypertrophic osteoarthropathy. Orphanet Journal of Rare Diseases, Apr 2025. URL: https://doi.org/10.1186/s13023-025-03722-3, doi:10.1186/s13023-025-03722-3. This article has 1 citations and is from a peer-reviewed journal.
(xu2021monoallelicmutationsin pages 1-2): Yang Xu, Zeng Zhang, Hua Yue, Shanshan Li, and Zhenlin Zhang. Monoallelic mutations in slco2a1 cause autosomal dominant primary hypertrophic osteoarthropathy. Journal of Bone and Mineral Research, 36:1459-1468, Apr 2021. URL: https://doi.org/10.1002/jbmr.4310, doi:10.1002/jbmr.4310. This article has 39 citations and is from a highest quality peer-reviewed journal.
(NCT02438709 chunk 1): Effect Observation Study of COX-2 Inhibitor to Treat Primary Hypertrophic Osteoarthropathy. Peking Union Medical College Hospital. 2012. ClinicalTrials.gov Identifier: NCT02438709
(lu2023primaryhypertrophicosteoarthropathy pages 2-4): Q. Lu, Yang Xu, Zeng Zhang, Shan-shan Li, and Zhenlin Zhang. Primary hypertrophic osteoarthropathy: genetics, clinical features and management. Frontiers in Endocrinology, Aug 2023. URL: https://doi.org/10.3389/fendo.2023.1235040, doi:10.3389/fendo.2023.1235040. This article has 51 citations.
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