👪

Inheritance

1

Autosomal dominant (de novo) HP:0000006

The syndrome follows autosomal dominant inheritance, with affected individuals typically carrying a de novo frameshift variant in HMGB1. Variable expressivity has been observed, with very mild features reported in a transmitting parent.

autosomal dominant inheritance

Show evidence (1 reference)

PMID:20661588 SUPPORT Human Clinical

"Autosomal dominant inheritance with variable expression has been suggested based on the presence of minor features in some parents and the fact that neither parental consanguinity nor pairs of affected siblings were observed."

The clinical review supports an autosomal dominant mode of inheritance with variable expressivity for this syndrome.

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Pathophysiology

5

HMGB1 Frameshift and Acidic-to-Basic Tail Replacement

De novo heterozygous frameshift variants in the final exon of HMGB1 shift the reading frame so that the protein's intrinsically disordered, negatively charged acidic C-terminal tail is replaced by an arginine-rich basic tail. This is the primary molecular lesion of the syndrome.

HMGB1 hgnc:4983

Downstream

Altered HMGB1 Phase Separation The arginine-rich basic tail changes the biophysical phase-separation behaviour of HMGB1.

Show evidence (2 references)

PMID:36755093 SUPPORT Human Clinical

"We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome."

Establishes that de novo frameshift variants in HMGB1 are the genetic cause of the syndrome.

PMID:36755093 SUPPORT In Vitro

"The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail."

Defines the molecular nature of the causative frameshift: replacement of the acidic C-terminal tail with an arginine-rich basic tail.

Altered HMGB1 Phase Separation

The mutant arginine-rich basic tail alters the liquid-liquid phase-separation behaviour of HMGB1, changing the condensates it forms and its partitioning between cellular compartments.

Downstream

Nucleolar Mispartitioning and Dysfunction Altered phase separation drives mispartitioning of HMGB1 into the nucleolus.

Show evidence (1 reference)

PMID:36755093 SUPPORT In Vitro

"The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction."

Demonstrates that the mutant tail alters HMGB1 phase separation.

Nucleolar Mispartitioning and Dysfunction

Aberrant phase separation enhances partitioning of mutant HMGB1 into nucleolar condensates, where it mislocalizes, displaces the normal granular component, and disrupts nucleolar organization and function.

Mispartitioning of HMGB1 into the nucleolus GO:1902570 ↑ INCREASED Nucleolar dysfunction GO:0007000 ⚠ ABNORMAL

Downstream

Impaired Ribosomal RNA Biogenesis Nucleolar dysfunction perturbs the nucleolus's core role in ribosomal RNA biogenesis.

Show evidence (2 references)

PMID:36755093 SUPPORT In Vitro

"The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction."

Shows enhanced nucleolar partitioning and the resulting nucleolar dysfunction.

PMID:36755093 SUPPORT In Vitro

"For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis."

Quantifies enhanced nucleolar partitioning across disease-associated variants.

Impaired Ribosomal RNA Biogenesis

Nucleolar dysfunction impairs ribosomal RNA biogenesis — the nucleolus's primary function — reducing ribosome production capacity in affected cells.

Impaired ribosomal RNA biogenesis GO:0042254 ↓ DECREASED

Downstream

Disrupted Skeletal and Craniofacial Morphogenesis Impaired ribosome biogenesis during development is proposed to disrupt morphogenesis of skeletal and craniofacial structures.

Show evidence (1 reference)

PMID:36755093 SUPPORT In Vitro

"For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis."

Demonstrates that disease-associated variants alter rRNA biogenesis.

Disrupted Skeletal and Craniofacial Morphogenesis

The cellular consequences of nucleolar dysfunction and impaired ribosome biogenesis manifest during development as disrupted morphogenesis of the limbs and craniofacial structures, producing the brachyphalangy, polydactyly, tibial aplasia, and craniofacial features that define the syndrome.

Downstream

Tibial aplasia/hypoplasia Disrupted limb morphogenesis produces tibial aplasia/hypoplasia.

Preaxial polydactyly Disrupted limb morphogenesis produces preaxial polydactyly.

Brachydactyly and brachyphalangy Disrupted digit morphogenesis produces brachydactyly/brachyphalangy.

Hypoplasia of the radius Disrupted forelimb morphogenesis produces radial hypoplasia.

Hypoplasia of the ulna Disrupted forelimb morphogenesis produces ulnar hypoplasia.

Blepharophimosis Disrupted craniofacial morphogenesis produces blepharophimosis.

Telecanthus Disrupted craniofacial morphogenesis produces telecanthus.

Depressed nasal bridge Disrupted craniofacial morphogenesis produces a depressed nasal bridge.

Short nose Disrupted craniofacial morphogenesis produces a short nose.

Narrow mouth Disrupted craniofacial morphogenesis produces a narrow mouth.

Genital hypoplasia Disrupted morphogenesis produces external genital hypoplasia.

Show evidence (1 reference)

PMID:36755093 SUPPORT Human Clinical

"We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome."

Links the HMGB1 molecular defect to the limb and craniofacial malformation phenotype that defines the syndrome.

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Pathograph

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Phenotypes

11

Head and Neck 3

Depressed nasal bridge Depressed nasal bridge HP:0005280

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Reports a flat nasal bridge as part of the craniofacial dysmorphism.

Short nose Short nose HP:0003196

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Reports a small nose as part of the craniofacial dysmorphism.

Narrow mouth Narrow mouth HP:0000160

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Reports a small mouth (narrow mouth/microstomia) as part of the craniofacial dysmorphism.

Limbs 4

Preaxial polydactyly Preaxial polydactyly HP:0100258

Onset: CONGENITAL

Show evidence (2 references)

PMID:20661588 SUPPORT Human Clinical

"Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs."

Documents preaxial polydactyly of the feet in an affected patient.

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Describes mirror-image preaxial polydactyly of the feet in an affected patient.

Brachydactyly and brachyphalangy Brachydactyly HP:0001156

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20661588 SUPPORT Human Clinical

"Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs."

Documents brachydactyly of the hands and feet, the basis for the "brachyphalangy" in the syndrome name.

Hypoplasia of the radius Hypoplasia of the radius HP:0002984

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20661588 SUPPORT Human Clinical

"Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs."

Documents shortening of the radius as part of the limb phenotype.

Hypoplasia of the ulna Hypoplasia of the ulna HP:0003022

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20661588 SUPPORT Human Clinical

"Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs."

Documents shortening of the ulna as part of the limb phenotype.

Other 4

Tibial aplasia/hypoplasia Aplasia/Hypoplasia of the tibia HP:0005772

Onset: CONGENITAL

Show evidence (2 references)

PMID:20661588 SUPPORT Human Clinical

"Clinical problems included brachydactyly of hands and feet, splaying of fingers and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened radius and ulna, and characteristic facial dysmorphic signs."

Documents bilateral tibial aplasia as a clinical feature of an affected patient.

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Confirms tibial aplasia as part of the syndrome's limb phenotype.

Blepharophimosis Blepharophimosis HP:0000581

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Reports blepharophimosis as part of the craniofacial dysmorphism.

Telecanthus Telecanthus HP:0000506

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Reports telecanthus as part of the craniofacial dysmorphism.

Genital hypoplasia External genital hypoplasia HP:0003241

Onset: CONGENITAL

Show evidence (1 reference)

PMID:15057119 SUPPORT Human Clinical

"The patient had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small mouth."

Documents external genital hypoplasia as a feature of the syndrome.

🧬

Genetic Associations

1

HMGB1 (Causal de novo frameshift variant (gain-of-function))

Gene: HMGB1 hgnc:4983 variant_origin: DE_NOVO

Show evidence (2 references)

PMID:36755093 SUPPORT Human Clinical

"We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome."

Identifies de novo frameshift variants in HMGB1 as the cause of the syndrome.

PMID:36755093 SUPPORT In Vitro

"The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail."

Describes the molecular nature of the causative frameshift variants.

💊

Medical Actions

1

Orthopedic and Reconstructive Surgery

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Management of the limb malformations (tibial aplasia/hypoplasia and polydactyly) is supportive and surgical, including orthopedic reconstruction, correction of polydactyly, and, where indicated, procedures to enable ambulation.

{ }

Source YAML

click to show

name: Brachyphalangy-Polydactyly-Tibial Aplasia Syndrome
creation_date: "2026-06-12T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Brachyphalangy-polydactyly-tibial aplasia syndrome
  term:
    id: MONDO:0700354
    label: HMGB1-related brachyphalangy, polydactyly and tibial aplasia syndrome
description: >-
  An extremely rare autosomal dominant complex malformation syndrome (also known
  by OMIM 609945) caused by de novo frameshift variants in HMGB1. The disorder is
  characterised by a distinctive combination of limb anomalies — brachydactyly and
  brachyphalangy of the hands and feet, preaxial (often mirror-image) polydactyly,
  and tibial aplasia/hypoplasia — together with craniofacial dysmorphism and
  genitourinary anomalies. The frameshift variants act through a gain-of-function
  mechanism: they replace the intrinsically disordered acidic C-terminal tail of
  HMGB1 with an arginine-rich basic tail that alters HMGB1 liquid-liquid phase
  separation, drives mispartitioning of the protein into the nucleolus, and
  disrupts nucleolar function and ribosomal RNA biogenesis.
parents:
- Limb Development Disorders
- hereditary disease
references:
- reference: PMID:36755093
  title: "Aberrant phase separation and nucleolar dysfunction in rare genetic diseases."
- reference: PMID:20661588
  title: "Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945): case report and review of the literature."
- reference: PMID:15057119
  title: "Tibial aplasia, lower extremity mirror image polydactyly, brachyphalangy, craniofacial dysmorphism and genital hypoplasia: further delineation and mutational analysis."
inheritance:
- name: Autosomal dominant (de novo)
  description: >-
    The syndrome follows autosomal dominant inheritance, with affected individuals
    typically carrying a de novo frameshift variant in HMGB1. Variable expressivity
    has been observed, with very mild features reported in a transmitting parent.
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant inheritance with variable expression has been suggested
      based on the presence of minor features in some parents and the fact that
      neither parental consanguinity nor pairs of affected siblings were observed.
    explanation: >-
      The clinical review supports an autosomal dominant mode of inheritance with
      variable expressivity for this syndrome.
pathophysiology:
- name: HMGB1 Frameshift and Acidic-to-Basic Tail Replacement
  description: >-
    De novo heterozygous frameshift variants in the final exon of HMGB1 shift the
    reading frame so that the protein's intrinsically disordered, negatively charged
    acidic C-terminal tail is replaced by an arginine-rich basic tail. This is the
    primary molecular lesion of the syndrome.
  gene:
    preferred_term: HMGB1
    term:
      id: hgnc:4983
      label: HMGB1
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discover de novo frameshift variants in HMGB1 that cause brachyphalangy,
      polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome.
    explanation: >-
      Establishes that de novo frameshift variants in HMGB1 are the genetic cause of
      the syndrome.
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with
      an arginine-rich basic tail.
    explanation: >-
      Defines the molecular nature of the causative frameshift: replacement of the
      acidic C-terminal tail with an arginine-rich basic tail.
  downstream:
  - target: Altered HMGB1 Phase Separation
    description: >-
      The arginine-rich basic tail changes the biophysical phase-separation
      behaviour of HMGB1.
- name: Altered HMGB1 Phase Separation
  description: >-
    The mutant arginine-rich basic tail alters the liquid-liquid phase-separation
    behaviour of HMGB1, changing the condensates it forms and its partitioning
    between cellular compartments.
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant tail alters HMGB1 phase separation, enhances its partitioning into
      the nucleolus and causes nucleolar dysfunction.
    explanation: >-
      Demonstrates that the mutant tail alters HMGB1 phase separation.
  downstream:
  - target: Nucleolar Mispartitioning and Dysfunction
    description: >-
      Altered phase separation drives mispartitioning of HMGB1 into the nucleolus.
- name: Nucleolar Mispartitioning and Dysfunction
  description: >-
    Aberrant phase separation enhances partitioning of mutant HMGB1 into nucleolar
    condensates, where it mislocalizes, displaces the normal granular component, and
    disrupts nucleolar organization and function.
  biological_processes:
  - preferred_term: Mispartitioning of HMGB1 into the nucleolus
    term:
      id: GO:1902570
      label: protein localization to nucleolus
    modifier: INCREASED
  - preferred_term: Nucleolar dysfunction
    term:
      id: GO:0007000
      label: nucleolus organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant tail alters HMGB1 phase separation, enhances its partitioning into
      the nucleolus and causes nucleolar dysfunction.
    explanation: >-
      Shows enhanced nucleolar partitioning and the resulting nucleolar dysfunction.
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For 12 out of the 13 disease-associated variants tested, the mutation enhanced
      partitioning into the nucleolus, and several variants altered rRNA biogenesis.
    explanation: >-
      Quantifies enhanced nucleolar partitioning across disease-associated variants.
  downstream:
  - target: Impaired Ribosomal RNA Biogenesis
    description: >-
      Nucleolar dysfunction perturbs the nucleolus's core role in ribosomal RNA
      biogenesis.
- name: Impaired Ribosomal RNA Biogenesis
  description: >-
    Nucleolar dysfunction impairs ribosomal RNA biogenesis — the nucleolus's primary
    function — reducing ribosome production capacity in affected cells.
  biological_processes:
  - preferred_term: Impaired ribosomal RNA biogenesis
    term:
      id: GO:0042254
      label: ribosome biogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For 12 out of the 13 disease-associated variants tested, the mutation enhanced
      partitioning into the nucleolus, and several variants altered rRNA biogenesis.
    explanation: >-
      Demonstrates that disease-associated variants alter rRNA biogenesis.
  downstream:
  - target: Disrupted Skeletal and Craniofacial Morphogenesis
    description: >-
      Impaired ribosome biogenesis during development is proposed to disrupt
      morphogenesis of skeletal and craniofacial structures.
- name: Disrupted Skeletal and Craniofacial Morphogenesis
  description: >-
    The cellular consequences of nucleolar dysfunction and impaired ribosome
    biogenesis manifest during development as disrupted morphogenesis of the limbs
    and craniofacial structures, producing the brachyphalangy, polydactyly, tibial
    aplasia, and craniofacial features that define the syndrome.
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discover de novo frameshift variants in HMGB1 that cause brachyphalangy,
      polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome.
    explanation: >-
      Links the HMGB1 molecular defect to the limb and craniofacial malformation
      phenotype that defines the syndrome.
  downstream:
  - target: Tibial aplasia/hypoplasia
    description: Disrupted limb morphogenesis produces tibial aplasia/hypoplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20661588
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      explanation: Supports tibial aplasia as a limb-morphogenesis phenotype of the syndrome.
  - target: Preaxial polydactyly
    description: Disrupted limb morphogenesis produces preaxial polydactyly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20661588
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      explanation: Supports preaxial polydactyly as a limb-morphogenesis phenotype of the syndrome.
  - target: Brachydactyly and brachyphalangy
    description: Disrupted digit morphogenesis produces brachydactyly/brachyphalangy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20661588
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical problems included brachydactyly of hands and feet, splaying of fingers
      explanation: Supports brachydactyly/brachyphalangy as a digit-morphogenesis phenotype of the syndrome.
  - target: Hypoplasia of the radius
    description: Disrupted forelimb morphogenesis produces radial hypoplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20661588
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: radius and ulna, and characteristic facial dysmorphic signs.
      explanation: Supports shortened radius as a forelimb phenotype of the syndrome.
  - target: Hypoplasia of the ulna
    description: Disrupted forelimb morphogenesis produces ulnar hypoplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20661588
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: radius and ulna, and characteristic facial dysmorphic signs.
      explanation: Supports shortened ulna as a forelimb phenotype of the syndrome.
  - target: Blepharophimosis
    description: Disrupted craniofacial morphogenesis produces blepharophimosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: blepharophimosis, a flat nasal bridge with a small nose and a small mouth.
      explanation: Supports blepharophimosis as part of the craniofacial dysmorphism.
  - target: Telecanthus
    description: Disrupted craniofacial morphogenesis produces telecanthus.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: genital hypoplasia as well as facial dysmorphism including telecanthus,
      explanation: Supports telecanthus as part of the craniofacial dysmorphism.
  - target: Depressed nasal bridge
    description: Disrupted craniofacial morphogenesis produces a depressed nasal bridge.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: blepharophimosis, a flat nasal bridge with a small nose and a small mouth.
      explanation: Supports flat/depressed nasal bridge as part of the craniofacial dysmorphism.
  - target: Short nose
    description: Disrupted craniofacial morphogenesis produces a short nose.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: blepharophimosis, a flat nasal bridge with a small nose and a small mouth.
      explanation: Supports small/short nose as part of the craniofacial dysmorphism.
  - target: Narrow mouth
    description: Disrupted craniofacial morphogenesis produces a narrow mouth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: blepharophimosis, a flat nasal bridge with a small nose and a small mouth.
      explanation: Supports small/narrow mouth as part of the craniofacial dysmorphism.
  - target: Genital hypoplasia
    description: Disrupted morphogenesis produces external genital hypoplasia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15057119
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: genital hypoplasia as well as facial dysmorphism including telecanthus,
      explanation: Supports genital hypoplasia as part of the syndrome's congenital malformation pattern.
prevalence:
- population: General population
  notes: >-
    Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM
    609945) is an ultra-rare congenital malformation disorder. Only a handful of
    affected individuals have been described in the literature (about seven
    reported as of 2010), so no reliable population prevalence estimate exists.
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM
      609945) is a rare congenital disorder. Only seven patients have been
      reported to date, and the etiology of this syndrome is unknown.
    explanation: >-
      Case report and literature review documenting the extreme rarity of the
      syndrome, with only seven reported patients at time of publication.
phenotypes:
- name: Tibial aplasia/hypoplasia
  description: >-
    Absence or marked underdevelopment of the tibia, frequently bilateral, is a
    cardinal feature of the syndrome.
  phenotype_term:
    preferred_term: Tibial aplasia/hypoplasia
    term:
      id: HP:0005772
      label: Aplasia/Hypoplasia of the tibia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical problems included brachydactyly of hands and feet, splaying of fingers
      and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      radius and ulna, and characteristic facial dysmorphic signs.
    explanation: >-
      Documents bilateral tibial aplasia as a clinical feature of an affected patient.
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Confirms tibial aplasia as part of the syndrome's limb phenotype.
- name: Preaxial polydactyly
  description: >-
    Preaxial (often mirror-image) polydactyly, most prominently affecting the feet.
  phenotype_term:
    preferred_term: Preaxial polydactyly
    term:
      id: HP:0100258
      label: Preaxial polydactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical problems included brachydactyly of hands and feet, splaying of fingers
      and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      radius and ulna, and characteristic facial dysmorphic signs.
    explanation: >-
      Documents preaxial polydactyly of the feet in an affected patient.
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Describes mirror-image preaxial polydactyly of the feet in an affected patient.
- name: Brachydactyly and brachyphalangy
  description: >-
    Shortening of the digits (brachydactyly) and of the phalanges (brachyphalangy)
    affecting the hands and feet.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical problems included brachydactyly of hands and feet, splaying of fingers
      and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      radius and ulna, and characteristic facial dysmorphic signs.
    explanation: >-
      Documents brachydactyly of the hands and feet, the basis for the "brachyphalangy"
      in the syndrome name.
- name: Hypoplasia of the radius
  description: >-
    Shortening/underdevelopment of the radius, reported as part of the upper-limb
    long-bone involvement.
  phenotype_term:
    preferred_term: Shortened radius
    term:
      id: HP:0002984
      label: Hypoplasia of the radius
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical problems included brachydactyly of hands and feet, splaying of fingers
      and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      radius and ulna, and characteristic facial dysmorphic signs.
    explanation: >-
      Documents shortening of the radius as part of the limb phenotype.
- name: Hypoplasia of the ulna
  description: >-
    Shortening/underdevelopment of the ulna, reported as part of the upper-limb
    long-bone involvement.
  phenotype_term:
    preferred_term: Shortened ulna
    term:
      id: HP:0003022
      label: Hypoplasia of the ulna
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20661588
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical problems included brachydactyly of hands and feet, splaying of fingers
      and toes, preaxial polydactyly of feet, bilateral tibial aplasia, shortened
      radius and ulna, and characteristic facial dysmorphic signs.
    explanation: >-
      Documents shortening of the ulna as part of the limb phenotype.
- name: Blepharophimosis
  description: >-
    Narrowing of the palpebral fissures, part of the characteristic craniofacial
    dysmorphism of the syndrome.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Reports blepharophimosis as part of the craniofacial dysmorphism.
- name: Telecanthus
  description: >-
    Increased distance between the inner canthi of the eyes, a craniofacial feature
    of the syndrome.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Reports telecanthus as part of the craniofacial dysmorphism.
- name: Depressed nasal bridge
  description: >-
    Flattening/depression of the nasal bridge, a craniofacial feature of the syndrome.
  phenotype_term:
    preferred_term: Flat nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Reports a flat nasal bridge as part of the craniofacial dysmorphism.
- name: Short nose
  description: >-
    A small/short nose, part of the craniofacial dysmorphism of the syndrome.
  phenotype_term:
    preferred_term: Small nose
    term:
      id: HP:0003196
      label: Short nose
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Reports a small nose as part of the craniofacial dysmorphism.
- name: Narrow mouth
  description: >-
    A small mouth (microstomia), part of the craniofacial dysmorphism of the syndrome.
  phenotype_term:
    preferred_term: Small mouth
    term:
      id: HP:0000160
      label: Narrow mouth
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Reports a small mouth (narrow mouth/microstomia) as part of the craniofacial
      dysmorphism.
- name: Genital hypoplasia
  description: >-
    Hypoplasia of the external genitalia (e.g., micropenis and hypoplastic scrotum in
    males; absent labia minora and a small clitoris in females).
  phenotype_term:
    preferred_term: External genital hypoplasia
    term:
      id: HP:0003241
      label: External genital hypoplasia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15057119
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had tibial aplasia, mirror image preaxial polydactyly involving her
      feet, brachyphalangy, genital hypoplasia as well as facial dysmorphism including
      telecanthus, blepharophimosis, a flat nasal bridge with a small nose and a small
      mouth.
    explanation: >-
      Documents external genital hypoplasia as a feature of the syndrome.
genetic:
- name: HMGB1
  association: Causal de novo frameshift variant (gain-of-function)
  gene_term:
    preferred_term: HMGB1
    term:
      id: hgnc:4983
      label: HMGB1
  variant_origin: DE_NOVO
  notes: >-
    De novo heterozygous frameshift variants in the final exon of HMGB1 (e.g.
    p.Glu186Argfs*42 and p.Lys184Argfs*44) replace the intrinsically disordered
    acidic C-terminal tail with an arginine-rich basic tail. Because the variants
    confer a new biochemical activity (altered phase separation and nucleolar
    mispartitioning) rather than simply abolishing protein function, the mechanism
    is gain-of-function.
  evidence:
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discover de novo frameshift variants in HMGB1 that cause brachyphalangy,
      polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome.
    explanation: >-
      Identifies de novo frameshift variants in HMGB1 as the cause of the syndrome.
  - reference: PMID:36755093
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with
      an arginine-rich basic tail.
    explanation: >-
      Describes the molecular nature of the causative frameshift variants.
treatments:
- name: Orthopedic and Reconstructive Surgery
  description: >-
    Management of the limb malformations (tibial aplasia/hypoplasia and polydactyly)
    is supportive and surgical, including orthopedic reconstruction, correction of
    polydactyly, and, where indicated, procedures to enable ambulation.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
notes: >-
  The broader phenotypic spectrum captured in disease ontologies (MONDO:0700354)
  also includes microcephaly, malformed ears, contractures of the large joints,
  developmental delay, and hearing impairment, drawn from the HMGB1 patient cohort.
  These features are not enumerated in the abstracts cited here and would need
  full-text or additional sources before being added as evidenced phenotype entries.
  "Splaying of fingers and toes" (PMID:20661588) is also reported but is not modeled
  as a phenotype entry because it denotes wide-spacing rather than syndactyly, and no
  precise HPO term was identified.

📚

References & Deep Research

References

3

PMID:36755093

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

No top-level findings curated for this source.

PMID:20661588

Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (OMIM 609945): case report and review of the literature.

No top-level findings curated for this source.

PMID:15057119

Tibial aplasia, lower extremity mirror image polydactyly, brachyphalangy, craniofacial dysmorphism and genital hypoplasia: further delineation and mutational analysis.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Brachyphalangy‑Polydactyly‑Tibial Aplasia/Hypoplasia Syndrome (BPTAS) — Comprehensive Disease Characteristics Report

Edison Scientific Literature 21 citations 2026-06-12T07:16:21.137396

Brachyphalangy‑Polydactyly‑Tibial Aplasia/Hypoplasia Syndrome (BPTAS) — Comprehensive Disease Characteristics Report

Target disease

Disease name: Brachyphalangy‑Polydactyly‑Tibial Aplasia/Hypoplasia Syndrome
Category: Mendelian / congenital malformation syndrome
Acronym used in recent literature: BPTAS (mensah2023aberrantphaseseparation pages 1-2)
OMIM: 609945 (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2)
MONDO / Orphanet / MeSH / ICD‑10/11: Not retrieved with the available tools in this run; this report therefore anchors identifiers to OMIM and primary literature (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2).

Executive summary

BPTAS is a rare complex malformation syndrome primarily affecting limb development, classically combining tibial aplasia/hypoplasia, (preaxial) polydactyly/polysyndactyly (sometimes described as “mirror” polydactyly), and brachyphalangy/brachydactyly. Historically it was described as autosomal dominant based on family reports, but 2023 work identified de novo heterozygous HMGB1 C‑terminal frameshift variants as a cause, providing a molecular diagnosis and a mechanistic hypothesis linking frameshift‑driven charge inversion in an intrinsically disordered tail to altered phase separation, nucleolar mispartitioning, impaired rRNA biogenesis, and nucleolar dysfunction (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2).

Key structured summary tables

Disease name	Acronym	OMIM	Key synonyms / alternative names	Core phenotype triad	Inheritance	Causal gene	Key variant(s)	Key references
Brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome	BPTAS	609945	Brachyphalangy, polydactyly and tibial aplasia syndrome; Brachyphalangy, polydactyly and absent tibiae; Brachyphalangy, feet polydactyly, absent/hypoplastic tibiae (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2, bernardi2009additionalfeaturesin pages 7-7)	Tibial aplasia/hypoplasia; preaxial polydactyly/polysyndactyly (sometimes described as mirror polydactyly); brachyphalangy/brachydactyly with irregular finger length (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5, bernardi2009additionalfeaturesin pages 2-4)	Historically described as autosomal dominant in pre-2023 case literature; 2023 molecular study identified de novo heterozygous pathogenic variants in affected individuals, refining recurrence risk toward mostly sporadic de novo disease with theoretical parental mosaicism not excluded (bernardi2009additionalfeaturesin pages 1-2, mensah2023aberrantphaseseparation pages 1-2)	HMGB1 (High Mobility Group Box 1) (mensah2023aberrantphaseseparation pages 1-2)	De novo heterozygous C-terminal frameshift variants in the final exon of HMGB1; recurrent example: *NM_002128.7(HMGB1): c.556_559delGAAG; p.(Glu186Argfs42); commentary also cites p.Lys184Argfs44* among disease-causing frameshifts that replace the acidic tail with an arginine-rich basic tail (mensah2023aberrantphaseseparation pages 1-2, roychowdhury2023ataleof pages 1-2, ahmed2023aberrantphaseseparation pages 1-2)	Mensah et al. Nature (Feb 2023), DOI: https://doi.org/10.1038/s41586-022-05682-1; Bernardi et al. Am J Med Genet A (Jul 2009), DOI: https://doi.org/10.1002/ajmg.a.32943 (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2)

Table: This table summarizes the key identifiers, synonyms, phenotype, inheritance, molecular etiology, and anchor references for brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome. It is useful as a compact knowledge-base entry scaffold grounded in the 2009 clinical delineation and the 2023 genetic discovery.

Clinical feature (plain language)	Suggested HPO term (HP:ID + label)	Evidence/notes	Typical onset	System
Absent or severely underdeveloped tibia	HP:0009736 Tibial aplasia / HP:0009766 Tibial hypoplasia	Core defining feature of BPTAS; Mensah 2023: all five individuals had “short and malformed lower limbs characterized by tibia aplasia or hypoplasia”; Bernardi 2009 also describes “agenesis of the tibiae” / “absent/hypoplastic tibiae” (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 2-4, bernardi2009additionalfeaturesin pages 1-2)	Congenital	Skeletal
Preaxial extra toes/fingers, often with fusion	HP:0100258 Preaxial polydactyly / HP:0001159 Syndactyly	Mensah 2023: all five had “preaxial polysyndactyly”; Bernardi 2009 repeatedly reports bilateral preaxial polydactyly of the feet and notes some cases were described as “mirror” polydactyly (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5, bernardi2009additionalfeaturesin pages 2-4)	Congenital	Skeletal
Short finger bones / short digits	HP:0009823 Brachydactyly / HP:0009843 Brachyphalangy	Hallmark feature in syndrome name; Mensah 2023: upper-limb findings included “brachydactyly or brachyphalangy of fingers with an irregular finger length”; Bernardi 2009: “The hands were short with brachydactyly” (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2)	Congenital	Skeletal
Irregular finger length pattern	HP:0011304 Abnormality of finger / HP:0009381 Short phalanx of finger	Mensah 2023 explicitly notes “irregular finger length”; likely reflects disproportionate phalangeal shortening, especially middle phalanges (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 2-4)	Congenital	Skeletal
Short radius and ulna	HP:0006505 Abnormality of radius / HP:0006495 Abnormality of ulna	Mensah 2023: “Short radius and ulna ... in four of five”; Bernardi 2009 also reports short radius and ulna in arms (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 2-4)	Congenital	Skeletal
Large-joint contractures	HP:0001371 Flexion contracture / HP:0002829 Arthrogryposis multiplex congenita (broad related term)	Mensah 2023: all five had lower-limb malformations with “contractures of large joints”; elbow contractures/pterygia were present in 4/5 (mensah2023aberrantphaseseparation pages 1-2)	Congenital	Skeletal
Elbow pterygia or elbow contractures	HP:0009769 Elbow pterygium / HP:0003040 Elbow contracture	Mensah 2023: “Short radius and ulna and contractures or pterygia of the elbow joints” in 4/5 (mensah2023aberrantphaseseparation pages 1-2)	Congenital	Skeletal
Short femora and fibulae	HP:0003097 Short femur / HP:0003084 Fibular hypoplasia	Bernardi 2009: hallmark limb pattern included “short fibulae and femurs”; Mensah 2023 also mentions hypoplastic fibulae in detailed clinical findings (mensah2023aberrantphaseseparation pages 13-15, bernardi2009additionalfeaturesin pages 2-4)	Congenital	Skeletal
Short metacarpals and shortened middle phalanges	HP:0010049 Short metacarpal / HP:0009803 Short middle phalanx of the finger	Bernardi 2009: “short metacarpals and phalanges (especially ... middle phalanges...)”; Mensah 2023 similarly notes short tubular bones with middle phalanges preferentially affected (mensah2023aberrantphaseseparation pages 13-15, bernardi2009additionalfeaturesin pages 2-4)	Congenital	Skeletal
Reduced palmar creases	HP:0006207 Single transverse palmar crease / HP:0006112 Abnormal palmar creases	Mensah 2023 detailed phenotype notes “reduced palmar creases” (mensah2023aberrantphaseseparation pages 13-15)	Congenital	Skeletal
Hypoplastic or absent nails	HP:0001804 Nail hypoplasia / HP:0001798 Anonychia	Mensah 2023 reports “hypoplastic or missing nails”; Bernardi 2009 notes hypoplastic nails in the mother of the proband, supporting variable expression (mensah2023aberrantphaseseparation pages 13-15, bernardi2009additionalfeaturesin pages 5-6)	Congenital	Skeletal
Pelvic/iliac hypoplasia	HP:0003173 Hypoplasia of the ilium	Mensah 2023 detailed findings include pelvic/iliac hypoplasia (mensah2023aberrantphaseseparation pages 13-15)	Congenital	Skeletal
Retarded bone age	HP:0002750 Delayed skeletal maturation	Mensah 2023 detailed findings include “retarded bone age” (mensah2023aberrantphaseseparation pages 13-15)	Congenital / infancy-childhood recognition	Skeletal
Characteristic ear anomalies	HP:0000377 Abnormality of the pinna	Bernardi 2009 review of prior cases lists “malformed ears” among common non-skeletal findings (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Blepharophimosis	HP:0000581 Blepharophimosis	Reported among commonly described craniofacial features in Bernardi 2009 (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Hypertelorism / telecanthus	HP:0000316 Hypertelorism / HP:0000506 Telecanthus	Bernardi 2009 summarizes prior cases with “hypertelorism/telecanthus” (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Micrognathia or retrognathia	HP:0000347 Micrognathia / HP:0000278 Retrognathia	Bernardi 2009 lists “micro/retrognathia” as recurrent craniofacial findings (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Microcephaly	HP:0000252 Microcephaly	Bernardi 2009 lists microcephaly among common non-skeletal findings; Mensah 2023 broadly notes craniofacial and neurological features (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial / Neurodevelopment
Carp-shaped mouth / wide mouth appearance	HP:0000194 Open mouth / HP:0000154 Abnormality of the mouth	Bernardi 2009 cites “carped-shaped mouth” in prior cases; exact HPO match may vary, so broad mouth abnormality term may be safest (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Short neck	HP:0000470 Short neck	Reported among recurrent craniofacial/neck features in Bernardi 2009 (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Craniofacial
Wormian bones	HP:0002645 Wormian bones	Bernardi 2009 reports wormian bones as a novel finding in the female proband (bernardi2009additionalfeaturesin pages 1-2)	Congenital	Craniofacial
Lacrimal sac fistula	HP:0007784 Lacrimal fistula	Bernardi 2009 describes lacrimal sac fistula as an additional, previously undescribed feature in their case (bernardi2009additionalfeaturesin pages 1-2)	Congenital	Craniofacial
Genital hypoplasia / ambiguous or abnormal genitalia	HP:0000078 Abnormality of the genital system / HP:0000047 Hypoplasia of the genitalia	Common associated finding across reports; Mensah 2023 notes “genitourinary features” and “abnormal female genitalia”; Bernardi 2009 highlights genital hypoplasia in the proband (mensah2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 13-15, bernardi2009additionalfeaturesin pages 1-2)	Congenital	Genitourinary
Small clitoris	HP:0000055 Hypoplasia of the clitoris	Bernardi 2009 female proband had “small clitoris” (bernardi2009additionalfeaturesin pages 2-4)	Congenital	Genitourinary
Hypoplastic labia / absent labia majora	HP:0010460 Hypoplasia of the labia majora / HP:0000050 Hypoplasia of the labia minora	Bernardi 2009 describes “absence of labia majora” and “hypoplasia of labia minora” (bernardi2009additionalfeaturesin pages 2-4)	Congenital	Genitourinary
Cryptorchidism in male cases	HP:0000028 Cryptorchidism	Bernardi 2009 review lists cryptorchidism among frequent genital anomalies in previously reported male patients (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Genitourinary
Small penis	HP:0000054 Micropenis	Bernardi 2009 review cites “small penis/clitoris” among frequent genital anomalies (bernardi2009additionalfeaturesin pages 4-5)	Congenital	Genitourinary
Ectopic kidney	HP:0000086 Ectopic kidney	Bernardi 2009 reports ectopic kidney as an additional feature in the new case (bernardi2009additionalfeaturesin pages 1-2)	Congenital	Genitourinary
Anteriorly placed anus	HP:0001545 Abnormality of the anus / HP:0012832 Anteriorly placed anus	Bernardi 2009 reports an anteriorly placed anus in the female proband (bernardi2009additionalfeaturesin pages 2-4, bernardi2009additionalfeaturesin pages 1-2)	Congenital	Genitourinary
Motor developmental delay	HP:0001270 Motor delay	Bernardi 2009 summary of prior cases notes motor delay as a common non-skeletal feature; Mensah 2023 also mentions neurological features broadly (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5)	Infancy / early childhood	Neurodevelopment
Speech delay	HP:0000750 Delayed speech and language development	Bernardi 2009 summary identifies speech delay as a common non-skeletal feature (bernardi2009additionalfeaturesin pages 4-5)	Early childhood	Neurodevelopment

Table: This table summarizes reported clinical features of brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome and maps them to suggested HPO terms. It integrates the modern HMGB1-defined cohort from Mensah 2023 with earlier clinical delineation from Bernardi 2009 to support phenotype curation.

1. Disease Information

1.1 What is the disease?

BPTAS (OMIM 609945) is described in recent genetic/mechanistic work as a “rare complex malformation syndrome” defined clinically by a distinct skeletal phenotype dominated by short/malformed lower limbs with tibial aplasia or hypoplasia, preaxial polysyndactyly, and large‑joint contractures, with milder but characteristic upper‑limb brachyphalangy/brachydactyly (mensah2023aberrantphaseseparation pages 1-2).

Bernardi et al. (July 2009; AJMG A; DOI https://doi.org/10.1002/ajmg.a.32943) describes the syndrome clinically as involving “agenesis of the tibiae and bilateral preaxial polydactyly of the feet, associated with genital hypoplasia” and emphasizes additional anomalies (wormian bones, lacrimal sac fistula, ectopic kidney, anteriorly placed anus) expanding the phenotype (bernardi2009additionalfeaturesin pages 1-2).

1.2 Common synonyms / alternative names

Reported names in the accessible primary literature include: - “Brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome” (BPTAS) (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2) - “A syndrome of brachyphalangy, polydactyly and absent tibiae” (historical case literature name) (bernardi2009additionalfeaturesin pages 7-7) - Reports note some polydactyly described as “mirror polydactyly” (bernardi2009additionalfeaturesin pages 4-5)

1.3 Evidence provenance

Clinical phenotype: aggregated across historical case reports/series and updated with a modern molecular cohort (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2).
Molecular mechanism: derived from experimental cellular/biophysical data in Nature 2023 plus expert commentary (mensah2023aberrantphaseseparation pages 1-2, ahmed2023aberrantphaseseparation pages 1-2, roychowdhury2023ataleof pages 1-2).

PMIDs: Not available in the retrieved tool outputs for the key papers in this run; therefore citations are provided via DOIs/URLs and the attached evidence IDs.

2. Etiology

2.1 Disease causal factors

Genetic

HMGB1 (High Mobility Group Box 1) is implicated as a causal gene in a subset of BPTAS via de novo heterozygous frameshift variants in the final exon, which replace the acidic intrinsically disordered C‑terminal tail with an arginine‑rich basic tail (mensah2023aberrantphaseseparation pages 1-2).

Example HGVS reported: NM_002128.7(HMGB1): c.556_559delGAAG; p.(Glu186Argfs*42) (mensah2023aberrantphaseseparation pages 1-2).

Mechanistic framing (gene → cellular dysfunction)

Mensah et al. explicitly state the causal frameshifts alter phase separation, increase nucleolar partitioning, and cause nucleolar dysfunction, and that several tested disease variants altered rRNA biogenesis (mensah2023aberrantphaseseparation pages 1-2).

2.2 Risk factors

Primary risk factor is the presence of a pathogenic HMGB1 frameshift variant (typically de novo) (mensah2023aberrantphaseseparation pages 1-2).
Pre‑molecular era case literature described BPTAS as “autosomal dominant” (bernardi2009additionalfeaturesin pages 1-2); with the 2023 discovery, sporadic de novo etiology is now strongly supported for at least the HMGB1‑related subset (mensah2023aberrantphaseseparation pages 1-2).

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved literature.

2.4 Gene–environment interactions

No gene–environment interaction evidence was identified in the retrieved literature.

3. Phenotypes

3.1 Core limb phenotype

Across the modern genetically characterized cohort, all five affected individuals had tibia aplasia or hypoplasia, preaxial polysyndactyly, and large‑joint contractures, with milder but characteristic upper limb findings (brachydactyly/brachyphalangy and irregular finger length) (mensah2023aberrantphaseseparation pages 1-2).

Bernardi et al. report a clinically similar pattern and note that limb abnormalities are the “hallmark,” with absent/hypoplastic tibiae, shortened fibulae/femora, and brachyphalangy/brachydactyly, plus extracranial findings including genital hypoplasia and renal/anorectal anomalies in the reported female patient (bernardi2009additionalfeaturesin pages 2-4, bernardi2009additionalfeaturesin pages 1-2).

3.2 Non‑skeletal phenotype

Bernardi et al. summarize commonly reported non‑skeletal findings across earlier cases, including motor delay, speech delay, characteristic craniofacial features (e.g., blepharophimosis, hypertelorism/telecanthus, micro/retrognathia, microcephaly) and frequent genital anomalies (e.g., small penis/clitoris, cryptorchidism, hypoplasia of labia/scrotum) (bernardi2009additionalfeaturesin pages 4-5).

Mensah et al. likewise state that patients have “distinct craniofacial, neurological and genitourinary features,” and their detailed phenotype extraction includes abnormal female genitalia alongside multiple skeletal features (mensah2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 13-15).

3.3 Ontology mappings

A phenotype-to-HPO mapping table is provided in artifact-01 (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 2-4, bernardi2009additionalfeaturesin pages 1-2).

3.4 Visual evidence (phenotype and mechanism)

Mensah et al. includes figures showing the limb phenotype and radiographs, the HMGB1 frameshift schematic, and mutant HMGB1 nucleolar localization (mensah2023aberrantphaseseparation media ca08d65d, mensah2023aberrantphaseseparation media 0c631fa2, mensah2023aberrantphaseseparation media 31b9c4a5, mensah2023aberrantphaseseparation media a3d781c6).

4. Genetic / Molecular Information

4.1 Causal gene

HMGB1 is implicated by de novo frameshift variants in BPTAS (mensah2023aberrantphaseseparation pages 1-2).

4.2 Pathogenic variant class and functional consequence

Variant class: C‑terminal frameshift in the final exon (ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).
Functional consequence: replacement of an acidic disordered tail with an arginine‑rich basic tail (charge inversion), altering phase separation behavior and nucleolar partitioning (mensah2023aberrantphaseseparation pages 1-2).

Expert‑level synthesis (authoritative commentary)

Ahmed & Forman‑Kay (Cell Research, Apr 2023; DOI https://doi.org/10.1038/s41422-023-00804-4) summarize that mutant HMGB1 has a decreased threshold concentration for phase separation and forms condensates with reduced diffusion; it partitions into the nucleolar granular component, displaces NPM1, correlates with reduced 28S rRNA levels, and decreased cell viability, consistent with nucleolar dysfunction (ahmed2023aberrantphaseseparation pages 1-2).

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities specific to BPTAS were identified in the retrieved sources.

5. Environmental Information

No non‑genetic environmental or lifestyle contributors were identified in the retrieved sources; the syndrome is currently best supported as genetically driven (mensah2023aberrantphaseseparation pages 1-2).

6. Mechanism / Pathophysiology

6.1 Current mechanistic model (2023–2024 state of the art)

Mensah et al. (Nature, Feb 2023; DOI https://doi.org/10.1038/s41586-022-05682-1) provide direct experimental evidence for the following chain:

1) Frameshift in HMGB1 C‑terminal IDR → acidic tail replaced by arginine‑rich basic tail (mensah2023aberrantphaseseparation pages 1-2).

2) Altered phase separation properties: the mutant tail “alters HMGB1 phase separation” (mensah2023aberrantphaseseparation pages 1-2) and is described as interfering with the “molecular grammar” of phase separation (mensah2023aberrantphaseseparation pages 7-8).

3) Nucleolar mispartitioning and condensate disruption: mutations “enhanced partitioning into the nucleolus” and “disrupt nucleolar function” (mensah2023aberrantphaseseparation pages 1-2). Mechanistic dissection emphasizes the combination of high arginine content (driving nucleolar partitioning) and a hydrophobic patch (contributing to nucleolar arrest/dysfunction) (mensah2023aberrantphaseseparation pages 7-8, ahmed2023aberrantphaseseparation pages 1-2).

4) Impaired rRNA biogenesis / nucleolar dysfunction: expert commentary summarizes reductions in rRNA (e.g., reduced 28S rRNA) and decreased viability consistent with nucleolar dysfunction (ahmed2023aberrantphaseseparation pages 1-2); Mensah et al. state that several variants altered rRNA biogenesis (mensah2023aberrantphaseseparation pages 1-2).

6.2 Evidence type

Human genetics: de novo variants in affected individuals (mensah2023aberrantphaseseparation pages 1-2).
Cellular and biophysical assays: in vitro phase separation and nucleolar localization/functional readouts (mensah2023aberrantphaseseparation pages 2-3, ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).
Review/commentary synthesis: mechanistic interpretation and generalization to other IDR frameshifts (roychowdhury2023ataleof pages 1-2, ahmed2023aberrantphaseseparation pages 1-2).

6.3 Ontology suggestions (mechanism)

GO Biological Process (suggested): - rRNA processing / ribosome biogenesis (e.g., “ribosome biogenesis”, “rRNA metabolic process”) — supported by altered rRNA biogenesis and nucleolar dysfunction (mensah2023aberrantphaseseparation pages 1-2, ahmed2023aberrantphaseseparation pages 1-2). - Regulation of biomolecular condensate organization / phase separation (supported conceptually by the demonstrated change in phase separation behavior) (mensah2023aberrantphaseseparation pages 1-2).

GO Cellular Component (suggested): - Nucleolus; nucleolar granular component (mechanistic localization) (ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).

Cell Ontology (CL) candidate cell types (context‑appropriate, inferential): - Limb bud mesenchymal cells / chondrocyte lineage progenitors (the syndrome’s main manifestations are skeletal and congenital). The retrieved sources do not specify an implicated cell type in vivo, so this remains an informed developmental hypothesis.

Important limitation: The link from nucleolar dysfunction to the specific pattern of tibial aplasia/polydactyly is currently best interpreted as developmental vulnerability to impaired nucleolar function rather than a fully mapped tissue‑specific pathway (ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).

7. Anatomical Structures Affected

7.1 Organ/system level (with UBERON suggestions)

Lower limb long bones, especially tibia (UBERON:0000979 tibia) (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2).
Hands/feet digits and phalanges (UBERON:0002389 phalanx of hand; UBERON:0001465 phalanx of foot) (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 2-4).
Joints (large‑joint contractures; elbows noted) (mensah2023aberrantphaseseparation pages 1-2).
Genital system (genital hypoplasia/abnormal genitalia) (bernardi2009additionalfeaturesin pages 1-2, mensah2023aberrantphaseseparation pages 13-15).
Kidney and anorectal region may be involved in some patients (ectopic kidney; anteriorly placed anus) (bernardi2009additionalfeaturesin pages 1-2).

7.2 Tissue/cell/subcellular levels

Subcellular localization and dysfunction in nucleolus is a central mechanistic feature (ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).

8. Temporal Development

Onset: Congenital; identified at birth/infancy based on limb malformations (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 1-2).
Course/progression: Structural congenital malformations are lifelong. The retrieved sources do not provide a formal staging system or longitudinal natural history statistics.

9. Inheritance and Population

9.1 Inheritance

Historical case literature describes BPTAS as “autosomal dominant” (Bernardi 2009) (bernardi2009additionalfeaturesin pages 1-2).
The 2023 molecular cohort identifies de novo heterozygous HMGB1 frameshift variants in affected individuals, indicating many cases may be sporadic de novo (mensah2023aberrantphaseseparation pages 1-2).

9.2 Epidemiology / frequency

Bernardi et al. (2009) state their patient represented the “ninth reported case” and only the second female case at that time (bernardi2009additionalfeaturesin pages 1-2).
Mensah et al. (2023) describe five individuals with a common BPTAS skeletal phenotype and identified de novo HMGB1 frameshifts (mensah2023aberrantphaseseparation pages 1-2).

Prevalence/incidence: Not retrieved from Orphanet or population registries in this run.

10. Diagnostics

10.1 Clinical evaluation

Diagnosis is suggested by the triad of tibial aplasia/hypoplasia + preaxial polydactyly/polysyndactyly + brachyphalangy/brachydactyly, often with contractures and possible craniofacial/genitourinary anomalies (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5, bernardi2009additionalfeaturesin pages 1-2).
Bernardi et al. emphasize the need for broad evaluation including ophthalmologic, audiometric, radiological and abdominal evaluation in this syndrome (bernardi2009additionalfeaturesin pages 5-6).

10.2 Imaging

Radiographs are central to documenting tibial aplasia/hypoplasia and digital anomalies; Mensah et al. provide radiographic/clinical figure evidence (mensah2023aberrantphaseseparation media ca08d65d, mensah2023aberrantphaseseparation media 0c631fa2).

10.3 Genetic testing

Based on Mensah et al. 2023, sequencing of HMGB1 (especially the final exon / C‑terminal tail region) is a key confirmatory test in HMGB1‑related BPTAS (mensah2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 13-15).

10.4 Differential diagnosis (examples from accessible case literature)

Bernardi et al. cite overlapping limb deficiency/polydactyly syndromes used historically in differential diagnosis, including: - Tibial hemimelia–polydactyly–triphalangeal thumb syndrome (bernardi2009additionalfeaturesin pages 4-5) - Laurin–Sandrow syndrome (bernardi2009additionalfeaturesin pages 4-5) - “Absence of tibiae with polydactyly” entries in OMIM (bernardi2009additionalfeaturesin pages 4-5)

11. Outcome / Prognosis

No survival or life expectancy statistics were available in the retrieved sources. Morbidity is expected to be dominated by severe congenital limb malformations (functional mobility limitations, orthopedic complications) and potential multisystem anomalies (genitourinary, craniofacial, developmental delay) (mensah2023aberrantphaseseparation pages 1-2, bernardi2009additionalfeaturesin pages 4-5, bernardi2009additionalfeaturesin pages 1-2).

12. Treatment

12.1 Current applications and real‑world implementations

No molecularly targeted therapies exist for BPTAS in the retrieved literature. Real‑world management is therefore supportive and orthopedic, consistent with care for tibial aplasia/hemimelia and complex polydactyly.

Surgical/orthopedic interventions (MAXO suggestions):
Corrective orthopedic surgery / limb reconstruction (MAXO: orthopedic surgical procedure; exact MAXO IDs not retrieved in this run)
Amputation with prosthetic fitting when reconstruction is not feasible (MAXO: limb amputation; MAXO: prosthetic device fitting)
Contracture management (MAXO: physical therapy; MAXO: orthopedic rehabilitation)
Rehabilitative care: physical therapy/occupational therapy, mobility aids.

These management statements are generalizable best practice for severe congenital limb deficiencies; syndrome‑specific treatment outcome data were not identified in the retrieved papers.

12.2 Clinical trials

ClinicalTrials.gov searches (terms: BPTAS/HMGB1/tibial aplasia/polydactyly) yielded no relevant BPTAS‑specific interventional trials in this run.

13. Prevention

Primary prevention is not established because most HMGB1‑related cases appear to be de novo.

Secondary prevention focuses on: - Prenatal detection by fetal ultrasound of limb deficiencies/polydactyly followed by confirmatory genetic testing when indicated. - Genetic counseling: recurrence risk assessment; while de novo is common in HMGB1‑related disease, parental mosaicism cannot be completely excluded without appropriate testing (a general genetic counseling principle; not directly quantified in retrieved sources).

14. Other Species / Natural Disease

No naturally occurring non‑human disease models specifically corresponding to HMGB1‑frameshift BPTAS were retrieved.

15. Model Organisms

No direct HMGB1 frameshift animal model recapitulating the BPTAS phenotype was retrieved in this run. Mechanistic work in Mensah et al. is primarily in vitro and cell‑based, supporting nucleolar/phase separation dysfunction as a plausible mechanism in human development (mensah2023aberrantphaseseparation pages 2-3, ahmed2023aberrantphaseseparation pages 1-2, mensah2023aberrantphaseseparation pages 1-2).

Recent developments (2023–2024 highlight)

1) Causal gene discovery and mechanism (2023): Mensah et al. identified de novo HMGB1 C‑terminal frameshift variants causing BPTAS and linked them experimentally to altered phase separation, nucleolar mispartitioning, and nucleolar dysfunction / altered rRNA biogenesis (Nature, Feb 2023; https://doi.org/10.1038/s41586-022-05682-1) (mensah2023aberrantphaseseparation pages 1-2).

2) Expert interpretation (2023): Cell Research commentary emphasized biophysical and nucleolar effects (e.g., NPM1 displacement; reduced 28S rRNA; decreased viability) as a compelling example of IDR frameshift mutations driving disease via condensate mispartitioning (Apr 2023; https://doi.org/10.1038/s41422-023-00804-4) (ahmed2023aberrantphaseseparation pages 1-2).

3) Broader conceptual integration (2023): Communications Biology commentary further interprets mutant HMGB1 as forming aberrant, arrested nucleolus‑like condensates and proposes a generalizable mechanism for other IDR charge‑inversion frameshifts (Apr 2023; https://doi.org/10.1038/s42003-023-04767-5) (roychowdhury2023ataleof pages 1-2).

Data gaps and curation notes

Ontology identifiers (MONDO/Orphanet/MeSH/ICD): Not retrieved in this run; should be added by targeted lookup in OMIM/Orphanet/MONDO.
PMIDs: Not provided by the current tool outputs; DOI-based citation is provided.
Population allele frequencies / ClinVar assertions: Not retrieved here; recommended follow‑up is ClinVar + gnomAD queries for HMGB1 frameshift variants.
Natural history/prognosis statistics: Not present in accessible sources; would require additional longitudinal case series.

References

(mensah2023aberrantphaseseparation pages 1-2): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(bernardi2009additionalfeaturesin pages 1-2): Pricila Bernardi, Carla Graziadio, Rafael F.M. Rosa, Lisiane Dall'Agnol, Paulo R.G. Zen, and Giorgio A. Paskulin. Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia. American Journal of Medical Genetics Part A, 149A:1532-1538, Jul 2009. URL: https://doi.org/10.1002/ajmg.a.32943, doi:10.1002/ajmg.a.32943. This article has 4 citations.
(bernardi2009additionalfeaturesin pages 7-7): Pricila Bernardi, Carla Graziadio, Rafael F.M. Rosa, Lisiane Dall'Agnol, Paulo R.G. Zen, and Giorgio A. Paskulin. Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia. American Journal of Medical Genetics Part A, 149A:1532-1538, Jul 2009. URL: https://doi.org/10.1002/ajmg.a.32943, doi:10.1002/ajmg.a.32943. This article has 4 citations.
(bernardi2009additionalfeaturesin pages 4-5): Pricila Bernardi, Carla Graziadio, Rafael F.M. Rosa, Lisiane Dall'Agnol, Paulo R.G. Zen, and Giorgio A. Paskulin. Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia. American Journal of Medical Genetics Part A, 149A:1532-1538, Jul 2009. URL: https://doi.org/10.1002/ajmg.a.32943, doi:10.1002/ajmg.a.32943. This article has 4 citations.
(bernardi2009additionalfeaturesin pages 2-4): Pricila Bernardi, Carla Graziadio, Rafael F.M. Rosa, Lisiane Dall'Agnol, Paulo R.G. Zen, and Giorgio A. Paskulin. Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia. American Journal of Medical Genetics Part A, 149A:1532-1538, Jul 2009. URL: https://doi.org/10.1002/ajmg.a.32943, doi:10.1002/ajmg.a.32943. This article has 4 citations.
(roychowdhury2023ataleof pages 1-2): Sumangal Roychowdhury and Krishnananda Chattopadhyay. A tale of (disordered) tail. Communications Biology, Apr 2023. URL: https://doi.org/10.1038/s42003-023-04767-5, doi:10.1038/s42003-023-04767-5. This article has 3 citations and is from a peer-reviewed journal.
(ahmed2023aberrantphaseseparation pages 1-2): Rashik Ahmed and Julie D. Forman-Kay. Aberrant phase separation: linking idr mutations to disease. Cell Research, 33:583-584, Apr 2023. URL: https://doi.org/10.1038/s41422-023-00804-4, doi:10.1038/s41422-023-00804-4. This article has 13 citations and is from a domain leading peer-reviewed journal.
(mensah2023aberrantphaseseparation pages 13-15): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(bernardi2009additionalfeaturesin pages 5-6): Pricila Bernardi, Carla Graziadio, Rafael F.M. Rosa, Lisiane Dall'Agnol, Paulo R.G. Zen, and Giorgio A. Paskulin. Additional features in a new case of a girl presenting brachyphalangy, polydactyly and tibial aplasia/hypoplasia. American Journal of Medical Genetics Part A, 149A:1532-1538, Jul 2009. URL: https://doi.org/10.1002/ajmg.a.32943, doi:10.1002/ajmg.a.32943. This article has 4 citations.
(mensah2023aberrantphaseseparation media ca08d65d): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(mensah2023aberrantphaseseparation media 0c631fa2): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(mensah2023aberrantphaseseparation media 31b9c4a5): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(mensah2023aberrantphaseseparation media a3d781c6): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(mensah2023aberrantphaseseparation pages 7-8): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.
(mensah2023aberrantphaseseparation pages 2-3): Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, and Denes Hnisz. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614:564-571, Feb 2023. URL: https://doi.org/10.1038/s41586-022-05682-1, doi:10.1038/s41586-022-05682-1. This article has 185 citations and is from a highest quality peer-reviewed journal.

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Deep Research

Brachyphalangy‑Polydactyly‑Tibial Aplasia/Hypoplasia Syndrome (BPTAS) — Comprehensive Disease Characteristics Report

Target disease

Executive summary

Key structured summary tables

1. Disease Information

1.1 What is the disease?

1.2 Common synonyms / alternative names

1.3 Evidence provenance

2. Etiology

2.1 Disease causal factors

Genetic

Mechanistic framing (gene → cellular dysfunction)

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core limb phenotype

3.2 Non‑skeletal phenotype

3.3 Ontology mappings

3.4 Visual evidence (phenotype and mechanism)

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variant class and functional consequence

Expert‑level synthesis (authoritative commentary)

4.3 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Current mechanistic model (2023–2024 state of the art)

6.2 Evidence type

6.3 Ontology suggestions (mechanism)

7. Anatomical Structures Affected

7.1 Organ/system level (with UBERON suggestions)

7.2 Tissue/cell/subcellular levels

8. Temporal Development

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology / frequency

10. Diagnostics

10.1 Clinical evaluation

10.2 Imaging

10.3 Genetic testing

10.4 Differential diagnosis (examples from accessible case literature)

11. Outcome / Prognosis

12. Treatment

12.1 Current applications and real‑world implementations

12.2 Clinical trials

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent developments (2023–2024 highlight)

Data gaps and curation notes

Artifacts