👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Feingold syndrome is typically inherited as an autosomal dominant trait, although de novo pathogenic variants or deletions can occur and expressivity is variable.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:35620261 SUPPORT Human Clinical

"dominant manner with full penetrance but with variable expressivity."

Case report abstract supports autosomal dominant inheritance and variable expressivity for FS1.

◆

Subtypes

2

Feingold syndrome type 1 MONDO:0008115

Feingold syndrome type 1 is associated with heterozygous MYCN pathogenic variants or deletions and is the more common subtype.

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"resulting in haploinsufficiency of MYCN"

Human family report states the MYCN haploinsufficiency basis of Feingold syndrome type 1.

Feingold syndrome type 2 MONDO:0013691

Feingold syndrome type 2 is associated with heterozygous MIR17HG deletions and clinically overlaps type 1, but gastrointestinal atresia is less typical.

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"include the MIR17HG gene were found in all three."

Human Feingold syndrome 2 report identifies MIR17HG-containing 13q microdeletions in affected patients.

⚙

Pathophysiology

6

MYCN haploinsufficiency

Loss of one functional MYCN allele disrupts MYCN-dependent transcriptional regulation during embryonic growth and organogenesis, contributing to the type 1 Feingold syndrome phenotype.

MYCN link

transcription by RNA polymerase II link ↓ DECREASED

Downstream

Impaired embryonic morphogenesis Reduced MYCN dosage perturbs developmental programs in multiple organ systems.

Impaired brain and neural development Reduced MYCN dosage is linked to abnormal brain and neural development, providing a mechanistic route to microcephaly.

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"The MYCN oncogene encodes a transcription factor belonging to the MYC family."

Human report supports MYCN as a transcription-factor gene relevant to Feingold syndrome.

Impaired brain and neural development

MYCN is expressed during normal embryonic development and is described as critical in brain and other neural development, linking MYCN haploinsufficiency to microcephaly in Feingold syndrome type 1.

neural progenitor cell link

MYCN link

nervous system development link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"critical in brain and other neural development."

Human Feingold syndrome case report links MYCN to brain and neural development, supporting a microcephaly-relevant mechanism.

Reduced PI3K signaling in limb mesenchyme

Mycn deficiency in mouse limb mesenchymal cells downregulates PI3K signaling, providing a model-organism mechanism for the skeletal component of Feingold syndrome type 1.

limb mesenchymal cell link

phosphatidylinositol-mediated signaling link ↓ DECREASED

Downstream

Impaired embryonic morphogenesis Decreased PI3K signaling contributes to skeletal developmental defects.

Show evidence (1 reference)

PMID:29636449 SUPPORT Model Organism

"upregulates TGF-β signaling, whereas Mycn-deficiency downregulates PI3K"

Mouse model abstract directly distinguishes Mycn deficiency as a PI3K-signaling defect in limb mesenchyme.

MIR17HG deletion

Heterozygous deletion of MIR17HG, which encodes the miR-17-92 microRNA cluster host gene, causes Feingold syndrome type 2 through reduced microRNA-mediated developmental regulation.

MIR17HG link

miRNA-mediated gene silencing link ↓ DECREASED

Downstream

Increased TGF-beta signaling in limb mesenchyme Reduced miR-17-92 dosage derepresses TGF-beta pathway activity in model systems.

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"include the MIR17HG gene were found in all three."

Human Feingold syndrome 2 report supports MIR17HG deletion as the genetic lesion.

Increased TGF-beta signaling in limb mesenchyme

Mir17-92 deficiency increases TGF-beta signaling in limb mesenchymal cells; rescue by TGF-beta pathway inhibition supports this as a causal skeletal mechanism for Feingold syndrome type 2 models.

limb mesenchymal cell link

TGF-beta receptor signaling pathway link ↑ INCREASED

Downstream

Impaired embryonic morphogenesis Excess TGF-beta signaling disrupts skeletal developmental programs.

Show evidence (1 reference)

PMID:29636449 SUPPORT Model Organism

"TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92"

Mouse model rescue experiment supports increased TGF-beta signaling as a causal FS2 skeletal mechanism.

Impaired embryonic morphogenesis

Developmental regulatory defects produce the craniofacial, limb, growth, and gastrointestinal malformation pattern recognized as Feingold syndrome.

skeletal system development link ⚠ ABNORMAL anatomical structure morphogenesis link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:35620261 SUPPORT Human Clinical

"microcephaly, short stature, and intestinal atresia."

Human case report abstract supports the multi-system developmental phenotype.

⬡

Pathograph

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

●

Phenotypes

12

Cardiovascular 2

Cardiac anomalies Abnormal heart morphology (HP:0001627)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"short stature, and cardiac anomalies."

Human FS2 report supports cardiac anomalies and aortic dilation in the phenotype spectrum.

Aortic dilation Aortic aneurysm (HP:0004942)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"growth hormone deficiency associated with adenohypophyseal compression, aortic"

Human FS2 report identifies aortic dilation as a newly reported feature and motivates echocardiographic surveillance.

Digestive 1

Gastrointestinal atresia FREQUENT Esophageal atresia (HP:0002032)

Show evidence (2 references)

PMID:34926353 SUPPORT Human Clinical

"present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula"

Familial MYCN report directly supports esophageal atresia with tracheoesophageal fistula as a Feingold syndrome manifestation.

PMID:35620261 SUPPORT Human Clinical

"microcephaly, short stature, and intestinal atresia."

FS1 case report abstract supports intestinal atresia as a common feature.

Head and Neck 1

Microcephaly VERY_FREQUENT Microcephaly (HP:0000252)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

Human FS2 report includes microcephaly among typical Feingold 2 features.

Context-specific annotations (1)

Type 2 14/16 (88%)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

The abstract supports microcephaly as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.

Limbs 1

Brachydactyly and brachymesophalangy VERY_FREQUENT Brachydactyly (HP:0001156)

Show evidence (2 references)

PMID:35620261 SUPPORT Human Clinical

"common phenotypical features described are finger and toe anomalies,"

Human FS1 case report abstract supports finger anomalies as a common feature.

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

Human FS2 report supports brachymesophalangy and phalangeal joint findings.

Context-specific annotations (1)

Type 2 17/17 (100%)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

The abstract supports brachymesophalangy as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.

Nervous System 1

Developmental delay or intellectual disability VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:35620261 SUPPORT Human Clinical

"intellectual disability and other organ anomalies are less frequently described."

FS1 case report abstract supports intellectual disability as a reported feature.

Context-specific annotations (1)

Type 2 16/16 (100%)

Quantitative frequency is from the Muriello 2019 FS2 cohort table as summarized in the Falcon report; the abstract provides cache-verifiable neurocognitive phenotype support but not the table value itself.

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"dilation, phalangeal joint contractures, memory"

The abstract supports neurocognitive involvement in FS2; frequency comes from the Falcon-cited Muriello cohort table.

Growth 1

Short stature VERY_FREQUENT Short stature (HP:0004322)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"short stature, and cardiac anomalies."

Human FS2 report includes short stature among typical features.

Context-specific annotations (1)

Type 2 13/14 (86%)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"short stature, and cardiac anomalies."

The abstract supports short stature as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.

Other 5

Toe syndactyly FREQUENT 2-3 toe syndactyly (HP:0004691)

Show evidence (2 references)

PMID:34926353 SUPPORT Human Clinical

"of our affected patients showed microcephaly and toe syndactyly"

Familial MYCN report supports toe syndactyly as a recurrent feature.

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

Human FS2 report supports toe syndactyly as a typical feature.

Growth hormone deficiency Decreased response to growth hormone stimulation test (HP:0000824)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"growth hormone deficiency associated with adenohypophyseal compression, aortic"

Human FS2 report identifies growth hormone deficiency as a newly reported feature.

Clinodactyly of the 5th finger Clinodactyly of the 5th finger (HP:0004209)

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"Just one patient exhibited clinodactyly."

MYCN family report supports clinodactyly as a Feingold syndrome digital finding.

Context-specific annotations (1)

Type 2 9/9 (100%)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"phalangeal joint contractures, memory, and sleep problems"

The abstract supports phalangeal joint involvement in FS2; frequency comes from the Falcon-cited Muriello cohort table.

Thumb hypoplasia FREQUENT Aplasia/Hypoplasia of the thumb (HP:0009601)

Show evidence (1 reference)

PMID:33442900 SUPPORT Human Clinical

"brachymesophalangy, hypoplastic thumbs, as well as"

FS1 clinical series abstract includes hypoplastic thumbs among typical clinical features.

Context-specific annotations (1)

Type 2 4/12 (33%)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"

The abstract supports FS2 digital anomalies; frequency comes from the Falcon-cited Muriello cohort table.

Short palpebral fissures FREQUENT Narrow palpebral fissure (HP:0045025)

Show evidence (1 reference)

PMID:33442900 SUPPORT Human Clinical

"short palpebral"

FS1 clinical series abstract lists short palpebral fissures among characteristic clinical features.

Context-specific annotations (1)

Type 1 57%

Quantitative frequency is from the Marcelis 2008 FS1 cohort table as summarized in the Falcon report; the PubMed abstract verifies the n=77 cohort provenance but not the table value itself.

Show evidence (1 reference)

PMID:18470948 SUPPORT Human Clinical

"in a total of 77 patients. We have reviewed the clinical features"

Marcelis 2008 provides the n=77 MYCN-related FS1 cohort used in the Falcon report for the 57% short-palpebral-fissure frequency.

🧬

Genetic Associations

2

MYCN pathogenic variants (Causative)

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"resulting in haploinsufficiency of MYCN"

Human report supports the MYCN loss-of-function gene-disease relationship.

MIR17HG deletion (Causative)

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"include the MIR17HG gene were found in all three."

Human FS2 report identifies MIR17HG-containing microdeletions in affected patients.

💊

Treatments

5

Surgical repair of gastrointestinal atresia

Action: surgical repair MAXO:0009072

Surgical repair is indicated for esophageal, duodenal, or other intestinal atresia and associated tracheoesophageal fistula when present.

Target Phenotypes: Esophageal atresia ↗

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula"

This supports esophageal atresia/tracheoesophageal fistula as a treatment-relevant complication requiring surgical management.

Supportive multidisciplinary care

Action: supportive care MAXO:0000950

Supportive care includes developmental support, nutrition and growth monitoring, and surveillance for cardiac, endocrine, and other congenital complications.

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"echocardiography at the time of diagnosis in all patients"

Human FS2 report supports surveillance and endocrine evaluation as supportive management.

Echocardiography at diagnosis

Action: echocardiography Ontology label: Echocardiography Test NCIT:C16525

Echocardiography is recommended at diagnosis in Feingold syndrome type 2 to evaluate aortic dilation or congenital cardiac anomalies.

Target Phenotypes: Cardiac anomalies ↗

Show evidence (1 reference)

PMID:30672094 SUPPORT Human Clinical

"echocardiography at the time of diagnosis in all patients"

Human FS2 report specifically recommends echocardiography at diagnosis.

Growth hormone therapy for documented deficiency

Action: hormone modifying therapy MAXO:0000283

Growth hormone therapy may be considered when formal endocrine evaluation documents growth hormone deficiency; evidence is limited to reported FS2 patients rather than controlled trials.

Target Phenotypes: Short stature ↗

Show evidence (1 reference)

PMID:30672094 PARTIAL Human Clinical

"treated successfully with growth hormone."

This is a single-patient report, so it partially supports growth hormone therapy only for documented deficiency in selected FS2 patients.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling supports recurrence-risk assessment and family planning for autosomal dominant Feingold syndrome with variable expressivity.

Show evidence (1 reference)

PMID:35620261 SUPPORT Human Clinical

"dominant manner with full penetrance but with variable expressivity."

Autosomal dominant inheritance and variable expressivity support genetic counseling for affected families.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Feingold Syndrome:

VACTERL association

Overlapping Features VACTERL-spectrum disorders can overlap through esophageal atresia, tracheoesophageal fistula, renal or cardiac anomalies, and limb findings.

Distinguishing Features

Microcephaly with characteristic toe syndactyly and MYCN or MIR17HG alterations favors Feingold syndrome.

Show evidence (1 reference)

PMID:34926353 SUPPORT Human Clinical

"differential diagnosis of Feingold syndrome even in cases"

The familial esophageal atresia report explicitly emphasizes differential diagnosis when Feingold features are subtle.

{ }

Source YAML

click to show

name: Feingold Syndrome
creation_date: "2026-05-11T12:17:17Z"
updated_date: "2026-05-11T13:27:26Z"
category: Mendelian
description: >-
  Feingold syndrome is a rare autosomal dominant congenital malformation
  syndrome characterized by microcephaly, digital skeletal anomalies, growth
  deficiency, variable gastrointestinal atresia, and neurodevelopmental
  involvement. The disorder includes MYCN-related Feingold syndrome type 1 and
  MIR17HG-related Feingold syndrome type 2.
disease_term:
  preferred_term: Feingold syndrome
  term:
    id: MONDO:0015267
    label: Feingold syndrome
parents:
- autosomal dominant disease
- syndromic disease
synonyms:
- Oculo-digito-esophageal-duodenal syndrome
- ODED syndrome
- Microcephaly-digital anomalies-normal intelligence syndrome
- Digital anomalies with short palpebral fissures and atresia of esophagus or duodenum
has_subtypes:
- name: Type 1
  display_name: Feingold syndrome type 1
  subtype_term:
    preferred_term: Feingold syndrome type 1
    term:
      id: MONDO:0008115
      label: Feingold syndrome type 1
  description: >-
    Feingold syndrome type 1 is associated with heterozygous MYCN pathogenic
    variants or deletions and is the more common subtype.
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in haploinsufficiency of MYCN"
    explanation: Human family report states the MYCN haploinsufficiency basis of Feingold syndrome type 1.
- name: Type 2
  display_name: Feingold syndrome type 2
  subtype_term:
    preferred_term: Feingold syndrome type 2
    term:
      id: MONDO:0013691
      label: Feingold syndrome type 2
  description: >-
    Feingold syndrome type 2 is associated with heterozygous MIR17HG deletions
    and clinically overlaps type 1, but gastrointestinal atresia is less
    typical.
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include the MIR17HG gene were found in all three."
    explanation: Human Feingold syndrome 2 report identifies MIR17HG-containing 13q microdeletions in affected patients.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Feingold syndrome is typically inherited as an autosomal dominant trait,
    although de novo pathogenic variants or deletions can occur and expressivity
    is variable.
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant manner with full penetrance but with variable expressivity."
    explanation: Case report abstract supports autosomal dominant inheritance and variable expressivity for FS1.
prevalence:
- population: Literature-reported cases
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feingold syndrome 1 (FS1) is a rare disorder"
    explanation: The report supports rarity, although it does not provide a population incidence estimate.
  notes: >-
    Robust population prevalence estimates were not available in the Falcon
    report. Available literature characterizes FS1 as rare and relies on case
    series rather than population-based ascertainment.
progression:
- phase: Congenital structural disorder
  age_range: Congenital to lifelong
  notes: >-
    Major congenital malformations are present at birth or recognized in
    infancy. Long-term morbidity depends on repaired gastrointestinal
    malformations, growth, neurodevelopment, cardiac findings, and endocrine
    complications.
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of our affected patients showed microcephaly and toe syndactyly"
    explanation: Familial report supports congenital or early-recognized structural manifestations.
pathophysiology:
- name: MYCN haploinsufficiency
  description: >-
    Loss of one functional MYCN allele disrupts MYCN-dependent transcriptional
    regulation during embryonic growth and organogenesis, contributing to the
    type 1 Feingold syndrome phenotype.
  genes:
  - preferred_term: MYCN
    term:
      id: hgnc:7559
      label: MYCN
  biological_processes:
  - preferred_term: transcription by RNA polymerase II
    modifier: DECREASED
    term:
      id: GO:0006366
      label: transcription by RNA polymerase II
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MYCN oncogene encodes a transcription factor belonging to the MYC family."
    explanation: Human report supports MYCN as a transcription-factor gene relevant to Feingold syndrome.
  downstream:
  - target: Impaired embryonic morphogenesis
    description: Reduced MYCN dosage perturbs developmental programs in multiple organ systems.
  - target: Impaired brain and neural development
    description: Reduced MYCN dosage is linked to abnormal brain and neural development, providing a mechanistic route to microcephaly.
- name: Impaired brain and neural development
  description: >-
    MYCN is expressed during normal embryonic development and is described as
    critical in brain and other neural development, linking MYCN
    haploinsufficiency to microcephaly in Feingold syndrome type 1.
  genes:
  - preferred_term: MYCN
    term:
      id: hgnc:7559
      label: MYCN
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "critical in brain and other neural development."
    explanation: Human Feingold syndrome case report links MYCN to brain and neural development, supporting a microcephaly-relevant mechanism.
- name: Reduced PI3K signaling in limb mesenchyme
  description: >-
    Mycn deficiency in mouse limb mesenchymal cells downregulates PI3K signaling,
    providing a model-organism mechanism for the skeletal component of Feingold
    syndrome type 1.
  cell_types:
  - preferred_term: limb mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  biological_processes:
  - preferred_term: phosphatidylinositol-mediated signaling
    modifier: DECREASED
    term:
      id: GO:0048015
      label: phosphatidylinositol-mediated signaling
  evidence:
  - reference: PMID:29636449
    reference_title: Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "upregulates TGF-β signaling, whereas Mycn-deficiency downregulates PI3K"
    explanation: Mouse model abstract directly distinguishes Mycn deficiency as a PI3K-signaling defect in limb mesenchyme.
  downstream:
  - target: Impaired embryonic morphogenesis
    description: Decreased PI3K signaling contributes to skeletal developmental defects.
- name: MIR17HG deletion
  description: >-
    Heterozygous deletion of MIR17HG, which encodes the miR-17-92 microRNA
    cluster host gene, causes Feingold syndrome type 2 through reduced
    microRNA-mediated developmental regulation.
  genes:
  - preferred_term: MIR17HG
    term:
      id: hgnc:23564
      label: MIR17HG
  biological_processes:
  - preferred_term: miRNA-mediated gene silencing
    modifier: DECREASED
    term:
      id: GO:0035195
      label: miRNA-mediated post-transcriptional gene silencing
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include the MIR17HG gene were found in all three."
    explanation: Human Feingold syndrome 2 report supports MIR17HG deletion as the genetic lesion.
  downstream:
  - target: Increased TGF-beta signaling in limb mesenchyme
    description: Reduced miR-17-92 dosage derepresses TGF-beta pathway activity in model systems.
- name: Increased TGF-beta signaling in limb mesenchyme
  description: >-
    Mir17-92 deficiency increases TGF-beta signaling in limb mesenchymal cells;
    rescue by TGF-beta pathway inhibition supports this as a causal skeletal
    mechanism for Feingold syndrome type 2 models.
  cell_types:
  - preferred_term: limb mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:29636449
    reference_title: Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92"
    explanation: Mouse model rescue experiment supports increased TGF-beta signaling as a causal FS2 skeletal mechanism.
  downstream:
  - target: Impaired embryonic morphogenesis
    description: Excess TGF-beta signaling disrupts skeletal developmental programs.
- name: Impaired embryonic morphogenesis
  description: >-
    Developmental regulatory defects produce the craniofacial, limb, growth, and
    gastrointestinal malformation pattern recognized as Feingold syndrome.
  biological_processes:
  - preferred_term: skeletal system development
    modifier: ABNORMAL
    term:
      id: GO:0001501
      label: skeletal system development
  - preferred_term: anatomical structure morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0009653
      label: anatomical structure morphogenesis
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, short stature, and intestinal atresia."
    explanation: Human case report abstract supports the multi-system developmental phenotype.
phenotypes:
- name: Microcephaly
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Congenital or early-onset microcephaly is a core feature in both Feingold syndrome types.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
    explanation: Human FS2 report includes microcephaly among typical Feingold 2 features.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "14/16 (88%)"
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
      explanation: The abstract supports microcephaly as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  description: Growth deficiency and short stature are common in Feingold syndrome, especially in FS2 cohorts.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature, and cardiac anomalies."
    explanation: Human FS2 report includes short stature among typical features.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "13/14 (86%)"
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "short stature, and cardiac anomalies."
      explanation: The abstract supports short stature as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.
- name: Brachydactyly and brachymesophalangy
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Digital malformations include brachymesophalangy, brachydactyly,
    clinodactyly, thumb anomalies, and short middle phalanges.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "common phenotypical features described are finger and toe anomalies,"
    explanation: Human FS1 case report abstract supports finger anomalies as a common feature.
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
    explanation: Human FS2 report supports brachymesophalangy and phalangeal joint findings.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "17/17 (100%)"
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
      explanation: The abstract supports brachymesophalangy as a typical FS2 feature; frequency comes from the Falcon-cited cohort table and is recorded as context.
- name: Toe syndactyly
  category: Musculoskeletal
  frequency: FREQUENT
  description: 2-3 toe syndactyly is a recurrent digital anomaly in both MYCN-related and MIR17HG-related disease.
  phenotype_term:
    preferred_term: 2-3 toe syndactyly
    term:
      id: HP:0004691
      label: 2-3 toe syndactyly
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of our affected patients showed microcephaly and toe syndactyly"
    explanation: Familial MYCN report supports toe syndactyly as a recurrent feature.
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
    explanation: Human FS2 report supports toe syndactyly as a typical feature.
- name: Gastrointestinal atresia
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Esophageal or intestinal atresia can occur, especially in MYCN-related
    Feingold syndrome type 1; esophageal atresia with tracheoesophageal fistula
    has been reported in affected siblings.
  phenotype_term:
    preferred_term: Esophageal atresia
    term:
      id: HP:0002032
      label: Esophageal atresia
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula"
    explanation: Familial MYCN report directly supports esophageal atresia with tracheoesophageal fistula as a Feingold syndrome manifestation.
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, short stature, and intestinal atresia."
    explanation: FS1 case report abstract supports intestinal atresia as a common feature.
- name: Developmental delay or intellectual disability
  category: Neurodevelopmental
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay, learning disability, or intellectual disability can
    occur; the Falcon report highlights particularly high DD/ID frequency in
    FS2 case summaries.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intellectual disability and other organ anomalies are less frequently described."
    explanation: FS1 case report abstract supports intellectual disability as a reported feature.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "16/16 (100%)"
    notes: >-
      Quantitative frequency is from the Muriello 2019 FS2 cohort table as
      summarized in the Falcon report; the abstract provides cache-verifiable
      neurocognitive phenotype support but not the table value itself.
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dilation, phalangeal joint contractures, memory"
      explanation: The abstract supports neurocognitive involvement in FS2; frequency comes from the Falcon-cited Muriello cohort table.
- name: Cardiac anomalies
  category: Cardiovascular
  description: Cardiac anomalies are reported in a subset of patients, especially in FS2 reports.
  phenotype_term:
    preferred_term: Cardiac anomalies
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature, and cardiac anomalies."
    explanation: Human FS2 report supports cardiac anomalies and aortic dilation in the phenotype spectrum.
- name: Aortic dilation
  category: Cardiovascular
  description: Aortic dilation is reported as an expanded Feingold syndrome type 2 feature.
  phenotype_term:
    preferred_term: Aortic dilation
    term:
      id: HP:0004942
      label: Aortic aneurysm
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone deficiency associated with adenohypophyseal compression, aortic"
    explanation: Human FS2 report identifies aortic dilation as a newly reported feature and motivates echocardiographic surveillance.
- name: Growth hormone deficiency
  category: Endocrine
  description: Growth hormone deficiency has been reported in Feingold syndrome type 2.
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone deficiency associated with adenohypophyseal compression, aortic"
    explanation: Human FS2 report identifies growth hormone deficiency as a newly reported feature.
- name: Clinodactyly of the 5th finger
  category: Musculoskeletal
  description: Fifth-finger clinodactyly is a recurrent Feingold syndrome type 2 digital anomaly.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Just one patient exhibited clinodactyly."
    explanation: MYCN family report supports clinodactyly as a Feingold syndrome digital finding.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "9/9 (100%)"
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "phalangeal joint contractures, memory, and sleep problems"
      explanation: The abstract supports phalangeal joint involvement in FS2; frequency comes from the Falcon-cited Muriello cohort table.
- name: Thumb hypoplasia
  category: Musculoskeletal
  frequency: FREQUENT
  description: Thumb hypoplasia occurs in a subset of Feingold syndrome cases.
  phenotype_term:
    preferred_term: Thumb hypoplasia
    term:
      id: HP:0009601
      label: Aplasia/Hypoplasia of the thumb
  evidence:
  - reference: PMID:33442900
    reference_title: "Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brachymesophalangy, hypoplastic thumbs, as well as"
    explanation: FS1 clinical series abstract includes hypoplastic thumbs among typical clinical features.
  phenotype_contexts:
  - subtype: Type 2
    frequency: "4/12 (33%)"
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "to the typical features of microcephaly, brachymesophalangy, toe syndactyly,"
      explanation: The abstract supports FS2 digital anomalies; frequency comes from the Falcon-cited Muriello cohort table.
- name: Short palpebral fissures
  category: Craniofacial
  frequency: FREQUENT
  description: Short or narrow palpebral fissures are part of the Feingold syndrome type 1 craniofacial spectrum.
  phenotype_term:
    preferred_term: Short palpebral fissures
    term:
      id: HP:0045025
      label: Narrow palpebral fissure
  evidence:
  - reference: PMID:33442900
    reference_title: "Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short palpebral"
    explanation: FS1 clinical series abstract lists short palpebral fissures among characteristic clinical features.
  phenotype_contexts:
  - subtype: Type 1
    frequency: "57%"
    notes: >-
      Quantitative frequency is from the Marcelis 2008 FS1 cohort table as
      summarized in the Falcon report; the PubMed abstract verifies the n=77
      cohort provenance but not the table value itself.
    evidence:
    - reference: PMID:18470948
      reference_title: Genotype-phenotype correlations in MYCN-related Feingold syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in a total of 77 patients. We have reviewed the clinical features"
      explanation: Marcelis 2008 provides the n=77 MYCN-related FS1 cohort used in the Falcon report for the 57% short-palpebral-fissure frequency.
      images:
      - Feingold_Syndrome-deep-research-falcon_artifacts/image-1.png
genetic:
- name: MYCN pathogenic variants
  gene_term:
    preferred_term: MYCN
    term:
      id: hgnc:7559
      label: MYCN
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: Type 1
  notes: >-
    Heterozygous MYCN pathogenic variants or deletions cause Feingold syndrome
    type 1. Reported variants include frameshift alleles in families with
    variable expressivity and esophageal atresia.
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in haploinsufficiency of MYCN"
    explanation: Human report supports the MYCN loss-of-function gene-disease relationship.
  variants:
  - name: Heterozygous loss-of-function variants
    description: >-
      Nonsense, frameshift, and other loss-of-function MYCN variants can cause
      Feingold syndrome type 1 through haploinsufficiency.
    evidence:
    - reference: PMID:34926353
      reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "resulting in haploinsufficiency of MYCN"
      explanation: Human report supports loss-of-function MYCN variants acting through haploinsufficiency.
- name: MIR17HG deletion
  gene_term:
    preferred_term: MIR17HG
    term:
      id: hgnc:23564
      label: MIR17HG
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: Type 2
  notes: >-
    Heterozygous MIR17HG deletions cause Feingold syndrome type 2; larger
    deletions can include neighboring genes and may broaden the phenotype.
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include the MIR17HG gene were found in all three."
    explanation: Human FS2 report identifies MIR17HG-containing microdeletions in affected patients.
  variants:
  - name: Heterozygous 13q microdeletions involving MIR17HG
    description: >-
      Copy-number losses that include MIR17HG cause Feingold syndrome type 2.
    evidence:
    - reference: PMID:30672094
      reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "include the MIR17HG gene were found in all three."
      explanation: Human FS2 report supports heterozygous microdeletions involving MIR17HG.
diagnosis:
- name: Clinical recognition and molecular testing
  description: >-
    Diagnosis is based on recognition of microcephaly, digital anomalies,
    growth deficiency, and gastrointestinal atresia, followed by molecular
    testing for MYCN sequence/deletion variants and MIR17HG-containing 13q
    deletions. Whole-exome sequencing can identify MYCN variants in familial
    esophageal atresia presentations.
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NGS-based whole-exome sequencing (WES)."
    explanation: Human family report supports WES-based diagnosis in familial esophageal atresia with Feingold features.
differential_diagnoses:
- name: VACTERL association
  description: >-
    VACTERL-spectrum disorders can overlap through esophageal atresia,
    tracheoesophageal fistula, renal or cardiac anomalies, and limb findings.
  distinguishing_features:
  - Microcephaly with characteristic toe syndactyly and MYCN or MIR17HG alterations favors Feingold syndrome.
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "differential diagnosis of Feingold syndrome even in cases"
    explanation: The familial esophageal atresia report explicitly emphasizes differential diagnosis when Feingold features are subtle.
treatments:
- name: Surgical repair of gastrointestinal atresia
  description: >-
    Surgical repair is indicated for esophageal, duodenal, or other intestinal
    atresia and associated tracheoesophageal fistula when present.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: MAXO:0009072
      label: surgical repair
  target_phenotypes:
  - preferred_term: Esophageal atresia
    term:
      id: HP:0002032
      label: Esophageal atresia
  evidence:
  - reference: PMID:34926353
    reference_title: "Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula"
    explanation: This supports esophageal atresia/tracheoesophageal fistula as a treatment-relevant complication requiring surgical management.
- name: Supportive multidisciplinary care
  description: >-
    Supportive care includes developmental support, nutrition and growth
    monitoring, and surveillance for cardiac, endocrine, and other congenital
    complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "echocardiography at the time of diagnosis in all patients"
    explanation: Human FS2 report supports surveillance and endocrine evaluation as supportive management.
- name: Echocardiography at diagnosis
  description: >-
    Echocardiography is recommended at diagnosis in Feingold syndrome type 2 to
    evaluate aortic dilation or congenital cardiac anomalies.
  treatment_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  target_phenotypes:
  - preferred_term: Cardiac anomalies
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "echocardiography at the time of diagnosis in all patients"
    explanation: Human FS2 report specifically recommends echocardiography at diagnosis.
- name: Growth hormone therapy for documented deficiency
  description: >-
    Growth hormone therapy may be considered when formal endocrine evaluation
    documents growth hormone deficiency; evidence is limited to reported FS2
    patients rather than controlled trials.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: MAXO:0000283
      label: hormone modifying therapy
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30672094
    reference_title: "Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "treated successfully with growth hormone."
    explanation: This is a single-patient report, so it partially supports growth hormone therapy only for documented deficiency in selected FS2 patients.
- name: Genetic counseling
  description: >-
    Genetic counseling supports recurrence-risk assessment and family planning
    for autosomal dominant Feingold syndrome with variable expressivity.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:35620261
    reference_title: A new variant of MYCN gene as a cause of Feingold syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant manner with full penetrance but with variable expressivity."
    explanation: Autosomal dominant inheritance and variable expressivity support genetic counseling for affected families.
animal_models:
- species: Mouse
  genotype: Limb mesenchyme conditional Mycn deficiency
  description: >-
    Conditional Mycn deficiency in mouse limb mesenchyme models FS1 skeletal
    pathogenesis through decreased PI3K signaling. The skeletal phenotype is
    partially rescued by Pten heterozygosity but not by TGF-beta inhibition.
  genes:
  - preferred_term: MYCN
    term:
      id: hgnc:7559
      label: MYCN
  associated_phenotypes:
  - Skeletal defects
  - Decreased PI3K signaling in limb mesenchyme
  evidence:
  - reference: PMID:29636449
    reference_title: Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "not by TGF-β inhibition."
    explanation: Mouse model directly supports a Mycn-dependent skeletal phenotype with PI3K/PTEN pathway involvement.
- species: Mouse
  genotype: Limb mesenchyme conditional Mir17-92 deficiency
  description: >-
    Conditional Mir17-92 deficiency in mouse limb mesenchyme models FS2 skeletal
    pathogenesis through increased TGF-beta signaling, with genetic or
    pharmacologic TGF-beta inhibition rescuing skeletal defects.
  genes:
  - preferred_term: MIR17HG
    term:
      id: hgnc:23564
      label: MIR17HG
  associated_phenotypes:
  - Skeletal defects
  - Increased TGF-beta signaling in limb mesenchyme
  evidence:
  - reference: PMID:29636449
    reference_title: Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92"
    explanation: Mouse model rescue experiment directly supports TGF-beta signaling as a model-organism FS2 mechanism.
notes: >-
  Falcon report integration prioritized cache-backed human clinical and mouse
  model evidence. The report's suggested duodenal atresia HPO mapping was not
  used because local OAK lookup showed HP:0002249 is Melena, not duodenal
  atresia.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Feingold Syndrome (Mendelian disorder) — Disease Characteristics Research Report

34 citations

Feingold Syndrome (Mendelian disorder) — Disease Characteristics Research Report

Target disease

Disease name: Feingold syndrome (Feingold syndrome type 1; Feingold syndrome type 2)
Category: Mendelian (autosomal dominant developmental syndrome)
MONDO ID: Not confirmed from retrieved evidence in this tool run (not present in extracted sources).

Executive overview

Feingold syndrome (FS) is an autosomal dominant congenital malformation syndrome defined by microcephaly, characteristic digital anomalies (classically brachymesophalangy of the 2nd and 5th fingers and toe syndactyly), variable learning disability/intellectual disability, and (for many patients) gastrointestinal atresias—especially esophageal and/or duodenal atresia. FS is genetically heterogeneous with two main molecular subtypes: FS1 due to MYCN haploinsufficiency and FS2 due to MIR17HG/miR-17~92 haploinsufficiency; phenotypic overlap is substantial, but GI atresia is a key discriminator favoring FS1. (marcelis2008genotype–phenotypecorrelationsin pages 1-3, nishio2024mycninhuman pages 7-8, nishio2024mycninhuman pages 1-2, grote2015expandingthephenotype pages 1-2)

1. Disease information

1.1 Definition and current understanding

Feingold syndrome (FS) is described as a syndromic microcephaly condition characterized by digital anomalies, microcephaly, and esophageal/duodenal atresia, with variable intellectual disability (cognet2011dissectionofthe pages 1-2).
In a large genotype–phenotype series of MYCN-positive individuals (n=77), the most common features were digital anomalies, microcephaly/small head size, and GI atresia (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34).

1.2 Key identifiers (from retrieved literature)

OMIM disease: 164280 (Feingold syndrome) (cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 1-3, klaniewska2021occurrenceofesophageal pages 1-2)
Orphanet: ORPHA:391641 (klaniewska2021occurrenceofesophageal pages 1-2)
FS2 / Feingold syndrome type 2: MIM 614326 referenced in MIR17HG-deletion reports (low2015tetralogyoffallot pages 1-2)
Causal gene OMIM (FS1): MYCN (MIM 164840) (cognet2011dissectionofthe pages 1-2, samara2026prenataldiagnosisof pages 2-5)

Not found in retrieved evidence: ICD-10/ICD-11 codes, MeSH descriptor, MONDO ID.

1.3 Synonyms / alternative names

“Feingold syndrome”, “Feingold syndrome type 1 (FS1)”, “Feingold syndrome type 2 (FS2)” (samara2026prenataldiagnosisof pages 2-5, nishio2024mycninhuman pages 1-2, low2015tetralogyoffallot pages 1-2).

1.4 Evidence provenance

The information summarized here is derived primarily from aggregated case series and gene-identified cohorts (e.g., MYCN-positive series and locus studies) and secondarily from individual case reports (familial atresia presentations, prenatal diagnosis). (cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 5-6, huynh2023geneticscornerfamiliala pages 1-2)

2. Etiology

2.1 Disease causal factors

Genetic causes (primary): - FS1: heterozygous loss-of-function (LoF) variants or deletions in MYCN leading to haploinsufficiency (nishio2024mycninhuman pages 1-2, samara2026prenataldiagnosisof pages 2-5). - FS2: heterozygous deletions affecting MIR17HG, which encodes the miR-17~92 microRNA cluster, leading to haploinsufficiency (low2015tetralogyoffallot pages 1-2, grote2015expandingthephenotype pages 1-2).

2.2 Risk factors

The main “risk factor” is carrying a pathogenic variant (familial autosomal dominant transmission), as illustrated by multigenerational families with MYCN frameshift variants and recurrent atresias (klaniewska2021occurrenceofesophageal pages 1-2, huynh2023geneticscornerfamiliala pages 1-2).

2.3 Protective factors

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

2.4 Gene–environment interactions

No gene–environment interaction data were identified in the retrieved evidence.

3. Phenotypes

3.1 Core phenotypes (with frequencies where available)

A major quantitative synthesis comes from a cohort of 77 patients with MYCN abnormalities (FS1) (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34).

Key frequencies (FS1, MYCN-positive, n=77): - Brachymesophalangy: 100% (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34) - Toe syndactyly: 97% (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34) - Microcephaly / small head size (OFC <10th percentile): 89–90% (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34) - GI atresia (any): 55% (esophageal 32%; duodenal 31%; multiple atresias 12%) (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34) - Short palpebral fissures: 73% (marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34) - Learning disability / mild-to-moderate intellectual disability: ~50% (marcelis2008genotype–phenotypecorrelationsin pages 5-6) - Renal anomalies: 18% (marcelis2008genotype–phenotypecorrelationsin pages 5-6) - Cardiac anomalies: 15% (marcelis2008genotype–phenotypecorrelationsin pages 5-6)

FS2 phenotype summary (MIR17HG deletions): - A 2015 review/case report stated that by that time 10 individuals with deletions involving MIR17HG had been described, and “those ten all had microcephaly, short stature, brachymesophalangy, and learning disabilities.” (grote2015expandingthephenotype pages 1-2) - FS2 is often described as overlapping with FS1 but generally lacking GI atresia (grote2015expandingthephenotype pages 1-2, grote2015expandingthephenotype pages 6-7).

3.2 Age of onset and progression

Phenotypes are typically congenital (microcephaly, digital anomalies, GI atresia). In one FS series, postnatal microcephaly was described as becoming constant after early childhood even if head circumference may be near-normal at birth in some (cognet2011dissectionofthe pages 1-2).

3.3 Quality-of-life and functional impact

GI atresias can require urgent neonatal surgery and may drive morbidity (huynh2023geneticscornerfamilial pages 2-4, laymanpleet2007feingoldsyndomea pages 1-3).
Children with repaired esophageal atresia may experience complications such as anastomotic stricture requiring repeated dilations and episodic feeding/swallowing issues, affecting daily functioning (klaniewska2021occurrenceofesophageal pages 1-2).

3.4 HPO term suggestions (non-exhaustive)

Microcephaly (HP:0000252) (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Brachymesophalangy (e.g., HP:0004100 / “Brachymesophalangy of fingers”) (cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 5-6)
2–3 toe syndactyly / 4–5 toe syndactyly (HP:0004691 / HP:0004689 or related toe syndactyly terms) (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Esophageal atresia (HP:0002032) (cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Duodenal atresia (HP:0002249) (marcelis2008genotype–phenotypecorrelationsin pages 5-6, huynh2023geneticscornerfamilial pages 1-2)
Intellectual disability / learning disability (HP:0001249 / HP:0001328) (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Short palpebral fissures (HP:0000584) (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Short stature (HP:0004322) (marcelis2008genotype–phenotypecorrelationsin pages 5-6)

4. Genetic / molecular information

4.1 Causal genes

MYCN (FS1): LoF variants/deletions causing haploinsufficiency (nishio2024mycninhuman pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 1-3).
MIR17HG (FS2): deletions affecting miR-17~92 cluster (low2015tetralogyoffallot pages 1-2, grote2015expandingthephenotype pages 1-2).

4.2 Variant spectrum (FS1)

In the MYCN-related genotype–phenotype analysis, pathogenic variation included premature termination codons/frameshifts and missense variants in the DNA-binding domain; deletions were also observed. (marcelis2008genotype–phenotypecorrelationsin pages 1-3, marcelis2008genotype–phenotypecorrelationsin pages 4-5, marcelis2008genotype–phenotypecorrelationsin pages 5-6)

4.3 Variant classification standards

A recent (2026) MYCN case report explicitly referenced applying ACMG/AMP variant classification with ACGS 2024 refinements (useful as an implementation example for modern labs), but this is outside the user-prioritized 2023–2024 window (torre2026expandingthemycn pages 2-5).

4.4 Allele frequencies / population databases

Specific gnomAD allele frequencies were not extractable from the retrieved evidence.

4.5 Somatic vs germline

FS is a germline developmental disorder; MYCN is also a cancer gene somatically, but FS pathogenesis is described in the retrieved evidence as germline haploinsufficiency (nishio2024mycninhuman pages 1-2).

4.6 Modifier genes / dual diagnoses

Severe or atypical phenotypes may reflect additional genetic diagnoses beyond MYCN; a 2021 series reported one FS1 patient with severe intellectual disability who had an MYCN variant plus a pathogenic GNAO1 variant, suggesting “further genetic testing” in severe cases (tedesco2021clinicalandmolecular pages 1-2).

4.7 Epigenetics / chromosomal abnormalities

Not a primary feature in the retrieved evidence; however, chromosomal microarray detects pathogenic deletions encompassing MYCN (2p24.3) or MIR17HG (13q31.3) (samara2026prenataldiagnosisof pages 2-5, low2015tetralogyoffallot pages 1-2).

5. Environmental information

No specific environmental, lifestyle, or infectious contributors were identified in the retrieved evidence, consistent with FS being a primarily genetic disorder.

6. Mechanism / pathophysiology

6.1 High-level causal chain (current model)

FS1 (MYCN haploinsufficiency): reduced MYCN transcription-factor dosage perturbs embryonic proliferation/differentiation programs in developing brain and limb and may contribute to foregut/midgut developmental anomalies, yielding microcephaly, digital anomalies, and GI atresias (nishio2024mycninhuman pages 1-2, lim2023transcriptionfactorsin pages 10-11).

FS2 (miR-17~92 haploinsufficiency): reduced MIR17HG/miR-17~92 dosage disrupts developmental gene regulation in skeletal and growth pathways, producing overlapping skeletal/growth phenotypes (low2015tetralogyoffallot pages 1-2, grote2015expandingthephenotype pages 1-2).

6.2 Molecular pathways and cell processes (with model-system evidence)

A 2024 mechanistic review synthesized evidence that MYCN regulates miR-17~92 and that FS1 and FS2 can be mechanistically distinct despite overlap: - “the expression of miR-17-92 … is controlled with transcriptional regulation by MYCN” (nishio2024mycninhuman pages 7-8). - In limb mesenchymal cells, Mir17-92 deficiency leads to upregulation of TGF-β signaling, whereas Mycn deficiency induces downregulation of PI3K signaling; these differences explain differential rescue responses (nishio2024mycninhuman pages 7-8).

Neurodevelopmental mechanisms (mouse/functional evidence, summarized in a 2023 review of microcephaly transcription factors): - Conditional MYCN loss in neuronal progenitors shows reduced proliferation and increased differentiation signatures; the review quotes: “Pathogenic variants of MYCN are found in ∼70% of the patients with FS1; 60% are point mutations, and 10% are chromosomal deletions encompassing the entire MYCN locus.” (lim2023transcriptionfactorsin pages 10-11)

6.3 GO/CL term suggestions (mechanism anchoring)

GO biological process: regulation of cell proliferation / cell cycle (MYCN targets and CDK inhibitor dysregulation in MYCN loss models are discussed) (nishio2024mycninhuman pages 7-8, lim2023transcriptionfactorsin pages 10-11)
GO biological process: TGF-β receptor signaling pathway (FS2 limb mesenchyme mechanism) (nishio2024mycninhuman pages 7-8)
GO biological process: PI3K signaling (FS1 limb mesenchyme mechanism) (nishio2024mycninhuman pages 7-8)
CL cell types: limb mesenchymal cells (cell type used in mechanism delineation) (nishio2024mycninhuman pages 7-8)

7. Anatomical structures affected

7.1 Organ/system level

Central nervous system: microcephaly/small head size (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Limbs (hands/feet): brachymesophalangy, toe syndactyly, clinodactyly, thumb hypoplasia (marcelis2008genotype–phenotypecorrelationsin pages 5-6)
Gastrointestinal tract: esophageal and duodenal atresia (FS1 particularly) (marcelis2008genotype–phenotypecorrelationsin pages 5-6, huynh2023geneticscornerfamilial pages 1-2)
Cardiorenal: congenital heart and renal anomalies occur in a minority (marcelis2008genotype–phenotypecorrelationsin pages 5-6)

7.2 UBERON term suggestions (non-exhaustive)

Brain (UBERON:0000955) / cerebrum (UBERON:0000956)
Hand (UBERON:0002387), foot (UBERON:0002389), digit (UBERON:0002544)
Esophagus (UBERON:0001043), duodenum (UBERON:0002114)
Heart (UBERON:0000948), kidney (UBERON:0002113)

8. Temporal development

Onset: Congenital; atresias present neonatally; microcephaly and digital anomalies typically present at birth or early infancy (laymanpleet2007feingoldsyndomea pages 1-3, klaniewska2021occurrenceofesophageal pages 1-2).
Course: Lifelong skeletal phenotype; developmental/learning issues may manifest in childhood; GI surgical sequelae may require repeated interventions (e.g., strictures/dilations) (klaniewska2021occurrenceofesophageal pages 1-2).

9. Inheritance and population

9.1 Inheritance pattern

Autosomal dominant with variable expressivity is consistently described (laymanpleet2007feingoldsyndomea pages 1-3, klaniewska2021occurrenceofesophageal pages 1-2).

9.2 Penetrance and expressivity

A surgical case report described FS as “fully penetrant” with variable expressivity (laymanpleet2007feingoldsyndomea pages 1-3). A 2023 genetics-focused case report also summarized penetrance as 100% with variable expression (huynh2023geneticscornerfamilial pages 2-4).

9.3 Epidemiology (prevalence/incidence)

FS1 is described as rare (<1/1,000,000) in one 2023 clinical summary, but population-based prevalence/incidence estimates were not otherwise available in retrieved evidence (huynh2023geneticscornerfamilial pages 2-4).

10. Diagnostics

10.1 Clinical criteria / recognition

One study used clinical ascertainment requiring ≥3 core features (microcephaly; brachymesophalangy of 2nd/5th fingers; toe syndactyly; esophageal atresia) before molecular evaluation of MYCN (cognet2011dissectionofthe pages 1-2).

10.2 Genetic testing strategy (implementation evidence)

Recommended approach supported by retrieved studies: 1) Phenotype-driven suspicion using microcephaly + characteristic digital anomalies ± GI atresia (cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 5-6). 2) MYCN sequencing (Sanger/NGS) plus copy-number assessment (MLPA, targeted locus CGH, or chromosomal microarray) to capture point variants and deletions (marcelis2008genotype–phenotypecorrelationsin pages 1-3, cognet2011dissectionofthe pages 1-2, samara2026prenataldiagnosisof pages 2-5). 3) If MYCN-negative or phenotype severe/atypical, consider broader genomic testing (genome-wide array-CGH; WES) to capture other etiologies or dual diagnoses (cognet2011dissectionofthe pages 1-2, tedesco2021clinicalandmolecular pages 1-2, klaniewska2021occurrenceofesophageal pages 1-2). 4) For suspected FS2, evaluate for 13q31.3 deletions involving MIR17HG by CMA/array-CGH (low2015tetralogyoffallot pages 1-2, grote2015expandingthephenotype pages 1-2).

Prenatal implementation: ultrasound features (microcephaly/clinodactyly) prompted amniocentesis and array-CGH identifying a pathogenic ~342 kb 2p24.3 deletion encompassing MYCN, followed by parental testing confirming inheritance (samara2026prenataldiagnosisof pages 2-5).

10.3 Differential diagnosis

In neonates with EA/TEF, Feingold syndrome is discussed as a syndromic cause distinct from VACTERL association; chromosomal etiologies account for a non-trivial fraction of EA/TEF and should be considered (laymanpleet2007feingoldsyndomea pages 3-3).

11. Outcome / prognosis

Prognosis is heavily influenced by the presence and severity of GI atresia and postoperative complications (klaniewska2021occurrenceofesophageal pages 1-2).
In a Feingold familial EA/TEF report, postoperative course included strictures requiring three dilations and later food impaction, with acceptable growth and good cognitive development by age ~3 in one child (klaniewska2021occurrenceofesophageal pages 1-2).
For the broader (not Feingold-specific) combined EA+DA population, a systematic review found high and variable mortality across historical reports (overall 41% across included series), underscoring the seriousness of combined atresias (miscia2021esophagealatresiaand pages 1-2).

12. Treatment

12.1 Pharmacotherapy

No disease-modifying pharmacotherapy for FS was identified in retrieved evidence.

12.2 Surgical/interventional (real-world implementation)

Duodenal atresia: duodenoduodenostomy is described with initiation of oral feeds by postoperative day 6 and good early weight gain in a familial FS case (huynh2023geneticscornerfamilial pages 1-2).
EA/TEF: thoracoscopic repair and endoscopic dilations for strictures were required in a familial FS case (klaniewska2021occurrenceofesophageal pages 1-2).

12.3 Supportive/rehabilitative

Ongoing developmental and hearing surveillance is recommended in older surgical/genetics discussions due to risk of developmental delay and hearing loss (laymanpleet2007feingoldsyndomea pages 3-3).

12.4 MAXO term suggestions (non-exhaustive)

Surgical repair of esophageal atresia / tracheoesophageal fistula
Surgical repair of duodenal atresia
Endoscopic dilation of esophageal stricture
Genetic counseling

13. Prevention

Primary prevention is not established (genetic condition).
Secondary/tertiary prevention centers on early recognition, prompt surgical correction of atresias, and long-term surveillance for feeding, growth, and developmental complications (laymanpleet2007feingoldsyndomea pages 1-3, klaniewska2021occurrenceofesophageal pages 1-2).
Genetic counseling and cascade testing are key for families due to autosomal dominant inheritance and variable expressivity (huynh2023geneticscornerfamiliala pages 1-2, laymanpleet2007feingoldsyndomea pages 3-3).

14. Other species / natural disease

No naturally occurring non-human Feingold syndrome analogs were identified in the retrieved evidence.

15. Model organisms

Evidence supporting developmental mechanisms derives from animal and cell models summarized in recent reviews: - MYCN loss-of-function models show impaired neural progenitor proliferation and microcephaly-like outcomes (review synthesis) (lim2023transcriptionfactorsin pages 10-11). - In limb mesenchymal cells, mechanistic divergence between FS1 and FS2 is described: miR-17~92 deficiency → TGF-β upregulation; Mycn deficiency → PI3K downregulation (nishio2024mycninhuman pages 7-8). - MYCN is described as transcriptionally regulating miR-17~92 (nishio2024mycninhuman pages 7-8, pontual2011germlinedeletionof pages 3-6).

Key statistics snapshot (with visual evidence)

The table below summarizes FS1 vs FS2 at a glance and consolidates the most useful quantitative phenotype frequencies and molecular-diagnostic estimates.

Subtype	Canonical disease label	Causal gene / locus	Inheritance	Core hallmark phenotypes	Distinguishing features	Key quantitative findings from extracted evidence
FS1	Feingold syndrome type 1	MYCN (2p24.3; OMIM gene 164840)	Autosomal dominant; complete/near-complete penetrance with variable expressivity reported (laymanpleet2007feingoldsyndomea pages 1-3, marcelis2008genotype–phenotypecorrelationsin pages 1-3)	Microcephaly; brachymesophalangy of 2nd/5th fingers; toe syndactyly; short palpebral fissures; short stature; learning disability/intellectual disability; esophageal and/or duodenal atresia (marcelis2008genotype–phenotypecorrelationsin pages 1-3, cognet2011dissectionofthe pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 5-6)	GI atresia is the major clinical discriminator from FS2; MYCN loss-of-function/haploinsufficiency is the established mechanism (samara2026prenataldiagnosisof pages 2-5, nishio2024mycninhuman pages 7-8, nishio2024mycninhuman pages 1-2)	In aggregated MYCN-positive series (n=77): brachymesophalangy 100%, toe syndactyly 97%, OFC <p10 / microcephaly 89–90%, GI atresia 55% (esophageal 32%, duodenal 31%), short palpebral fissures 73%, mild MR/learning disability 51%, renal anomalies 18%, cardiac anomalies 15% (marcelis2008genotype–phenotypecorrelationsin pages 1-3, marcelis2008genotype–phenotypecorrelationsin pages 5-6, marcelis2008genotype–phenotypecorrelationsin media c1476c34). Recent review/case-series estimate pathogenic MYCN variants in ~70% of FS1 patients; ~60% point variants and ~10% deletions (lim2023transcriptionfactorsin pages 10-11, tedesco2021clinicalandmolecular pages 1-2). In one clinically defined FS cohort, MYCN mutation/deletion detection was 47% (7/15 evaluable cases), supporting genetic heterogeneity among clinically suspected patients (cognet2011dissectionofthe pages 1-2).
FS2	Feingold syndrome type 2	MIR17HG / miR-17~92 cluster (13q31.3; OMIM phenotype 614326 referenced)	Autosomal dominant due to heterozygous deletion / haploinsufficiency (low2015tetralogyoffallot pages 1-2, grote2015expandingthephenotype pages 1-2, pontual2011germlinedeletionof pages 3-6)	Overlapping skeletal/growth phenotype with FS1: microcephaly, short stature, brachymesophalangy, clinodactyly/toe syndactyly, learning/neurocognitive issues (grote2015expandingthephenotype pages 1-2, muriello2019growthhormonedeficiency pages 5-6, grote2015expandingthephenotype pages 6-7)	Usually lacks gastrointestinal atresia; some reports expand phenotype to congenital heart disease, hearing loss, growth hormone deficiency, aortic dilation, neurocognitive/psychiatric issues (grote2015expandingthephenotype pages 1-2, muriello2019growthhormonedeficiency pages 5-6, grote2015expandingthephenotype pages 6-7)	Reported literature up to 2015 described 10 individuals with deletions involving MIR17HG; those ten had microcephaly, short stature, brachymesophalangy, and learning disabilities (grote2015expandingthephenotype pages 1-2). Additional cited summary: brachymesophalangia 100% (16/16), short stature 81% (13/16), fifth-finger clinodactyly 68% (11/16) (samara2026prenataldiagnosisof pages 5-6). Cardiac anomalies were reported in 50% of FG2 patients in whom cardiac examination was described in one review of published cases/series (muriello2019growthhormonedeficiency pages 5-6).
Cross-subtype comparison	Feingold syndrome (disease-level summary; OMIM 164280, ORPHA 391641 reported for Feingold syndrome)	FS1 = MYCN; FS2 = MIR17HG	Mendelian, autosomal dominant	Shared syndrome core = microcephaly + characteristic digital anomalies + variable developmental issues; disease-level data come from aggregated case series/case reports rather than EHR-derived datasets (klaniewska2021occurrenceofesophageal pages 1-2, marcelis2008genotype–phenotypecorrelationsin pages 1-3, cognet2011dissectionofthe pages 1-2)	Mechanistically distinct despite phenotypic overlap: MIR17HG/miR-17~92 deficiency upregulates TGF-β signaling, whereas MYCN deficiency downregulates PI3K signaling in limb mesenchymal cells; MYCN also transcriptionally regulates miR-17~92 (nishio2024mycninhuman pages 7-8, pontual2011germlinedeletionof pages 3-6)	Historical/clinical summaries note Feingold syndrome is probably the most frequent single-gene cause of esophageal and duodenal atresia, with esophageal/duodenal atresia in about 1/3 of reported patients in older summaries (laymanpleet2007feingoldsyndomea pages 1-3), whereas larger aggregated MYCN datasets place GI atresia closer to 55% among molecularly confirmed carriers (marcelis2008genotype–phenotypecorrelationsin pages 5-6). More than 120 patients/families with FS1 had been reported in the literature by recent case-series/reviews (klaniewska2021occurrenceofesophageal pages 1-2, tedesco2021clinicalandmolecular pages 1-2).

Table: This table summarizes the core knowledge-base facts for Feingold syndrome, contrasting FS1 and FS2 by causal gene, inheritance, hallmark phenotype pattern, and the most useful quantitative statistics extracted from the cited literature. It is designed for rapid disease-entry curation and genotype-phenotype comparison.

A key primary source for these frequency estimates is the MYCN-positive cohort phenotype table (n=77) (marcelis2008genotype–phenotypecorrelationsin media c1476c34).

Recent developments (2023–2024 prioritized)

Diagnostic yield framing for FS1 (2023): A 2023 review of transcription factors in microcephaly provides a current synthesis that “Pathogenic variants of MYCN are found in ∼70% of the patients with FS1; 60% are point mutations, and 10% are chromosomal deletions encompassing the entire MYCN locus,” supporting modern diagnostic workflows that pair sequence and CNV analysis (lim2023transcriptionfactorsin pages 10-11).
Mechanistic refinement (2024): A 2024 review integrates evidence that MYCN transcriptionally regulates miR-17~92 and argues that FS1 and FS2 have distinct downstream signaling abnormalities (PI3K vs TGF-β) despite shared skeletal phenotypes, highlighting subtype-specific biology that could matter for future targeted therapies (nishio2024mycninhuman pages 7-8).

Limitations of this report (evidence availability)

Many retrieved articles did not include PMIDs in the captured text snippets; therefore, PMID-preferred citations could not always be provided from this run’s evidence.
MONDO/MeSH/ICD identifiers and robust population prevalence/incidence estimates were not present in retrieved sources and are not asserted here.

References

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(huynh2023geneticscornerfamilial pages 1-2): MC Huynh and RD Clark. Genetics corner: familial duodenal atresia due to feingold syndrome. Unknown journal, 2023.
(marcelis2008genotype–phenotypecorrelationsin pages 4-5): Carlo L.M. Marcelis, Frans A. Hol, Gail E. Graham, Paul N.M.A. Rieu, Richard Kellermayer, Rowdy P.P. Meijer, Dorien Lugtenberg, Hans Scheffer, Hans van Bokhoven, Han G. Brunner, and Arjan P.M. de Brouwer. Genotype–phenotype correlations in mycn‐related feingold syndrome. Human Mutation, 29:1125-1132, Sep 2008. URL: https://doi.org/10.1002/humu.20750, doi:10.1002/humu.20750. This article has 105 citations and is from a domain leading peer-reviewed journal.
(torre2026expandingthemycn pages 2-5): Francisco Javier Mérida De la Torre, Javier Porta Pelayo, and Inmaculada Ortiz-Martín. Expanding the mycn variant spectrum in feingold syndrome type 1: a novel n-terminal missense variant segregating in an affected family. Genes, 17:552, May 2026. URL: https://doi.org/10.3390/genes17050552, doi:10.3390/genes17050552. This article has 0 citations.
(tedesco2021clinicalandmolecular pages 1-2): Maria Giovanna Tedesco, Fortunato Lonardo, Caterina Ceccarini, Carla Cesarano, Maria Cristina Digilio, Monia Magliozzi, Daniela Rogaia, Amedea Mencarelli, Chiara Leoni, Carmelo Piscopo, Valentina Imperatore, Maria Teresa Falco, Paolo Fontana, Anna Maria Nardone, Antonio Novelli, Stefania Troiani, Marco Seri, and Paolo Prontera. Clinical and molecular characterizations of 11 new patients with type 1 feingold syndrome: proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype. American Journal of Medical Genetics Part A, 185:1204-1210, Jan 2021. URL: https://doi.org/10.1002/ajmg.a.62068, doi:10.1002/ajmg.a.62068. This article has 9 citations.
(lim2023transcriptionfactorsin pages 10-11): Youngshin Lim. Transcription factors in microcephaly. Frontiers in Neuroscience, Nov 2023. URL: https://doi.org/10.3389/fnins.2023.1302033, doi:10.3389/fnins.2023.1302033. This article has 13 citations and is from a peer-reviewed journal.
(laymanpleet2007feingoldsyndomea pages 3-3): Leah Layman-Pleet, Carl-Christian A. Jackson, Shirley Chou, and Kym M. Boycott. Feingold syndome: a rare but important cause of syndromic tracheoesophageal fistula. Journal of pediatric surgery, 42 9:E1-3, Sep 2007. URL: https://doi.org/10.1016/j.jpedsurg.2007.06.005, doi:10.1016/j.jpedsurg.2007.06.005. This article has 6 citations and is from a peer-reviewed journal.
(miscia2021esophagealatresiaand pages 1-2): Maria Enrica Miscia, Giuseppe Lauriti, Dacia Di Renzo, Angela Riccio, Gabriele Lisi, and Pierluigi Lelli Chiesa. Esophageal atresia and associated duodenal atresia: a cohort study and review of the literature. European Journal of Pediatric Surgery, 31:445-451, Sep 2021. URL: https://doi.org/10.1055/s-0040-1716884, doi:10.1055/s-0040-1716884. This article has 13 citations and is from a peer-reviewed journal.
(pontual2011germlinedeletionof pages 3-6): Loïc de Pontual, Evelyn Yao, Patrick Callier, Laurence Faivre, Valérie Drouin, Sandra Cariou, Arie Van Haeringen, David Geneviève, Alice Goldenberg, Myriam Oufadem, Sylvie Manouvrier, Arnold Munnich, Joana Alves Vidigal, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude, Andrea Ventura, and Jeanne Amiel. Germline deletion of the mir-17∼92 cluster causes skeletal and growth defects in humans. Nature Genetics, 43:1026-1030, Sep 2011. URL: https://doi.org/10.1038/ng.915, doi:10.1038/ng.915. This article has 385 citations and is from a highest quality peer-reviewed journal.
(muriello2019growthhormonedeficiency pages 5-6): Michael Muriello, Alexander Y. Kim, Krista Sondergaard Schatz, Natalie Beck, Meral Gunay‐Aygun, and Julie E. Hoover‐Fong. Growth hormone deficiency, aortic dilation, and neurocognitive issues in feingold syndrome 2. American Journal of Medical Genetics Part A, 179:410-416, Mar 2019. URL: https://doi.org/10.1002/ajmg.a.61037, doi:10.1002/ajmg.a.61037. This article has 16 citations.
(samara2026prenataldiagnosisof pages 5-6): Athina A. Samara, Paraskevas Perros, Antonios Koutras, Michel B. Janho, Emmanuil Manolakos, Nikoletta Daponte, Apostolos C. Ziogas, Antonios Garas, Chara Skentou, and Sotirios Sotiriou. Prenatal diagnosis of a feingold syndrome pregnancy complicated with severe preeclampsia: a report of a challenging case. Genes, 17:54, Jan 2026. URL: https://doi.org/10.3390/genes17010054, doi:10.3390/genes17010054. This article has 0 citations.

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Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Differential Diagnoses

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References & Deep Research

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Feingold Syndrome (Mendelian disorder) — Disease Characteristics Research Report

Target disease

Executive overview

1. Disease information

1.1 Definition and current understanding

1.2 Key identifiers (from retrieved literature)

1.3 Synonyms / alternative names

1.4 Evidence provenance

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotypes (with frequencies where available)

3.2 Age of onset and progression

3.3 Quality-of-life and functional impact

3.4 HPO term suggestions (non-exhaustive)

4. Genetic / molecular information

4.1 Causal genes

4.2 Variant spectrum (FS1)

4.3 Variant classification standards

4.4 Allele frequencies / population databases

4.5 Somatic vs germline

4.6 Modifier genes / dual diagnoses

4.7 Epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 High-level causal chain (current model)

6.2 Molecular pathways and cell processes (with model-system evidence)

6.3 GO/CL term suggestions (mechanism anchoring)

7. Anatomical structures affected

7.1 Organ/system level

7.2 UBERON term suggestions (non-exhaustive)

8. Temporal development

9. Inheritance and population

9.1 Inheritance pattern

9.2 Penetrance and expressivity

9.3 Epidemiology (prevalence/incidence)

10. Diagnostics

10.1 Clinical criteria / recognition

10.2 Genetic testing strategy (implementation evidence)

10.3 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Pharmacotherapy

12.2 Surgical/interventional (real-world implementation)

12.3 Supportive/rehabilitative

12.4 MAXO term suggestions (non-exhaustive)

13. Prevention

14. Other species / natural disease

15. Model organisms

Key statistics snapshot (with visual evidence)

Recent developments (2023–2024 prioritized)

Limitations of this report (evidence availability)

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