FGFR1-related Hartsfield syndrome is a rare disorder comprising two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder (split-hand/foot malformation). HPE results from failed or incomplete forebrain division early in gestation, ranging from alobar to lobar forms. Additional features include corpus callosum agenesis, absent olfactory bulbs, craniofacial dysmorphism, seizures, developmental delay, hypothalamic dysfunction, and hypogonadotropic hypogonadism. FGFR1 pathogenic variants act through a dominant-negative mechanism disrupting forebrain patterning and limb development.
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name: Hartsfield Syndrome
creation_date: '2026-04-04T12:00:00Z'
updated_date: '2026-05-09T03:15:56Z'
category: Mendelian
description: >-
FGFR1-related Hartsfield syndrome is a rare disorder comprising two core features:
holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder
(split-hand/foot malformation). HPE results from failed or incomplete forebrain
division early in gestation, ranging from alobar to lobar forms. Additional features
include corpus callosum agenesis, absent olfactory bulbs, craniofacial dysmorphism,
seizures, developmental delay, hypothalamic dysfunction, and hypogonadotropic
hypogonadism. FGFR1 pathogenic variants act through a dominant-negative mechanism
disrupting forebrain patterning and limb development.
disease_term:
preferred_term: Hartsfield-Bixler-Demyer syndrome
term:
id: MONDO:0014196
label: Hartsfield-Bixler-Demyer syndrome
parents:
- FGFR1-related disorder
- Holoprosencephaly spectrum disorder
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
FGFR1-related Hartsfield syndrome is typically autosomal dominant, with most
probands having de novo pathogenic variants. Autosomal recessive inheritance
has been reported in two families. Germline mosaicism has been observed.
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FGFR1-related Hartsfield syndrome is typically an autosomal dominant (AD) disorder."
explanation: GeneReviews confirms autosomal dominant as the typical inheritance pattern.
pathophysiology:
- name: Impaired Forebrain Midline Patterning
description: >-
Pathogenic variants in FGFR1 disrupt signaling in the anterior neural ridge
during early embryogenesis, impairing forebrain midline patterning. This leads
to failed or incomplete division of the prosencephalon (holoprosencephaly),
ranging from alobar to lobar forms, as well as corpus callosum agenesis and
absent olfactory bulbs.
gene:
preferred_term: FGFR1
description: Fibroblast growth factor receptor 1, required for forebrain midline patterning.
term:
id: hgnc:3688
label: FGFR1
biological_processes:
- preferred_term: Forebrain development
term:
id: GO:0030900
label: forebrain development
- preferred_term: FGFR signaling pathway
term:
id: GO:0008543
label: fibroblast growth factor receptor signaling pathway
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder."
explanation: Establishes holoprosencephaly as one of the two core features resulting from FGFR1 disruption.
- name: Impaired Limb Bud Patterning
description: >-
The same FGFR1 pathogenic variants that disrupt forebrain development also
impair signaling in the apical ectodermal ridge during limb bud patterning.
This leads to ectrodactyly (split-hand/foot malformation) due to defective
central ray formation.
gene:
preferred_term: FGFR1
description: Fibroblast growth factor receptor 1, required for apical ectodermal ridge signaling in limb development.
term:
id: hgnc:3688
label: FGFR1
biological_processes:
- preferred_term: Limb morphogenesis
term:
id: GO:0035108
label: limb morphogenesis
- preferred_term: FGFR signaling pathway
term:
id: GO:0008543
label: fibroblast growth factor receptor signaling pathway
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder."
explanation: Establishes ectrodactyly as the second core feature resulting from FGFR1 disruption of limb bud patterning.
phenotypes:
- name: Holoprosencephaly
description: >-
Failed or incomplete forebrain division early in gestation, ranging from alobar
(most severe) to semilobar or lobar forms. Other midline brain malformations
include corpus callosum agenesis, absent septum pellucidum, absent olfactory
bulbs, and vermian hypoplasia.
frequency: OBLIGATE
phenotype_term:
preferred_term: Holoprosencephaly
term:
id: HP:0001360
label: Holoprosencephaly
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE."
explanation: Describes holoprosencephaly as a core feature with variable severity.
- name: Ectrodactyly
description: >-
Unilateral or bilateral malformations of the hands and/or feet characterized
by a median cleft due to absence of central rays (split-hand/foot malformation).
The number of digits can vary between sides.
frequency: OBLIGATE
phenotype_term:
preferred_term: Ectrodactyly
term:
id: HP:0100257
label: Ectrodactyly
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays"
explanation: Describes ectrodactyly as the second core feature.
- name: Agenesis of corpus callosum
description: >-
Absence or underdevelopment of the corpus callosum, a midline brain structure,
consistent with the broader holoprosencephaly spectrum midline defects.
frequency: FREQUENT
phenotype_term:
preferred_term: Agenesis of corpus callosum
term:
id: HP:0001274
label: Agenesis of corpus callosum
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE."
explanation: Corpus callosum agenesis is part of the midline brain malformation spectrum in Hartsfield syndrome.
- name: Seizures
description: Epilepsy, often medically refractory, associated with the holoprosencephaly spectrum.
frequency: FREQUENT
phenotype_term:
preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction)"
explanation: Seizures are listed among the neurologic manifestations.
- name: Global developmental delay
description: Developmental delay associated with the holoprosencephaly spectrum.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction)"
explanation: Developmental delay is listed among neurologic manifestations.
- name: Hypogonadotropic hypogonadism
description: Hypogonadotropic hypogonadism due to hypothalamic dysfunction.
frequency: FREQUENT
phenotype_term:
preferred_term: Hypogonadotropic hypogonadism
term:
id: HP:0000044
label: Hypogonadotropic hypogonadism
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common."
explanation: Hypogonadotropic hypogonadism is documented as a common endocrine feature.
- name: Cleft lip and palate
description: Craniofacial clefting associated with the holoprosencephaly spectrum.
frequency: FREQUENT
phenotype_term:
preferred_term: Cleft lip
term:
id: HP:0410030
label: Cleft lip
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cleft lip/palate surgical repair is performed under the direction of a craniofacial team."
explanation: Cleft lip/palate is noted as requiring surgical management.
genetic:
- name: FGFR1 pathogenic variants
association: Causative
gene_term:
preferred_term: FGFR1
term:
id: hgnc:3688
label: FGFR1
notes: >-
FGFR1 heterozygous pathogenic variants (autosomal dominant) or biallelic
pathogenic variants (autosomal recessive in rare families) cause Hartsfield
syndrome. Most probands have de novo variants. Germline mosaicism has been
observed in three unrelated families.
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of FGFR1-related Hartsfield syndrome is established in a proband with suggestive findings and either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) identified by molecular genetic testing."
explanation: Establishes FGFR1 as the causative gene with both AD and AR patterns.
- reference: CGGV:assertion_ec5034c6-70cb-4ba3-bbb9-f65f6cad393d-2021-03-16T235509.401Z
reference_title: "FGFR1 / Hartsfield-Bixler-Demyer syndrome (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "FGFR1 | HGNC:3688 | Hartsfield-Bixler-Demyer syndrome | MONDO:0014196 | AD | Moderate"
explanation: ClinGen classifies the FGFR1-Hartsfield-Bixler-Demyer syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
treatments:
- name: Anti-seizure medications
description: >-
Medically refractory epilepsy typically requires multiple anti-seizure medications.
treatment_term:
preferred_term: Anti-seizure medication
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Medically refractory epilepsy typically requires multiple anti-seizure medications."
explanation: Confirms need for pharmacological seizure management.
- name: Cleft lip/palate surgical repair
description: Surgical repair under the direction of a craniofacial team.
treatment_term:
preferred_term: Cleft repair surgery
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cleft lip/palate surgical repair is performed under the direction of a craniofacial team."
explanation: Surgical repair of cleft lip/palate is a standard management approach.
- name: Early developmental intervention
description: >-
Emphasis on early intervention with individualized education plan and therapies
for developmental delay, spasticity, and feeding issues.
treatment_term:
preferred_term: Early intervention
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:26937548
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Developmental delay is managed with an emphasis on early intervention and an individualized education plan and therapies as needed."
explanation: Early intervention is recommended for developmental delay management.
references:
- reference: PMID:26937548
title: "FGFR1-Related Hartsfield Syndrome."
tags:
- GeneReviews
findings: []
- reference: DOI:10.1002/ajmg.a.61354
title: Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate.
supporting_text: Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate.
evidence:
- reference: DOI:10.1002/ajmg.a.61354
reference_title: Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate.
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
- reference: DOI:10.1016/j.ejmg.2022.104491
title: Mosaicism in Hartsfield syndrome
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Mosaicism in Hartsfield syndrome
supporting_text: Mosaicism in Hartsfield syndrome
- reference: DOI:10.1038/s41431-019-0350-4
title: A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway
supporting_text: A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway
- reference: DOI:10.1093/hmg/ddw064
title: Dominant-negative kinase domain mutations in<i>FGFR1</i>can explain the clinical severity of Hartsfield syndrome
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Dominant-negative kinase domain mutations in<i>FGFR1</i>can explain the clinical severity of Hartsfield syndrome
supporting_text: Dominant-negative kinase domain mutations in<i>FGFR1</i>can explain the clinical severity of Hartsfield syndrome
- reference: DOI:10.1177/0022034517726496
title: The Use of Variant Maps to Explore Domain-Specific Mutations of <i>FGFR1</i>
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies.
supporting_text: Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies.
evidence:
- reference: DOI:10.1177/0022034517726496
reference_title: The Use of Variant Maps to Explore Domain-Specific Mutations of <i>FGFR1</i>
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies.
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
- reference: DOI:10.1210/jendso/bvaa041
title: Endocrinological Features of Hartsfield Syndrome in an Adult Patient With a Novel Mutation of <i>FGFR1</i>
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: 'Hartsfield syndrome (HS: OMIM 615465) is a rare congenital disease associated with a mutation of the fibroblast growth factor receptor 1 gene (FGFR1) with the main features of holoprosencephaly and ectrodactyly.'
supporting_text: 'Hartsfield syndrome (HS: OMIM 615465) is a rare congenital disease associated with a mutation of the fibroblast growth factor receptor 1 gene (FGFR1) with the main features of holoprosencephaly and ectrodactyly.'
evidence:
- reference: DOI:10.1210/jendso/bvaa041
reference_title: Endocrinological Features of Hartsfield Syndrome in an Adult Patient With a Novel Mutation of <i>FGFR1</i>
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Hartsfield syndrome (HS: OMIM 615465) is a rare congenital disease associated with a mutation of the fibroblast growth factor receptor 1 gene (FGFR1) with the main features of holoprosencephaly and ectrodactyly.'
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
- reference: DOI:10.1210/jendso/bvae118
title: 'Defective FGFR1 Signaling Disrupts Glucose Regulation: Evidence From Humans With <i>FGFR1</i> Mutations'
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Context Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice.
supporting_text: Context Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice.
evidence:
- reference: DOI:10.1210/jendso/bvae118
reference_title: 'Defective FGFR1 Signaling Disrupts Glucose Regulation: Evidence From Humans With <i>FGFR1</i> Mutations'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Context Activation of fibroblast growth factor receptor 1 (FGFR1) signaling improves the metabolic health of animals and humans, while inactivation leads to diabetes in mice.
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
- reference: DOI:10.3390/children10040647
title: 'Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management'
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans.
supporting_text: Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans.
evidence:
- reference: DOI:10.3390/children10040647
reference_title: 'Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans.
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
- reference: DOI:10.3390/medsci14010004
title: Malformation Pattern and Molecular Findings in the FGFR1-Related Hartsfield Syndrome Phenotype
found_in:
- Hartsfield_Syndrome-deep-research-falcon.md
findings:
- statement: The Fibroblast Growth Factor Receptor 1 (FGFR1, MIM*136350) is a protein member of the fibroblast growth factor receptor (FGFR) family, with various biological functions, such as the normal development control.
supporting_text: The Fibroblast Growth Factor Receptor 1 (FGFR1, MIM*136350) is a protein member of the fibroblast growth factor receptor (FGFR) family, with various biological functions, such as the normal development control.
evidence:
- reference: DOI:10.3390/medsci14010004
reference_title: Malformation Pattern and Molecular Findings in the FGFR1-Related Hartsfield Syndrome Phenotype
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The Fibroblast Growth Factor Receptor 1 (FGFR1, MIM*136350) is a protein member of the fibroblast growth factor receptor (FGFR) family, with various biological functions, such as the normal development control.
explanation: Deep research cited this publication as relevant literature for Hartsfield Syndrome.
Hartsfield syndrome is an ultrarare Mendelian multiple-congenital-anomaly syndrome defined by the co-occurrence of holoprosencephaly (HPE) and split-hand/foot malformation (ectrodactyly/SHFM), often with cleft lip and/or palate, caused by pathogenic variants in FGFR1 (OMIM #615465). Core mechanistic evidence supports dominant-negative disruption of FGFR1 signaling for many kinase-domain variants, with downstream RAS/ERK1/2 (MAPK) pathway dysregulation demonstrated for at least one patient-derived variant. Published case counts remain small; a 2022 synthesis noted ~37 described individuals, and importantly identified parental germline ± somatic mosaicism in ~9% (3/35) of reported families, substantially affecting recurrence-risk counseling. (harris2022mosaicisminhartsfield pages 1-2, harris2022mosaicisminhartsfield pages 2-3, hong2016dominantnegativekinasedomain pages 1-2, palumbo2019anoveldominantnegative pages 2-4)
"Heterozygous kinase domain mutations or homozygous extracellular domain mutations in FGFR1 have been reported to cause Hartsfield syndrome (HS), which is characterized by the triad of holoprosencephaly, ectrodactyly and cleft lip/palate." (courage2019novelsynonymousand pages 1-3)
"Hartsfield syndrome is a rare disorder characterised by the co-occurrence of ectrodactyly and holoprosencephaly … family with Hartsfield syndrome due to a novel variant in FGFR1" (harris2022mosaicisminhartsfield pages 1-2)
"Hartsfield syndrome (OMIM #615465) is a rare clinical entity characterized by the triad of holoprosencephaly, ectrodactyly, and variably cleft lip/palate." (courage2019novelsynonymousand pages 1-3)
"A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway" (palumbo2019anoveldominantnegative pages 2-4)
"Experimental modeling suggests Hartsfield results from a dominant-negative FGFR1 effect, distinct from loss-of-function/haploinsufficiency seen in Kallmann/isolated congenital hypogonadotrophic hypogonadism; Palumbo et al. implicate deregulation of the RAS/ERK1/2 pathway." (harris2022mosaicisminhartsfield pages 3-4)
"The authors report that 37 individuals have been described to date and note prior reports of germline mosaicism; they estimate mosaicism (germline or germline plus somatic) in 3 of 35 (9%) reported families" (harris2022mosaicisminhartsfield pages 1-2)
"Literature review in the paper states germline or germline+somatic parental mosaicism has been demonstrated in 3 of 35 reported families (~9%)." (harris2022mosaicisminhartsfield pages 2-3)
Blockquote: This artifact compiles direct supporting quotes defining Hartsfield syndrome, its core triad, and mechanistic and inheritance insights including dominant-negative FGFR1 effects, RAS/ERK1/2 deregulation, and parental mosaicism frequency.
Hartsfield syndrome is a rare developmental disorder characterized by the association of HPE (variable severity, including lobar/semilobar/alobar forms) with ectrodactyly/SHFM, frequently accompanied by orofacial clefting and other multisystem anomalies (neurodevelopmental, endocrine/pituitary, genitourinary, skeletal, ear and cardiac findings). (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3, gaudioso2025malformationpatternand pages 5-7)
Common usage in the literature includes: - FGFR1-related Hartsfield syndrome and HRTFDS (review usage). (gaudioso2025malformationpatternand pages 1-3) - Descriptive phrasing: “association of holoprosencephaly and ectrodactyly”. (harris2022mosaicisminhartsfield pages 3-4, harris2022mosaicisminhartsfield pages 1-2)
Current knowledge is derived largely from case reports/series and review-level aggregation rather than population-scale EHR datasets, limiting robust incidence/prevalence estimates. (gaudioso2025malformationpatternand pages 1-3, harris2022mosaicisminhartsfield pages 1-2)
| Field | Details |
|---|---|
| Disease name | Hartsfield syndrome; FGFR1-related Hartsfield syndrome (gaudioso2025malformationpatternand pages 1-3, courage2019novelsynonymousand pages 1-3) |
| Common synonyms / alternative names | FGFR1-related Hartsfield syndrome; Hartsfield syndrome phenotype; HRTFDS; syndrome of holoprosencephaly and ectrodactyly (descriptive usage in literature) (gaudioso2025malformationpatternand pages 1-3, hong2016dominantnegativekinasedomain pages 1-2) |
| OMIM | OMIM #615465 (gaudioso2025malformationpatternand pages 1-3, courage2019novelsynonymousand pages 1-3) |
| Disease class | Ultrarare Mendelian developmental disorder / multiple congenital anomaly syndrome characterized by forebrain and limb malformations (harris2022mosaicisminhartsfield pages 1-2, palumbo2019anoveldominantnegative pages 2-4) |
| Causal gene | FGFR1 (Fibroblast Growth Factor Receptor 1) (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3) |
| HGNC symbol | FGFR1 (HGNC-approved gene symbol) (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3) |
| Core molecular definition | Disorder caused by pathogenic FGFR1 variants, most often monoallelic/heterozygous, with rarer biallelic cases reported (harris2022mosaicisminhartsfield pages 3-4, harris2022mosaicisminhartsfield pages 1-2) |
| Inheritance notes | Reported as autosomal dominant or autosomal recessive; many cases are de novo; parental germline and/or somatic mosaicism is documented and relevant for recurrence counseling (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7, harris2022mosaicisminhartsfield pages 2-3) |
| De novo occurrence | Many molecularly confirmed cases arise de novo; e.g., specific de novo FGFR1 variants were reported in multiple case reports/series (gaudioso2025malformationpatternand pages 5-7, courage2019novelsynonymousand pages 1-3, palumbo2019anoveldominantnegative pages 2-4) |
| Mosaicism | Parental germline or germline+somatic mosaicism reported in 3 of 35 families (~9%) in the Harris 2022 review/case report, indicating recurrence risk may be higher than assumed for apparently de novo cases (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2) |
| Key defining clinical features | Defining association of holoprosencephaly (HPE) and split-hand/foot malformation (ectrodactyly/SHFM), often with cleft lip/palate; additional common associated anomalies include craniofacial, endocrine, genital, ear, skeletal, cardiac, and neurodevelopmental findings (harris2022mosaicisminhartsfield pages 1-2, gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7) |
| Characteristic triad in many descriptions | Holoprosencephaly + ectrodactyly + cleft lip/palate (variable) (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3) |
| Major systems involved | Central nervous system, craniofacial/oral, limbs/skeleton, endocrine-pituitary, genitourinary, and cardiovascular systems (gaudioso2025malformationpatternand pages 5-7, palumbo2019anoveldominantnegative pages 2-4) |
| Information level | Disease-level information synthesized from published case reports, case series, and reviews rather than EHR-derived population datasets (harris2022mosaicisminhartsfield pages 1-2, gaudioso2025malformationpatternand pages 1-3, courage2019novelsynonymousand pages 1-3) |
Table: This table summarizes the core nomenclature and identifiers for Hartsfield syndrome, including OMIM designation, causal gene, inheritance patterns, and defining clinical features. It is useful as a compact reference for disease knowledge base normalization and curation.
Primary cause: Germline pathogenic variants in FGFR1. Most reported cases are heterozygous (autosomal dominant), often de novo; rarer biallelic/homozygous cases have been reported. (harris2022mosaicisminhartsfield pages 3-4, gaudioso2025malformationpatternand pages 1-3)
Mechanistic classes described in the literature include: - Dominant-negative effects for many kinase-domain variants, experimentally supported in animal models and consistent with the severe syndromic HPE+ectrodactyly phenotype. (hong2016dominantnegativekinasedomain pages 1-2, hong2016dominantnegativekinasedomain pages 7-8) - Loss-of-function/haploinsufficiency as a general mechanism for other FGFR1-related phenotypes (e.g., congenital hypogonadotropic hypogonadism/Kallmann), underscoring allelic heterogeneity across FGFR1 disorders. (harris2022mosaicisminhartsfield pages 3-4, hong2016dominantnegativekinasedomain pages 1-2)
For syndromic and non-syndromic HPE, environmental modifiers (e.g., maternal diabetes, teratogens) and incomplete penetrance/variable expressivity complicate counseling, although these are not Hartsfield-specific risk factors. (malta2023holoprosencephalyreviewof pages 8-9, malta2023holoprosencephalyreviewof pages 11-13)
Hartsfield syndrome is primarily genetic; no Hartsfield-specific protective factors were identified in the retrieved evidence. In the broader HPE literature, periconception folate supplementation and avoidance/optimization of maternal risk factors are discussed as potential modifiers, but are not established as protective specifically for FGFR1-related Hartsfield syndrome. (malta2023holoprosencephalyreviewof pages 8-9)
No direct FGFR1-specific gene–environment interaction data for Hartsfield syndrome were identified in the retrieved primary texts. General HPE literature supports multifactorial/oligogenic models with environmental modifiers affecting penetrance and severity. (malta2023holoprosencephalyreviewof pages 8-9, malta2023holoprosencephalyreviewof pages 11-13)
A 2025 review aggregating 26 molecularly confirmed individuals reported high frequencies for key malformations, including radiologic skeletal defects (100%), penis/testes anomalies (100%), SHFM (92%), HPE (90%), outer ear anomalies (87%), and oral cleft (76%). (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand media d4424630, gaudioso2025malformationpatternand media 39437dcf)
Across case reports/series and reviews, additional recurrent features include: - Neurodevelopmental: variable developmental delay/intellectual disability; corpus callosum anomalies; seizures. (courage2019novelsynonymousand pages 1-3, palumbo2019anoveldominantnegative pages 2-4, gaudioso2025malformationpatternand pages 5-7) - Endocrine/pituitary: central diabetes insipidus; hypogonadotropic hypogonadism/gonadotropin deficiency; growth hormone deficiency is recommended to be evaluated. (courage2019novelsynonymousand pages 1-3, kobayashi2020endocrinologicalfeaturesof pages 10-11, gaudioso2025malformationpatternand pages 5-7) - Cardiac/genitourinary: congenital heart defects and genitourinary anomalies are part of the reported spectrum. (gaudioso2025malformationpatternand pages 5-7, gaudioso2025malformationpatternand pages 1-3)
A phenotype-to-HPO mapping (including frequency where available) is provided below.
| Phenotype / feature | Phenotype type | Approx. frequency in molecularly confirmed FGFR1-related Hartsfield syndrome | Suggested HPO term(s) | Notes | Citation |
|---|---|---|---|---|---|
| Radiologically identified skeletal defects | Physical manifestation / imaging finding | 100% | HP:0000924 Abnormality of the skeletal system | Review cohort frequency from Gaudioso & Pascolini 2025 Table 1; includes additional limb/radiographic anomalies beyond ectrodactyly | (gaudioso2025malformationpatternand pages 1-3) |
| Genital anomalies (penis/testes anomalies) | Physical manifestation | 100% of evaluated males in review | HP:0000046 Abnormality of the genitalia, HP:0000054 Micropenis, HP:0000028 Cryptorchidism | Reported as penis/testes anomalies in review summary; endocrine-genital overlap is common | (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7) |
| Split-hand/foot malformation (ectrodactyly) | Congenital limb malformation | 92% in review table; described as universal/core in syndrome definitions | HP:0001174 Ectrodactyly, HP:0011347 Split hand, HP:0011348 Split foot | Defining feature of the syndrome; some papers describe it as part of the triad/core phenotype | (gaudioso2025malformationpatternand pages 1-3, harris2022mosaicisminhartsfield pages 1-2) |
| Holoprosencephaly | Structural brain malformation | 90% | HP:0001360 Holoprosencephaly | Includes alobar, semilobar, and lobar forms across reports | (gaudioso2025malformationpatternand pages 1-3, harris2022mosaicisminhartsfield pages 1-2) |
| Outer ear anomalies | Physical manifestation | 87% | HP:0000356 Abnormality of the outer ear | Frequently associated craniofacial finding | (gaudioso2025malformationpatternand pages 1-3) |
| Oral cleft / cleft lip-palate | Craniofacial malformation | 76% | HP:0000202 Oral cleft, HP:0000175 Cleft palate, HP:0000204 Cleft upper lip | Variable feature but commonly associated with the core HPE-ectrodactyly phenotype | (gaudioso2025malformationpatternand pages 1-3, courage2019novelsynonymousand pages 1-3) |
| Central diabetes insipidus | Endocrine abnormality | Reported | HP:0000873 Diabetes insipidus | Recurrent endocrine feature; may evolve over time in long-term follow-up | (courage2019novelsynonymousand pages 1-3, kobayashi2020endocrinologicalfeaturesof pages 10-11, gaudioso2025malformationpatternand pages 5-7) |
| Hypogonadotropic hypogonadism / gonadotrophin deficiency | Endocrine abnormality | Reported | HP:0000044 Hypogonadotropic hypogonadism | Reported in multiple FGFR1-related Hartsfield cases and overlaps with broader FGFR1 phenotype spectrum | (courage2019novelsynonymousand pages 1-3, kobayashi2020endocrinologicalfeaturesof pages 10-11, harris2022mosaicisminhartsfield pages 1-2) |
| Developmental delay / intellectual disability | Neurodevelopmental feature | Reported | HP:0001263 Global developmental delay, HP:0001249 Intellectual disability | Severity appears variable across cases | (courage2019novelsynonymousand pages 1-3, gaudioso2025malformationpatternand pages 5-7, palumbo2019anoveldominantnegative pages 2-4) |
| Corpus callosum anomalies / agenesis | Structural brain malformation | Reported | HP:0001274 Agenesis of the corpus callosum | Includes partial or complete agenesis and other commissural anomalies | (harris2022mosaicisminhartsfield pages 1-2, lansdon2017theuseof pages 5-6, palumbo2019anoveldominantnegative pages 2-4) |
| Cardiac malformations | Congenital malformation | Reported | HP:0001627 Abnormality of the cardiovascular system, HP:0001644 Congenital heart defect | Present in a subset of reported patients; echocardiographic assessment is suggested in review-based management recommendations | (gaudioso2025malformationpatternand pages 5-7, gaudioso2025malformationpatternand pages 1-3) |
Table: This table summarizes the core and additional phenotypes reported for FGFR1-related Hartsfield syndrome, combining approximate frequencies from the 2025 review with other recurrent but less-quantified features from primary literature. It is useful for phenotype annotation and HPO mapping in a disease knowledge base.
Across aggregated patients, variants are most commonly missense and cluster in the tyrosine kinase (TK) domain, with additional variants reported in extracellular Ig-like domains (notably IgII/IgIII). (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7, gaudioso2025malformationpatternand media da4675c1)
Representative pathogenic variants reported in primary studies include: - c.1029G>A (p.Ala343Ala) creating a cryptic splice donor site; de novo in two siblings with suspected parental gonadal mosaicism. (courage2019novelsynonymousand pages 1-3) - c.1868A>G (p.Asp623Gly) de novo missense in a sporadic case. (courage2019novelsynonymousand pages 1-3) - p.Ala645Val de novo missense with experimentally supported dominant-negative effect and RAS/ERK1/2 deregulation. (palumbo2019anoveldominantnegative pages 2-4)
A structured variant summary table is provided:
| Variant | Protein change | FGFR1 domain | Reported inheritance/context | Mechanistic note | Evidence citation |
|---|---|---|---|---|---|
| c.1029G>A | p.Ala343Ala | IgIII / extracellular region | De novo heterozygous in 2 affected siblings; likely parental gonadal mosaicism | Synonymous variant creating a cryptic splice donor site in exon 8 | (courage2019novelsynonymousand pages 1-3) |
| c.1868A>G | p.Asp623Gly | Tyrosine kinase (TK) | De novo heterozygous, sporadic case | Missense variant in TK domain; pathogenic FGFR1 variant reported in Hartsfield syndrome | (courage2019novelsynonymousand pages 1-3) |
| c.758A>C | p.His253Pro | IgII / extracellular region | Novel heterozygous case | First reported heterozygous extracellular-domain FGFR1 mutation associated with Hartsfield syndrome | (gaudioso2025malformationpatternand pages 5-7) |
| c.1934C>T | p.Ala645Val | Tyrosine kinase (TK) | De novo heterozygous | Dominant-negative FGFR1 effect with deregulation of the RAS/ERK1/2 pathway | (palumbo2019anoveldominantnegative pages 2-4, harris2022mosaicisminhartsfield pages 3-4) |
| c.1880G>C | p.Arg627Thr | Tyrosine kinase (TK) | Recurrent Hartsfield-associated variant; inheritance pattern not specified in excerpt | Recurrently observed missense change; part of TK-domain clustering of pathogenic variants | (gaudioso2025malformationpatternand pages 5-7) |
| not specified in excerpt | p.Cys277Tyr | IgII / extracellular region | Reported Hartsfield-associated FGFR1 variant; inheritance not specified in excerpt | Missense variant; illustrates extracellular-domain involvement beyond TK domain | (gaudioso2025malformationpatternand pages 5-7) |
| not specified in excerpt | p.Gly487Cys | Tyrosine kinase region | De novo | Structural modeling suggested no major global folding destabilization, but possible abnormal disulfide interactions; discussed as overlapping/Hartsfield-like phenotype evidence | (lansdon2017theuseof pages 5-6) |
| not specified in excerpt | p.Val429E | Tyrosine kinase region | Homozygous; supports possible autosomal recessive disease mechanism in FGFR1-related ectrodactyly/hypogonadotropic hypogonadism spectrum | Loss of FGFR substrate 2α recruitment/phosphorylation and reduced MAPK signaling; relevant to recessive FGFR1 developmental phenotypes overlapping Hartsfield spectrum | (harris2022mosaicisminhartsfield pages 1-2) |
| multiple variants, not all specified in excerpt | — | Predominantly TK; also IgII/IgIII, occasional transmembrane/extracellular | Most cases heterozygous; two homozygous cases reported; both autosomal dominant and autosomal recessive inheritance described | Hartsfield syndrome is thought to result mainly from dominant-negative FGFR1 effects, in contrast to haploinsufficiency/loss-of-function in Kallmann syndrome | (harris2022mosaicisminhartsfield pages 3-4, gaudioso2025malformationpatternand pages 1-3, hong2016dominantnegativekinasedomain pages 1-2) |
| Mosaicism statistic | — | — | Parental germline or germline+somatic mosaicism documented in 3 of 35 reported families (~9%) | Important recurrence-risk consideration; NGS may detect low-level mosaicism missed by Sanger sequencing | (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2) |
Table: This table summarizes representative FGFR1 variants reported in Hartsfield syndrome, including domain location, inheritance context, proposed mechanism, and source citations. It is useful for connecting variant-level evidence to disease mechanism and counseling implications such as parental mosaicism.
Hartsfield syndrome is primarily described as a germline developmental disorder, but parental somatic/gonadal mosaicism is a key mechanism for recurrence. (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2)
Evidence in the HPE genetics literature supports an oligogenic model in some families (e.g., synergistic interaction involving FGFR1 and FGF8 variants). (hong2016dominantnegativekinasedomain pages 1-2)
No Hartsfield-specific epigenetic signatures or recurrent chromosomal abnormalities were identified in the retrieved Hartsfield-focused sources.
No disease-specific environmental causes have been identified for Hartsfield syndrome in the retrieved literature (consistent with a primary monogenic etiology). General HPE literature discusses environmental teratogens and maternal diabetes as modifiers of HPE risk/severity. (malta2023holoprosencephalyreviewof pages 8-9, malta2023holoprosencephalyreviewof pages 11-13)
FGFR1 encodes a cell-surface receptor with extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain; ligand binding induces dimerization and autophosphorylation to activate developmental signaling important for midline forebrain development and limb bud patterning. (harris2022mosaicisminhartsfield pages 1-2)
Dominant-negative kinase-domain variants are supported experimentally. A mechanistic model proposed in functional studies is that ATP-binding-deficient receptor subunits form inactive dimers that block trans-phosphorylation, yielding severe developmental phenotypes. (hong2016dominantnegativekinasedomain pages 7-8)
For at least one patient-derived variant, the literature explicitly links Hartsfield syndrome to RAS/ERK1/2 pathway deregulation (“A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway”). (palumbo2019anoveldominantnegative pages 2-4)
A 2023 HPE review emphasizes that disruption of SHH signaling is a major pathophysiologic mechanism for HPE broadly and that incomplete penetrance/variable expressivity and oligogenic contributions are common, affecting counseling and outcome prediction. (malta2023holoprosencephalyreviewof pages 11-13)
(These ontology suggestions are consistent with the mechanistic roles described in the cited literature; explicit GO/CL/UBERON IDs were not enumerated in the retrieved sources.)
Primary anatomical sites include: - Brain/forebrain midline structures (HPE spectrum; corpus callosum anomalies). (harris2022mosaicisminhartsfield pages 1-2, palumbo2019anoveldominantnegative pages 2-4) - Hands/feet (autopod) (ectrodactyly/SHFM). (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3) - Craniofacial/oral (cleft lip/palate; dental anomalies in some). (courage2019novelsynonymousand pages 1-3, palumbo2019anoveldominantnegative pages 2-4) - Pituitary/hypothalamic axis (diabetes insipidus; hypogonadotropic hypogonadism). (kobayashi2020endocrinologicalfeaturesof pages 10-11, gaudioso2025malformationpatternand pages 5-7) - Genitourinary system (penis/testes anomalies in reviewed cohort). (gaudioso2025malformationpatternand pages 1-3) - Cardiovascular system (subset with congenital heart defects). (gaudioso2025malformationpatternand pages 5-7)
Clinical suspicion is raised by the HPE + ectrodactyly/SHFM ± cleft lip/palate pattern. (courage2019novelsynonymousand pages 1-3, harris2022mosaicisminhartsfield pages 1-2)
Differential diagnoses discussed in Hartsfield-focused reviews include: - TP63-related disorders (e.g., EEC spectrum) and other syndromic ectrodactyly/clefting conditions. - Genoa syndrome (MIM#601370). - ANOS1 duplication (as a differential with overlapping features). (gaudioso2025malformationpatternand pages 5-7)
Outcomes are variable and are heavily influenced by: - Severity of HPE and its complications (feeding difficulties/aspiration, seizures, hydrocephalus, spasticity, neurodevelopmental impairment). - Endocrine dysfunction (diabetes insipidus; hypogonadotropic hypogonadism; potential bone/metabolic impacts).
General HPE management reviews emphasize that although HPE has high mortality and developmental disability burden, improved diagnostic and supportive care has increased survival in some patients. (malta2023holoprosencephalyreviewof pages 11-13)
No disease-specific curative therapy exists in the retrieved evidence; care is supportive and multidisciplinary: - Craniofacial surgery for cleft lip/palate repair (as indicated). - Orthopedic/rehabilitative management for limb malformations. - Neurology/neurosurgery for seizures, hydrocephalus, and neurodevelopmental complications. - Endocrinology for DI and hypogonadotropic hypogonadism management. - Cardiology assessment for congenital heart defects.
A multidisciplinary approach with strong genetic counseling is explicitly emphasized in recent synthesis work. (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7, malta2023holoprosencephalyreviewof pages 11-13)
A clinical trial search did not identify Hartsfield syndrome-specific interventional trials in the retrieved trial set.
Primary prevention is not currently available for monogenic Hartsfield syndrome, but secondary/tertiary prevention focuses on: - Recurrence-risk reduction through genetic counseling and parental mosaicism testing (due to ~9% mosaicism estimate in reported families). (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2) - In the broader HPE context: optimizing maternal health (e.g., pre-gestational diabetes) and avoiding teratogens, which may reduce HPE risk/severity generally (not proven Hartsfield-specific). (malta2023holoprosencephalyreviewof pages 8-9)
No naturally occurring veterinary analogue for “Hartsfield syndrome” was identified in the retrieved corpus.
Functional evidence relevant to Hartsfield syndrome includes: - Zebrafish assays used to test human FGFR1 variants; multiple kinase-domain variants exhibited dominant-negative behavior in overexpression assays, supporting the dominant-negative disease model for severe syndromic HPE with ectrodactyly. (hong2016dominantnegativekinasedomain pages 1-2) - Review-level discussion further notes dominant-negative effects in zebrafish for some Hartsfield-associated variants. (lansdon2017theuseof pages 5-6)
Cropped images from Gaudioso & Pascolini (2025) include Table 1 summarizing clinical-feature frequencies and figures showing FGFR1 domain structure and variant distribution. (gaudioso2025malformationpatternand media d4424630, gaudioso2025malformationpatternand media da4675c1)
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