Hartsfield Syndrome (FGFR1-related): Disease Characteristics Research Report

Executive summary

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)

High-value abstract/text quotes supporting key claims

"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.

1. Disease information

1.1 What is the disease?

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)

1.2 Key identifiers

• OMIM: 615465 (Hartsfield syndrome / FGFR1-related Hartsfield syndrome). (gaudioso2025malformationpatternand pages 1-3, courage2019novelsynonymousand pages 1-3)
• Causal gene: FGFR1 (Fibroblast Growth Factor Receptor 1). (harris2022mosaicisminhartsfield pages 1-2)
• MONDO / Orphanet / MeSH / ICD-10/ICD-11: Not retrievable from the currently accessed full-text corpus and therefore should be curated from external disease-ontology resources (OMIM/Orphanet/MONDO browsers) as a data-completeness step.

1.3 Synonyms / alternative names

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)

1.4 Evidence provenance

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)

Identifier/nomenclature table

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.

2. Etiology

2.1 Disease causal factors

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)

2.2 Risk factors

Genetic risk factors

• FGFR1 pathogenic variants (missense, cryptic splice from synonymous variants, and variants across extracellular and kinase domains) are causal. (courage2019novelsynonymousand pages 1-3, gaudioso2025malformationpatternand pages 5-7, palumbo2019anoveldominantnegative pages 2-4)
• Parental mosaicism (germline ± somatic) is an important recurrence risk factor: a 2022 review/case report estimated mosaicism in 3/35 families (~9%), with reports of low-level mosaicism detectable by NGS (e.g., ~3% in saliva; ~23% in sperm). (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2)
• Oligogenic/modifier effects: FGFR1 variation can interact with other pathway genes; an example described in the HPE genetics literature includes combined deleterious variants in FGFR1 and FGF8 contributing to HPE. (hong2016dominantnegativekinasedomain pages 1-2)

Environmental and maternal factors (HPE context)

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)

2.3 Protective factors

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)

2.4 Gene–environment interactions

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)

3. Phenotypes

3.1 Core phenotype and frequencies (molecularly confirmed cohort)

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)

3.2 Expanded phenotypic spectrum (selected examples)

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)

3.3 Onset, progression, and quality-of-life impact

• Onset: Congenital (structural malformations detectable prenatally or neonatally). (harris2022mosaicisminhartsfield pages 2-3, gaudioso2025malformationpatternand pages 5-7)
• Course: Lifelong, with major morbidity driven by HPE severity and complications (feeding/aspiration, seizures, hydrocephalus, spasticity, endocrine dysfunction). General HPE management reviews emphasize multidisciplinary longitudinal care and note improved survival with advances in care. (malta2023holoprosencephalyreviewof pages 11-13)
• QoL impact: Not systematically quantified in disease-specific QoL instruments in the retrieved sources; impact is inferred from neurodevelopmental disability, endocrine disease burden, and surgical/rehabilitation needs. (malta2023holoprosencephalyreviewof pages 11-13, gaudioso2025malformationpatternand pages 5-7)

3.4 HPO term suggestions

A phenotype-to-HPO mapping (including frequency where available) is provided below.

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.

4. Genetic / molecular information

4.1 Causal gene(s)

• FGFR1 is the established causal gene for Hartsfield syndrome in the retrieved evidence base. (harris2022mosaicisminhartsfield pages 1-2, courage2019novelsynonymousand pages 1-3)

4.2 Pathogenic variant spectrum

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:

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.

4.3 Somatic vs germline

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)

4.4 Modifier genes / oligogenicity

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)

4.5 Epigenetics and chromosomal abnormalities

No Hartsfield-specific epigenetic signatures or recurrent chromosomal abnormalities were identified in the retrieved Hartsfield-focused sources.

5. Environmental information

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)

6. Mechanism / pathophysiology

6.1 FGFR1 developmental signaling and the Hartsfield phenotype

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)

6.2 Dominant-negative mechanism and MAPK pathway involvement

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)

6.3 HPE pathway context (2023 understanding)

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)

6.4 Suggested ontology terms (mechanism)

• GO biological process (examples): fibroblast growth factor receptor signaling pathway; MAPK cascade; forebrain development; limb development; embryonic morphogenesis.
• CL (cell types, examples): cranial neural crest cell (relevant to craniofacial development; FGFR1 expression discussed in cranial neural crest-derived mesenchyme). (courage2019novelsynonymousand pages 1-3)
• UBERON (anatomy, examples): forebrain; prosencephalon; limb bud; palate; pituitary gland.

(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.)

7. Anatomical structures affected

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)

8. Temporal development

• Typical onset: Congenital; often detected prenatally (ultrasound/MRI) or at birth due to limb and craniofacial anomalies. (harris2022mosaicisminhartsfield pages 2-3, gaudioso2025malformationpatternand pages 5-7)
• Course: Chronic lifelong; manifestations may evolve (e.g., endocrine status and metabolic/bone health during adulthood reported in long-term follow-up). (kobayashi2020endocrinologicalfeaturesof pages 10-11)

9. Inheritance and population

9.1 Inheritance pattern

• Reported as autosomal dominant or autosomal recessive, with many cases de novo. (gaudioso2025malformationpatternand pages 1-3, gaudioso2025malformationpatternand pages 5-7)
• Parental mosaicism: documented and clinically important; estimated at ~9% (3/35 families) in a 2022 synthesis. (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2)

9.2 Epidemiology

• A 2022 review/case report stated 37 individuals had been described to date (as of publication). (harris2022mosaicisminhartsfield pages 1-2)
• No robust incidence/prevalence estimates were identified in the retrieved sources.

10. Diagnostics

10.1 Clinical recognition

Clinical suspicion is raised by the HPE + ectrodactyly/SHFM ± cleft lip/palate pattern. (courage2019novelsynonymousand pages 1-3, harris2022mosaicisminhartsfield pages 1-2)

10.2 Imaging and specialist evaluation

• Brain MRI to characterize HPE and associated CNS anomalies; EEG when seizures suspected. (gaudioso2025malformationpatternand pages 5-7)
• Endocrine evaluation for pituitary hormone deficiencies (central diabetes insipidus, hypogonadotropic hypogonadism, growth hormone deficiency). (gaudioso2025malformationpatternand pages 5-7, kobayashi2020endocrinologicalfeaturesof pages 10-11)
• Cardiac evaluation (echocardiography suggested in review-based management). (gaudioso2025malformationpatternand pages 5-7)

10.3 Genetic testing strategy

• Next-generation sequencing (WES/targeted panels including FGFR1) is central for diagnosis and for detecting low-level mosaicism; NGS is emphasized as more sensitive than Sanger sequencing for mosaicism. (harris2022mosaicisminhartsfield pages 2-3)
• Parental testing is recommended for recurrence-risk assessment due to nontrivial mosaicism frequency. (harris2022mosaicisminhartsfield pages 2-3, harris2022mosaicisminhartsfield pages 1-2)

10.4 Differential diagnosis

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)

11. Outcome / prognosis

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)

12. Treatment

12.1 Current applications and real-world implementations

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)

12.2 Experimental / trials

A clinical trial search did not identify Hartsfield syndrome-specific interventional trials in the retrieved trial set.

12.3 Suggested MAXO terms (examples; to be mapped to exact IDs externally)

• Genetic counseling; prenatal diagnosis; preimplantation genetic testing (where appropriate).
• Brain MRI; echocardiography.
• Cleft lip/palate repair.
• Management of diabetes insipidus; hormone replacement therapy for hypogonadotropic hypogonadism.
• Physical therapy / occupational therapy.

13. Prevention

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)

14. Other species / natural disease

No naturally occurring veterinary analogue for “Hartsfield syndrome” was identified in the retrieved corpus.

15. Model organisms

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)

Recent developments and latest research (prioritizing 2023–2024)

1. Holoprosencephaly (HPE) 2023 review (Malta et al., Children, Mar 2023; DOI/URL: https://doi.org/10.3390/children10040647) provides updated clinical-management framing for HPE (multidisciplinary care; endocrine monitoring; counseling complexity due to variable expressivity and incomplete penetrance) and explicitly lists FGFR1 as associated with syndromic HPE including Hartsfield syndrome. (malta2023holoprosencephalyreviewof pages 8-9, malta2023holoprosencephalyreviewof pages 11-13)
2. Human genetic evidence for FGFR1 signaling beyond development (2024): Stamou et al., Journal of the Endocrine Society, Jun 2024 (DOI/URL: https://doi.org/10.1210/jendso/bvae118) used a recall-by-genotype design to show that carriers of deleterious FGFR1 variants have measurable alterations in insulin sensitivity/β-cell function, supporting FGFR1 pathway relevance to human metabolic health. While not Hartsfield-specific, this is a notable 2024 expansion of FGFR1 “experiments of nature” into metabolic phenotyping, potentially relevant to long-term care as more Hartsfield patients survive to adulthood. (Note: full-text excerpts for this paper were not successfully extracted into the evidence set here, so disease-specific mechanistic integration should be confirmed directly from the paper.)

Figures/tables (visual corroboration from a 2025 review)

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)

Evidence gaps and curation notes

• Ontology identifiers (MONDO, Orphanet, MeSH, ICD-10/11) were not available from the retrieved sources and should be added using authoritative external resources (OMIM/Orphanet/MONDO).
• Population epidemiology (incidence/prevalence) remains poorly defined; current best quantitative statements are based on reported case counts and family-series synthesis. (harris2022mosaicisminhartsfield pages 1-2)
• Phenotype frequencies are based on small aggregated cohorts; additional registry-scale harmonized phenotyping is needed.

Key references (with dates/URLs as available in retrieved texts)

• Harris E et al. European Journal of Medical Genetics (May 2022). “Mosaicism in Hartsfield syndrome.” https://doi.org/10.1016/j.ejmg.2022.104491 (harris2022mosaicisminhartsfield pages 1-2)
• Hong S et al. Human Molecular Genetics (Feb 2016). “Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.” https://doi.org/10.1093/hmg/ddw064 (hong2016dominantnegativekinasedomain pages 1-2)
• Palumbo P et al. European Journal of Human Genetics (Feb 2019). “A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway.” https://doi.org/10.1038/s41431-019-0350-4 (palumbo2019anoveldominantnegative pages 2-4)
• Courage C et al. American Journal of Medical Genetics Part A (Dec 2019). “Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome.” https://doi.org/10.1002/ajmg.a.61354 (courage2019novelsynonymousand pages 1-3)
• Malta M et al. Children (Mar 2023). “Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management.” https://doi.org/10.3390/children10040647 (malta2023holoprosencephalyreviewof pages 8-9)
• Gaudioso F, Pascolini G. Medical Sciences (Published 22 Dec 2025). “Malformation Pattern and Molecular Findings in the FGFR1-Related Hartsfield Syndrome Phenotype.” https://doi.org/10.3390/medsci14010004 (gaudioso2025malformationpatternand pages 1-3)

References

1. (harris2022mosaicisminhartsfield pages 1-2): Elizabeth Harris, Ruth Richardson, Srinivas Annavarapu, James Tellez, David Butteriss, Therese Hannon, and Miranda Splitt. Mosaicism in hartsfield syndrome. European Journal of Medical Genetics, 65:104491, May 2022. URL: https://doi.org/10.1016/j.ejmg.2022.104491, doi:10.1016/j.ejmg.2022.104491. This article has 2 citations and is from a peer-reviewed journal.

2. (harris2022mosaicisminhartsfield pages 2-3): Elizabeth Harris, Ruth Richardson, Srinivas Annavarapu, James Tellez, David Butteriss, Therese Hannon, and Miranda Splitt. Mosaicism in hartsfield syndrome. European Journal of Medical Genetics, 65:104491, May 2022. URL: https://doi.org/10.1016/j.ejmg.2022.104491, doi:10.1016/j.ejmg.2022.104491. This article has 2 citations and is from a peer-reviewed journal.

3. (hong2016dominantnegativekinasedomain pages 1-2): Sungkook Hong, Ping Hu, Juliana Marino, Sophia B. Hufnagel, Robert J. Hopkin, Alma Toromanović, Antonio Richieri-Costa, Lucilene A. Ribeiro-Bicudo, Paul Kruszka, Erich Roessler, and Maximilian Muenke. Dominant-negative kinase domain mutations in fgfr1 can explain the clinical severity of hartsfield syndrome. Human molecular genetics, 25 10:1912-1922, Feb 2016. URL: https://doi.org/10.1093/hmg/ddw064, doi:10.1093/hmg/ddw064. This article has 59 citations and is from a domain leading peer-reviewed journal.

4. (palumbo2019anoveldominantnegative pages 2-4): Pietro Palumbo, Antonio Petracca, Roberto Maggi, Tommaso Biagini, Grazia Nardella, Michele Carmine Sacco, Elia Di Schiavi, Massimo Carella, Lucia Micale, and Marco Castori. A novel dominant-negative fgfr1 variant causes hartsfield syndrome by deregulating ras/erk1/2 pathway. European Journal of Human Genetics, 27:1113-1120, Feb 2019. URL: https://doi.org/10.1038/s41431-019-0350-4, doi:10.1038/s41431-019-0350-4. This article has 25 citations and is from a domain leading peer-reviewed journal.

5. (courage2019novelsynonymousand pages 1-3): Carolina Courage, Christopher B. Jackson, Marta Owczarek‐Lipska, Aleksander Jamsheer, Anna Sowińska‐Seidler, Małgorzata Piotrowicz, Lucjusz Jakubowski, Fanny Dallèves, Erik Riesch, John Neidhardt, and Johannes R. Lemke. Novel synonymous and missense variants in fgfr1 causing hartsfield syndrome. American Journal of Medical Genetics Part A, 179:2447-2453, Dec 2019. URL: https://doi.org/10.1002/ajmg.a.61354, doi:10.1002/ajmg.a.61354. This article has 22 citations.

6. (harris2022mosaicisminhartsfield pages 3-4): Elizabeth Harris, Ruth Richardson, Srinivas Annavarapu, James Tellez, David Butteriss, Therese Hannon, and Miranda Splitt. Mosaicism in hartsfield syndrome. European Journal of Medical Genetics, 65:104491, May 2022. URL: https://doi.org/10.1016/j.ejmg.2022.104491, doi:10.1016/j.ejmg.2022.104491. This article has 2 citations and is from a peer-reviewed journal.

7. (gaudioso2025malformationpatternand pages 5-7): Federica Gaudioso and Giulia Pascolini. Malformation pattern and molecular findings in the fgfr1-related hartsfield syndrome phenotype. Medical Sciences, 14:4, Dec 2025. URL: https://doi.org/10.3390/medsci14010004, doi:10.3390/medsci14010004. This article has 0 citations.

8. (gaudioso2025malformationpatternand pages 1-3): Federica Gaudioso and Giulia Pascolini. Malformation pattern and molecular findings in the fgfr1-related hartsfield syndrome phenotype. Medical Sciences, 14:4, Dec 2025. URL: https://doi.org/10.3390/medsci14010004, doi:10.3390/medsci14010004. This article has 0 citations.

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