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FGFR1-Related Hartsfield Syndrome

, MD, FAAP and , MD.

Author Information

Initial Posting: ; Last Update: December 2, 2021.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder.

  • HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction), feeding problems, and endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common.
  • 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 (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Diabetes insipidus may require treatment with desmopressin; temperature dysregulation can be managed by modifying the environment; disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, use of melatonin or other sleep aids such as clonidine. Medically refractory epilepsy typically requires multiple anti-seizure medications. Developmental delay is managed with an emphasis on early intervention and an individualized education plan and therapies as needed. Spasticity can be treated with physical and occupational therapy and bracing, as well as muscle relaxants (when moderate or severe). Some children may require a gastrostomy and/or tracheostomy for feeding issues. Cleft lip/palate surgical repair is performed under the direction of a craniofacial team. Hand and foot malformations are managed with therapy and adaptive devices; surgery may be needed to improve dexterity.

Genetic counseling.

FGFR1-related Hartsfield syndrome is typically an autosomal dominant (AD) disorder. In two families reported to date, FGFR1-related Hartsfield syndrome was inherited in an autosomal recessive (AR) manner.

  • AD inheritance. Most probands have a de novo FGFR1 pathogenic variant. Germline mosaicism has been observed in three unrelated families.
  • AR inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible.

Diagnosis

Suggestive Findings

FGFR1-related Hartsfield syndrome should be suspected in individuals with the following two core features:

  • Holoprosencephaly (HPE) spectrum disorder. The spectrum results from failed or incomplete forebrain division early in gestation and includes brain malformations such as alobar, semilobar, or lobar HPE, corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Facial malformations such as hypotelorism, cleft lip and palate (either median or bilateral), ocular malformations, and microcephaly are common.
  • Ectrodactyly spectrum disorder. These unilateral or bilateral malformations of the hands and/or feet are characterized by a median cleft of hand or foot due to absence of longitudinal central rays (also called split-hand/foot malformation). The number of digits on the right and left hand/foot can vary. Polydactyly and syndactyly can be part of the spectrum.

Establishing the Diagnosis

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) [Simonis et al 2013, Dhamija et al 2014] identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous FGFR1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of FGFR1-related Hartsfield syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of FGFR1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.

A multigene panel that includes FGFR1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in FGFR1-Related Hartsfield Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
FGFR1 Sequence analysis 335/35 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

FGFR1-related Hartsfield syndrome is characterized by findings of the holoprosencephaly (HPE) spectrum in combination with findings of the ectrodactyly spectrum.

To date, 35 individuals with FGFR1-related Hartsfield syndrome have been identified [Metwalley Kalil & Fargalley 2012, Simonis et al 2013, Dhamija et al 2014, Hong et al 2016, Shi et al 2016, Takagi et al 2016, Lansdon et al 2017, Oliver et al 2017, Courage et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

HPE spectrum malformations include alobar, semilobar, or lobar holoprosencephaly. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues, feeding problems, and endocrine issues are common and detailed later in this section.

Ectrodactyly spectrum malformations 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 (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.

Craniofacial dysmorphism

  • Microcephaly; hypotelorism or hypertelorism; eye anomalies such as microphthalmia and coloboma; malformed, low-set, and posteriorly rotated ears; and cleft lip and or palate (median or bilateral) are common.
  • Craniosynostosis (metopic and coronal) has been reported [Vilain et al 2009].

Neurologic issues

  • Varying degrees of developmental delay can occur.
  • Spasticity is common.
  • Seizures are common and may be difficult to control.
  • Hypothalamic dysfunction, manifesting as temperature dysregulation and erratic sleep patterns, can occur.

Gastrointestinal problems. Feeding difficulties due to axial hypotonia, gastrointestinal reflux, and oromotor dysfunction may be a major problem and result in slow growth.

Respiratory concerns. Aspiration pneumonia can result from poorly coordinated suck and swallow.

Endocrine issues. Due to midline brain defects that involve the pituitary, central endocrine disorders (including growth hormone deficiency, central diabetes insipidus, and hypogonadotropic hypogonadism) are common.

Genitourinary findings. Some males have micropenis, cryptorchidism (due to hypogonadotropic hypogonadism), and hypospadias.

Skeletal anomalies. Other skeletal anomalies include vertebral anomalies and radial and ulnar aplasia.

Cardiovascular malformations are rare but reported [Courage et al 2019].

Phenotype of Autosomal Recessive FGFR1-Related Hartsfield Syndrome

Compared with four individuals with a heterozygous FGFR1 pathogenic variant, the two with biallelic FGFR1 pathogenic variants had a more severe phenotype [Simonis et al 2013]:

  • HPE spectrum
    • Alobar holoprosencephaly (1/2)
    • Diminished cortical thickening (2/2)
    • Absent corpus callosum (2/2)
    • Median cleft (1/2)
    • Hypotelorism (2/2)
    • Severe developmental delay and growth restriction (2/2)
  • Ectrodactyly spectrum. Split-hand/foot malformation of both hands and feet, and fewer than three digits bilaterally (2/2)
  • Death before age five years (2/2)

Nomenclature

In the older literature, FGFR1-related Hartsfield syndrome has been referred to as:

  • Holoprosencephaly and split-hand/foot syndrome;
  • Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES).

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Biallelic pathogenic variants in FGFR1 have been found in two individuals with a more severe Hartsfield syndrome phenotype as compared to those with a heterozygous pathogenic variant [Simonis et al 2013].

Prevalence

Thirty-five individuals with FGFR1-related Hartsfield syndrome have been reported in the literature.

Differential Diagnosis

Holoprosencephaly (HPE). See Holoprosencephaly Overview.

Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) – an autosomal dominant disorder caused by pathogenic variants in TP63 (see TP63-Related Disorders) – is associated with:

  • Limb anomalies in 68%-90% of individuals, with 60% having tetramelic involvement. A cohort of 152 individuals with EEC3 showed split-hand/foot malformation in 68% and syndactyly in 43%.
  • Ectodermal defects. Skin tends to be dry but erosions are not present. Hair changes become more obvious with age and are seen in 60%-80% of individuals. Hair is typically silvery blond, coarse, and dry. Eyebrows and eyelashes are sparse. Nail dysplasia is common. Dental anomalies include malformed teeth and hypodontia.
  • Cleft lip with or without cleft palate, present in 60%-75% and bilateral in half of cases. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate.
  • Absent lacrimal puncta (90% of individuals)
  • Genitourinary malformations (45% of individuals)

Overexpression of ANOS1 (formerly KAL1). One male with hyperosmia, ectrodactyly, genital anomalies, and mild intellectual disability had partial duplication of the X-linked gene ANOS1. ANOS1 protein at high levels may interfere with FGFR1 signaling activity, leading to an overlapping phenotype [Sowińska-Seidler et al 2015].

Microduplication of Xq24. One individual with duplication of Xq24 and a Hartsfield syndrome phenotype has been reported [Takenouchi et al 2012]. This individual was reported prior to the identification of FGFR1 as the causative gene for FGFR1-related Hartsfield syndrome and so did not have molecular genetic testing for a pathogenic variant.

Management

No clinical practice guidelines for FGFR1-related Hartsfield syndrome have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FGFR1-related Hartsfield syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with FGFR1-Related Hartsfield Syndrome

System/ConcernEvaluationComment
Neurologic Brain MRIDetermine type of holoprosencephaly (alobar, semilobar, or lobar).
Neurologic eval
  • Consider EEG if seizures are a concern.
  • Eval for evidence of central diabetes insipidus, temperature dysregulation, &/or disturbance of sleep-wake cycles
Development Developmental assessment incl evidence for spasticity
  • Incl motor, adaptive, cognitive, & speech/language eval
  • Eval for early intervention / special education
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval for evidence of problems that may result from cleft lip/palate &/or oromotor dysfunction
  • Incl eval of aspiration risk & nutritional status
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Cleft lip/palate Referral to craniofacial team
Endocrine Evaluate for evidence of endocrine deficiency (growth hormone deficiency, hypogonadotropic hypogonadism).
Musculoskeletal Orthopedics / physical medicine & rehab / PT/OT evalIncl assessment of:
  • Extent of ectrodactyly
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Neuroimaging for tethered spinal cord if suspicion (rare)
Cardiac Referral to pediatric cardiologist for eval for cardiovascular malformationIncl echocardiogram
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support
& resources
Assess need for:

ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with FGFR1-Related Hartsfield Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
Hypothalamic dysfunction assoc w/holoprosencephaly
  • Central diabetes insipidus may require treatment w/desmopressin.
  • Temperature dysregulation can be managed by modifying environment.
  • Manage disturbance of sleep-wake cycles w/good sleep hygiene & (if needed) use of melatonin or other sleep aids such as clonidine.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Medically refractory epilepsy typically requires multiple ASMs.
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Developmental delay /
Intellectual disability
See Developmental Delay / Intellectual Disability Management Issues.
Spasticity
  • PT, OT, & bracing
  • Muscle relaxants may be used to treat moderate or severe spasticity.
Surgery may be required.
Tethered spinal cord (rare) Surgery may be required.
Feeding issues
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Tracheostomy may be needed to prevent aspiration in some.
Cleft lip/palate Surgical repair under direction of craniofacial team
Hand & foot malformations
  • OT, PT, & adaptive devices
  • Surgery may be needed to improve dexterity.

ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Table 5.

Recommended Surveillance for Individuals with FGFR1-Related Hartsfield Syndrome

System/ConcernEvaluationFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Respiratory Monitor for evidence of aspiration, respiratory insufficiency.
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
Development Monitor developmental progress & educational needs.
Psychiatric/
Behavioral
Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Musculoskeletal Physical medicine, OT/PT assessment of mobility, self-help skills

OT = occupational therapy; PT = physical therapy

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FGFR1-related Hartsfield syndrome is typically an autosomal dominant disorder. In two families reported to date, FGFR1-related Hartsfield syndrome was inherited in an autosomal recessive manner [Simonis et al 2013].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. To date, individuals with FGFR1-related Hartsfield syndrome are not known to reproduce.

Other family members. Given that most probands with autosomal dominant FGFR1-related Hartsfield syndrome reported to date have the disorder as a result of a de novo FGFR1 pathogenic variant or an FGFR1 pathogenic variant inherited from a parent with germline mosaicism, the risk to other family members is presumed to be low.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one FGFR1 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FGFR1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The heterozygous parents of a proband with autosomal recessive FGFR1-related Hartsfield syndrome are expected to be asymptomatic (in 1 of the 2 families with autosomal recessive inheritance reported to date, the heterozygous parents of the proband were asymptomatic; the parents of the other proband with biallelic FGFR1 pathogenic variants were not evaluated [Simonis et al 2013]).

Sibs of a proband

Offspring of a proband. To date, individuals with FGFR1-related Hartsfield syndrome are not known to reproduce.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an FGFR1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FGFR1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for FGFR1-related Hartsfield syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FGFR1-Related Hartsfield Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FGFR1 8p11​.23 Fibroblast growth factor receptor 1 FGFR1 database FGFR1 FGFR1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for FGFR1-Related Hartsfield Syndrome (View All in OMIM)

136350FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
615465HARTSFIELD SYNDROME; HRTFDS

Molecular Pathogenesis

FGFR1 is a member of the receptor tyrosine kinase superfamily. The fibroblast growth factor (FGF) signaling pathway is a major factor in embryonic development. FGFR1 is expressed in cranial neural crest cell-derived mesenchyme and plays an important role during embryogenesis by deregulating cell death at early stages of limb initiation. A full-length representative protein consists of an extracellular region, comprising three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation [Groth & Lardelli 2002, Li et al 2005, Tole et al 2006, Mason 2007]. FGFR1 pathogenic variants perturb RAS/ERK1/2 signaling and indicate that dysregulated autophagy is a contributing mechanism to developmental anomalies in Hartsfield syndrome [Palumbo et al 2019].

Mechanism of disease causation. Loss-of-function variants in FGFR1 are associated with a wide phenotypic spectrum and identical variants may present with a variable phenotype attributable to incomplete penetrance and variable expressivity [Simonis et al 2013]. Hartsfield syndrome can result from loss-of-function variants of FGFR1 [Simonis et al 2013, Dhamija et al 2014]. Some pathogenic variants affecting the tyrosine kinase domain of FGFR1 have been demonstrated to result in dominant-negative effects altering normal signaling in zebrafish [Hong et al 2016].

Cancer and Benign Tumors

Sporadic tumors occurring as single tumors in the absence of any other findings of Hartsfield syndrome may harbor somatic variants and/or copy number changes in FGFR1 that are not present in the germline; thus, predisposition to these tumors is not heritable [Ahmad et al 2012].

Chapter Notes

Revision History

  • 2 December 2021 (ha) Comprehensive update posted live
  • 3 March 2016 (bp) Review posted live
  • 12 November 2015 (rd) Original submission

References

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