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 and preimplantation genetic testing for a pregnancy at increased risk are possible.

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 (or likely pathogenic) variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic (or likely 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: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous FGFR1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, 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).

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 as a result of 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. Because of 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].

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.

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.

Treatment of Manifestations

Surveillance

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.

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

• Most probands reported to date with FGFR1-related Hartsfield syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo FGFR1 pathogenic variant.
• Molecular genetic testing for the FGFR1 pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Dhamija et al 2014, Shi et al 2016, Courage et al 2019]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If the FGFR1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism has been observed in 3 unrelated families) [Dhamija et al 2014, Shi et al 2016, Courage et al 2019].

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:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• 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

• If both parents are known to be heterozygous for an FGFR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial FGFR1 pathogenic variants.
• The heterozygous sibs of a proband with autosomal recessive FGFR1-related Hartsfield syndrome are expected to be asymptomatic.

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.

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.

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 reduced 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 contain 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].

Revision History

• 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to Genetically Related Disorders
• 2 December 2021 (ha) Comprehensive update posted live
• 3 March 2016 (bp) Review posted live
• 12 November 2015 (rd) Original submission

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