Hartsfield Syndrome

Clinical characteristics.

Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorders and ectrodactyly spectrum disorders.

• HPE spectrum disorders, resulting from failed or incomplete forebrain division early in gestation, include alobar, semilobar, or lobar HPE. Other brain malformations observed in persons with Hartsfield syndrome include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Varying degrees of developmental delay are observed. Microcephaly, spasticity, seizures, and feeding difficulties are common. Hypothalamic dysfunction (manifest as temperature dysregulation and erratic sleep patterns) can occur, as well as hypogonadotropic hypogonadism and central insipidus diabetes.
• 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 is established in a proband with the two core features: an HPE spectrum disorder and an ectrodactyly spectrum disorder. It can be confirmed by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance).

Management.

Treatment of manifestations: Medically refractory epilepsy typically requires multiple antiepileptic drugs. Spasticity can be treated with physical and occupational therapy and bracing, as well as muscle relaxants (when moderate or severe). Sometimes surgery may be required. Diabetes insipidus may need 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, with use of melatonin or other sleep aids such as clonidine. Some children may require a gastrostomy and/or a tracheostomy.

Genetic counseling.

Hartsfield syndrome is inherited most commonly in an autosomal dominant (AD) and less commonly in an autosomal recessive (AR) manner.

• AD inheritance: Most probands have a de novo FGFR1 pathogenic variant. Germline mosaicism has been observed in two 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 or preimplantation genetic diagnosis for a pregnancy at increased risk is possible.

Suggestive Findings

Hartsfield syndrome should be suspected in individuals with the following core features:

• Holoprosencephaly (HPE) spectrum disorders. The spectrum results from failed or incomplete forebrain division early in gestation and includes alobar, semilobar, or lobar HPE. Other brain malformations can include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Microcephaly is common.
• Ectrodactyly spectrum disorders. 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.

Additional features that may be present [Imaizumi et al 1998, Abdel-Meguid & Ashour 2001, Keaton et al 2010, Simonis et al 2013]:

• Facial dysmorphism (hypertelorism or hypotelorism)
• Cleft lip and/or palate (midline or bilateral)
• Malformed ears
• Cardiac defects
• Abnormal genitalia (micropenis, cryptorchidism)
• Vertebral anomalies
• Radial or ulnar defects
• Central diabetes insipidus
• Growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus
• Varying degrees of developmental delay, seizures

Establishing the Diagnosis

The diagnosis of Hartsfield syndrome is established clinically in a proband with the two core features of a holoprosencephaly (HPE) spectrum disorder and an ectrodactyly spectrum disorder and can be confirmed on molecular genetic testing by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) (see Table 1) [Simonis et al 2013, Dhamija et al 2014].

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of FGFR1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found [Simonis et al 2013, Dhamija et al 2014].
• A multigene panel that includes FGFR1 and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes FGFR1) fails to confirm a diagnosis in an individual with features of Hartsfield syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Hartsfield syndrome, comprising malformations of the two major groups holoprosencephaly (HPE) spectrum malformations and ectrodactyly spectrum malformations, has been reported to date in fewer than 20 individuals [Keaton et al 2010, Simonis et al 2013]. Among the individuals reported, all but two were males.

Following discovery of the genetic basis of Hartsfield syndrome, the diagnosis has been molecularly confirmed in ten probands: 6/7 reported by Simonis et al [2013], 1/1 reported by Dhamija et al [2014], and 3/3 unreported cases [C Vilain and G Smits, unpublished data].

In addition to HPE spectrum malformations and ectrodactyly spectrum malformations, Hartsfield syndrome may include the following features:

Craniofacial dysmorphism

• Hypotelorism or hypertelorism; malformed, low-set and posteriorly rotated ears; eye anomalies; and cleft lip and or palate (median or bilateral) are common.
• Craniosynostosis (metopic and coronal) has been reported.

Central nervous system

• HPE is associated with varying degrees of developmental delay.
• Spasticity is common.
• Seizures are common, and may be difficult to control.
• Hypothalamic dysfunction, manifest as temperature dysregulation and erratic sleep patterns, can occur.
• Microphthalmia and coloboma have been reported as a part of the HPE spectrum of malformations.
• Tethered cord has been seen in a few patients.

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

Gastrointestinal. Feeding difficulties due to axial hypotonia, gastrointestinal reflux, and oro-motor dysfunction may be a major problem and result in failure to thrive.

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

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

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

Cardiovascular. One individual had coarctation of the aorta.

Nomenclature

In the older literature, Harstfield 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 established among the small number of affected individuals with a molecularly confirmed diagnosis of Hartsfield syndrome reported to date.

FGFR1 pathogenic variants described to date in individuals with Hartsfield syndrome cluster in specific domains of the receptor [Simonis et al 2013; C Vilain and G Smits, unpublished data]:

• A heterozygous pathogenic variant affecting amino acid residues located in the ATP binding pocket of the intracellular tyrosine kinase domain (TKD) is found in most affected individuals with variable phenotypes.
• Biallelic pathogenic variants affecting amino acid residues located in the extracellular ligand binding domain D2 of FGFR1 have been found in two individuals with a severe phenotype.
• A heterozygous pathogenic variant in the intracellular C-terminal loop of the TKD was found in one individual with a mild phenotype.

Prevalence

Hartsfield syndrome is very rare: of the fewer than 20 individuals reported in the medical literature only 13 (from 10 families) have been confirmed to have loss-of-function variants in FGFR1.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Hartsfield syndrome, the following evaluations are recommended:

• Determine the type of holoprosencephaly (alobar, semilobar, or lobar) by neuroimaging, preferably a brain MRI.
• Assess development including evidence of spasticity.
• Evaluate suspicious activity for evidence of seizures.
• Evaluate nutritional status and feeding for evidence of problems that may result from cleft lip/palate and/or oromotor dysfunction and other problems that may result from gastrointestinal involvement (e.g., slow gastric emptying, gastroesophageal reflux, constipation).
• Evaluate for evidence of diabetes insipidus, temperature dysregulation, and/or disturbance of sleep-wake cycles.
• Evaluate for evidence of endocrine deficiency (growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus).
• Consult with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Neurologic. Medically refractory epilepsy typically requires multiple antiepileptic drugs (AEDs).

Spasticity can be treated with physical and occupational therapy and bracing. Muscle relaxants may be used to treat moderate or severe spasticity. Surgery may be required.

Hypothalamic involvement

• Central 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, with use of melatonin or other sleep aids such as clonidine.

Skeletal. Surgery of hand and foot defects can improve dexterity.

Other

• Tethered cord may require surgical intervention.
• Cleft lip and palate: reparative surgery is needed in most.
• Some children may require a gastrostomy and/or tracheostomy.

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.