FOXP1
Characteristics
Characteristics of FOXP1 syndrome vary widely from person to person. Every mutation of the FOXP1 gene can present with unique physical, mental, sensory, medical, and emotional differences. The following clinical characteristics, diagnosis, and clinical descriptions are documented in the FOXP1 Syndrome article in the GeneReviews® [Internet]. More detailed statistics are available in the GeneReviews® [Internet]. To date,[2023] more than 200 individuals have been identified with FOXP1 syndrome.
Clinical Characteristics
FOXP1 syndrome is characterized by:
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Delays in early motor and language milestones,
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Mild-to-severe intellectual deficits,
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Speech and language impairment in all individuals regardless of level of cognitive abilities, and
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Behaviour abnormalities including:
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autism spectrum disorder or autistic features,
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attention-deficit/hyperactivity disorder,
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anxiety,
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repetitive behaviors,
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sleep disturbances, and
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sensory symptoms.
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Other common findings are :
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Oromotor dysfunction (contributing to speech and feeding difficulties),
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Refractive errors,
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Strabismus,
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Cardiac abnormalities,
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Renal abnormalities,
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Cryptorchidism,
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Hypertonia,
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Hearing loss, and
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Epilepsy
Diagnosis
No consensus clinical diagnostic criteria for FOXP1 syndrome have been published.
Suggestive Findings
FOXP1 syndrome should be considered in a proband with the following clinical findings, imaging findings, and family history.
Clinical findings
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Generalized hypotonia of infancy
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Infant feeding issues
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Mild-to-severe intellectual disability
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Speech and language disorder
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Delays in early motor and language milestones
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Behavior abnormalities:
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Attention-deficit/hyperactivity disorder
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Anxiety, combined with other clinical signs
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Autism spectrum disorder or autistic features
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Repetitive behaviors
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Strabismus, refractive errors
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Cryptorchidism
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Congenital abnormalities of the heart and/or kidneys
Facial features. Nonspecific dysmorphic facial features include a prominent forehead, ocular hypertelorism, down-slanting palpebral fissures, ptosis, short nose with a broad tip or base, thick vermilion, frontal hair upsweep, and irregular dentition, usually with wide spacing between the front teeth [Sollis et al 2016, Meerschaut et al 2017, Siper et al 2017, Lozano et al 2021, Trelles et al 2021].
Brain MRI findings. Structural brain abnormalities, observed on brain MRI in approximately half of affected individuals, include dilated lateral ventricles, white matter abnormalities, arachnoid cysts, large cisterna magna, corpus callosum defects, moderate frontal atrophy, cerebellar defects (including atrophy), and Chiari I malformation [Meerschaut et al 2017, Lozano et al 2021].
Family history. Because FOXP1 syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations).
Clinical Description
Developmental delay (DD) and intellectual disability (ID). Common neurologic features include global developmental delay (i.e., language, motor, cognitive) in young children and, with time, mild-to-severe intellectual disability. While intellectual disability is mild to moderate in the majority of individuals, several individuals have borderline to average cognitive functioning. Importantly, even in individuals who do not have intellectual disability, other persistent issues are likely to include learning disabilities, motor problems, and speech and language deficits.
Motor delays. Impairments in both gross and fine motor skills have been identified. Despite motor delays and hypotonia, individuals with FOXP1 syndrome learn to walk (range: age 13-38 months (21.75 ± 5.49); a subset of individuals display gait abnormalities and the majority of individuals display deficits in motor coordination and visual-motor integration. [Trelles et al 2021] Fine motor weakness can affect handwriting and written expression.
Speech deficits. Dysarthria, the most common speech disorder, is a defining feature of FOXP1 syndrome. Apraxic features and phonologic deficits may also co-occur. [Braden et al 2021]
The speech difficulties lead listeners to presume expression of language (vocabulary, grammar) is more affected than understanding, but this is not the case.
Language deficits. While all individuals have language deficits to various degrees, language ability ranges from no words to fluent, complex sentences. While language impairment generally persists beyond early childhood, the majority of individuals do develop some expressive language. While language is typically low for most individuals, expressive language (i.e., the ability to express vocabulary and grammar) is a relative strength compared to receptive language (the understanding of vocabulary and grammar). [Braden et al 2021]
Oromotor dysfunction, likely due to poor motor planning and the presence of hypotonia, can contribute to speech and feeding difficulties. Excessive drooling is present until late childhood in around 30% of individuals [Braden et al 2021].
Autism spectrum disorder and other behavioral issues. Although autistic features occur in the majority of individuals, only about 25% meet DSM-5 criteria for autism spectrum disorder (ASD), based on clinical judgement due to strengths in social reciprocity and nonverbal communication (i.e., gestures, eye contact, facial expression).
Development and maintenance of friendships is an area of particular challenge.
Despite certain social communication strengths, repetitive behaviors, restricted interests, and sensory symptoms are highly prevalent even in those who do not meet DSM-5 criteria for ASD. Specifically, long-standing restricted interests are common and can be all encompassing in their intensity (e.g., collecting objects of interest).
Sensory manifestations are characterized by frequent sensory seeking (finger picking is also common), tactile hyporeactivity (i.e., high pain threshold), and auditory hyperreactvity. Repetitive behaviors and sensory manifestations are present in the majority of individuals with FOXP1 syndrome regardless of the diagnosis of ASD.
Behavioral problems include hyperactivity, attention problems, impulsivity, aggression, anxiety, mood lability, obsessions, and compulsions. Attention-deficit/hyperactivity disorder (ADHD) is present in the majority of individuals, often combined with hyperactivity and inattention.
Aggressive behavior is common, often emerging during early childhood and likely due to low frustration tolerance and communication challenges. In most individuals, hyperactivity and aggressive behavior appear to improve with age.
Motor impairments involve both gross and fine motor skills. Despite motor delays and hypotonia, individuals with FOXP1 syndrome learn to walk; some display gait abnormalities, and the majority display deficits in motor coordination and visual-motor integration. Fine motor weakness can affect handwriting and written expression.
Hypotonia, seen in half of affected individuals, can be either generalized or axial. Some individuals have peripheral hypertonia and axial hypertonia. In the latter instance, movement disorder / gait disturbance can include the presence of spastic contractures. Muscle spasms have also been reported.
Ophthalmologic involvement, common in FOXP1 syndrome, includes refractive errors (hypermetropia and myopia) and strabismus (including esotropia). Central vision loss may be present. Although nystagmus has been reported, no specific information is available on the age of onset or cause. Developmental defects of the iris (coloboma, aniridia) and optic nerve hypoplasia have been reported in single individuals.
Cardiac. Congenital heart defects are present in approximately 25% of individuals [Lozano et al 2021], with rates ranging from 14% [Trelles et al 2021] to 47% in older studies [Meerschaut et al 2017]. Atrial septal defects are most common. Patent ductus arteriosus, patent foramen ovale, and pulmonary stenosis are less common. In individual case reports heart defects included hypoplastic left ventricle with atrioventricular septal defect, hypoplastic left ventricle with mitral valve and aortic valve atresia, atrioventricular septal defect, and pulmonary atresia with a single ventricle in the presence of heterotaxy syndrome.
Feeding difficulties. Some feeding problems may be present at birth (e.g., difficulty latching).
Gastrointestinal problems. Constipation and gastroesophageal reflux disease (GERD), the most commonly reported gastrointestinal problems, are frequently overlooked. GERD that emerged during infancy resolved in some individuals.
Swallowing problems may also result from esophageal achalasia, resulting from failure of the lower esophageal sphincter to relax after swallowing [Myers et al 2017].
Hearing impairment. Although reported occasionally, little is known about the specific type of loss (e.g., sensorineural vs conductive). Twelve percent of individuals had frequent ear infections.
Epilepsy. The semiology of seizures in FOXP1 syndrome is highly heterogeneous; to date no pattern specific to FOXP1 syndrome has emerged. Likewise, age of onset of seizures is variable. Anecdotally, most affected individuals respond to standard anti-seizure medications; treatment-refractory seizures appear to be rare.
Other associated features
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Gastrointestinal. There are individual reports of gut atresia (no information available on location or length), hepatic and bile duct abnormality (no other details available), esophageal dysmotility, and anal malformation.
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Genital abnormalities in males include cryptorchidism and micropenis. It is unknown if genital abnormalities occur in females.
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CAKUT (congenital anomalies of the kidney and urinary tract) have been reported in ~7% of individuals. Upper and lower urinary tract defects represent the majority of the detected abnormalities, including unilateral renal agenesis, hydronephrosis, and duplicated renal collecting system.
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Incontinence may be present for a longer duration than expected based on cognitive development.
Prognosis. Based on current data, life span is not limited in FOXP1 syndrome [Palumbo et al 2013, Song et al 2015]. Progression of neurologic findings in adulthood has not been described. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with FOXP1 syndrome are underrecognized and underreported.