Nfia-Related Disorder
Summary
Clinical characteristics.
For the purposes of this chapter, NFIA-related disorder is defined as heterozygous inactivation or disruption of only NFIA without involvement of adjacent or surrounding genes. NFIA-related disorder comprises central nervous system abnormalities (most commonly abnormalities of the corpus callosum) with or without urinary tract defects, such as unilateral or bilateral vesicoureteral reflux and hydronephrosis. Additional features include macrocephaly, seizures, developmental delay and/or cognitive impairment, nonspecific dysmorphic features, ventriculomegaly, and hypotonia, which can exacerbate motor delay and feeding issues in infancy. Rarer features may include strabismus, cutis marmorata, or craniosynostosis of the metopic, lambdoid, or sagittal suture.
Diagnosis/testing.
The diagnosis of NFIA-related disorder is established in a proband by detection of one of the following: a heterozygous intragenic NFIA pathogenic variant; a heterozygous deletion of the 1p31.3 region that includes part or all of NFIA with surrounding genes intact; or a chromosome translocation/other rearrangement with a 1p31.3 breakpoint that disrupts NFIA.
Management.
Treatment of manifestations: Standard treatment of seizure disorder, tethered spinal cord, recurrent urinary tract infections, hydronephrosis, strabismus, craniosynostosis, and developmental delays.
Surveillance: Affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features.
Genetic counseling.
NFIA-related disorder is inherited in an autosomal dominant manner. Each child of an individual with NFIA-related disorder has a 50% chance of inheriting the causative genetic alteration. The proportion of NFIA-related disorder caused by de novo variants is approximately 75%-80%. Prenatal diagnosis for a pregnancy at increased risk is possible if the causative genetic alteration in an affected family member is known.
Diagnosis
NFIA-related disorder is defined here as heterozygous inactivation or disruption of only NFIA; larger, nonrecurrent chromosome 1p32-p31 deletions are discussed in Genetically Related Disorders.
Suggestive Findings
An NFIA-related disorder should be suspected in individuals with the following clinical and radiographic findings.
Clinical features
- Macrocephaly
- Seizures including:
- Generalized tonic-clonic
- Pseudo-seizures
- Nonspecific seizure disorders
- Hypotonia (generalized/neonatal)
- Developmental delay
- Frequent urinary tract infections
- Nonspecific dysmorphic features (see Clinical Characteristics)
- Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata
Radiographic abnormalities
- Brain
- Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum
- Ventriculomegaly (typically non-progressive)
- Hydrocephalus
- Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage
- Urinary tract
- Vesicoureteral reflux
- Hydronephrosis
- Renal cysts
- Spine. Tethered spinal cord
- Skull. Rarely, craniosynostosis, which may involve the metopic, lambdoid, or sagittal sutures
Establishing the Diagnosis
The diagnosis of NFIA-related disorder (defined here as heterozygous inactivation or disruption of only NFIA) is established in a proband by detection of one of the following (see Table 1):
- Heterozygous intragenic NFIA pathogenic variant
- Heterozygous deletion of the 1p31.3 region that includes part or all of NFIA with surrounding genes intact
- Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts NFIA
Note: Molecular testing by CMA or karyotyping may detect a large and/or complex heterozygous rearrangement that inactivates NFIA and one or more (often adjacent) genes. Because individuals with such rearrangements (sometimes termed the chromosome 1p32-p31 deletion syndrome) have additional features, they are not the focus of this GeneReview and are described in Genetically Related Disorders.
Molecular genetic testing approaches can include a combination of chromosomal microarray analysis (CMA), a multigene panel, and exome or genome sequencing:
- If not already performed, CMA may be obtained to detect genome-wide deletions that include NFIA. The ability to determine the size of the deletion depends on the type of microarray used, the density of the probes in the 1p31.3 region, and the size cutoff for reporting. The genomic size of the NFIA locus is 380 kb.
- A multigene panel that includes NFIA and other genes of interest (see Differential Diagnosis) may 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. (3) 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.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes 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.
Karyotype. If clinical suspicion is high and other molecular genetic testing methods have not identified a pathogenic variant involving NFIA, a high-resolution karyotype to detect a balanced chromosomal rearrangement involving the 1p31 region, followed by custom MLPA to confirm deletion of NFIA, or sequencing of the breakpoints to confirm disruption of NFIA, could be considered.
Table 1.
Molecular Genetic Testing Used in NFIA-Related Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| NFIA | Sequence analysis 3 | 5/13 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | See footnotes 7 & 8 | |
| CMA 9 | 5/13 5, 10 | |
| Karyotype 11 | 3/13 12 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.
Iossifov et al [2012], Negishi et al [2015], Revah-Politi et al [2017]
- 5.
The number of probands is 13; some probands have other affected family members. The total number of individuals reported with NFIA-related disorder is 20 (see Revah-Politi et al [2017], Table 2).
- 6.
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.
- 7.
Intragenic deletions that affect one or multiple exons within NFIA but disrupt no other genes have been identified in five probands [Mikhail et al 2011, Rao et al 2014, Nyboe et al 2015, Bayat et al 2017, Hollenbeck et al 2017].
- 8.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
- 9.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use typically cover the 1p31.3 region.
- 10.
Lu et al [2007], Mikhail et al [2011], Rao et al [2014], Nyboe et al [2015], Coci et al [2016], Bayat et al [2017], Hollenbeck et al [2017]
- 11.
Karyotype can detect balanced chromosome rearrangements that are not detectable through chromosomal microarray analysis.
- 12.
Chromosome rearrangements, including translocations and inversions, which disrupt NFIA (in some cases, shown to result in deletions at the breakpoints), have been identified in three probands [Lu et al 2007, Coci et al 2016].
Note: For NFIA somatic variants, see Genetically Related Disorders, Cancer and benign tumors.
Clinical Characteristics
Clinical Description
NFIA-related disorder comprises central nervous system abnormalities (see Suggestive Findings) with or without urinary tract defects. Additional features include macrocephaly, seizures, developmental delay, dysmorphic features (see below), ventriculomegaly, and hypotonia.
Central nervous system (CNS) abnormalities. Abnormalities of the corpus callosum are the most consistent feature of this disorder, present in virtually all affected individuals (all but one published individual to date). These abnormalities can include agenesis of the corpus callosum, hypoplasia of the corpus callosum, or other defects (including dysgenesis of the corpus callosum, agenesis of the rostral part of the corpus callosum, or thin corpus callosum). Other CNS phenotypes that may be present include non-progressive ventriculomegaly, hydrocephalus, Chiari type I malformation, and tethered spinal cord. Less common CNS findings include polymicrogyria and decreased periventricular white matter. There appears to be variable expressivity of the CNS phenotype, with no one affected individual presenting with all of the different features listed here.
Seizures are present in approximately half of reported individuals. The types of seizures range from tonic-clonic seizures [Lu et al 2007] to pseudo-seizures [Revah-Politi et al 2017] to nonspecific seizure disorders [Lu et al 2007, Revah-Politi et al 2017].
Developmental delay, ranging from mild to severe, includes both motor and speech delays. Some affected individuals also have hypotonia, which can exacerbate motor delays and feeding issues (particularly in infancy). Despite early delays, most affected individuals are able to walk and use verbal language to communicate. The oldest reported affected individual was a male age 42 years (father of the proband in Nyboe et al [2015]) who was not reported to have any developmental delays. Of probands with developmental delay, the oldest reported individual was a female age 25 years, who at the time of evaluation was experiencing some cognitive delays and behavioral issues [Mikhail et al 2011]. Behavioral abnormalities reported in affected individuals include autism [Iossifov et al 2012, Revah-Politi et al 2017] and bipolar disorder / depression [Mikhail et al 2011, Revah-Politi et al 2017]. Intellectual disability (which may be mild) has also been reported [Mikhail et al 2011, Coci et al 2016, Hollenbeck et al 2017].
Urinary tract defects described in individuals with NFIA-related disorder most commonly include vesicoureteral reflux and hydronephrosis (which may be unilateral or bilateral); additional phenotypes include pyelonephritis, ureterovesical junction diverticulum, dysplastic kidneys, and renal cysts. Sometimes the defects manifest as recurrent urinary tract infections. Urinary tract defects are present in approximately half of affected individuals [Revah-Politi et al 2017], with reported intrafamilial variation [Nyboe et al 2015, Revah-Politi et al 2017].
Dysmorphic features associated with NFIA-related disorder are typically described as mild and have variable penetrance. Recurrent features include relative macrocephaly, frontal bossing / prominent forehead, low-set ears, and proximally placed first digits [Revah-Politi et al 2017].
Eye abnormalities have been reported in rare instances and include strabismus divergens in two individuals [Coci et al 2016], ptosis in two individuals [Coci et al 2016, Hollenbeck et al 2017], and esotropia in one individual [Hollenbeck et al 2017].
Dermatologic findings. Cutis marmorata has been reported in one individual with an intragenic deletion of NFIA [Rao et al 2014].
Note: Cutis marmorata has been described in multiple individuals with deletions that include NFIA and surrounding genes (see Genetically Related Disorders), suggesting the existence of another rare phenotype associated with NFIA haploinsufficiency.
Craniosynostosis has been seen in a minority of individuals with NFIA pathogenic variants [Rao et al 2014, Nyboe et al 2015]. Types of craniosynostosis reported include metopic, lambdoid, and sagittal.
Prognosis. It is unknown if life span in NF1A-related disorder is abnormal. One reported individual is alive at age 42 years [Nyboe et al 2015], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified to date, with the exception of individuals who have larger, nonrecurrent 1p31.3 deletions that include NFIA and other, often adjacent, genes (see Genetically Related Disorders) [Lu et al 2007, Koehler et al 2010, Chen et al 2011, Ji et al 2014, Labonne et al 2016].
Nomenclature
Early reports that identified deletions affecting NFIA referred to the phenotypic presentation as "chromosome 1p32-p31 deletion syndrome" or "chromosome 1p31 deletion." The identification of intragenic deletions and single-nucleotide variants within NFIA that lead to a similar phenotypic presentation have demonstrated that loss of function of NFIA is responsible for most of the phenotypes associated with the 1p31 deletion.
NFIA-related disorder is referred to as "brain malformations with or without urinary tract defects" (BRMUTD) in OMIM (613735).
Prevalence
NFIA-related disorder is rare, having been described in only 13 families representing 20 affected individuals.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of NFIA-Related Disorder
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/NFIA-related disorder | Distinguishing from NFIA-related disorder | |||
| Sotos syndrome 1 | NSD1 | AD |
|
|
| Acquired macrocephaly w/impaired intellectual development (OMIM 618286) | NFIB | AD |
| No urinary tract defects (in affected individuals reported to date) |
| Malan syndrome 2 (OMIM 614753) | NFIX | AD |
| Individuals w/Malan syndrome generally have an overgrowth phenotype. |
| Joubert syndrome 9 | CC2D2A | AR |
|
|
| Stromme syndrome (OMIM 243605) | CENPF | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance
- 1.
Because Sotos syndrome and Malan syndrome have overlapping features, Sotos syndrome is sometimes referred to as Sotos syndrome 1.
- 2.
Malan syndrome is also referred to as Sotos syndrome 2.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with NFIA-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with NFIA-Related Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Brain MRI | To evaluate for brain anomalies, incl Chiari type I malformation |
| Spinal imaging 1 | To evaluate for tethered cord | |
| EEG | If seizures are suspected; referral to neurologist if EEG is abnormal or if strong suspicion of seizures | |
| Development | Developmental assessment | To incl motor, adaptive, cognitive, & speech/language evaluation |
| Evaluation for early intervention / special education | ||
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | For individuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Gastrointestinal/ Feeding | Consider feeding evaluation for feeding problems related to hypotonia. | 1 reported individual w/NFIA-related disorder was able to tolerate only a soft diet at age 5 yrs but could eat other foods by age 8 yrs. 2 |
| Genitourinary | Renal ultrasound | To detect renal anomalies |
| Consider voiding cystourethrogram. | In those w/suggestive renal ultrasound findings or w/urinary tract infections | |
| Eyes | Ophthalmologic evaluation | For possible strabismus |
| Craniofacial | Consider craniofacial 3D-computed tomographic scanning in those w/abnormal head shape. | Consider referral to craniofacial team if concern for craniosynostosis. |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
| Family support/resources | Use of community or online resources such as Parent to Parent |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
- 1.
The choice of imaging depends on the age of the affected individuals. In infants <3 months of age, spinal ultrasound may be used. In those >3 months of age, typically spinal MRI is required.
- 2.
Shanske et al [2004], Lu et al [2007]
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with NFIA-Related Disorder
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Seizures | Standard treatment w/AEDs by experienced neurologist | Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder. |
| Tethered spinal cord | Standard treatment per neurosurgeon | |
| Developmental delay / intellectual disability | See Developmental Delay / Intellectual Disability Management Issues. | |
| Recurrent urinary tract infections &/or hydronephrosis | Standard treatment per urologist | |
| Strabismus | Standard treatment per ophthalmologist | |
| Craniosynostosis | Standard treatment | Consider referral to a craniofacial team w/experience in treating craniosynostosis. |
AEDs = antiepileptic drugs
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); 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. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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.
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. If feeding difficulty is present, particularly in infancy, referral to an occupational or speech therapist for evaluation and treatment, including feeding therapy, is recommended. At least one individual with NFIA-related disorder has been reported with a history of feeding issues [Shanske et al 2004, Lu et al 2007].
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
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 is 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 ADHD, when necessary.
Surveillance
Following initial evaluation, affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the genetic alteration identified in the proband in order to identify as early as possible those who would benefit from prompt initiation of treatment.
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.