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.

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.

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.

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 (or likely 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: (1) 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. (2) 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. (3) Identification of a heterozygous NFIA variant of uncertain significance does not establish or rule out the diagnosis.

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 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.

Note: For NFIA somatic variants, see Genetically Related Disorders, Cancer and benign tumors.

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.

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.

Treatment of Manifestations

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.

Mode of Inheritance

NFIA-related disorder is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with NFIA-related disorder have the disorder as a result of a de novo genetic alteration.
• Approximately 20%-25% of reported individuals inherited an NFIA-related disorder alteration from an affected parent.
• Recommendations for the evaluation of parents of an individual with NFIA-related disorder include genetic/genomic testing capable of detecting the genetic alteration identified in the proband.
• If the genetic alteration identified in the proband cannot be detected in either parent, the most likely explanation is that the genetic alteration is de novo in the proband. Another possible explanation is parental germline mosaicism (germline mosaicism has not been reported to date).

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the genetic alteration identified in the proband, the risk to the sibs is 50%. However, the disorder is known to have variable expressivity; i.e., a sib who inherits the same genetic alteration may not have the same manifestation of the phenotype as the proband. Intrafamilial variation of the phenotype for the same genetic variant has been reported [Nyboe et al 2015, Coci et al 2016, Hollenbeck et al 2017, Revah-Politi et al 2017].
• If a parent of the proband has a chromosome translocation, recurrence risk to sibs depends on the specific structural variant.
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. Parental germline mosaicism for NFIA genetic alterations has not been reported in the literature thus far.

Offspring of a proband

• Each child of an individual with an NFIA-related disorder has a 50% chance of inheriting the genetic alteration.
• Risk to offspring of an individual with a chromosome translocation depends on the specific structural variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the genetic alteration identified in the proband, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 the parents of an affected child.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the causative 1p31.3 deletion, NFIA intragenic pathogenic variant, or chromosome translocation has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. Some features of NFIA-related disorder may be identifiable on prenatal ultrasound examination; these include agenesis/hypoplasia of the corpus callosum, ventriculomegaly, and macrocephaly [Negishi et al 2015, Revah-Politi et al 2017]. Poor fetal movement has been described in one case [Shanske et al 2004, Lu et al 2007].

Cancer and Benign Tumors

Numerous sporadic tumors (e.g., glioblastoma) occurring as single tumors in the absence of any other findings of NFIA-related disorder may contain somatic NFIA nucleotide variants and/or show changes in NFIA expression that are not present in the germline; thus, predisposition to these tumors is not known to be heritable.

Author Notes

Fabiola Quintero-Rivera, MD web page

Revision History

• 13 June 2019 (ma) Review posted live
• 2 March 2018 (fqr) Original submission

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