Lateral Meningocele Syndrome

Clinical characteristics.

Lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelae of the meningoceles depend on size and location and can include neurogenic bladder, paresthesias, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include mixed or conductive hearing loss and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Although developmental delay is common, cognition is often preserved. Feeding difficulties and gastroesophageal reflux disease (GERD) are common.

Diagnosis/testing.

The diagnosis of LMS syndrome is established in a proband with consistent clinical findings and a heterozygous pathogenic variant in NOTCH3.

Management.

Treatment of manifestations: Routine management of neurologic sequelae of lateral meningoceles (neurogenic bladder, paresthesias, back pain, and/or paraparesis). Although rarely required, surgical intervention may be necessary for neurologic manifestations secondary to meningocele size and location. As needed: management by specialists in chronic pain management or rehabilitation medicine; physiotherapy to reduce the risk for joint subluxation and dislocation. Routine management of: cleft palate, hearing loss, congenital cardiac defects, GU abnormalities, feeding difficulties.

Surveillance: Ongoing monitoring by the appropriate subspecialists for neurologic, developmental, musculoskeletal, cardiovascular, genitourinary, and/or gastrointestinal issues.

Genetic counseling.

LMS is inherited in an autosomal dominant manner. Although most probands have the disorder as a result of a de novo NOTCH3 pathogenic variant, affected parent-child pairs have been reported. Each child of an individual with LMS has a 50% chance of inheriting the NOTCH3 pathogenic variant. When the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk are possible options.

Suggestive Findings

LMS should be suspected in individuals with the following findings:

• Multiple lateral spinal meningoceles (protrusion of the arachnoid and dura through the spinal foramina). Present in all affected individuals (Figure 1). Associated neurologic findings can include: Chiari I malformation, hydrocephalus, syringomyelia, and neurogenic bladder.
• Characteristic craniofacial appearance [Castori et al 2014, Gripp et al 2015, Ejaz et al 2016] including widely spaced eyes, highly arched eyebrows, downslanted palpebral fissures, ptosis, malar flattening, long philtrum, thin vermilion of the upper lip, high and narrow palate (cleft palate present in some individuals), micrognathia, and coarse hair with a low posterior hairline (Figure 2)
• High nasal voice
• Mixed or conductive hearing loss (present in some individuals)
• Developmental delay or (rarely) intellectual disability
• Musculoskeletal. Hypotonia, decreased muscle bulk, joint hyperextensibility with possibility of frequent dislocations, hernias, scoliosis, vertebral fusion, and scalloping of vertebrae
• Congenital cardiovascular malformations. Aortic abnormalities (bicuspid aortic valve, aortic dilation, and coarctation of the aortic arch) and ventricular septal defects
• Genitourinary. Cryptorchidism and hydronephrosis
• Gastrointestinal. Poor feeding, dysphagia, and gastroesophageal reflux disease (GERD)

Figure 1.

Numerous lateral meningoceles (see arrows) protrude through the thoracic foramina in a sagittal view (a) and through the lumbar foramina in a sagittal (b) and axial (c) view. The curved arrow in (a) shows a meningocele protruding from the middle cranial (more...)

Figure 2.

Photographs of individuals with lateral meningocele syndrome A-D. Patient 1 at age 24 years:

Establishing the Diagnosis

The diagnosis of LMS syndrome is established in a proband with consistent clinical findings and identification of a heterozygous pathogenic variant in NOTCH3 by molecular genetic testing (see Table 1).

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

• Single-gene testing. Sequence analysis of NOTCH3 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. Note: To date all causative pathogenic variants have been in exon 33, the last exon of NOTCH3 [Gripp et al 2015, Ejaz et al 2016]; see Molecular Genetics, Pathogenic variants.
• A multigene panel that includes NOTCH3 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. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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 if single-gene testing (and/or use of a multigene panel that includes NOTCH3) fails to confirm a diagnosis in an individual with features of LMS. 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). Note: Clinicians should ensure that exome sequencing or genome sequencing has sufficient coverage to detect small deletions in the last exon of NOTCH3 as these pathogenic variants could otherwise be missed [Ejaz et al 2016].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies.

LMS is a recognizable clinical phenotype, with half of known affected individuals having a molecularly confirmed diagnosis [Gripp et al 2015]; to date, most others have not been tested for a NOTCH3 pathogenic variant.

Multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through the spinal foramina) are found in all affected individuals. Neurologic sequelae of the meningoceles can include neurogenic bladder, paresthesias, back pain, and/or paraparesis depending on size and location. Other neurologic findings can include Chiari I malformation (4/14), syringomyelia (3/14) and rarely, hydrocephalus [Gripp et al 1997, Castori et al 2014, Gripp et al 2015, Ejaz et al 2016].

Head and neck. Mixed or conductive hearing loss has been noted in seven of 14 individuals with LMS. Cleft palate is occasionally seen. Eye abnormalities can include iris coloboma, proptosis, and oculomotor restriction [Castori et al 2014, Gripp et al 2015, Ejaz et al 2016].

Developmental delay is frequently seen in individuals with LMS but cognition is often preserved. All seven individuals with a molecularly confirmed diagnosis had developmental delay, and one also had intellectual disability [Gripp et al 2015, Ejaz et al 2016]. Psychomotor development may vary within a family; for example, in an affected mother-daughter pair only the daughter had developmental delay [Lehman et al 1977].

Musculoskeletal. Overlap with features of connective tissue disorders include neonatal hypotonia (11/14), abdominal hernias (9/14), ligamentous laxity (12/14), keloid scars (5/14), and back pain (3/14) in later life.

Nonspecific muscle or generalized pain has been described. One woman age 55 years had multiple joint dislocations [Castori et al 2014].

Many individuals have skeletal changes including scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones [Gripp et al 1997, Castori et al 2014, Gripp et al 2015].

Congenital cardiovascular malformations described in five individuals with a molecularly confirmed diagnosis include ventricular septal defect (3), bicuspid aortic valve (2), dilatation of the aorta (2), and coarctation of the aortic arch (1) [Alves et al 2013, Gripp et al 2015, Ejaz et al 2016].

Genitourinary. Cryptorchidism is frequently seen. Hydronephrosis has been occasionally reported [Castori et al 2014].

Gastrointestinal. Infants with LMS may demonstrate dysphagia with poor weight gain. Dysphagia was severe enough to warrant gastrostomy tube feeding in one [Ejaz et al 2016].

Gastroesophageal reflux disease (GERD) which can persist into adulthood has been described in a woman age 55 years, the oldest reported individual with LMS to date [Castori et al 2014]. Of note, she did not have a NOTCH3 pathogenic variant on exome sequencing and targeted sequencing [Kym Boycott, MD; email communication 2-17-16].

Genotype-Phenotype Correlations

Given that lateral meningocele syndrome (LMS) is a rare disorder with fewer than 20 reported cases, no genotype-phenotype correlations have been determined.

Penetrance

Penetrance appears to be complete but data are limited.

Nomenclature

Lehman et al [1977] first described a woman with dysmorphic facial features, skeletal sclerosis, and multiple meningoceles, and her mother with similar craniofacial dysmorphisms. Philip et al [1995], who published a second case, named the syndrome after Lehman. The authors prefer the term "lateral meningocele syndrome" as it emphasizes the hallmark feature of the condition.

Prevalence

Lateral meningocele syndrome is very rare, with approximately 14 reported individuals, seven of whom have a molecularly confirmed diagnosis. There does not appear to be increased prevalence in specific populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with lateral meningocele syndrome (LMS), the following evaluations are recommended:

• Spine MRI to assess for meningoceles (if not performed at time of diagnosis) and neurosurgical assessment to evaluate the effect of lateral spinal meningocele size and location on neurologic function
• Brain MRI to assess for Chiari I malformation or hydrocephalus, if not performed at time of diagnosis
• Thorough physical and neurologic examination for signs of neuropathy, joint abnormalities, and abdominal hernias
• Neurocognitive assessment
• Assessment by general surgery for abdominal hernia repair
• Assessment by orthopedic surgery for symptomatic skeletal deformities
• Visualization of the aortic arch by echocardiogram or MRI
• Urologic assessment for cryptorchidism if present
• Feeding assessment
• Hearing assessment
• Ophthalmologic assessment
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Specific treatment for LMS does not currently exist. Supportive management of the clinical finding depends on the involved system as outlined below.

Lateral spinal meningoceles. Symptomatic treatment of neurologic sequelae (e.g., neurogenic bladder, paresthesias, back pain, and/or paraparesis) is as per routine.

Although rarely required, surgical intervention may be necessary for neurologic manifestations secondary to meningocele size and location. When required, surgical approach is individualized and can include laminectomy for smaller meningoceles and costotransversectomy for larger meningoceles [Kim et al 2011]. Of note, the 55-year-old woman with LMS experienced irreversible nerve damage following surgery for two lumbosacral meningoceles (to manage back and referred neuropathic pain) [Castori et al 2014].

Psychomotor development. Provide timely supportive interventions as needed to optimize development through occupational therapy and education resources.

Musculoskeletal

• Management by specialists in chronic pain management or rehabilitation medicine as needed
• Physiotherapy to reduce risk for joint subluxation and dislocation

Routine management of the following:

• Cleft palate
• Hearing loss
• Congenital cardiac defects
• Genitourinary abnormalities
• GERD. Note that a feeding tube may be necessary if persistent feeding difficulties result in failure to thrive.

Surveillance

No surveillance guidelines for LMS have been published.

Ongoing monitoring by the appropriate subspecialists for neurologic, developmental, musculoskeletal, cardiovascular, genitourinary, and/or gastrointestinal issues is indicated.

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.