Clinical characteristics.

NOTCH3-related 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 sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Infants may demonstrate feeding difficulties with poor weight gain.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Surgical intervention of lateral spinal meningoceles is generally avoided, but may be necessary due to neurologic manifestations secondary to meningocele size and location. Symptomatic treatment of neurologic sequelae of lateral meningoceles (neurogenic bladder, paresthesias, back pain, and/or paraparesis) provided as needed. As needed: timely supportive interventions to optimize development; 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, cardiovascular issues, genitourinary abnormalities, ophthalmologic issues, hearing loss, feeding difficulties.

Surveillance: Close clinical and radiographic monitoring for progressive neurologic symptoms and increase in meningocele size; an initial yearly scan to monitor for stability and subsequent spacing to every two years if meningoceles are small in size. Ongoing monitoring by the appropriate subspecialists for developmental, musculoskeletal, cardiovascular, genitourinary, gastrointestinal, ophthalmologic, and/or hearing issues.

Genetic counseling.

All probands reported to date with NOTCH3-related LMS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo NOTCH3 pathogenic variant. Each child of an individual with NOTCH3-related LMS has a 50% chance of inheriting the pathogenic variant. Once the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for NOTCH3-related LMS are possible.

Suggestive Findings

NOTCH3-related LMS should be suspected in individuals with the following findings.

Multiple lateral spinal meningoceles (protrusion of the arachnoid and dura through the spinal foramina) are present in all affected individuals (Figure 1).

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...)

Characteristic craniofacial appearance [Gripp et al 2015, Ejaz et al 2016, Yamada et al 2022] includes widely spaced eyes, highly arched eyebrows, downslanted palpebral fissures, ptosis, malar flattening, long philtrum, thin vermilion of the upper lip, high and narrow palate, micrognathia, and coarse hair with a low posterior hairline (Figure 2).

Figure 2.

Photographs of individuals with NOTCH3-related lateral meningocele syndrome A-D. Patient 1 at age 24 years:

Additional findings that may be present:

• Neurologic. Chiari I malformation, hydrocephalus, syringomyelia, and neurogenic bladder.
• Developmental delay or (rarely) intellectual disability
• Musculoskeletal. Hypotonia and joint hypermobility
• Dermatologic. Hyperextensibility of the skin
• Cardiovascular malformations. Aortic abnormalities (bicuspid aortic valve, aortic dilatation, and coarctation of the aortic arch) and ventricular septal defects
• Genitourinary. Cryptorchidism and (rarely) renal anomaly
• Gastrointestinal. Feeding difficulties, dysphagia, and gastroesophageal reflux disease

Establishing the Diagnosis

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

Note: (1) 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 section is understood to include likely pathogenic variants.. (2) Identification of a heterozygous NOTCH3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of LMS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies.

To date, 11 individuals have been identified with a pathogenic variant in NOTCH3 [Gripp et al 2015, Ejaz et al 2016, Brown et al 2017, Cappuccio et al 2020, Han et al 2022, Yamada et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through the spinal foramina) are found in all affected individuals. Neurologic sequelæ of the meningoceles can include neurogenic bladder, paresthesia, back pain, and/or paraparesis depending on size and location. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus [Gripp et al 2015, Ejaz et al 2016, Cuoco et al 2020].

Craniofacial features include widely spaced eyes with downslanted palpebral fissures, highly arched eyebrows, ptosis, malar flattening, long philtrum, thin vermilion of the upper lip, high and narrow palate, micrognathia, and angulated ears (Figure 2). Cleft palate, dental crowding, epicanthal folds, dolichocephaly, and coarse hair with a low posterior hairline can also be seen.

A high nasal voice is noted in many individuals [Gripp et al 2015].

Developmental delay, particularly gross motor delay, is frequently seen in individuals with NOTCH3-related LMS, but cognition is typically preserved. Of ten individuals with NOTCH3-related LMS, all had developmental delay; only one also had intellectual disability [Gripp et al 2015, Ejaz et al 2016, Yamada et al 2022].

Musculoskeletal. Overlap with features of connective tissue disorders include neonatal hypotonia, abdominal hernias, ligamentous laxity, keloid scars, and back pain in later life.

Many individuals have skeletal changes including scoliosis, kyphosis, vertebral fusion, scalloping of vertebrae, and wormian bones [Gripp et al 2015, Cappuccio et al 2020].

Cardiovascular concerns have included atrial septal defect, ventricular septal defect, bicuspid aortic valve, dilatation of the aorta, and coarctation of the aortic arch [Gripp et al 2015, Ejaz et al 2016, Cappuccio et al 2020].

Genitourinary. Cryptorchidism is frequently seen. Prenatal hydronephrosis with postnatal left renal hypoplasia and bilateral renal cysts was reported in one individual [Cappuccio et al 2020].

Gastrointestinal. Infants with NOTCH3-related LMS may demonstrate feeding difficulties with poor weight gain. Feeding difficulties were severe enough to warrant gastrostomy tube feeding in two individuals [Ejaz et al 2016, Brown et al 2017].

Eye abnormalities can include proptosis and oculomotor restriction.

Hearing loss. Mixed or conductive hearing loss has been noted. Brain MRI of one individual showed an apical turn of the cochlea and modiolus, and dysmorphic vestibule [Cappuccio et al 2020]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

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 report, named the syndrome after Lehman. The authors prefer the term "lateral meningocele syndrome" as it emphasizes the hallmark feature of the condition.

The title of this GeneReview, NOTCH3-related lateral meningocele syndrome, is based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

NOTCH3-related lateral meningocele syndrome is very rare, with 11 reported individuals. 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 NOTCH3-related lateral meningocele syndrome (LMS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The following medical issues are managed in a routine manner: cleft palate, cardiovascular issues, genitourinary abnormalities, ophthalmologic issues, hearing loss, feeding difficulties.

Surveillance

There are no established surveillance guidelines for lateral spinal meningoceles. Close clinical and radiographic monitoring is recommended for progressive neurologic symptoms and meningocele size enlargement [Cuoco et al 2020]. MRI of the spine can be considered at a one- to two-year interval; an initial yearly scan to monitor for stability and subsequent spacing to every two years if meningoceles are small in size has been suggested. Larger lesions may require closer follow up [JA Cuoco 2022, personal communication].

Ongoing monitoring by the appropriate subspecialists for developmental, musculoskeletal, cardiovascular, genitourinary, gastrointestinal, ophthalmologic, and/or hearing 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.

Mode of Inheritance

NOTCH3-related lateral meningocele syndrome (LMS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• All probands reported to date with NOTCH3-related LMS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo NOTCH3 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the NOTCH3 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

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 NOTCH3 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the NOTCH3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is presumed to be low but slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with NOTCH3-related LMS has a 50% chance of inheriting the NOTCH3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the NOTCH3 pathogenic variant, members of the parent's family may be at risk.

Related Genetic Counseling Issues

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 affected individuals and young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for NOTCH3-related LMS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NOTCH3 encodes the neurogenic locus notch homolog protein 3 (NOTCH3), a transmembrane receptor involved in cell signaling and activation of target genes. It appears to be universally expressed and is a part of a highly conserved signaling pathway that is responsible for cell differentiation, proliferation, and apoptosis, through regulating transcription of target genes.

In Notch3 variant mouse models, an osteopenic phenotype was thought to result from induction of RANKL by cells of osteoblast lineages with subsequent increased osteoclastogenesis [Canalis 2021].

In all individuals with NOTCH3-related LMS to date, the causative pathogenic variants (nonsense and frameshift) have been in exon 33, the last exon of NOTCH3 [Gripp et al 2015, Ejaz et al 2016, Han et al 2022, Yamada et al 2022]. It is predicted that the transcripts of such variants in this location escape nonsense-mediated decay and express a truncated NOTCH3 protein, which has been documented in the cells of one individual [Gripp et al 2015]. Through negative regulation of protein stability these truncated NOTCH3 proteins would lack the C-terminal PEST domain, which is responsible for degradation of the intracellular signaling portion of activated NOTCH3. The truncated protein is more likely to escape degradation, thereby prolonging its cellular half-life [Wang et al 2015, Canalis 2021].

Mechanism of disease causation. NOTCH3-related LMS is thought to be caused by a gain-of-function mechanism [Gripp et al 2015, Wang et al 2015]. The precise mechanism by which excess NOTCH3 results in NOTCH3-related LMS is not understood.

Author Notes

Web page: Resham Ejaz - McMaster Experts

Acknowledgments

We thank the individuals with NOTCH3-related LMS and their families for their participation in research related to the condition.

Revision History

• 5 May 2022 (ha) Comprehensive update posted live
• 23 June 2016 (bp) Review posted live
• 19 February 2016 (re) Original submission

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