Lateral meningocele syndrome

The lateral meningocele syndrome is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction.

Presentation

Facial features found in this syndrome include

• dolichocephaly
• hypertelorism
• ptosis
• microretrognathia
• high arched palate
• long flat philtrum
• low set ears

Non facial features of this syndrome include

• hyperextensibility
• hypotonia
• lateral meningoceles

The lateral meningocoles are a common finding in this syndrome. They may be associated with neurological abnormalities and result in bladder dysfunction and neuropathy.

Cause

• Lateral meningocele syndrome is caused by mutations in the NOTCH3 gene.
• This gene provides instructions for making a protein with one end (the intracellular end) that remains inside the cell, a middle (transmembrane) section that spans the cell membrane, and another end (the extracellular end) that projects from the outer surface of the cell.
• The NOTCH3 protein is called a receptor protein because certain other proteins, called ligands, attach (bind) to the extracellular end of NOTCH3, fitting like a key into a lock.
• This binding causes detachment of the intracellular end of the NOTCH3 protein, called the NOTCH3 intracellular domain, or NICD.
• The NICD enters the cell nucleus and helps control the activity (transcription) of other genes.

Gene mutations

• The NOTCH3 gene mutations that cause lateral meningocele syndrome occur at the end of the gene in a region known as exon 33.
• These gene mutations result in a NOTCH3 protein with an abnormally short (truncated) NICD.
• The shortened protein is missing the portion that normally causes the breakdown of the NICD after it has performed its function in the cell nucleus and is no longer needed.
• As a result, the presence of the NICD in the cell is prolonged, and the protein continues to affect the activity of other genes.
• However, the result of this prolonged NICD activity and its connection to the specific features of lateral meningocele syndrome are not well understood.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. Occasionally, an affected person inherits the mutation from one affected parent.

Diagnosis

Formal diagnostic clinical criteria for lateral meningocele syndrome (LMS) have not been established.[1].

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 . Associated neurologic findings can include: Chiari I malformation, hydrocephalus, syringomyelia, and neurogenic bladder.
• Characteristic craniofacial appearance 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 .
• 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)

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.

Treatment

• 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.[2].

History

This syndrome was first described by Lehman et al. in 1977. This paper described a 14-year-old girl with a number of unusual findings. Her mother shared some of the same findings. Since then over a dozen additional cases have been reported.

External links

Classification	ICD-10: Q87.5 OMIM: 130720
External resources	Orphanet: 2789