Lateral Meningocele syndrome (LMNS)

What is Lateral Meningocele syndrome?

This rare disease is a genetic condition that affects multiple parts of the body including the bones, muscles, nervous system and other systems in the body.

The syndrome is identified by the presence of lateral meningoceles which are when the membranes that surround the spinal cord protrude through gaps in the bones of the spine. These are more likely to be found in the lower part of the spine where they are often bigger also.

There are only a few cases of the syndrome reported worldwide to date.

Syndrome Synonyms:
Lateralmenigocelesyndrome Lateralmeningocelesyndrome Lehman (1977) - osteosclerosis; abnormalities of nervous system/meninges Lehman Syndrome; Lehman syndrome; LMS Lms

What gene change causes Lateral Meningocele syndrome?

Mutations in the NOTCH3 gene are responsible for causing the syndrome. It is inherited in an autosomal dominant pattern but most cases are the result of a de novo or new mutation in the gene.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Lateral Meningocele syndrome?

The presence of lateral meningoceles causes damage to the nerves that originate from the spine to the rest of the body.
This may also cause damage to the nerves responsible for bladder control.

Damage to the nervous system may also cause a tingling sensation in the legs, a weakness or stiffness in the legs and related back pain.

Delayed motor development in infancy is also a common symptom.

Unique facial features associated with the syndrome include highly arched eyebrows, wide-spaced eyes, droopy eyelids and corners of the eyes that point downwards. A thin upper lip, long philtrum, low set ears, small jaw, coarse hair and a flattened facial appearance are also facial features of the syndrome.

How does someone get tested for Lateral Meningocele syndrome?

The initial testing for Lateral Meningocele syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical Information on Lateral Meningocele syndrome

Disease Overview:
Lateral Meningocele syndrome (LMNS) is an autosomal dominant multi-system connective tissue disorder presenting with lateral spinal meningoceles, hypotonia, characteristic facial features, joint hyperextensibility and skeletal abnormalities (scalloping of the vertebra, worsmian bones, calvarial hyperostosis, acro-osteolysis). It is caused by heterozygous pathogenic variants in exon 33, the last exon, of NOTCH3, resulting in an abnormal protein product that lacks a functional C-terminal PEST domain. Other common features include neurologic abnormalities (Chiari I malformation, syringomelia, tethered cord), feeding difficulties, cleft palate, hearing loss, congenital heart defects, and cryptorchidism. Intellect is often preserved.

Clinical Description:
Main clinical features/phenotypes: Lehman et al. [1977] described a 14-year-old female with craniofacial dysmorphisms, including narrow face, proptosis, downslanted palpebral fissures, poorly-developed ear canals, malar flattening, high-arched palate, dental crowding, microretrognathia, left conductive hearing loss, and fine horizontal nystagmus, who presented with lower limb weakness, back pain, and neurogenic bladder. Radiologic assessment revealed skeletal sclerosis, most prominent in the calvarium, scoliosis, enlarged sella turcica, platybasia, cerebellar hypoplasia, and multiple meningoceles. Intellect was normal. She underwent osteoplastic laminectomy at the level of the thoracic meningoceles with symptomatic relief. Her mother shared her craniofacial and skeletal features with mild enlargement of the spinal canal and congenital vaginal stenosis. Philip et al. [1995] reported a 19-year-old Italian male with multiple lateral meningoceles and similar facial features as previously described. New findings included bilateral iris colobomas, bilateral ptosis, and a marfanoid body habitus. Skin electron microscopy showed microfibril excess and abnormal elastic fibres. A further three unrelated individuals were described by Gripp et al. [1997] expanding the phenotype to include neonatal hypotonia, congenital heart defect (ventricular septal defect, aberrant right subclavian artery, interrupted inferior vena cava, aortic root dilatation), hydrocephalus, Chiari 1 malformation, syringomelia, cervicomedullary instability due to malformed C1 vertebra, joint hyperextensibility, keloid scars, pectus malformation, short umbilical cord, and cryptorchidism in males. Other notable craniofacial dysmorphisms were coarse hair, low posterior hairline, widely spaced eyes, tented upper lip, and prominence of the metopic suture. Collagen studies were normal. One individual had intellectual disability. Another affected mother and daughter pair were reported by Chen et al. [2005)] supporting autosomal dominant inheritance. The 11-year-old daughter had lumbar vertebral fusion and both her and her 33-year-old mother had bilateral hearing loss, umbilical or inguinal hernia, and joint hyperextensibility. An additional individual had a V-shaped cleft palate Avela et al. [2011] initially reported a 6-year-old male with Hajdu-Cheney syndrome due to presence of acro-osteolysis and abnormal dental enamel, but this was later classified as LMNS by Gripp et al. [2011]. Alves et al. [2011] et Correia-Sa et al. [2013] reported a 5-year-old male with a bicuspid aortic valve, Pierre-Robin sequence and prenatal cystic hygroma. A 55-year-old female presenting with chronic back pain, neuropathy, and joint hyperextensibility with multiple dislocations was described by Castori et al. [2014]. Features in adulthood included chronic headaches, occipital neuralgia, occasional nocturnal limb movements, Raynaud’s phenomenon, dysphagia, gastroesophageal reflux disease, uterine prolapse, vaginal dryness, dry mouth and eyes, and early tooth loss. Of note, this individual had no pathogenic variants in NOTCH3 at later assessment. Pathogenic variants in the NOTCH3 gene were found to be causative of LMNS in 6 individuals by Gripp et al. in 2015. Ejaz et al. [2016] also identified a pathogenic variant in NOTCH3 in a 2-year-old male with characteristic features as well as feeding difficulties requiring gastrostomy tube, developmental delay and a complex cardiac defect (coarctation of the aorta, large VSD, large atrial septal defect, bicuspid aortic valve, and bilateral superior vena cavae). There had been prenatal note of nuchal edema and echogenic bowel. Brown et al. [2017] also described prenatal presence of nuchal edema, along with L2 hemivertebra, in a 6-month-old female. She required Chiari 1 malformation decompression with ventriculoperitoneal (VP) shunt, which was thought to be an effective technique to reduce the load on lateral meningoceles by diverting cerebrospinal fluid. She had a history of intestinal malrotation, and tethered cord. A pathogenic variant in NOTCH3 was found.

Prenatal presentation:
Congenital heart defects may be detected prenatally. Three individuals had a prenatal finding of nuchal edema or cystic hygroma (Alves et al., 2011; Ejaz et al., 2016; Brown et al., 2017). Age of onset: Lateral meningocele syndrome is due to germline pathogenic variants in NOTCH3. The evolution of lateral meningoceles over time is unknown. Age of diagnosis ranges from 6 months to 50 years [Castori et al, 2014; Brown et al, 2017].

Genotype-phenotype correlations:
Given the rarity of the condition in published literature, genotype-phenotype correlations are presently unknown. Lateral meningocele syndrome is caused by heterozygous, truncating, pathogenic variants in the last exon, exon 33, of NOTCH3 [Gripp et al., 2015]. All reported pathogenic variants result in loss of function of the C-terminal PEST domain, and include 3 missense variants, 3 deletions, and 1 insertion.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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