Fig 2 - uploaded by Joshua Cuoco
Content may be subject to copyright.
![Phenotypic representation of individuals diagnosed with LMS. a, b Individual at the age of 24 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, and angulated ears. c, d Same individual with pseudoclubbing of the second and third digits. e Individual at the age of 13 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, angulated ears, coarse hair, and micrognathia. f, g Same individuals at the age of 4 years with similar facial features. h, i Individual at the age of 6 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, angulated eyes, and flattening of the midface. Adapted from Ejaz et al. [33] Lateral meningocele syndrome. GeneReviews [Internet]; 2016. © 1993-2019 University of Washington. GeneReviews ® is a registered trademark of the University of Washington, Seattle. The content is used with permission. All rights reserved.](profile/Joshua-Cuoco/publication/337935591/figure/fig1/AS:836124771618816@1576359088034/Phenotypic-representation-of-individuals-diagnosed-with-LMS-a-b-Individual-at-the-age.png)
Phenotypic representation of individuals diagnosed with LMS. a, b Individual at the age of 24 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, and angulated ears. c, d Same individual with pseudoclubbing of the second and third digits. e Individual at the age of 13 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, angulated ears, coarse hair, and micrognathia. f, g Same individuals at the age of 4 years with similar facial features. h, i Individual at the age of 6 years with facial characteristics including eyelid ptosis, arched eyebrows, a thin upper lip, angulated eyes, and flattening of the midface. Adapted from Ejaz et al. [33] Lateral meningocele syndrome. GeneReviews [Internet]; 2016. © 1993-2019 University of Washington. GeneReviews ® is a registered trademark of the University of Washington, Seattle. The content is used with permission. All rights reserved.
Source publication
Background:
Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue disease with phenotypic anomalies similar to those seen in Marfan syndrome, Ehler-Danlos syndrome, and Loeys-Dietz syndrome. However, this syndrome is invariably associated with the presence of multiple lateral thoracolumbar spinal meningoceles: a distinct poin...
Similar publications
Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndrom...
Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires.
Methods:
This observational, multicen...
A 53-year-old patient with a history of Loeys-Dietz syndrome (LDS) presented with cutout after a right femoral neck fracture treated with a dynamic hip screw. This was treated with conversion total hip arthroplasty (THA), the second reported THA in a patient with LDS and the first in a post-traumatic reconstruction setting. The patient had 2 episod...
Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification‐based next‐gener...
Mitral valve prolapse (MVP) due to myxomatous degeneration is one of the most important chronic degenerative cardiovascular diseases in people and dogs. It is a common cause of heart failure leading to significant morbidity and mortality in both species. Human MVP is usually classified into primary or non-syndromic, including Barlow’s Disease (BD),...
Citations
... Several other connective tissue disorders could also exhibit an overlapping phenotype with LMS [4]. For example, Loeys-Dietz syndrome, Marfan syndrome, Nevo syndrome, Ehlers-Danlos syndrome, and neurofibromatosis type 1 (NF1) could also lead to dural ectasia but not commonly to the degree observed in LMS [4,5]. Due to the rarity of LMS, the diagnosis based on clinical manifestations alone would be practically impossible. ...
... Due to the rarity of LMS, the diagnosis based on clinical manifestations alone would be practically impossible. There is still debate about neurosurgical indications and appropriate treatment for LMS [5][6][7]. Here, we report one patient with LMS and conduct a literature review of this disease. It would help clinicians recognize signs and symptoms suggestive of LMS and then start the appropriate diagnostic workup. ...
... All of the patients who underwent genetic testing had heterozygous truncating variants in the last exon of the NOTCH3 gene [4,11,12]. Exome sequencing of NOTCH3 has identified several novel diseases restricted to specific exons on chromosome 19p13, including LMS [5]. Notch receptors are highly conserved transmembrane glycoproteins which could regulate many cellular functions, such as cell differentiation, self-renewal, proliferation, and survival [2,5]. ...
Purpose
Lateral meningocele syndrome (LMS) is a rare genetic connective tissue disorder which is associated with meningocele-related neurologic dysfunction. Several patients with LMS have been reported. But, guidelines for screening and treatment of LMS have not been established.
Method and results
We review the current knowledge of LMS in the article. Then, we describe a boy for whom a genomic analysis which allowed us to make a diagnosis of LMS and to begin monitoring of his condition for possible neurological complications.
Conclusion
It would be difficult to make a diagnosis of LMS on the basis of clinical manifestations alone. The natural history of dural ectasia in patients with LMS needs to be better defined to establish surgical indications. Based upon the current literature, ventriculoperitoneal shunting (V-Ps) has been recommended as the first-line surgical treatment option for patients with symptomatic thoracolumbar meningoceles.
... Currently, there are no therapeutic interventions to ameliorate the LMS phenotype other than the surgical interventions aimed at correcting or ameliorating selected neurological and skeletal defects (Brown et al., 2017;Cuoco et al., 2020). A central problem with LMS is the genetic nature of the disease and the fact that the phenotype becomes established during embryogenesis with multiple organs affected at birth. ...
Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.
b> Introduction: Lateral meningocele syndrome (LMS), also known as Lehman syndrome, is caused by pathogenic variants in exon 33 of NOTCH3 . Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life. Individuals with LMS are expected to have multiple lateral meningoceles, developmental delay, neonatal hypotonia, dysmorphic facial features, and feeding difficulties. Case Presentation: We report an 8-year-old male with a history of autism, feeding difficulties, developmental delay, severe intellectual disability, and self-injurious behavior. Genetic testing revealed a NOTCH3 c.6663C>G (p.Y2221*) pathogenic variant in exon 33, consistent with a diagnosis of LMS. A follow-up spine MRI showed a ventral sacral extradural arachnoid cyst but no lateral meningoceles. This individual’s most recent exam noted multiple dysmorphic features including prominent metopic ridging, broad forehead, downslanting palpebral fissures, high-arched palate, long narrow philtrum, mild pectus excavatum, and wide-based gait. Discussion/Conclusion: This individual shares the dysmorphic facial features, ongoing G-tube dependence, failure to thrive, and developmental delay seen in other individuals with LMS. His lack of lateral meningoceles expands the phenotype for this condition, as all previously reported individuals with molecularly confirmed LMS had multiple lateral meningoceles before age 8 years with an average age of identification at 4 years.
Lateral meningocele syndrome is characterized by multiple lateral meningoceles with a distinctive craniofacial appearance, hyperextensibility of the skin, and hypermobility of the joints. The syndrome is caused by heterozygous truncating variants in the last exon, exon 33, of the NOTCH3 gene. Here, we present a 2-year-old girl for whom an early genomic analysis allowed us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurological complications. She had a characteristic facial appearance, hyperextensibility of the skin and mobility of the joints, and developmental delays. Given that lateral meningocele syndrome is a rare syndrome, the existence of lateral meningoceles is suspected only when the causative gene is detected by genetic testing. MRI scans are unlikely to be performed in infancy in the absence of neurological symptoms suggestive of meningoceles. No formal guidelines have been established for the neurosurgical indications for lateral meningocele syndrome. Given the features of hyperextensibility of the skin and hypermobility of the joints, lateral meningocele syndrome can be categorized as a connective tissue disease and may be progressive, as with the dural ectasia in Marfan syndrome and Loeys-Dietz syndrome. Watchful monitoring of dural ectasia may be warranted in patients with lateral meningocele syndrome.
