Lateral Meningocele Syndrome

A number sign (#) is used with this entry because of evidence that lateral meningocele syndrome (LMNS) is caused by heterozygous mutation in the NOTCH3 gene (600276) on chromosome 19p13.

Description

Lateral meningocele syndrome is a rare disorder characterized by distinctive facial features, hyperextensibility, hypotonia, and characteristic lateral meningoceles, which can result in neurologic complications such as bladder dysfunction and neuropathy. Dysmorphic features include dolichocephaly, hypertelorism, ptosis, microretrognathia, high-arched palate, long, flat philtrum, and low-set ears. Multiple additional variable features may also be observed, including cryptorchidism, vertebral anomalies, and connective tissue abnormalities. Early motor development is delayed, but cognition is usually normal (summary by Gripp et al., 2015).

Clinical Features

Lehman et al. (1977) reported a 14-year-old girl with generalized osteosclerosis, distinctive craniofacial features, and multiple thoracic and lateral meningoceles. She had downslanting palpebral fissures, high-arched palate, mandibular and facial bone hypoplasia, a large sella turcica and spacious foramen magnum, platybasia, basilar impression, widened spinal cord, and scalloping of the posterior surfaces of the vertebral bodies. Radiographic studies suggested maldevelopment of the spinal cord, cerebellum, and cerebral cortex. Her asymptomatic mother showed similar craniofacial skeletal features.

Katz et al. (1978) reported an isolated case. Merle et al. (1979) may have described the same disorder in 2 sisters, aged 6 and 9 years. They had short stature and facial dysmorphism similar to that reported by Lehman et al. (1977). Other features included enlarged sella turcica and enlargement of the optic foramina and internal auditory meatus. The mother had a large sella. Merle et al. (1979) suggested a general dysplastic syndrome rather than a local disease.

Philip et al. (1995) reported a 19-year-old boy with facial dysmorphism, skeletal anomalies, and multiple lateral meningoceles. He had increased bone density of the skull base and sutures. Intelligence was normal. Electron microscopy of skin showed nonspecific abnormalities suggesting a connective tissue disorder. The clinical features closely resembled those reported by Lehman et al. (1977).

Gripp et al. (1997) described 1 female and 2 male patients with multiple lateral meningoceles. One patient had thickened calvaria, and 2 had prominent metopic sutures. Other shared features included wormian bones, malar hypoplasia, downslanting palpebral fissures, a high narrow palate, keloid formation, and cryptorchidism in males. One had a hypoplastic posterior arch of the atlas and an enlarged sella, as reported by Lehman et al. (1977).

Chen et al. (2005) reported 3 additional cases of LMS, including an affected mother and daughter. The daughter presented at the age of 10 years for neurosurgery for increasing lower back pain, which was treated by L4-L5 and S1 laminectomy and excision of an extradural arachnoid cyst. Multiple abnormalities had been demonstrated by MRI, including a Chiari I malformation (CM1; 118420) and a large dorsal extradural arachnoid cyst expanding the canal and extending from the lower thoracic spine into the sacrum. Facies showed hypertelorism, mildly downslanting palpebral fissures, and ptosis. There was mild micrognathia and a high narrow palate. In the mother, bilateral flank masses and an umbilical hernia were noted at birth. She had had multiple surgeries to correct malformed auditory ossicles. At the age of 33 years she was found to have dural ectasia and multiple lateral meningoceles. At that time the mother's height was 143 cm (50th centile for a 10-year-old child). She had the appearance of hypertelorism, mildly downslanting palpebral fissures, ptosis, and micrognathia. All features were strikingly similar to those of the daughter. The affected male reported by Chen et al. (2005) had telecanthus and micrognathia, bilateral inguinal hernias, and multiple lateral meningoceles in the thoracic and lumbar regions. Chen et al. (2005) suggested that lateral meningocele syndrome may be a connective tissue disorder.

Avela et al. (2011) reported a 6-year-old boy, born of unrelated Finnish parents, with dolichocephaly, hypertelorism, epicanthal folds, high-arched palate,, micrognathia, and scoliosis. He was hypotonic and learned to walk at age 24 months; cognition was normal. Spine MRI, performed due to progressive kyphoscoliosis, showed extensive multilobar ductal ectasia resulting in hydronephrosis, as well as erosion of the thoracic and lumbar vertebral pedicles and abnormal vertebral bony elements. Additional features included coarse hair, ptosis, posteriorly angulated ears, nasal voice, and slender long bones with biochemical evidence of osteolysis. Avela et al. (2011) suggested that the diagnosis in this patient was consistent with Hajdu-Cheney syndrome (HJCYS; 102500). However, Gripp (2011) concluded that the patient reported by Avela et al. (2011) had lateral meningocele syndrome, although she noted that the 2 disorders have overlapping features and may either be allelic or caused by mutations in genes in the same pathway.

Alves et al. (2013) reported a 6-year-old boy with lateral meningocele syndrome. He presented at birth with feeding difficulties and hypotonia, and was noted to have dysmorphic features, including ptosis, microretrognathia, long and smooth philtrum, low-set ears, and cryptorchidism. Echocardiography showed a bicuspid aortic valve. During the next few years, he developed sleep apnea, conductive hearing loss, hypertelorism, pectus excavatum, hyperextensibility, and skin keloid scarring. At age 6 years, he had normal motor and cognitive development. Imaging of the spine showed scoliosis with expansion of the spinal canal and intervertebral foramina with scalloping of the posterior wall of the vertebrae. There was no evidence of acroosteolysis or wormian bones. Genetic analysis excluded mutations in the PLOD1 (153454), FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes. Alves et al. (2013) emphasized the connective tissue defects often observed in lateral meningocele syndrome.

Gripp et al. (2015) reported a boy with lateral meningocele syndrome who developed acute back pain, urinary incontinence, worsening stool incontinence, and abnormal gait around 5 years of age. Prior to that, he was noted to have dysmorphic facial features, hypotonia, pectus excavatum, and delayed motor development. Imaging studies at age 5 showed multiple lateral meningoceles and a tethered cord, which was surgically repaired. He also developed neuropathic pain.

Inheritance

Chen et al. (2005) suggested autosomal dominant inheritance, but noted that X-linked inheritance could not be completely excluded. Of the 9 reported cases, 5 were male and 4 female, and the males did not appear to be more severely affected than the females, making autosomal dominant inheritance most likely.

Molecular Genetics

In 6 unrelated patients with LMNS, including 5 patients reported by Gripp et al. (1997), Chen et al. (2005), Avela et al. (2011), and Alves et al. (2013), Gripp et al. (2015) identified 5 different de novo heterozygous truncating mutations in exon 33 of the NOTCH3 gene (600276.0013-600276.0017). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of the cells of 1 patient showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. The truncated NOTCH3 proteins predicted to result from these mutations would lack a functional PEST domain, which could prolong the half-life and thus increase signaling effects. Gripp et al. (2015) postulated that the de novo mutations in exon 33 would result in a dominant gain-of-function effect.