Mn1 C-Terminal Truncation Syndrome

Clinical characteristics.

Individuals with MN1 C-terminal truncation (MCTT) syndrome have mild-to-moderate intellectual disability, severe expressive language delay, dysmorphic facial features (midface hypoplasia, downslanting palpebral fissures, hypertelorism, exophthalmia, short upturned nose, and small low-set ears), and distinctive findings on brain imaging (including perisylvian polymicrogyria and atypical rhombencephalosynapsis). Mild-to-moderate prelingual hearing loss (usually bilateral, conductive, and/or sensorineural) is common. Generalized seizures (observed in the minority of individuals) are responsive to antiepileptic drugs. There is an increased risk for craniosynostosis and, thus, increased intracranial pressure. To date, 25 individuals with MCTT syndrome have been identified.

Diagnosis/testing.

No consensus clinical diagnostic criteria for MCTT syndrome have been published. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in MN1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary specialists to help manage developmental delay / intellectual disability, feeding issues, seizures, hearing loss, and speech and language needs, especially alternative communication.

Surveillance: Routine follow up by multidisciplinary specialists per their recommendations.

Genetic counseling.

MCTT syndrome is an autosomal dominant disorder typically caused by a de novo MN1 pathogenic variant. The risk to the sibs of a proband depends on the genetic status of the proband's parents: if the MN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental somatic/germline mosaicism. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible once the MN1 pathogenic variant has been identified in an affected family member.

Suggestive Findings

MN1 C-terminal truncation (MCTT) syndrome should be suspected in individuals with the following clinical findings and brain MRI findings.

Clinical findings

• Intellectual disability (ID) with severe expressive language delay
• Hypotonia
• Delays in motor development
• Hearing loss (conductive or sensorineural)
• Distinctive craniofacial features (see Figure 1)

Figure 1.

Facial features of individuals with C-terminal truncating variants in MN1, illustrating how features evolve from before to after age five years. Frontal bossing may be more prominent at infancy, with a tall forehead at later stages. Skull shape anomalies (more...)

Brain MRI findings. In MCTT syndrome, an atypical distinctive form of rhombencephalosynapsis is observed in which there is partial or complete loss of the cerebellar vermis landmarks with fusion of the cerebellar hemispheres characterized by abnormal midline crossing of cerebellar folia and white matter tracts. Other distinctive brain MRI findings are summarized in Table 1 (see Figure 2 and Figure 3).

Figure 2.

Partial rhombencephalosynapsis in patients with C-terminal truncating MN1 variants. Changes of the cerebellum include foliar dysplasia, abnormal folia crossing the midline, and small or almost absent vermis. For details, refer to Figure 4 of Mak et al (more...)

Figure 3.

Persistent trigeminal artery and prominent posterior clinoid process in patients with C-terminal truncating MN1 variants A. Carotid and basilar arteries (axial view): persistent trigeminal artery flow-voids (dark signal) connecting the carotid (C) and (more...)

Establishing the Diagnosis

The diagnosis of MN1 C-terminal truncation (MCTT) syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in MN1 identified by molecular genetic testing (see Table 2).

Note: Identification of a heterozygous MN1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and 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 craniofacial or brain MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MCTT syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, 25 individuals have been identified with a germline (de novo or inherited from a mosaic parent) pathogenic C-terminal variant in MN1 [Mak et al 2020, Miyake et al 2020]. Individuals with MN1 C-terminal truncation (MCTT) syndrome have intellectual disability, severe expressive language delay, dysmorphic facial features (see Figure 1), and distinctive findings on brain imaging (including perisylvian polymicrogyria and atypical rhombencephalosynapsis) (see Table 1). The summary of the phenotypic features associated with MCTT syndrome in Table 3 is based on these reports.

Developmental delay (DD) / intellectual disability (ID). Individuals with MCTT syndrome have mild-to-moderate intellectual disability and severe expressive language delay. The majority have nonverbal communication with notable exceptions. For example, one child was able to speak at age two years, and at age 14 years was able to function at the level of a seven-year-old. For others, single-word speech began between ages three and six years. Some can communicate in sign language with up to 50 signs [Mak et al 2020].

Delay in gross motor development included hypotonia; at least four of 22 children walked independently by age two to three years. Others required orthotics or a wheelchair for mobilization. As for fine motor and self-help skills, most individuals require help with writing, feeding, or dressing [Mak et al 2020].

Hearing loss, when present, is mild to moderate and prelingual. It is usually bilateral, conductive, and/or sensorineural. Dysplasia of the cochlea, semicircular canals, and bony structures of the middle ear (e.g., incus) has been reported.

Feeding difficulties are more prominent early in infancy and may resolve after the first year of life. Hyperphagia has also been reported in three children [Miyake et al 2020].

Spinal anomalies include lordosis, scoliosis, or kyphosis, which may be detected clinically or by imaging.

Dental anomalies can include conical teeth, crowded teeth, and serrated teeth. Malocclusion has also been reported.

Ophthalmologic anomalies can include oculomotor defects, strabismus, and/or shallow orbits, giving the appearance of exorbitism.

Cardiovascular anomalies include atrial septal defect or ventricular septal defects.

Seizures are generalized and may be myoclonic in nature. Among the six individuals with seizures, the majority were isolated events and were responsive to antiepileptic drugs. While polymicrogyria may be associated with increased risk of seizures, more information is needed.

Craniosynostosis. Individuals with MCTT syndrome are at increased risk for craniosynostosis with no specific pattern to the sutures affected. Although head circumference is normal in individuals with craniosynostosis, head shape is consistently affected. Skull shape anomalies that may be observed with or without underlying craniosynostosis include dolichocephaly, turricephaly, and/or bitemporal narrowing, plagiocephaly, and macrocephaly. Individuals with craniosynostosis are at increased risk for elevated intracranial pressure.

Behavioral problems. While some affected individuals may experience frustration due to poor verbal communication, no consistent behavior problems have been reported. The natural history into adulthood has not yet been delineated.

Growth. Growth parameters tend to remain within the normal range.

Prognosis. It is unknown if life span is affected in MCTT syndrome. One individual is alive at age 21 years [Mak et al 2020]. An unreported male is well at age 39 years [Angela Lin, personal commmunication], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are unrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

MCTT syndrome is referred to as CEBALID (craniofacial defects, dysmorphic ears, structural brain abnormalities, expressive language delay, and impaired intellectual development) syndrome in OMIM (OMIM 618774).

Prevalence

To date, 25 individuals with MCTT syndrome have been reported [Mak et al 2020, Miyake et al 2020]. This disorder is expected to be rare; the prevalence among individuals with unexplained developmental disorders is estimated at 4.2:10,000 (see bioRxiv).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MN1 C-terminal truncation (MCTT) syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations