NFIX variants may cause a neurodevelopmental disorder without the dysmorphic features of Malan syndrome
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Malan syndrome is an autosomal dominant disorder associated with distinctive facial features, developmental delay/intellectual disability as well as prenatal and postnatal overgrowth. Distinctive facial features are thought to be universal including a long and triangular face, high posterior hairline with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip and prominent chin. Less frequently, high-arched palate, dental crowding, sparse hair, loose and soft skin, and facial asymmetry are noted. We present a pair of non-dysmorphic siblings with developmental delays and autism in whom a novel likely pathogenic variant in NFIX was identified.
Case Presentation
We report a pair of non-dysmorphic siblings with a history of developmental delays and autism. The youngest sibling, a female, was 4 years old at the time of examination. Chromosomal microarray and fragile X testing did not reveal any abnormalities. On whole exome sequencing she was found to have the novel variant c.469 C>T, p.(R157W) in the gene NFIX. This variant was not found in either of her unaffected parents and was classified as “likely pathogenic” by the performing laboratory. Targeted testing for this variant was performed on her 14-year-old autistic brother. He was also found to have the variant, suggesting parental germline mosaicism.
Both siblings were found to have height and weight between the 50th and 75th percentiles for age. The 4-year-old’s head circumference was at the 98th percentile at the time of the visit, while her brother’s head circumference was at the 97th percentile at the time of his visit. Neither sibling was noted to have the characteristic facial features associated with Malan syndrome. Neither sibling was noted to have the slender body habitus noted in other people with Malan syndrome; the 4-year-old sister was noted to have a body mass index at the 73rd percentile at the time of initial genetics clinic visit, while her brother was found to have a body mass index at the 70th percentile at the time of his initial genetics clinic visit.
Diagnostic Workup
The younger female sibling had a normal chromosome microarray and Fragile X methylation analysis. Mitochondrial sequencing and deletion/duplication analysis was normal. Exome sequencing noted a de novo likely pathogenic variant in NFIX, c.469C>T (p.R157W). The older male sibling had targeted familial variant NFIX testing which noted the same variant present in his sample.
Treatment and Management
Both patients were referred for an echocardiogram to rule out possible related cardiac anomalies.
Outcome and Follow-Up
Both siblings had normal echocardiograms. Given both siblings were noted to have this novel variant, the parents were counseled regarding germline mosaicism.
Discussion
Malan syndrome is associated with developmental delay/intellectual disability, characteristic facial features, overgrowth and slender body habitus. We report two siblings with this rare condition who were noted to have borderline macrocephaly and developmental delays with autism, but in which other distinctive facial features were absent. Additional studies to determine whether they had related cardiac anomalies were negative.
Conclusion
In summary, this case suggests that certain disease-causing variants in NFIX may be associated with developmental delays/intellectual disability and macrocephaly in the absence of suggestive facial features, thus expanding on the phenotype associated with disease-causing NFIX variants.
Malan syndrome is an autosomal dominant disorder associated with distinctive facial features, developmental delay/intellectual disability as well as prenatal and postnatal overgrowth. Distinctive facial features are thought to be universal including a long and triangular face, high posterior hairline with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip and prominent chin. Less frequently, high-arched palate, dental crowding, sparse hair, loose and soft skin, and facial asymmetry are noted. We present a pair of non-dysmorphic siblings with developmental delays and autism in whom a novel likely pathogenic variant in NFIX was identified.
Case Presentation
We report a pair of non-dysmorphic siblings with a history of developmental delays and autism. The youngest sibling, a female, was 4 years old at the time of examination. Chromosomal microarray and fragile X testing did not reveal any abnormalities. On whole exome sequencing she was found to have the novel variant c.469 C>T, p.(R157W) in the gene NFIX. This variant was not found in either of her unaffected parents and was classified as “likely pathogenic” by the performing laboratory. Targeted testing for this variant was performed on her 14-year-old autistic brother. He was also found to have the variant, suggesting parental germline mosaicism.
Both siblings were found to have height and weight between the 50th and 75th percentiles for age. The 4-year-old’s head circumference was at the 98th percentile at the time of the visit, while her brother’s head circumference was at the 97th percentile at the time of his visit. Neither sibling was noted to have the characteristic facial features associated with Malan syndrome. Neither sibling was noted to have the slender body habitus noted in other people with Malan syndrome; the 4-year-old sister was noted to have a body mass index at the 73rd percentile at the time of initial genetics clinic visit, while her brother was found to have a body mass index at the 70th percentile at the time of his initial genetics clinic visit.
Diagnostic Workup
The younger female sibling had a normal chromosome microarray and Fragile X methylation analysis. Mitochondrial sequencing and deletion/duplication analysis was normal. Exome sequencing noted a de novo likely pathogenic variant in NFIX, c.469C>T (p.R157W). The older male sibling had targeted familial variant NFIX testing which noted the same variant present in his sample.
Treatment and Management
Both patients were referred for an echocardiogram to rule out possible related cardiac anomalies.
Outcome and Follow-Up
Both siblings had normal echocardiograms. Given both siblings were noted to have this novel variant, the parents were counseled regarding germline mosaicism.
Discussion
Malan syndrome is associated with developmental delay/intellectual disability, characteristic facial features, overgrowth and slender body habitus. We report two siblings with this rare condition who were noted to have borderline macrocephaly and developmental delays with autism, but in which other distinctive facial features were absent. Additional studies to determine whether they had related cardiac anomalies were negative.
Conclusion
In summary, this case suggests that certain disease-causing variants in NFIX may be associated with developmental delays/intellectual disability and macrocephaly in the absence of suggestive facial features, thus expanding on the phenotype associated with disease-causing NFIX variants.