Mosaic double aneuploidy: a rare case of 45,X/47,XX,+18 mosaicism and review of the literature
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Mosaic double aneuploidy of monosomy X and trisomy 18 is a rare occurrence in live newborns and has only been reported in 7 cases in the medical literature since 1974. Presentation can vary from a predominantly Turner phenotype, to multiple congenital anomalies more suggestive of trisomy 18. Previous molecular genetic studies demonstrate the presence of both cell lines in multiple tissues, with trisomy 18 representative in leukocytes relative to alternative sample types. Mechanistically, a combination of meiotic and/or independent postzygotic events are theorized but have yet to be conclusively proven. Since the last publications in 2009, there have been an increase in techniques allowing us to determine mechanism of this rare condition.
Case Presentation
Our patient is a now 14 month old female who initially presented at 3 months of age for concerns of hypotonia, dysphagia, moderate secundum atrial septal defect, and poor growth. Pregnancy was significant for an abnormal prenatal ultrasound, showing a single umbilical artery and short femur length. Noninvasive prenatal testing reported a female fetus with low risk for aneuploidy (16% fetal fraction). Postnatal physical examination was not suggestive of a skeletal dysplasia (length >60th%ile), with deep palmar creases, larger ears, and hirsutism of the forehead noted. Neurologically the patient was active and engaged. Trio exome sequencing via buccal sample was coordinated, which reported monosomy X, or Turner syndrome, and biallelic rare variants of uncertain significance in the NEB gene. Given the degree of hypotonia, the possibility of a dual diagnosis of NEB-related myopathy and Turner syndrome was discussed.
Diagnostic Workup
A 30 cell count karyotype on leukocytes was recommended as part of routine care for Turner syndrome. Unexpectedly, all 30 metaphase cells evaluated had an extra copy of chromosome 18 with two copies of chromosome X, consistent with trisomy 18 (47,XX,+18). To confirm patient identity, patient DNA from this blood sample was tested for the presence of the previously identified NEB variants. Both variants were present in the blood sample, confirming mosaic double aneuploidy of 45,X/47,XX,+18.
Treatment and Management
Given this unexplained finding, exome sequencing data was re-evaluated and monosomy X was noted in 90-95% of the reads with only the paternal haplotype present. Review of select loci across the X chromosome showed the presence of a maternally inherited variant with a variant allele fraction between 5-10%. This data suggests there is low-level mosaicism for an XX cell line in the buccal specimen. Diploid biparental inheritance of chromosome 18 was observed, but this analysis may not sensitive enough to detect low level mosaicism for trisomy 18. Additional molecular studies are currently underway to assess level of mosaicism in varying tissues and the possibility of uniparental disomy.
Outcome and Follow-Up
Parental reaction to this dual diagnosis was understandably complex due to a rarity of this condition and accompanying uncertainty. Guidelines for the care of children with trisomy 18 and Turner syndrome are being referenced for long-term follow-up as clinically appropriate.
Discussion
Here we present a unique case of 45,X/47,XX,+18 mosaicism in a young female with hypotonia and motor delays, without other features of trisomy 18. A challenge remains determine the appropriate screening recommendations for this child, most significantly for solid tumor risk reported in individuals with complete trisomy 18. Recommendations include an abdominal ultrasound and serum AFP screening every 3 months for the first years of life, which is burdensome and challenging for families.
Conclusion
Given the rarity of this condition, updates to the previous case reports of double aneuploidy are currently being attempted in the hopes of expanding the natural history of 45X/47,XX,+18 in older individuals.
Mosaic double aneuploidy of monosomy X and trisomy 18 is a rare occurrence in live newborns and has only been reported in 7 cases in the medical literature since 1974. Presentation can vary from a predominantly Turner phenotype, to multiple congenital anomalies more suggestive of trisomy 18. Previous molecular genetic studies demonstrate the presence of both cell lines in multiple tissues, with trisomy 18 representative in leukocytes relative to alternative sample types. Mechanistically, a combination of meiotic and/or independent postzygotic events are theorized but have yet to be conclusively proven. Since the last publications in 2009, there have been an increase in techniques allowing us to determine mechanism of this rare condition.
Case Presentation
Our patient is a now 14 month old female who initially presented at 3 months of age for concerns of hypotonia, dysphagia, moderate secundum atrial septal defect, and poor growth. Pregnancy was significant for an abnormal prenatal ultrasound, showing a single umbilical artery and short femur length. Noninvasive prenatal testing reported a female fetus with low risk for aneuploidy (16% fetal fraction). Postnatal physical examination was not suggestive of a skeletal dysplasia (length >60th%ile), with deep palmar creases, larger ears, and hirsutism of the forehead noted. Neurologically the patient was active and engaged. Trio exome sequencing via buccal sample was coordinated, which reported monosomy X, or Turner syndrome, and biallelic rare variants of uncertain significance in the NEB gene. Given the degree of hypotonia, the possibility of a dual diagnosis of NEB-related myopathy and Turner syndrome was discussed.
Diagnostic Workup
A 30 cell count karyotype on leukocytes was recommended as part of routine care for Turner syndrome. Unexpectedly, all 30 metaphase cells evaluated had an extra copy of chromosome 18 with two copies of chromosome X, consistent with trisomy 18 (47,XX,+18). To confirm patient identity, patient DNA from this blood sample was tested for the presence of the previously identified NEB variants. Both variants were present in the blood sample, confirming mosaic double aneuploidy of 45,X/47,XX,+18.
Treatment and Management
Given this unexplained finding, exome sequencing data was re-evaluated and monosomy X was noted in 90-95% of the reads with only the paternal haplotype present. Review of select loci across the X chromosome showed the presence of a maternally inherited variant with a variant allele fraction between 5-10%. This data suggests there is low-level mosaicism for an XX cell line in the buccal specimen. Diploid biparental inheritance of chromosome 18 was observed, but this analysis may not sensitive enough to detect low level mosaicism for trisomy 18. Additional molecular studies are currently underway to assess level of mosaicism in varying tissues and the possibility of uniparental disomy.
Outcome and Follow-Up
Parental reaction to this dual diagnosis was understandably complex due to a rarity of this condition and accompanying uncertainty. Guidelines for the care of children with trisomy 18 and Turner syndrome are being referenced for long-term follow-up as clinically appropriate.
Discussion
Here we present a unique case of 45,X/47,XX,+18 mosaicism in a young female with hypotonia and motor delays, without other features of trisomy 18. A challenge remains determine the appropriate screening recommendations for this child, most significantly for solid tumor risk reported in individuals with complete trisomy 18. Recommendations include an abdominal ultrasound and serum AFP screening every 3 months for the first years of life, which is burdensome and challenging for families.
Conclusion
Given the rarity of this condition, updates to the previous case reports of double aneuploidy are currently being attempted in the hopes of expanding the natural history of 45X/47,XX,+18 in older individuals.