Prenatal diagnosis of a rare immunodeficiency prompted by increased nuchal translucency
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Since the advent and near universal uptake of prenatal cell free DNA screening (cfDNA), the clinical utility of first trimester screening has been called into question and less patients are being referred. However, first trimester ultrasound and nuchal translucency (NT) measurement remain an important diagnostic tool. A recent study found that incorporation of first-trimester ultrasound to cfDNA screening identified an additional 5.4% of fetuses that required high risk surveillance. Increased nuchal translucency has been associated with the common aneuploidies, congenital heart disease, and hundreds of single gene disorders. This case highlights the importance of first trimester ultrasound in paving a path to early prenatal diagnosis of a rare potentially treatable disorder, as well as the synergistic diagnostic possibility when sent with expanded carrier screening in the setting of consanguinity.
Case Presentation
A 35 yo P3003, with no significant medical history yet known consanguinity with her partner (first cousins) presented for genetic consultation after first trimester revealed an increased nuchal translucency of 3.2mm.
Diagnostic Workup
Chorionic villus sampling was performed at 13w0d with normal routine testing (FISH, karyotype, and microarray). Expanded carrier screening revealed the couple to be carriers for the likely pathogenic c.3317+1G>A variant in CIITA, associated with Bare Lymphocyte Syndrome, and fetal CIITA analysis on CVS demonstrated homozygosity for the likely pathogenic variant, consistent with a diagnosis of Bare Lymphocyte Syndrome.
Treatment and Management
The patient and her partner were counseled that Bare Lymphocyte Syndrome, or MHC II Deficiency syndrome, is a rare primary immunodeficiency syndrome with >200 known cases to date. It is characterized by recurrent, severe respiratory and gastrointestinal tract infections, failure to thrive, and early mortality. Additional clinical manifestations of MHC II deficiency may include neurological symptoms, septicemia, and cutaneous infections. With supportive care alone, most patients fail to reach puberty and die of severe infections. Hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment; studies have historically shown a high rate of post-HSCT death because of severe infections, graft versus host diseases and organ failure, although recent studies demonstrate higher rates of overall survival due to factors such as HLA matching and younger age at transplantation. Option of pregnancy termination was discussed.
Following results disclosure, multi-disciplinary consultations were arranged with both pediatric immunology and transplant medicine. The autosomal recessive inheritance was reviewed, as well as future reproductive options including IVF with preimplantation genetic testing. The couple planned to notify their close relatives who are of reproductive age.
Outcome and Follow-Up
Prenatal diagnosis for the family has informed delivery planning and postnatal measures to prevent initial infections prior to anticipated HSCT. The patient currently follows with Fetal Medicine and HLA typing via amniocentesis is being considered for accelerated sibling matching.
Discussion
Immune deficiency has been associated with increased nuchal translucency, yet the mechanism remains unclear. Median age of diagnosis of Bare lymphocyte syndrome is typically 16 months, and median age of symptom onset is 4 months. Therefore, knowing this crucial and potentially lethal diagnosis in the prenatal period could be life-saving. To our knowledge, this is a rare case of prenatal diagnosis of Bare Lymphocyte Syndrome, which may not have occurred without the ultrasound finding if the couple declined carrier screening and subsequent diagnostic testing. With the expansion of carrier screening, especially in the setting of consanguinity, future studies can assess whether outcomes and survival improve when prenatal diagnosis is made. In addition, while the yield of prenatal exome sequencing has been shown to be ~1.4% in fetuses with isolated increased NT, the yield in pregnancies with known parental consanguinity and increased NT should be specifically studied.
Conclusion
Immunodeficiency should be considered in the differential of increased nuchal translucency measurement.
Since the advent and near universal uptake of prenatal cell free DNA screening (cfDNA), the clinical utility of first trimester screening has been called into question and less patients are being referred. However, first trimester ultrasound and nuchal translucency (NT) measurement remain an important diagnostic tool. A recent study found that incorporation of first-trimester ultrasound to cfDNA screening identified an additional 5.4% of fetuses that required high risk surveillance. Increased nuchal translucency has been associated with the common aneuploidies, congenital heart disease, and hundreds of single gene disorders. This case highlights the importance of first trimester ultrasound in paving a path to early prenatal diagnosis of a rare potentially treatable disorder, as well as the synergistic diagnostic possibility when sent with expanded carrier screening in the setting of consanguinity.
Case Presentation
A 35 yo P3003, with no significant medical history yet known consanguinity with her partner (first cousins) presented for genetic consultation after first trimester revealed an increased nuchal translucency of 3.2mm.
Diagnostic Workup
Chorionic villus sampling was performed at 13w0d with normal routine testing (FISH, karyotype, and microarray). Expanded carrier screening revealed the couple to be carriers for the likely pathogenic c.3317+1G>A variant in CIITA, associated with Bare Lymphocyte Syndrome, and fetal CIITA analysis on CVS demonstrated homozygosity for the likely pathogenic variant, consistent with a diagnosis of Bare Lymphocyte Syndrome.
Treatment and Management
The patient and her partner were counseled that Bare Lymphocyte Syndrome, or MHC II Deficiency syndrome, is a rare primary immunodeficiency syndrome with >200 known cases to date. It is characterized by recurrent, severe respiratory and gastrointestinal tract infections, failure to thrive, and early mortality. Additional clinical manifestations of MHC II deficiency may include neurological symptoms, septicemia, and cutaneous infections. With supportive care alone, most patients fail to reach puberty and die of severe infections. Hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment; studies have historically shown a high rate of post-HSCT death because of severe infections, graft versus host diseases and organ failure, although recent studies demonstrate higher rates of overall survival due to factors such as HLA matching and younger age at transplantation. Option of pregnancy termination was discussed.
Following results disclosure, multi-disciplinary consultations were arranged with both pediatric immunology and transplant medicine. The autosomal recessive inheritance was reviewed, as well as future reproductive options including IVF with preimplantation genetic testing. The couple planned to notify their close relatives who are of reproductive age.
Outcome and Follow-Up
Prenatal diagnosis for the family has informed delivery planning and postnatal measures to prevent initial infections prior to anticipated HSCT. The patient currently follows with Fetal Medicine and HLA typing via amniocentesis is being considered for accelerated sibling matching.
Discussion
Immune deficiency has been associated with increased nuchal translucency, yet the mechanism remains unclear. Median age of diagnosis of Bare lymphocyte syndrome is typically 16 months, and median age of symptom onset is 4 months. Therefore, knowing this crucial and potentially lethal diagnosis in the prenatal period could be life-saving. To our knowledge, this is a rare case of prenatal diagnosis of Bare Lymphocyte Syndrome, which may not have occurred without the ultrasound finding if the couple declined carrier screening and subsequent diagnostic testing. With the expansion of carrier screening, especially in the setting of consanguinity, future studies can assess whether outcomes and survival improve when prenatal diagnosis is made. In addition, while the yield of prenatal exome sequencing has been shown to be ~1.4% in fetuses with isolated increased NT, the yield in pregnancies with known parental consanguinity and increased NT should be specifically studied.
Conclusion
Immunodeficiency should be considered in the differential of increased nuchal translucency measurement.
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