Challenges of genetic counseling in prenatal setting: follow up of a child born after conspicuous result for Pallister Killian Syndrome
Prenatal Genetics
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Primary Categories:
- Genetic Counseling
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Secondary Categories:
- Genetic Counseling
Introduction
Pallister Killian Syndrome (PKS) is a rare dysmorphic condition caused by mosaic tissue-limited presence of a supernumerary isochromosome 12p i(12)(p10) that determines 12p tetrasomy mostly related to advanced maternal age. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. The supernumerary isochromosome 12p is usually not detectable in blood lymphocyte cultures, but can be identified in skin fibroblasts and other tissues including buccal smears, chorionic villi and amniocytes. The tissue specificity and clinical variability of this mosaic syndrome may make diagnosis challenging.
Case Presentation
A subfertile couple presented for genetic counseling after two miscarriages at the woman´s age of 38 years. A chromosome analysis revealed a balanced translocation in the male partner (46,XY,t(9;13)(q21;q21)). Given her age and the parental translocation, the couple opted to pursue preimplantation diagnosis for the translocation and age related aneuploidies. A total of 17 blastocysts were analyzed, yet no viable results were obtained. Eight blastocysts examined exhibited aneuploidy, while 9 displayed an unbalanced paternal translocation. The patient elected to forego further fertility treatments and became pregnant naturally at the age of 40. A whole genome non-invasive prenatal testing (NIPT) was conducted at gestation week 12+4, revealing a 30 Mb gain in the short arm of chromosome 12 (12p). The fetal ultrasound was unremarkable.
Diagnostic Workup
To elucidate the result of the NIPT, an invasive diagnostic procedure was conducted. At 15+2 weeks of gestation, chorionic villus sampling was conducted, demonstrating a normal karyotype following short- and long-term culture as well as a rapid test (PCR). In contrast, the array-CGH revealed a gain of 12p of 34.2 Mb in 10% of the cells. At 17+3 weeks gestation, an amniocentesis was performed, yielding normal results. The rapid-test PCR did not indicate any anomalies. The fetal ultrasound did not reveal any discernible abnormalities.
Treatment and Management
In light of the amniocentesis results, a hypothesis of placenta-confined mosaicism was postulated, although the potential impact on the fetus could not be ascertained with absolute certainty. The couple chose to continue with the pregnancy. Further ultrasound analysis yielded negative results.
Outcome and Follow-Up
The infant was delivered without complications. At two years of age, the child is exhibiting typical developmental milestones.
Discussion
The prenatal diagnosis of PKS is challenging due to the wide range of possible abnormalities and the tissue-specific distribution of i(12p). In some instances, fetuses with PKS were diagnosed incidentally after karyotyping due to advanced maternal age. Moreover, ultrasound detection of fetal anomalies has been demonstrated to be a valuable addition in the diagnosis of PKS. In some cases, the pregnancies were terminated, while in others, the offspring were confirmed to have a phenotype for PKS, with some exhibiting abnormalities in tissues other than the blood. Our case demonstrated a low mosaic for 12p, which has not yet been documented in the existing literature. The couple opted to forego postnatal analysis of the child. The psychological impact during the diagnostic period was considerable, to the extent that the decision to perform the NIPT analysis was regretted.
Conclusion
This case highlights the importance of genetic counseling before prenatal tests as well as following a high-risk call on NIPT, particularly in light of the increasing capabilities of NIPT detection for sub-chromosomal deletions and duplications. Pre-test counseling should focus on explaining the different results that NIPT can generate. Parents who choose to undergo this test may be aware of its positive features, however, they may be less aware of the required decisions and accompanying internal conflicts that may arise following a potential positive test result.
Pallister Killian Syndrome (PKS) is a rare dysmorphic condition caused by mosaic tissue-limited presence of a supernumerary isochromosome 12p i(12)(p10) that determines 12p tetrasomy mostly related to advanced maternal age. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. The supernumerary isochromosome 12p is usually not detectable in blood lymphocyte cultures, but can be identified in skin fibroblasts and other tissues including buccal smears, chorionic villi and amniocytes. The tissue specificity and clinical variability of this mosaic syndrome may make diagnosis challenging.
Case Presentation
A subfertile couple presented for genetic counseling after two miscarriages at the woman´s age of 38 years. A chromosome analysis revealed a balanced translocation in the male partner (46,XY,t(9;13)(q21;q21)). Given her age and the parental translocation, the couple opted to pursue preimplantation diagnosis for the translocation and age related aneuploidies. A total of 17 blastocysts were analyzed, yet no viable results were obtained. Eight blastocysts examined exhibited aneuploidy, while 9 displayed an unbalanced paternal translocation. The patient elected to forego further fertility treatments and became pregnant naturally at the age of 40. A whole genome non-invasive prenatal testing (NIPT) was conducted at gestation week 12+4, revealing a 30 Mb gain in the short arm of chromosome 12 (12p). The fetal ultrasound was unremarkable.
Diagnostic Workup
To elucidate the result of the NIPT, an invasive diagnostic procedure was conducted. At 15+2 weeks of gestation, chorionic villus sampling was conducted, demonstrating a normal karyotype following short- and long-term culture as well as a rapid test (PCR). In contrast, the array-CGH revealed a gain of 12p of 34.2 Mb in 10% of the cells. At 17+3 weeks gestation, an amniocentesis was performed, yielding normal results. The rapid-test PCR did not indicate any anomalies. The fetal ultrasound did not reveal any discernible abnormalities.
Treatment and Management
In light of the amniocentesis results, a hypothesis of placenta-confined mosaicism was postulated, although the potential impact on the fetus could not be ascertained with absolute certainty. The couple chose to continue with the pregnancy. Further ultrasound analysis yielded negative results.
Outcome and Follow-Up
The infant was delivered without complications. At two years of age, the child is exhibiting typical developmental milestones.
Discussion
The prenatal diagnosis of PKS is challenging due to the wide range of possible abnormalities and the tissue-specific distribution of i(12p). In some instances, fetuses with PKS were diagnosed incidentally after karyotyping due to advanced maternal age. Moreover, ultrasound detection of fetal anomalies has been demonstrated to be a valuable addition in the diagnosis of PKS. In some cases, the pregnancies were terminated, while in others, the offspring were confirmed to have a phenotype for PKS, with some exhibiting abnormalities in tissues other than the blood. Our case demonstrated a low mosaic for 12p, which has not yet been documented in the existing literature. The couple opted to forego postnatal analysis of the child. The psychological impact during the diagnostic period was considerable, to the extent that the decision to perform the NIPT analysis was regretted.
Conclusion
This case highlights the importance of genetic counseling before prenatal tests as well as following a high-risk call on NIPT, particularly in light of the increasing capabilities of NIPT detection for sub-chromosomal deletions and duplications. Pre-test counseling should focus on explaining the different results that NIPT can generate. Parents who choose to undergo this test may be aware of its positive features, however, they may be less aware of the required decisions and accompanying internal conflicts that may arise following a potential positive test result.
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