Prenatal Findings of Mevalonate Kinase Deficiency in an MVK I268T Homozygous Fetus
Prenatal Genetics
-
Primary Categories:
- Prenatal Genetics
-
Secondary Categories:
- Prenatal Genetics
Introduction
Mevalonate Kinase Deficiency (MKD), associated with various degrees of decreased activity of this enzyme, encompasses a spectrum of diseases caused by variants in the MVK gene in autosomal recessive manner. The phenotypic severity depends on the specific combination of variants involved. On the one hand, cases on the mild end of the spectrum are marked by recurrent febrile attacks accompanied by mevalonic aciduria and other possible symptoms such as abdominal distress, joint involvement, headaches, skin lesions, and elevated serum IgD, with relatively asymptomatic periods in between. The most severe cases, on the other hand, include death in utero or during the first months or years of life accompanied by dysmorphic features, cerebellar atrophy associated with ataxia, failure to thrive, and developmental delay.
Case Presentation
A pregnant 37-year-old female of Moroccan ancestry with a history of 2 previous miscarriages (G3P0020) at 8 and 9 weeks of gestational age (GA) presented for a prenatal appointment with anatomy ultrasound (US) at 20 weeks and 2 days (20w2d) GA. The pregnancy had resulted from a natural menstrual cycle with the use of implantation enhancement and gestational support protocol including progesterone injections and IV infusions of fat emulsion. Pregnancy was complicated by advanced maternal age, hypothyroidism with thyroid hormone replacement), use of enoxaparin up to 14w GA, and consanguinity, whereby the parents were first cousins. Prenatal cfDNA screening (Panorama) showed low risk for aneuploidies. There had been no specific concerns about this pregnancy before this visit.
Diagnostic Workup
The anatomy US at 20w2d GA revealed thickened and enlarged placenta, fetal growth restriction (FGR), enlarged heart with thickened myocardium and possible ASD, large pericardial effusion, and bilateral clubbed feet. Attempts at amniocentesis 3 and 4 days later were both deferred due to oligohydramnios. Instead, samples were collected for prenatal whole-genome cfDNA screening (MaterniT Genome) as well as comprehensive carrier screens for both parents. At 20w6d GA, a fetal echocardiogram was unable to rule out non-immune hydrops fetalis (HF) due to pericardial effusion and middle cerebral artery (MCA) peak velocity just above 1.5x the median for gestational age. Subsequent at 21w5d and 22w1d additionally showed echogenic bowel and unilateral pleural effusion.
Treatment and Management
Based on poor pregnancy prognosis in the fetus with abnormal anatomical findings with likely genetic etiology, patient elected to terminate her pregnancy using an US-guided intracardiac KCl injection at 22w1d GA. At the time, the whole-genome cfDNA screen had yielded a negative result and the parental comprehensive carrier screen was still pending.
Outcome and Follow-Up
The termination procedure was uncomplicated. The surgical pathology report showed immature placenta with placentomegaly and hypocoiled 3-vessel umbilical cord with marginal insertion. The comprehensive carrier screen subsequently showed both parents to be carriers for MVK I268T. The chromosomal microarray of the fetal tissue detected 9 long contiguous stretches of homozygosity (LCHSs, >=3Mb) amounting to 3.98% of the genome, which included the entire MVK gene.
Discussion
The most common variant in the MVK gene causing MKD is V377I (estimated frequency 43-50%), followed by I268T (estimated frequency 8-15%), the latter of which is associated with strongly reduced enzyme activity and low protein levels. Accordingly, in the few cases previously described in the literature, homozygosity for the I268T variant has been shown to lead to severe phenotypes including neurological manifestations and significantly limited lifespan, if fetus survives through birth. Notably, HF, FGR, and GI complications have all been associated with MKD. No treatment has been previously shown to be effective for patients with this genotype.
Conclusion
This case presents highly valuable findings for future situations where parents who are both carriers for this potentially lethal deficiency may face a similarly difficult decision in the face of highly suggestive prenatal clinical findings.
Mevalonate Kinase Deficiency (MKD), associated with various degrees of decreased activity of this enzyme, encompasses a spectrum of diseases caused by variants in the MVK gene in autosomal recessive manner. The phenotypic severity depends on the specific combination of variants involved. On the one hand, cases on the mild end of the spectrum are marked by recurrent febrile attacks accompanied by mevalonic aciduria and other possible symptoms such as abdominal distress, joint involvement, headaches, skin lesions, and elevated serum IgD, with relatively asymptomatic periods in between. The most severe cases, on the other hand, include death in utero or during the first months or years of life accompanied by dysmorphic features, cerebellar atrophy associated with ataxia, failure to thrive, and developmental delay.
Case Presentation
A pregnant 37-year-old female of Moroccan ancestry with a history of 2 previous miscarriages (G3P0020) at 8 and 9 weeks of gestational age (GA) presented for a prenatal appointment with anatomy ultrasound (US) at 20 weeks and 2 days (20w2d) GA. The pregnancy had resulted from a natural menstrual cycle with the use of implantation enhancement and gestational support protocol including progesterone injections and IV infusions of fat emulsion. Pregnancy was complicated by advanced maternal age, hypothyroidism with thyroid hormone replacement), use of enoxaparin up to 14w GA, and consanguinity, whereby the parents were first cousins. Prenatal cfDNA screening (Panorama) showed low risk for aneuploidies. There had been no specific concerns about this pregnancy before this visit.
Diagnostic Workup
The anatomy US at 20w2d GA revealed thickened and enlarged placenta, fetal growth restriction (FGR), enlarged heart with thickened myocardium and possible ASD, large pericardial effusion, and bilateral clubbed feet. Attempts at amniocentesis 3 and 4 days later were both deferred due to oligohydramnios. Instead, samples were collected for prenatal whole-genome cfDNA screening (MaterniT Genome) as well as comprehensive carrier screens for both parents. At 20w6d GA, a fetal echocardiogram was unable to rule out non-immune hydrops fetalis (HF) due to pericardial effusion and middle cerebral artery (MCA) peak velocity just above 1.5x the median for gestational age. Subsequent at 21w5d and 22w1d additionally showed echogenic bowel and unilateral pleural effusion.
Treatment and Management
Based on poor pregnancy prognosis in the fetus with abnormal anatomical findings with likely genetic etiology, patient elected to terminate her pregnancy using an US-guided intracardiac KCl injection at 22w1d GA. At the time, the whole-genome cfDNA screen had yielded a negative result and the parental comprehensive carrier screen was still pending.
Outcome and Follow-Up
The termination procedure was uncomplicated. The surgical pathology report showed immature placenta with placentomegaly and hypocoiled 3-vessel umbilical cord with marginal insertion. The comprehensive carrier screen subsequently showed both parents to be carriers for MVK I268T. The chromosomal microarray of the fetal tissue detected 9 long contiguous stretches of homozygosity (LCHSs, >=3Mb) amounting to 3.98% of the genome, which included the entire MVK gene.
Discussion
The most common variant in the MVK gene causing MKD is V377I (estimated frequency 43-50%), followed by I268T (estimated frequency 8-15%), the latter of which is associated with strongly reduced enzyme activity and low protein levels. Accordingly, in the few cases previously described in the literature, homozygosity for the I268T variant has been shown to lead to severe phenotypes including neurological manifestations and significantly limited lifespan, if fetus survives through birth. Notably, HF, FGR, and GI complications have all been associated with MKD. No treatment has been previously shown to be effective for patients with this genotype.
Conclusion
This case presents highly valuable findings for future situations where parents who are both carriers for this potentially lethal deficiency may face a similarly difficult decision in the face of highly suggestive prenatal clinical findings.
)
)
)
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
)
){kind=logo}
)
)
)
)
)
)
){kind=logo}
){kind=logo}
){kind=logo}