Persistent clenched hands with or without adducted thumbs, a fetal ultrasound finding in neuronopathic Gaucher disease
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction:
Fetal diagnosis of neuronopathic Gaucher (nGaucher) is most often made in the setting of a positive family history or, less commonly, positive carrier screening. Prenatal ultrasound findings are not well defined, but vary broadly from no abnormalities to hydrops fetalis. Appreciating subtle features of this disease on prenatal ultrasound is important for expanding the fetal phenotype. In our experience with a clinical trial and prospective registry of pregnancies with lysosomal storage disorders (LSDs), we observed a potential association between nGaucher and fetal clenched hands with or without adducted thumbs. We sought to understand the potential association of this prenatal finding in cases of confirmed nGaucher.
Methods:
Our center is enrolling for a Phase I FDA approved study to understand the utility of in utero enzyme replacement therapy (ERT) for lysosomal storage disorders (LSDs), as well as a prospective registry of patients with prenatally diagnosed LSDs to improve our understanding of prenatal phenotypes and natural history of these conditions. The diseases covered in these protocols include mucopolysaccharidosis (MPS) types I, II, IVa, VI and VII, nGaucher, infantile onset Pompe disease (IOPD) and Wolman disease. We reviewed available second and third trimester 2 and 3-D ultrasounds performed in pregnancies with a fetal diagnosis of nGaucher to identify the frequency of persistently clenched hands with or without adducted thumbs.
Results:
There were 6 pregnancies affected with nGaucher enrolled in our LSD patient registry. Five of these resulted in a livebirth and 1 pregnancy was terminated at 18 weeks’ gestation. Detailed prenatal imaging was available to review for 3 of the 6 pregnancies and we report the findings in those 3 pregnancies here. One of these 3 fetuses received in utero ERT through our clinical trial, while the other 2 were not treated in utero. The genotypes in GBA of these pregnancies were homozygous c.1448T>C (p.Leu483Pro; historic nomenclature p.L444P) in one case; two cases were both compound heterozygous for recombinant allele, Rec Int-2 and c.887G>A, p.Arg296Gln. Anatomical surveys were normal with the exception of persistently and bilaterally clenched hands with or without adducted thumbs in all 3 fetuses. In the fetus that received in utero ERT, we detected resolution of adducted thumbs after three in utero ERT procedures. Brain MRI was normal before and after birth. This patient was born at term and demonstrated mobile thumbs without fist clenching, although the thumbs were in a partially adducted position.
Conclusion:
Observation of persistent hand clenching and/or adducted thumbs can suggest the presence of neuronopathic disease even in the absence of structural brain anomalies; in such patients, genetic testing (such as gene panels or exome sequencing after a non-diagnostic chromosome microarray) to uncover monogenic etiologies including nGaucher should be considered. We recommend special attention to fetal imaging of the hands to identify fetuses with persistently clenched hands with or without adducted thumbs that may be at risk for a neuronopathic disease specific phenotype. Recognition of this association is particularly important given the limited utilization of carrier screening that includes these conditions and the emerging availability of prenatal and neonatal therapies. Improvement of adducted thumbs in one patient who received in utero ERT suggests these neurologic changes may be reversible in the prenatal period, particularly when initiated prior to the formation of the blood-brain barrier. Monitoring of this finding in those receiving in utero ERT may be useful to understand impact of treatment. Further study of disease-specific prenatal phenotypes through patient registries is critical to improve our understanding of this association with nGaucher and other neuronopathic conditions.
Fetal diagnosis of neuronopathic Gaucher (nGaucher) is most often made in the setting of a positive family history or, less commonly, positive carrier screening. Prenatal ultrasound findings are not well defined, but vary broadly from no abnormalities to hydrops fetalis. Appreciating subtle features of this disease on prenatal ultrasound is important for expanding the fetal phenotype. In our experience with a clinical trial and prospective registry of pregnancies with lysosomal storage disorders (LSDs), we observed a potential association between nGaucher and fetal clenched hands with or without adducted thumbs. We sought to understand the potential association of this prenatal finding in cases of confirmed nGaucher.
Methods:
Our center is enrolling for a Phase I FDA approved study to understand the utility of in utero enzyme replacement therapy (ERT) for lysosomal storage disorders (LSDs), as well as a prospective registry of patients with prenatally diagnosed LSDs to improve our understanding of prenatal phenotypes and natural history of these conditions. The diseases covered in these protocols include mucopolysaccharidosis (MPS) types I, II, IVa, VI and VII, nGaucher, infantile onset Pompe disease (IOPD) and Wolman disease. We reviewed available second and third trimester 2 and 3-D ultrasounds performed in pregnancies with a fetal diagnosis of nGaucher to identify the frequency of persistently clenched hands with or without adducted thumbs.
Results:
There were 6 pregnancies affected with nGaucher enrolled in our LSD patient registry. Five of these resulted in a livebirth and 1 pregnancy was terminated at 18 weeks’ gestation. Detailed prenatal imaging was available to review for 3 of the 6 pregnancies and we report the findings in those 3 pregnancies here. One of these 3 fetuses received in utero ERT through our clinical trial, while the other 2 were not treated in utero. The genotypes in GBA of these pregnancies were homozygous c.1448T>C (p.Leu483Pro; historic nomenclature p.L444P) in one case; two cases were both compound heterozygous for recombinant allele, Rec Int-2 and c.887G>A, p.Arg296Gln. Anatomical surveys were normal with the exception of persistently and bilaterally clenched hands with or without adducted thumbs in all 3 fetuses. In the fetus that received in utero ERT, we detected resolution of adducted thumbs after three in utero ERT procedures. Brain MRI was normal before and after birth. This patient was born at term and demonstrated mobile thumbs without fist clenching, although the thumbs were in a partially adducted position.
Conclusion:
Observation of persistent hand clenching and/or adducted thumbs can suggest the presence of neuronopathic disease even in the absence of structural brain anomalies; in such patients, genetic testing (such as gene panels or exome sequencing after a non-diagnostic chromosome microarray) to uncover monogenic etiologies including nGaucher should be considered. We recommend special attention to fetal imaging of the hands to identify fetuses with persistently clenched hands with or without adducted thumbs that may be at risk for a neuronopathic disease specific phenotype. Recognition of this association is particularly important given the limited utilization of carrier screening that includes these conditions and the emerging availability of prenatal and neonatal therapies. Improvement of adducted thumbs in one patient who received in utero ERT suggests these neurologic changes may be reversible in the prenatal period, particularly when initiated prior to the formation of the blood-brain barrier. Monitoring of this finding in those receiving in utero ERT may be useful to understand impact of treatment. Further study of disease-specific prenatal phenotypes through patient registries is critical to improve our understanding of this association with nGaucher and other neuronopathic conditions.