The presence of fetal and neonatal alloimmune thrombocytopenia (FNAIT) and other single-gene disorders may be associated with the occurrence of fetal intracranial hemorrhage (ICH), according to findings from a case report published recently in the journal Prenatal Diagnosis.
The case study describes the initial pregnancy of a 41-year-old woman who was referred for a fetal ICH that was detected. At the same time, she underwent a routine ultrasound examination at 31 weeks gestational age (GA). The ultrasound was performed to evaluate fetal growth in her pregnancy.
The patient’s family history comprised a remote paternal relative who had a history of ICH at an older age. An ultrasound conducted at 32 weeks’ GA revealed the presence of bilateral ICH and macrocephaly.
Magnetic resonance imaging (MRI) of the fetal brain at 32 weeks’ GA demonstrated “multiple compartment hemorrhage.” A large “left hemispheric multi-compartment hematoma with a heterogeneous appearance exerting significant mass effect” was observed as well. Also seen on MRI were a smaller right insular hemorrhage and a germinal matrix hemorrhage.
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Other tests conducted in the pregnant patient at 32 weeks’ GA included amniocentesis. A single nucleotide polymorphism (SNP) chromosomal microarray (CMA) and trio genome sequencing were initiated as well. Additional analyses included antibody evaluation for FNAIT, along with amniotic fluid polymerase chain reaction testing for cytomegalovirus, parvovirus, and toxoplasmosis.
Findings from FNAIT testing and possible viral causes were all negative. Results of CMA revealed “a variant of uncertain significance.” Further, “a region of homozygosity encompassing chromosome 1, consistent with isodisomy of chromosome 1” was reported. Genome sequencing showed “a likely pathogenic homozygous frameshift variant, c.1225dupG, in [the] MPL [variant].”
Of note, at the time the patient had undergone genetic testing, the presence of this variant had not been identified in an affected individual. Although other disease-causing loss-of-function variants had been reported downstream, the variant revealed was absent from large population datasets as well. In fact, the biological father was heterozygous for the MPL variant; the biological mother was wild-type for the variant.
The MPL gene is located on chromosome 1. In the setting of the uniparental disomy seen on CMA, autosomal MPL-linked congenital amegakaryocytic thrombocytopenia (CAMT) became unmasked. MPL-associated CAMT is a “rare autosomal recessive bone marrow failure syndrome.” Among individuals with CAMT, ICH diagnosed either in utero or following delivery has been reported.
This study demonstrates the “[i]llustrative value of broad testing with genome sequencing to detect rare causes of fetal [ICH], the authors concluded.
