Lifesaving diagnosis through prenatal genomic sequencing

Fennell AP; Roscioli T; Buckley M; Horton AE; Long S; harande P; Clucas LM

doi:10.1530/ey.22.15.1

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 15.1 | DOI: 10.1530/ey.22.15.1

ESPEYB25 15. Editors' Choice Genetics (9 abstracts)

15.1. Lifesaving diagnosis through prenatal genomic sequencing

Fennell AP , Roscioli T , Buckley M , Horton AE , Long S , Pharande P & Clucas LM

N Engl J Med 2025;393:93-95. PMID: 40601945 doi: 10.1056/NEJMc2506080

In Brief: This case report describes the management of a male infant born after prenatal genetic diagnosis of congenital thrombotic thrombocytopenic purpura (TTP) resulting in marked thrombocytopenia (platelet count, 8×10⁹/L) and severe hyperbilirubinemia. Antenatal diagnosis allowed urgent lifesaving interventions to be started within the first hour after birth. On follow-up at age 17 months, growth, development, and cardiac, renal, and hepatic function were normal.

Comment: This remarkable case report describes the power of anticipatory genetic testing to allow the timely implementation of essential, lifesaving healthcare. Prenatal trio exome sequencing had been undertaken at 31 weeks gestation to investigate left ventricular dilatation on antenatal ultrasound scan. This revealed the diagnosis of filamin C (FLNC)-related cardiomyopathy. A second, incidental genetic diagnosis of congenital TTP was made, due to compound heterozygous missense variants in ADAMTS13 (his ADAMTS13 activity measured at birth was <1%).

Congenital TTP is a severe, early-onset but treatable condition, and this newborn showed early radiographic evidence of microangiopathy, indicatingperipartum or prenatal sequelae of the disease. Early imaging showed a chronic internal jugular veinthrombosis, cerebral punctate haemorrhagic venous infarcts, small subdural haemorrhages, and appearance consistent with thrombosed small veins. He was given fresh frozen plasma (FFP) and intensive phototherapy within the first hour after birth. FFP was continued every 4-6 hours until Day 12 of life. He also had a platelet transfusion on Day 2 of life due to gastrointestinal bleeding. Coincidentally, recombinant ADAMTS13 therapy was approved by the US Food and Drug Administration only days before his delivery, but was available (on compassionate grounds) only from Day 15 onwards. This was continued weekly and the child has since been free of further TTP exacerbations.