Objective: Somatic mutations in PIK3CA cause segmental, progressive overgrowth of subcutaneous, muscular, skeletal and visceral
tissue, encompassing a condition termed PIK3CA-Related Overgrowth Spectrum (PROS). PROS is thought to occur due to somatic mutation
arising during embryonic development. Genetic testing of individuals is typically
performed on affected tissue specimens; thus, diagnosis is often in childhood or adolescence.
Literature regarding prenatal diagnosis for PROS is limited with two reports to our
knowledge. We present prenatal findings and genetic analysis of a fetus with PROS
adding to the published literature.
Methods: A 21-year-old woman, gravida 1, para 0 was referred for genetic counseling at 28w4d
due to multiple congenital anomalies. Notable findings included an abnormality of
the fetal body wall and left retroperitoneum most consistent with lymphatic malformation.
Prenatal ultrasound at our center was confirmatory also identifying abnormal toe positioning,
number. To explore the differential diagnosis of chromosomal abnormalities, Rasopathy,
and overgrowth syndromes including Proteus, PROS, or PTEN Hamartoma Tumor Syndrome, diagnostic testing via amniocentesis was pursued (SNParray,
a Rasopathy panel, and custom next generation sequencing panel including AKT1, PTEN, and PIK3CA).
Results: SNParray and Rasopathy panel results were negative. Custom genetic testing panel
identified a pathogenic missense variant PIK3CA c.3140A>G (p.His1047Arg) at an apparently heterozygous (~50%) allele fraction, 128x
coverage. This pathogenic variant occurred in a non-mosaic fashion. Other cell types
were not sampled from this individual as the molecular finding correlated well with
the fetus’ clinical features confirming a diagnosis of PROS.
Conclusion: Post-birth, the child's clinical history has continued to follow the natural history
of this condition. Literature review identified this variant in over 30 individuals
with PROS, two of whom developed Wilms tumor. Wilms tumor screening was recommended
and to date has been normal.
This case adds to the scant but growing literature regarding prenatal diagnosis for
PROS. Literature review identified two cases of prenatal PROS diagnosis. Emrick et
al (2014) report prenatal diagnosis of PROS by amniocyte culture. Fraissenon et al
(2020) recently described identifying PROS in the first trimester prior to a pregnancy
termination. Both cases highlight prenatal imaging findings of lymphatic malformation
and extremity abnormalities like our case. Treatment for patients with PROS currently
relies on supportive care. Efforts are underway to develop novel treatments for this
often progressive disease. Earlier diagnosis not only provides information for multidisciplinary
care and recurrence risk but may also allow for novel therapy options in the future.
