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PIK3CA-related Overgrowth Syndrome: To Exome or Not?

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
PIK3CA-related overgrowth syndrome (PROS) is a heterogenous disorder with early-onset asymmetric overgrowth with or without cellular dysplasia. The predominant overgrowth areas can include the brain, limbs, trunk and face. Cellular dysplasia can present as vascular anomalies, including capillary, venous, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Molecular diagnosis of PROS is challenging due to underlying somatic mosaicism and the diagnostic test utilized. Here, we describe a 12-month-old female with a diagnosis of PROS through exome sequencing (ES) performed on peripheral blood.

 

Case Presentation
A 12-month-old female who was born at 37 weeks gestational age presented with prenatal complications of macrocephaly, left hydrocephalus, enlarged abdomen, polyhydramnios and a 2-vessel umbilical cord. Pre-natal chromosomal microarray (CMA) and karyotype were both normal. The pregnancy and labor and delivery were otherwise uncomplicated. She was noted to have macrocephaly, right neck swelling with dysmorphic features at birth. Post-natal computed tomography of the head showed evidence of frontal bossing and prominence of the extra-axial fluid spaces with no evidence of hydrocephalus, parenchymal hemorrhage, midline shift or herniation. Renal ultrasound showed echogenic appearance in bilateral kidneys with moderate hydronephrosis of the left kidney with distension of the urinary tract which measured about 8 mm. A magnetic resonance imaging (MRI) of her brain at day 11 of life showed mild prominence of the extra-axial spaces overlying the bilateral frontal convexities and mild T1 hyperintense thickening at the posterior tentorium which no evidence of hydrocephalus.

 

Diagnostic Workup
She presented with fever and vomiting at nine months of age. A MRI brain showed mild hydrocephalus of the lateral ventricles with an enlarged cerebellum with an 9 mm herniation of the tonsils. Ophthalmological exam showed grade one papilledema in both eyes. Parents had also noticed that her left upper and lower limbs were larger than her right side. Subsequent MRI and magnetic resonance venography (MRV) of the brain showed similar moderate hydrocephalus with prominent cerebellar size without herniation. A neck ultrasound showed a superficial subcutaneous lesion measuring up to 1.3 cm consistent with a lymphaticovenous malformation. A targeted next generation sequencing (NGS) panel for RASopathies was sent which returned negative. In view of the concerns for an overgrowth syndrome, an exome sequencing was performed on peripheral blood which showed a mosaic, de novo pathogenic variant in exon 6 of the PIK3CA gene (NM_006218.2)(c.1133G>A, p.C378Y) in approximately 25% of 71 NGS reads.

 

Treatment and Management
At 11 months of age, she developed obstructive hydrocephalus requiring a ventriculoperitoneal shunt (VPS) insertion.  A repeat MRI brain showed persistent low-lying cerebellar tonsils which have not resolved and concerning for a Chiari I malformation.

Outcome and Follow-Up
Clinically, she has made significant developmental gains since her VPS insertion.

 

Discussion
Molecular confirmation of PROS is crucial as it has significant impact on the management and surveillance of each individual patient. A recent consensus statement for the standard of care of individuals with PROS (specifically for those with megalencephaly-capillary malformation-polymicrogyria syndrome) recommends a two-step process for diagnosis and to request a tissue biopsy of affected tissue only if the initial peripheral blood or saliva samples are negative.

 

Conclusion
This case highlights the possibility of establishing a molecular diagnosis of PROS through exome sequencing via peripheral blood in a patient with a phenotype highly suggestive of this disorder. Although, the diagnostic yield would depend on the depth of the sequencing and the degree of mosaicism in peripheral blood, given the relatively non-invasive nature of exome sequencing in peripheral blood, it could be considered as a first line testing in a patient with PROS without an affected tissue sample.

 

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