Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes

Abstract

Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, a segmental overgrowth syndrome, is caused by post zygotic somatic mutations in PIK3CA, a gene involved in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. Prenatal ultrasound findings of lymphovascular malformations, segmental overgrowth and skeletal defects can raise suspicion for CLOVES syndrome, but molecular confirmation of PIK3CA mutations on prenatally obtained samples is challenging because of somatic mosaicism. We detected a mosaic disease-causing mutation in PIK3CA by sequencing of DNA extracted from cultured amniotic cells, but not from DNA directly prepared from an amniotic fluid sample in a fetus with prenatally suspected CLOVES syndrome. The infant was born prematurely and displayed severe lymphovascular malformations and segmental overgrowth consistent with a clinical diagnosis of CLOVES syndrome; he passed away at 29 days of life. We discuss the complexities and limitations of genetic testing for somatic mosaic mutations in the prenatal period and highlight the potential need for multiple approaches to arrive at a molecular diagnosis.

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

“…We have previous experience with a prenatal diagnosis of another PIK3CA ‐related segmental overgrowth disorder (CLOVES syndrome), where a mosaic mutation that was not detected on DNA prepared from amniocytes but became detectable after cell culture. We hypothesized that this was the result of a proliferative advantage in culture of the cells carrying the mutation . Focal cortical dysplasias are another class of brain malformations, with focal areas of dysplastic cortex abnormal gyri and sulci and caused by somatic mutations that activate the mTOR pathway.…”

A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

“…Ventriculomegaly may be seen with NIHF in the setting of aneuploidy as well as with genetic disorders such as Costello syndrome and PIK3CA ‐associated segmental overgrowth syndromes . The presence of ventriculomegaly should also prompt the investigation of viral etiologies, which may also present with this feature .…”

“…Cardiac arrhythmias may also lead to NIHF, with genetic etiologies including Costello, Barth, long QT, and Wolff‐Parkinson White syndromes . More rarely reported vascular disorders associated with NIHF include Klippel‐Trenaunay‐Weber syndrome, RASA1 ‐related disorders, and PIK3CA ‐associated segmental overgrowth syndromes . Further details as well as other more rare genetic etiologies of cardiovascular anomalies and NIHF are listed in Table .…”

“…Fetal movement disorders have also been associated with NIHF, including lethal multiple pterygium syndrome, fetal akinesia/hypokinesia sequence (Pena‐Shokeir type I), and myotonic dystrophy . Examples of specific abnormalities of the musculoskeletal system seen in disorders associated with NIHF are rocker bottom feet and clenched hands with trisomy 18, undermineralization of bone and fractures with osteogenesis imperfecta, shortened long bones with congenital disorders of glycosylation type 1, contractures with arthrogryposis, and limb asymmetry with PIK3CA ‐associated segmental overgrowth syndromes . Table lists further details of typical features associated with skeletal dysplasias and fetal akinesia sequences associated with NIHF.…”

“…Although skin manifestations beyond edema are quite rare in cases of NIHF, there are several that should be mentioned. Enlargement of soft tissues in the limb as well as lipomatous truncal masses can be seen in PIK3CA‐ associated mutations, and cutaneous cystic lesions with multiple pterygium and Klippel‐Trenaunay‐Weber syndromes . Severe cases of ichthyosis have been reported in the setting of NIHF with Neu‐Laxova, Gaucher, and sphingosine‐1‐phosphate lyase deficiency syndromes .…”