Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K-AKT-mTOR signaling pathway.

OBJECTIVES: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway. METHODS: We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid. RESULTS: During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K-AKT-mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA-related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11th case with HMEG. Four fetuses with limb overgrowth also had one or more lymphatic malformations (LM) and harbored a postzygotic PIK3CA variant. NGS on cultured amniocytes performed in 10 cases, of which nine had been found positive on analysis of pathological fetal tissue, showed variants in four, in either PIK3CA, PIK3R2 or AKT3. CONCLUSIONS: Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K-AKT-mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Cerebriform sebaceous nevus: a subtype of organoid nevus due to specific postzygotic FGFR2 mutations.

BACKGROUND: Postzygotic mutations in FGFR2 have been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans / rounded and velvety epidermal nevus and in two fetuses with papillomatous pedunculated sebaceous nevus (PPSN). OBJECTIVES: To determine the clinical and genetic characteristics of children with cerebriform, papillomatous and pedunculated variants of sebaceous nevi. METHODS: Infants diagnosed with sebaceous nevi characterized by a cerebriform, papillomatous and/or pedunculated morphology over a 10-year period (2010-2019) at three paediatric dermatology centres in Switzerland and France were included in this case series. Clinical and histological characteristics were assessed. Next-generation sequencing was used to assess for FGFR2 mutations. RESULTS: All nevi were located on the head, with a rounded or linear shape and a typical cerebriform, sometimes papillomatous and pedunculated, surface. No associated extracutaneous anomalies were found. Nevi harboured postzygotic mutations in the transmembrane domain of FGFR2 in 6/8 children (75%), either the known specific p.(Cys382Arg) mutation in 5 cases, or a novel mutation, p.(Val395Asp), in one. CONCLUSIONS: We found an exquisite genotype-phenotype correlation in these rare nevi, with specific postzygotic mutations in the transmembrane domain of FGFR2. As not all lesions were truly papillomatous and pedunculated, the term cerebriform sebaceous nevus (CSN) appears more suitable than PPSN to describe this entity. The cerebriform pattern of CSN is reminiscent of cutis gyrata, as seen in Beare-Stevenson syndrome, which is caused by closely related germline FGFR2 mutations. While clinically impressive, CSN seem to carry a good prognosis and a low risk for extracutaneous associations.

Performance of semiconductor sequencing platform for non-invasive prenatal genetic screening for fetal aneuploidy: results from a multicenter prospective cohort study in a clinical setting.

OBJECTIVE: To validate and evaluate the performance metrics of the high-throughput semiconductor sequencing platform, Ion Proton®, in non-invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting. METHODS: This prospective cohort study included 2505 pregnant women from eight academic genetics laboratories (695 high risk for trisomy 21 (risk ≥ 1/250) pregnancies in a validation study, and 1810 such pregnancies, without ultrasound anomalies, in a real-life NIPS clinical setting). Outcome was available for all cases in the validation cohort and for 521 in the clinical cohort. Cell-free DNA from plasma samples was sequenced using the Ion Proton sequencer, and sequencing data were analyzed using the open-access software, WISECONDOR. Performance metrics for detection of trisomies 21, 18 and 13 were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, and DEFRAG and SANEFALCON software). RESULTS: Results from both cohorts were consistent and their gestational age was not significantly different so their data were combined to increase the sample size for analysis. Sensitivities and specificities, respectively, were as follows: for trisomy 21, 98.3% (95% CI, 93.5-99.7%) and 99.9% (95% CI, 99.4-100%); for trisomy 18, 96.7% (95% CI, 80.9-99.8%) and 100% (95% CI, 99.6-100%); and for trisomy 13, 94.1% (95% CI, 69.2-99.7%) and 100% (95% CI, 99.6-100%). Our failure rate was 1.2% initially and as low as 0.6% after retesting some of the failed samples. Fetal fraction estimation by the RASSF1A assay was consistent with DEFRAG results, and both were adequate for routine diagnosis. CONCLUSIONS: We describe one of the largest studies evaluating Ion Proton-based NIPS and the first clinical study reporting pregnancy outcome in a large series of patients. This platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be implemented easily in any medical genetics laboratory. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Endocrine disorders in Woodhouse-Sakati syndrome: a systematic review of the literature.

First described in 1983, Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic disorder that leads to a spectrum of hypogonadal symptoms in adolescence. The responsible gene, DCAF17 located on chromosome 2q31.1, was discovered in 2008 and to date nine mutations have been reported in the literature. The aim of the study was to review WSS descriptively in the light of new case reports with focus on endocrine features. Phenotypic description of three patients (two females, one male) with WSS followed in the Endocrinology Department of the University Hospital of Nancy, France, and exhaustive review of the literature using the PUBMED database were performed. Of 72 patients from 29 families with documented WSS who were identified, 39 had undergone genetic testing. WSS was invariably associated with hypogonadism, decreased IGF1 and frontotemporal alopecia starting in childhood. In addition to this triad, some patients exhibited intellectual disabilities of varying severity (87 %), bilateral deafness (76 %), cervicofacial dystonia and limb pain (42 % of cases, rising to 89 % after 25 years) and diabetes (66 %, rising to 96 % after 25 years). The pathophysiology of WSS remains unclear.