Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22.

This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in SHANK3. It is one of a series of papers written by the European PMS consortium as a consensus guideline. We reviewed the available literature based on pre-set questions to formulate recommendations on counselling, diagnostic work-up and surveillance for tumours related to ring chromosome 22. All recommendations were approved by the consortium, which consists of professionals and patient representatives, using a voting procedure. PMS can only rarely be diagnosed based solely on clinical features and requires confirmation via genetic testing. In most cases, the family will be referred to a clinical geneticist for counselling after the genetic diagnosis has been made. Family members will be investigated and, if indicated, the chance of recurrence discussed with them. Most individuals with PMS have a de novo deletion or a pathogenic variant of SHANK3. The 22q13.3 deletion can be a simple deletion, a ring chromosome 22, or the result of a parental balanced chromosomal anomaly, influencing the risk of recurrence. Individuals with a ring chromosome 22 have an increased risk of NF2-related schwannomatosis (formerly neurofibromatosis type 2) and atypical teratoid rhabdoid tumours, which are associated with the tumour-suppressor genes NF2 and SMARCB1, respectively, and both genes are located on chromosome 22. The prevalence of PMS due to a ring chromosome 22 is estimated to be 10-20%. The risk of developing a tumour in an individual with a ring chromosome 22 can be calculated as 2-4%. However, those individuals who do develop tumours often have multiple. We recommend referring all individuals with PMS and their parents to a clinical geneticist or a comparably experienced medical specialist for genetic counselling, further genetic testing, follow-up and discussion of prenatal diagnostic testing in subsequent pregnancies. We also recommend karyotyping to diagnose or exclude a ring chromosome 22 in individuals with a deletion 22q13.3 detected by molecular tests. If a ring chromosome 22 is found, we recommend discussing personalised follow-up for NF2-related tumours and specifically cerebral imaging between the age of 14 and 16 years.

Parental perspectives on Phelan-McDermid syndrome: Results of a worldwide survey.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder characterised by hypotonia, speech problems, intellectual disability and mental health issues like regression, autism and mood disorders. In the development, implementation and dissemination of a new clinical guideline for a rare genetic disorder like PMS, the parental experienced perspective is essential. As information from literature is scarce and often conflicting the European Phelan-McDermid syndrome guideline consortium created a multi-lingual survey for parents of individuals with PMS to collect their lived experiences with care needs, genotypes, somatic issues, mental health issues and parental stress. In total, we analysed 587 completed surveys from 35 countries worldwide. Based on parental reporting, PMS appeared to be caused by a deletion of chromosome 22q13.3 in 78% (379/486) of individuals and by a variant in the SHANK3 gene in 22% (107/486) of the individuals. Parents reported a wide variety of developmental, neurological, and other clinical issues in individuals with PMS. The most frequently experienced issues were related to speech and communication, learning disabilities/intellectual disability, and behaviour. While most reported issues were present across all age groups and genotypes, the prevalence of epilepsy, lymphoedema, and mental health issues do appear to vary with age. Developmental regression also appeared to begin earlier in this cohort than described in literature. Individuals with PMS due to a 22q13.3 deletion had a higher rate of kidney issues and lymphoedema compared to individuals with SHANK3 variants. Parental stress was high, with specific contributing factors being child and context related in accordance with the PMS phenotype. The survey results led to various validated recommendations in the European PMS guideline including an age specific surveillance scheme, specific genetic counselling, structured healthcare evaluations on sleep and communication and a focus on family well-being.

Value of 18F-FES PET in Solving Clinical Dilemmas in Breast Cancer Patients: A Retrospective Study.

Breast cancer (BC) is a heterogeneous disease in which estrogen receptor (ER) expression plays an important role in most tumors. A clinical dilemma may arise when a metastasis biopsy to determine the ER status cannot be performed safely or when ER heterogeneity is suspected between tumor lesions. Whole-body ER imaging, such as 16α-18F-fluoro-17ß-estradiol (18F-FES) PET, may have added value in these situations. However, the role of this imaging technique in routine clinical practice remains to be further determined. Therefore, we assessed whether the physician's remaining clinical dilemma after the standard workup was solved by the 18F-FES PET scan. Methods: This retrospective study included 18F-FES PET scans of patients who had (or were suspected to have) ER-positive metastatic BC and for whom a clinical dilemma remained after the standard workup. The scans were performed at the University Medical Center of Groningen between November 2009 and January 2019. We investigated whether the physician's clinical dilemma was solved, defined either as solving the clinical dilemma through the 18F-FES PET results or as basing a treatment decision directly on the 18F-FES PET results. In addition, the category of the clinical dilemma was reported, as well as the rate of 18F-FES-positive or -negative PET scans, and any correlation to the frequency of solved dilemmas was determined. Results: One hundred 18F-FES PET scans were performed on 83 patients. The clinical dilemma categories were inability to determine the extent of metastatic disease or suspected metastatic disease with the standard workup (n = 52), unclear ER status of the tumor (n = 31), and inability to determine which primary tumor caused the metastases (n = 17). The dilemmas were solved by 18F-FES PET in 87 of 100 scans (87%). In 81 of 87 scans, a treatment decision was based directly on 18F-FES PET results (treatment change, 51 scans; continuance, 30 scans). The frequency of solved dilemmas was not related to the clinical dilemma category (P = 0.334). However, the frequency of solved dilemmas was related to whether scans were 18F-FES-positive (n = 63) or 18F-FES-negative (n = 37; P < 0.001). Conclusion: For various indications, the 18F-FES PET scan can help to solve most clinical dilemmas that may remain after the standard workup. Therefore, the 18F-FES PET scan has added value in BC patients who present the physician with a clinical dilemma.