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.</p

Value of 18F-FES-PET to solve clinical dilemmas in breast cancer patients:a retrospective study

Background: Breast cancer (BC) is a heterogeneous disease, in which estrogen receptor (ER) expression plays an important role in the majority of breast 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-17β-estradiol (18F-FES) positron emission tomography (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 the value of 18F-FES-PET by evaluating if the physician's clinical dilemma that remained after standard workup was solved by the 18F-FES-PET scan. Methods: In this retrospective study, 18F-FES-PET scans, performed in patients with (suspected) ER+ metastatic BC with remaining clinical dilemma after standard workup, at the University Medical Center of Groningen between November 2009 and January 2019, were included. We investigated whether the physician's clinical dilemma was solved, defined as 1) 18F-FES-PET provided a solution for the clinical dilemma, and/or 2) a treatment decision was based directly on the 18F-FES-PET. In addition, category of clinical dilemma, and rate of 18F-FES positive or negative PET scans were reported, and related to frequency of solved dilemmas. Results: One hundred 18F-FES-PET scans were performed in 83 patients. Clinical dilemma categories were: 1) inability to determine extent of (suspected) metastatic disease with standard workup (n = 52), 2) unclear ER status of the tumor (n = 31), and 3) inability to determine which primary tumor caused metastases (n = 17). Dilemmas were solved by 18F-FES-PET in 87/100 cases (87%). In 81/87 cases a treatment decision was made based directly on the 18F-FES-PET (treatment change: n = 51 cases; continuance: n = 30 cases). 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 negative (n = 37; p<0.001). Conclusion: For various indications, the 18F-FES-PET scan can help to solve the vast majority of clinical dilemmas that may remain after standard workup. Therefore, the 18F-FES-PET scan has added value in BC patients presenting with a clinical dilemma

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders.</p

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

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders