Consensus recommendations on lymphedema in Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by deletions 22q13.3 or pathogenic variants in the SHANK3 gene. Lymphedema can be a clinical feature in 10–25% of individuals with PMS due to a deletion 22q13.3, but is not observed in those with a SHANK3 variant. This paper forms a part of the European consensus guideline for PMS and focuses on what is known regarding lymphedema in PMS in order to present clinical recommendations. The mechanism causing lymphedema in PMS is unknown. Lymphedema can be suggested by pitting oedema of the extremities or, in later stages, non-pitting swelling. It can occur already at a young age and be progressive if untreated, impacting daily functioning. Lymphedema can be treated using existing general multidisciplinary management guidelines, taking the functioning of the individual with PMS into account. Furthermore, well-known risk factors for the development of lymphedema as lack of physical activities and weight gain/obesity should be addressed. Diagnosis and treatment are best performed in a multidisciplinary centre of expertise.</p

Mechanism of Disease:Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis

Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). LDS and SGS have many similarities common to fibrillinopathies, specifically Marfan syndrome (MFS), which is caused by mutations in FBN1. Historically discriminating features of MFS from LDS and SGS are (1) the presence of ectopia lentis (the subluxation/dislocation of the ocular lens) and (2) the absence of craniosynostosis. Curiously, several instances of a seemingly novel syndrome involving only craniosynostosis and ectopia lentis have recently been reported to be caused by recessive mutations in ADAMTSL4, a poorly characterized gene as of yet. Here, we report on two new cases of craniosynostosis with ectopia lentis, each harboring recessive mutations in ADAMTSL4. We also discuss a proposed mechanism for the relationship between ADAMTSL4, FBN1, and TGFb pathway-related syndromes.</p

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

CHARGE syndrome and related disorders:A mechanistic link

CHARGE syndrome is an autosomal dominant malformation disorder caused by pathogenic variants in the chromatin remodeler CHD7. Affected are craniofacial structures, cranial nerves and multiple organ systems. Depending on the combination of malformations present, its distinction from other congenital disorders can be challenging. To gain a better insight into the regulatory disturbances in CHARGE syndrome, we performed RNA-Seq analysis on blood samples of 19 children with CHARGE syndrome and a confirmed disease-causing CHD7 variant in comparison to healthy control children. Our analysis revealed a distinct CHARGE syndrome pattern with downregulation of genes that are linked to disorders described to mimic the CHARGE phenotype, i.e. KMT2D and KDM6A (Kabuki syndrome), EP300 and CREBBP (Rubinstein-Taybi syndrome) and ARID1A and ARID1B (Coffin-Siris syndrome). Furthermore, by performing protein-protein interaction studies using co-immunoprecipitation, direct yeast-two hybrid and in situ proximity ligation assays, we could demonstrate an interplay between CHD7, KMT2D, KDM6A and EP300. In summary, our data demonstrate a mechanistic and regulatory link between the developmental disorders CHARGE-, Kabuki- and Rubinstein Taybi-syndrome providing an explanation for the overlapping phenotypes

Copy number variation in a hospital-based cohort of children with epilepsy

Objective: To evaluate the diagnostic yield of microarray analysis in a hospital-based cohort of children with seizures and to identify novel candidate genes and susceptibility loci for epilepsy. Methods: Of all children who presented with their first seizure in the University Medical Center Groningen (January 2000 through May 2013) (n = 1,368), we included 226 (17%) children who underwent microarray analysis before June 2014. All 226 children had a definite diagnosis of epilepsy. All their copy number variants (CNVs) on chromosomes 1-22 and X that contain protein-coding genes and have a prevalence of <1% in healthy controls were evaluated for their pathogenicity. Results: Children selected for microarray analysis more often had developmental problems (82% vs. 25%, p < 0.001), facial dysmorphisms (49% vs. 8%, p < 0.001), or behavioral problems (41% vs. 13%, p < 0.001) than children who were not selected. We found known clinically relevant CNVs for epilepsy in 24 of the 226 children (11%). Seventeen of these 24 children had been diagnosed with symptomatic focal epilepsy not otherwise specified (71%) and five with West syndrome (21%). Of these 24 children, many had developmental problems (100%), behavioral problems (54%) or facial dysmorphisms (46%). We further identified five novel CNVs comprising four potential candidate genes for epilepsy:MYT1L, UNC5D, SCN4B,andNRXN3. Significance: The 11% yield in our hospital-based cohort underscores the importance of microarray analysis in diagnostic evaluation of children with epilepsy

Understanding Behavior in Phelan-McDermid Syndrome

BackgroundPhelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare genetic disorder characterized by developmental delay, hypotonia and severely delayed speech. Behavioral difficulties are often reported in PMS, although knowledge of behavioral profiles and the interpretation of reported behavior remains limited. Understanding the meaning of behavior requires considering the context as well as other domains of functioning, for example the individual's level of cognitive, social and emotional development. Combining structured direct in-person neurodevelopmental assessments with contextual assessments to enable meaningful interpretations of reported behavior on functional dimensions across multiple units of analysis, as proposed by the RDoc framework, is essential. MethodsIn this article we present a structured multidisciplinary method of assessment through direct in-person neurodevelopmental assessments and assessment of contextual factors. Our study sample includes data of 33 children with an average age of 6.2 years (range 1.1 to 15.7) with PMS, obtained through individual in-person assessments in combination with parent informed questionnaires. We assessed developmental age using the Bayley-III, adaptive behavior was assessed with the Vineland screener, social-emotional development with the ESSEON-R and behavior by using the CBCL. ResultsOur results show a great deal of variability in phenotypic presentation with regard to behavior, symptom expression and symptom severity in individuals with PMS. The data on behavior is interpreted in the context of the individual's level of cognitive, adaptive development and the (genetic) context. Behavioral data showed high levels of withdrawn behavior and attention problems. More than half of the children showed borderline or clinical symptoms related to Autism Spectrum Disorder (ASD). ConclusionsThe interpretation of the meaning of certain behavior in PMS is often based on questionnaires and descriptions without taking the specific context of development into account. Combining questionnaires with direct in-person assessments measuring different domains of functioning should be considered a more accurate method to interpret the meaning of findings in order to understand behavior in rare genetic disorders associated with developmental delay such as PMS. Direct in-person assessment provides valuable and specific information relevant to understanding individual behavior and inform treatment as well as increase knowledge of the neurodevelopmental phenotype in individuals with PMS. More specific application of the proposed frameworks on behavior in PMS is desirable in making useful interpretations

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.</p

Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli–Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and, therefore, our approach is especially applicable to low- or middle-income countries

Changes in empowerment and anxiety of patients and parents during genetic counselling for epilepsy

Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents & rsquo; perspectives is, however, unknown. We studied the counseleereported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment - a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope - and anxiety. We asked patients or their parents (for those (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

The Results of CHD7 Analysis in Clinically Well-Characterized Patients with Kallmann Syndrome

Item does not contain fulltextCONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients