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Reports of constitutional ring chromosome 22, r(22) are rare. Individuals with r(22) present similar features as those with the 22q13 deletion syndrome. The instability in the ring chromosome contributes to the development of variable phenotypes. Central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRTs) are rare, highly malignant tumor...
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... well a majority of the time. The patient weighed 7.4 kg (50th percentile), and was 65 cm tall (50th percentile). Results of the brain and abdominal ultrasound and the echocardiography revealed nonspecific findings. Cytogenetic analysis on peripheral blood lymphocytes revealed an r (22) in all analyzed cells, specifically 46,XY,r(22)(p13q13.3) ( Fig. 1). To specify the breakpoint, high-resolution microarray analysis was performed. Upon analyses of the genomic DNA using an Affymetrix Cytoscan 750K array analysis (Santa Clara, CA, USA), a 3.5-Mb deletion at 22q13.31q13.33 was revealed (Fig 2). However, the SMARCB1 (INI1/hSNF5) gene at 22q11.2, which lies proximal to the break point, was ...Similar publications
Atypical teratoid rhabdoid tumors of the central nervous system are rare, highly malignant, embryonal tumors most often occurring in children under age 3 years. Most are due to a somatic change in tumor suppressor gene SMARCB1 followed by a second-hit, typically loss of heterozygosity, best detected on immunohistochemical staining. Despite the note...
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... Complete somatic loss of SMARCB1 can lead to formation of a central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT; Byers et al., 2017). There are case reports of ATRT in individuals with ring chromosome 22 (Byers et al., 2017;Cho et al., 2014;Sathyamoorthi et al., 2009 (Ahn et al., 2020;Bisgaard et al., 2009;Mingbunjerdsuk et al., 2021). ...
Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.
... The same mechanism may also apply to other tumour-suppressor genes located on chromosome 22. Indeed, this has incidentally been reported for SMARCB1 (located at 22q11.23, formerly known as INI1), resulting in atypical teratoid rhabdoid tumours (AT/RT) (Cho et al., 2014;Byers et al., 2017). AT/RT of the central nervous system are rare and highly malignant embryonal tumours that most often occur in children under the age of 3 years. ...
... In total, five individuals with a ring chromosome 22 and AT/RT tumours were identified in the current literature (Rubio, 1997;Sathyamoorthi et al., 2009;De Amorim Bernstein et al., 2013;Cho et al., 2014;Byers et al., 2017). The median age at tumour presentation was 22 months (range 11 months-4 years). ...
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.
... AT/RT has been previously reported in patients with r22 (5)(6)(7)(8) and recently also in PMDS (OMIM# 606232) (9)(10)(11). Ring chromosome 22 syndrome is an autosomal anomaly with most features common to 22q13 deletion syndrome. ...
... To our knowledge, this is the first reported patient with PMDS and r22 that survived a childhood metastatic AT/RT. Furthermore, he is the third reported case of r22 and 22q13 deletion not including SMARCB1 associated to this rare malignant tumor (8,11). This underlines the importance of regular screening for early detection of central nervous system rhabdoid tumors in patients with r22 and deletion of 22q13 (although not involving mutations of the SMARCB1 gene). ...
Atypical teratoid/rhabdoid tumors (AT/RTs) in the rhabdoid tumor predisposition syndromes are most often caused by germline mutations of the SMARCB1 gene located in chromosome 22q11.2. Although rarely, it can also result from the constitutional ring chromosome 22 (r22): during mitosis the ring chromosome may lead to an increased rate of somatic mutations, resulting in rhabdoid tumor predispositions when the tumor-suppressor gene SMARCB1 is involved. Individuals with r22 may present similar features as those with Phelan-McDermid syndrome (PMDS) due to 22q13.3 deletion, including the SHANK3 gene. Despite several reports on AT/RT in children with r22 and/or PMDS have been published, the role of constitutional r22 as new oncogenic mechanism for AT/RT is still under investigation. There is not a lot of data available on therapeutic and prognostic implications of r22 in AT/RT and PMDS. Herein, we present the first case of a child with constitutional r22, PMDS and AT/RT of the brain, who is a long term survivor and is been treated with growth hormone. We also describe an unexpected adverse reaction to midazolam.
... The subsequent loss of INI1 protein expression comprises a relatively specific and sensitive diagnostic marker for ATRT. [3] ATRT to retain the SMARCB1/INI1 positivity is a very atypical and rare phenomenon. Bertozzi et al. have reported two cases of ATRT in which SMARCB1/INI1 staining was retained. ...
... AT/RT has been previously reported in patients with ring chromosome 22 (r(22)) [Rubio, 1997;Biegel et al., 1999;Korones et al., 1999;Cho et al., 2014] and Phelan-McDermid syndrome (PMS, OMIM# 606232) [Sathyamoorthi et al., 2009;De Amorim Bernstein et al., 2013]. Herein, we report a patient with Phelan-McDermid syndrome, constitutional ring chromosome 22, and CNS AT/RT. ...
... To date, four patients with AT/RT and r(22) have been described [Rubio, 1997;Biegel et al., 1999;Korones et al., 1999;Cho et al., 2014]. The patient described by Cho et al. [2014] had a 3.5 Mb deletion at 22q13.31q13.33; ...
... To date, four patients with AT/RT and r(22) have been described [Rubio, 1997;Biegel et al., 1999;Korones et al., 1999;Cho et al., 2014]. The patient described by Cho et al. [2014] had a 3.5 Mb deletion at 22q13.31q13.33; deletion breakpoints were either not investigated or noted for other cases [Bonaglia et al., 2011]. ...
Atypical teratoid rhabdoid tumors of the central nervous system are rare, highly malignant, embryonal tumors most often occurring in children under age 3 years. Most are due to a somatic change in tumor suppressor gene SMARCB1 followed by a second-hit, typically loss of heterozygosity, best detected on immunohistochemical staining. Despite the noteworthy genetic homogeneity of atypical teratoid rhabdoid tumors, relatively little is known about the oncogenic mechanisms that lead to biallelic inactivation of SMARCB1. Herein, we describe a patient with constitutional ring chromosome 22, Phelan–McDermid syndrome and atypical teratoid rhabdoid tumor of the brain. During mitosis, sister chromatids of a ring chromosome may form interlocking and dicentric rings, resulting in chromosomal loss, complex karyotypes, and ongoing somatic variation. We hypothesized that the inherent instability of the patient's ring chromosome could lead to mosaic monosomy chromosome 22, resulting in allelic inactivation of the tumor-suppressor gene SMARCB1 and AT/RT if a second-hit occurred. Utilizing high-density microarray technology to analyze peripheral blood and tumor tissue, we confirmed this oncogenic mechanism, previously undescribed in patients with atypical teratoid rhabdoid tumors. Our data demonstrate chromosomal loss as a consequence of ring chromosome instability serving as the first hit in oncogenesis. This rare but possibly under-recognized mechanism is important to note in children with ATRT and syndromic features. Further investigation is warranted to assess if this oncogenic mechanism has management and/or prognostic implications.
... Кариотипирование выявило кольцевую хромосому 22, при сравнительной геномной гибридизации выявлена мутация 22q13.31q13.33. Кариотип обоих родителей в норме [5]. Сходный случай описан у девочки в возрасте 4 лет [14]. ...
... К тому же у нескольких пациентов выявлены не только генетические, но и другие возможные причины эпилепсии (перенесенная перинатальная гипоксия, менингит). В данном исследовании не выявлена взаимосвязь между тяжестью эпилепсии и умственной отсталостью или расстройствами поведения [5]. ...
Phelan–McDermid syndrome (PMS) is a microdeletion syndrome associated with the loss of terminal segments in chromosome 22, sometimes with development of the ring chromosome 22. Clinical manifestations of PMS include epilepsy and mental disorders (autism, mental deficiency, lack of expressive speech, sleep disorders, mood disorders since adolescence). Neurologic status is characterized by diffuse muscle hypotonia since birth, delayed development of motor skills, functional gastrointestinal disorder. Children over 1 year develop autism spectrum disorders; they have a specific awkward gait with frequent falls and decreased sensitivity to pain. Severe delay in the development of verbal intelligence (when expressive speech is absent or represented by individual words) are typical for these patients. Epileptiform activity appearing in a form of benign epileptiform discharges of childhood is usually diagnosed in all PMS patients; epileptic seizures are documented in half of the cases. The disease is characterized by secondarily generalized, age-related epileptic seizures with oral-pharyngeal manifestations. In some cases epilepsy becomes drug-resistant. Current article describes 2 clinical cases of PMS.
... Atypical Teratoid/Rhabdoid Tumors (AT/RT) is a very rare and highly malignant embryonal tumor of central nervous system (CNS) and predominantly occurs in young children under 3 years old [8][9][10][11]. Characteristic feature of AT/RT is aberrations of the SMARCB1 (hSNF5/INI1) gene [8]. It was first decribed by Roker in 1996 and was introduced to the WHO brain tumor classification in 2000 [8]. ...
Lymphedema is a chronic progressive and multifactorial disorder of lymphatic vessels which is characterised by the regional accumulation of excessive amounts of protein-rich fluid in intersititial space. It may be primary as obstruction of lymphatic drainage due to genetic structural deformity of lymphatic vessels or secondary to infections, surgery, venous insufficiency, trauma and malignancy. Clinical manifestation may vary according to the underlying etiology and duration of pathogenesis.
We want to present a 2 month-old caucasian boy with a pink, slowly growing flaccid, protruding tumoral lesion on his neck that exists since birth. Punch biopsy specimen was consistent with lymphedema. Two weeks after the diagnosis he was taken to emergency service with a sudden onset nausea, vomiting and loss of consciousness, cranial computed tomography performed him and a 5x4 cm in diameter, heterogenous tumor was detected in posterior fossa. Because of accompanying symptoms of hydrocephalus, patient received an urgent operation. Excisional biopsy of the tumour was consistent with stage 4 atypical rhabdoid/teratoid tumor. Unfortunately patient was lost on postoperative day 0.
Atypical rhabdoid/teratoid tumour is a rare and highly aggressive tumour of central nervous system that is usually seen in infancy and early childhood. In our patient neck localized lymphedema was probably associated with cerebellar atypical rhabdoid/teratoid tumor. To our knowledge this is the first case report in the literature.
About 250 cases of ring chromosome 22 (RC22) have been reported in the literature. Approximately 90% of RC22 cases have a deletion of the terminal band, 22q13, compatible with the clinical diagnosis of Phelan-McDermid syndrome (PMS), previously called 22q13 deletion syndrome. The phenotype of these RC22 is consistent with PMS, with intellectual impairment, motor delays, neonatal hypotonia, absent or severely delayed speech, and minor dysmorphic features, although there is a greater predisposition to growth delay in RC22 than in simple deletion of 22q13. It is estimated that about 14% of individuals with PMS have a RC22 but this is likely to be an underestimate. Many individuals with deletion of 22q13 are now diagnosed by chromosomal microarray analysis (CMA), which does not detect the RC. A follow-up karyotype is required, and recommended, to detect the ring following the identification of a terminal deletion of chromosome 22 by CMA. It is imperative to determine if a ring is present, as the additional health risk of developing neurofibromatosis type 2 (NF2) and atypical teratoid rhabdoid tumors (ATRT) accompany the presence of a RC22 in individuals with PMS.
Phelan–McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development.
