Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Images: Atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea.

Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan. CITATION: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med. 2024;20(3):478-481.

A novel mobile health application to support cancer surveillance needs of patients and families with cancer predisposition syndromes.

BACKGROUND: At least 5%-10% of malignancies occur secondary to an underlying cancer predisposition syndrome (CPS). For these families, cancer surveillance is recommended with the goal of identifying malignancy earlier, in a presumably more curable form. Surveillance protocols, including imaging studies, bloodwork, and procedures, can be complex and differ based on age, gender, and syndrome, which adversely affect adherence. Mobile health (mHealth) applications (apps) have been utilized in oncology and could help to facilitate adherence to cancer surveillance protocols. METHODS: Applying a user-centered mobile app design approach, patients with a CPS and/or primary caregivers were interviewed to identify current methods for care management and barriers to compliance with recommended surveillance protocols. Broad themes from these interviews informed the design of the mobile app, HomeTown, which was subsequently evaluated by usability experts. The design was then converted into software code in phases, evaluated by patients and caregivers in an iterative fashion. User population growth and app usage data were assessed. RESULTS: Common themes identified included general distress surrounding surveillance protocol scheduling and results, difficulty remembering medical history, assembling a care team, and seeking resources for self-education. These themes were translated into specific functional app features, including push reminders, syndrome-specific surveillance recommendations, ability to annotate visits and results, storage of medical histories, and links to reliable educational resources. CONCLUSIONS: Families with CPS demonstrate a desire for mHealth tools to facilitate adherence to cancer surveillance protocols, reduce related distress, relay medical information, and provide educational resources. HomeTown may be a useful tool for engaging this patient population.

Nervous system (NS) Tumors in Cancer Predisposition Syndromes.

Genetic syndromes which develop one or more nervous system (NS) tumors as one of the manifestations can be grouped under the umbrella term of NS tumor predisposition syndromes. Understanding the underlying pathological pathways at the molecular level has led us to many radical discoveries, in understanding the mechanisms of tumorigenesis, tumor progression, interactions with the tumor microenvironment, and development of targeted therapies. Currently, at least 7-10% of all pediatric cancers are now recognized to occur in the setting of genetic predisposition to cancer or cancer predisposition syndromes. Specifically, the cancer predisposition rate in pediatric patients with NS tumors has been reported to be as high as 15%, though it can approach 50% in certain tumor types (i.e., choroid plexus carcinoma associated with Li Fraumeni Syndrome). Cancer predisposition syndromes are caused by pathogenic variation in genes that primarily function as tumor suppressors and proto-oncogenes. These variants are found in the germline or constitutional DNA. Mosaicism, however, can affect only certain tissues, resulting in varied manifestations. Increased understanding of the genetic underpinnings of cancer predisposition syndromes and the ability of clinical laboratories to offer molecular genetic testing allows for improvement in the identification of these patients. The identification of a cancer predisposition syndrome in a CNS tumor patient allows for changes to medical management to be made, including the initiation of cancer surveillance protocols. Finally, the identification of at-risk biologic relatives becomes feasible through cascade (genetic) testing. These fundamental discoveries have also broadened the horizon of novel therapeutic possibilities and have helped to be better predictors of prognosis and survival. The treatment paradigm of specific NS tumors may also vary based on the patient's cancer predisposition syndrome and may be used to guide therapy (i.e., immune checkpoint inhibitors in constitutional mismatch repair deficiency [CMMRD] predisposition syndrome) [8]. Early diagnosis of these cancer predisposition syndromes is therefore critical, in both unaffected and affected patients. Genetic counselors are uniquely trained master's level healthcare providers with a focus on the identification of hereditary disorders, including hereditary cancer, or cancer predisposition syndromes. Genetic counseling, defined as "the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease" plays a vital role in the adaptation to a genetic diagnosis and the overall management of these diseases. Cancer predisposition syndromes that increase risks for NS tumor development in childhood include classic neurocutaneous disorders like neurofibromatosis type 1 and type 2 (NF1, NF2) and tuberous sclerosis complex (TSC) type 1 and 2 (TSC1, TSC2). Li Fraumeni Syndrome, Constitutional Mismatch Repair Deficiency, Gorlin syndrome (Nevoid Basal Cell Carcinoma), Rhabdoid Tumor Predisposition syndrome, and Von Hippel-Lindau disease. Ataxia Telangiectasia will also be discussed given the profound neurological manifestations of this syndrome. In addition, there are other cancer predisposition syndromes like Cowden/PTEN Hamartoma Tumor Syndrome, DICER1 syndrome, among many others which also increase the risk of NS neoplasia and are briefly described. Herein, we discuss the NS tumor spectrum seen in the abovementioned cancer predisposition syndromes as with their respective germline genetic abnormalities and recommended surveillance guidelines when applicable. We conclude with a discussion of the importance and rationale for genetic counseling in these patients and their families.

Acute myeloid leukemia and dilated cardiomyopathy in a pediatric patient with D-2-hydroxyglutaric aciduria type I.

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D-2-hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D-2-HGA. Murine models have demonstrated how D-2-hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D-2-HGA type I, who was treated with an anthracycline-free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long-term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D-2-HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.

Comprehensive Genomic Profiling of High-Risk Pediatric Cancer Patients Has a Measurable Impact on Clinical Care.

PURPOSE: Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined. METHODS: We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors. RESULTS: We identified somatic tumor alterations in 121/127 (95.3%) tumor samples and identified cancer predisposition syndromes on the basis of known pathogenic or likely pathogenic germline mutations in cancer predisposition genes in 9/126 patients (7.1%). Additionally, we developed a novel scoring system for measuring the impact of tumor and germline sequencing, encompassing therapeutically relevant genomic alterations, cancer-related germline findings, recommendations for treatment, and refinement of risk stratification or prognosis. At least one impactful finding from the genomic results was identified in 108/127 (85%) samples sequenced. A recommendation to consider a targeted agent was provided for 82/126 (65.1%) patients. Twenty patients ultimately received therapy with a molecularly targeted agent, representing 24% of those who received a targeted agent recommendation and 16% of the total cohort. CONCLUSION: Paired tumor/normal whole-exome sequencing and tumor RNA Seq of de novo or relapsed/refractory tumors was feasible and clinically impactful in high-risk pediatric cancer patients.

Reticular Dysgenesis: A Rare Immunodeficiency in a Neonate With Cytopenias and Bacterial Sepsis.

Severe combined immunodeficiency (SCID) consists of a group of disorders defined by abnormal B and T cell development that typically results in death within the first year of life if undiagnosed or untreated. Reticular dysgenesis (RD) is a rare but especially severe form of SCID that is caused by adenylate kinase 2 deficiency and is characterized not only by lymphopenia but also by profound neutropenia. RD predisposes patients to viral and fungal infections typical of SCID as well as serious bacterial infections atypical in the neonatal period in other SCID types. RD is also associated with sensorineural hearing loss not typically seen in other forms of SCID. Without rapid diagnosis and curative hematopoietic stem cell transplantation, RD is fatal within days to months due to overwhelming bacterial infection. The inclusion of the T cell receptor excision circle assay nationally in 2017 on the newborn screen has facilitated diagnosis of SCID in the neonatal period. This case reports on a male infant with RD who presented after preterm birth with severe cytopenias and a gastrointestinal anomaly and ultimately developed severe bacterial sepsis. Postmortem bone marrow evaluation and panel-based gene sequencing identifying 2 novel variants in the adenylate kinase 2 gene provided confirmation for a diagnosis of RD. This case emphasizes the importance of thorough diagnostic evaluation, including the newborn screen, in neonates and infants with persistent and unexplained cytopenias. Prompt hematology and/or immunology referral is advised for disease management and to facilitate hematopoietic stem cell transplantation to optimize long-term survival.

Cancer Predisposition in Neonates and Infants: Recognition, Tumor Types, and Surveillance.

Pediatric cancer is rare, and malignancy during the neonatal period even rarer. However, several malignancies can present in infancy, most commonly in the form of solid tumors. Specific cancer types, bilateral or multifocal disease, associated congenital malformations, and/or cancers in close relatives may herald a diagnosis of an underlying cancer predisposition syndrome. For many patients, surveillance protocols are recommended beginning at birth or during the course of maternal prenatal care. Advantages and disadvantages of genetic testing and surveillance should be discussed with families using a multidisciplinary approach, with input from a genetic counselor with expertise in pediatric cancer predisposition.

Cancer genetic counseling for childhood cancer predisposition is associated with improved levels of knowledge and high satisfaction in parents.

Previous surveys of adults with cancer have revealed increased levels of genetic knowledge, varying levels of worry, and high satisfaction with cancer genetic counseling. We sought to determine the impact of cancer genetic counseling on parental levels of genetic knowledge, worry about cancer, and satisfaction in the context of suspected cancer predisposition in a child. We hypothesized that parents would be satisfied with cancer genetic counseling and that cancer genetic counseling would improve baseline parental genetic knowledge and decrease levels of worry. Parents were recruited from a pediatric cancer predisposition clinic in the United States. A survey was administered to two cohorts: One cohort had received cancer genetic counseling in the past and only completed one survey (post-only, n = 26), and another cohort completed the survey before and after cancer genetic counseling (pre/post, n = 23). The survey included questions on demographics, knowledge of genetics, worry levels, and satisfaction with the cancer genetic counseling service. The post-genetic counseling survey also contained a free-text section for parents to indicate what they took away from the sessions. Parental levels of genetics knowledge increased by an average of 1.9 points (p = .01), with 65.2% of parents demonstrating an increase in genetics knowledge score. Average worry levels did not change significantly (p = .37), with 52.2% of parents indicating decreased worry, and 34.8% indicating increased worry. Overall, 91.8% of parents reported high levels of satisfaction. Our results show that cancer genetic counseling in a pediatric cancer predisposition clinic improves parental levels of genetics knowledge. Satisfaction rates suggest that parents find this service beneficial. These results demonstrate the positive impacts of cancer genetic counseling on parents of children in which a hereditary cancer syndrome is known or suspected.

Germline Genetics and Childhood Cancer: Emerging Cancer Predisposition Syndromes and Psychosocial Impacts.

PURPOSE OF REVIEW: Germline genetic variants contribute to a substantial proportion of cases of cancer in childhood. The purpose of this review is to describe two emerging pediatric cancer predisposition syndromes, including published surveillance protocols, as well as the psychological impacts related to childhood cancer predisposition. RECENT FINDINGS: DICER1 syndrome is pleotropic, predisposing to a variety of tumors and likely phenotypically broader than currently realized. Rhabdoid tumor predisposition syndrome carries a risk for development of aggressive malignancies occurring in nearly any tissue. New pediatric hereditary cancer syndromes are likely to be identified as genetic evaluation evolves. Advantages and disadvantages of genetic testing and surveillance protocols need to be discussed with patients and families in a team-based approach, with the input of a genetic counselor holding expertise in pediatric cancer predisposition. Finally, literature on psychosocial impacts of hereditary cancer syndromes in pediatric patients is sparse, necessitating further research.

Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome.

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.