Abstract Children with certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. ...Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in other HM. For some hematopoietic malignancy predisposition (HMP) disorders, specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation (HSCT) can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by an HSCT specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The ...syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.
•There is a unique genotype-cancer association in FANCD1 and FANCN Fanconi anemia.•FANCN and FANCD1 Fanconi anemia patients often develop embryonic tumors early in life.•Mouse embryonic stem ...cell-based functional testing improves FANCD1 variant curation.
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and a cancer predisposition disorder. Cancers in FA include acute leukemia and solid tumors; the most frequent solid tumor is head and neck squamous cell carcinoma. FA is a primarily autosomal recessive disorder. Several of the genes in which biallelic pathogenic variants cause FA are also autosomal monoallelic cancer predisposition genes e.g. FANCD1 (BRCA2) and FANCN (PALB2). We observed that patients with FA due to biallelic or homozygous pathogenic variants in FANCD1 and FANCN have a unique cancer association. We curated published cases plus our NCI cohort cases, including 71 patients in the FANCD1 group (94 cancers and 69 variants) and 16 patients in the FANCN group (23 cancers and 20 variants). Only patients in FANCD1 and FANCN groups had one or more of these tumors: brain tumors (primarily medulloblastoma), Wilms tumor and neuroblastoma; this is a genotype-specific cancer combination of tumors of embryonal origin. Acute leukemias, seen in all FA genotypes, also occurred in FANCD1 and FANCN group patients at young ages. In silico predictions of pathogenicity for FANCD1 variants were compared with results from a mouse embryonic stem cell-based functional assay. Patients with two null FANCD1 variants did not have an increased frequency of cancer nor earlier onset of cancer compared with those with hypomorphic variants. Patients with FA and these specific cancers should consider genetic testing focused on FANCD1 and FANCN, and patients with these genotypes may consider ongoing surveillance for these specific cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical ...features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.
We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.
We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 56% cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts.
Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
National Institute of Health.
•We developed a machine-learning algorithm to guide differential diagnosis of BMF.•Acquired vs inherited prediction relied on 25 variables recorded through a comprehensive physical and laboratory ...evaluation at the time of first evaluation.
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The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A–specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.
Gutierrez-Rodrigues et al report on the development of a machine-learning model to distinguish inherited bone marrow failure syndromes from acquired aplastic anemia. The model performed well on a well-defined cohort of patients and is confirmed in an independent cohort with 89% accuracy in predicting inherited vs immune cases. The most important clinical variable in the score is telomere length. The authors have provided a link to an online tool to make the analysis available for practitioners.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre‐transplant short (<10th percentile‐for‐age) or very short (<5th or <1st ...percentile‐for‐age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre‐transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre‐HCT RTL <10th percentile‐for‐age, with the majority below the 5th percentile (N = 80, 71·43%). RTL <10th percentile‐for‐age was associated with a higher risk of post‐HCT mortality (hazard ratio HR = 1·78, 95% confidence interval CI=1·18–2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P > 0·10). Time‐dependent effects for post‐HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P < 0·0001, thereafter, P‐heterogeneity = 0·008; the corresponding HRs for RTL <1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P < 0·0001, P‐heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and ...patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene.
Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant NM_001363.4: c.1054A > G: p.Thr352Ala in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres 0.38, compared to a control median of 0.71 (range 0.44-1.19), which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing.
The novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being ...reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis ...congenita, Hoyeraal–Hreidarsson syndrome, Revesz syndrome, and Coats plus.
Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record.
Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor.
GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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