Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non‐oncologic disorders

Botto, Lorenzo D.; Meeths, Marie; Campos‐Xavier, Belinda; Bergamaschi, R.; Mazzanti, Laura; Scarano, Emanuela; Finocchi, Andrea; Cancrini, Caterina; Zirn, Birgit; Kühnle, Ingrid; Kramm, Christof M.; Alanay, Yasemin; Jones, Wendy D.; Irving, Melita; Sabir, Ataf; Henter, Jan Inge; Borgström, Birgit; Nordgren, Ann; Hammarsjö, Anna; Putti, Caterina; Mozzato, Chiara; Zuccarello, Daniela; Nishimura, Gen; Bonafé, Luisa; Grigelioniené, Giedré; Unger, Sheila; Superti‐Furga, Andrea

doi:10.1002/ajmg.a.62021

Cited by 4 publications

(12 citation statements)

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“…WES (and subsequent WGS) was negative for a skeletal cause. An international group of SD experts noted the similarity of this case and several others, concluding a potentially new disorder manifesting with growth failure and a chondrodysplasia phenocopy post early HSCT for non-oncological disorders [ 26 ]. This case highlights the utility of WES to reduce the likelihood of a genetic cause significantly and increase the confidence of an acquired cause [ 26 ].…”

Section: Discussionmentioning

confidence: 89%

“…Secondly, patient 13, is potentially the fifth reported family with AREXT2 syndrome providing further expansion of the phenotype. Lastly, patient 15, is one of seven patients who have collectively provided evidence for a new disease, ‘chondrodysplasia phenocopy post early HSCT for non-oncological disorders’ and has been submitted for publication [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

et al. 2021

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Background Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. Methods We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. Results Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. Conclusions Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

et al. 2021

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“…An international group of SD experts noted the similarity of this case and several others concluded a potentially new disorder is manifesting with growth failure and a chondrodysplasia phenocopy post early HSCT for non-oncological disorders. 26 This case highlights the utility of WES to reduce the likelihood of a genetic cause signi cantly and increase the con dence of an acquired cause. 26…”

Section: 5%mentioning

confidence: 86%

“…26 This case highlights the utility of WES to reduce the likelihood of a genetic cause signi cantly and increase the con dence of an acquired cause. 26…”

Section: 5%mentioning

confidence: 86%

“…Lastly, patient 15, is one of seven patients who have collectively provided evidence for a new disease, 'chondrodysplasia phenocopy post early HSCT for non-oncological disorders' and has been submitted for publication. 26 Although WES remains the current 'go-to' diagnostic test in many rare disease scenarios, we increasingly see a shift to WGS, especially for the acutely ill child. Even then, a large body of undiagnosed patients remain.…”

Section: Further Discussionmentioning

confidence: 99%

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Diagnostic Yield of Rare Skeletal Dysplasia Conditions in the Radiogenomics Era – A UK Experience

Sabir

Morley

Sheikh

et al. 2020

Preprint

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BACKGROUNDSkeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n=54) and South Korea (n=185) respectively.We discuss a single-centre UK experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. RESULTSSignificant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n= 7/15) having a definite molecular diagnosis and 6.7% (n= 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n=10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns.CONCLUSIONSOur results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

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A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT)

Kavanagh,

Coleman,

O'Connell

et al. 2024

American J of Med Genetics Pt A

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There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia.

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Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non‐oncologic disorders

Cited by 4 publications

References 19 publications

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

Diagnostic Yield of Rare Skeletal Dysplasia Conditions in the Radiogenomics Era – A UK Experience

A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT)

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