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. 2022 Jan 11;6(1):297-306.
doi: 10.1182/bloodadvances.2021005539.

Hematologic complications with age in Shwachman-Diamond syndrome

Elissa Furutani  1 , Shanshan Liu  2 , Ashley Galvin  3 , Sarah Steltz  2 , Maggie M Malsch  3 , Sara K Loveless  4   5 , Leann Mount  4   5 , Jordan H Larson  3 , Kelan Queenan  3 , Alison A Bertuch  6 , Mark D Fleming  7 , John M Gansner  8 , Amy E Geddis  9 , Rabi Hanna  10 , Sioban B Keel  11 , Bonnie W Lau  12 , Jeffrey M Lipton  13 , Robert Lorsbach  4   5 , Taizo A Nakano  14 , Adrianna Vlachos  13 , Winfred C Wang  15 , Stella M Davies  4   5 , Edie Weller  2 , Kasiani C Myers  4   5 , Akiko Shimamura  1
Affiliations

Hematologic complications with age in Shwachman-Diamond syndrome

Elissa Furutani et al. Blood Adv. .

Abstract

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Severe phenotype of the subject with SBDS c.183_184delTAinsCT/c.523C>T (p.Lys62*/p.Arg175Trp) and lacking the c.258 + 2T>C variant. (A-B) Bone marrow biopsy demonstrating irregular islands of cartilage surrounded by osteoid with increased bone-to-marrow space ratio and a loose fibroblastic network surrounding the bone islands. Original magnification ×40 (A), original magnification ×200 (B); hematoxylin and eosin stain.
Figure 2.
Figure 2.
Blood counts by age in subjects with SDS. A piecewise regression model (green shaded area) was used to determine the association between blood counts and age, allowing for a potential breakpoint for 2114 blood counts from 119 subjects. The locally estimated scatterplot smoothing (LOESS) curve is shown in purple. LogANC (A), hemoglobin (B), and log platelet count (C) as a function of age.
Figure 3.
Figure 3.
Marrow cellularity vs age in subjects with SDS. Scatter plot showing bone marrow cellularity vs age. Bone marrow was taken for 414 marrow examinations in 112 subjects.
Figure 4.
Figure 4.
Overall survival of subjects with SDS. Kaplan-Meier curve showing overall survival of all subjects. Time is expressed in years since birth.
See this image and copyright information in PMC

References

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