What is the morbidity and mortality associated with Shwachman-Diamond syndrome (SDS)?

Updated: Nov 17, 2020
  • Author: Antoinette C Spoto-Cannons, MD, FAAP; Chief Editor: Hassan M Yaish, MD  more...
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Answer

Prognosis for individuals with the disorder is uncertain. Because Shwachman-Diamond syndrome was described relatively recently, limited data are available regarding follow-up in these patients.

A study by Pichler et al found that a large percentage of children with Shwachman-Diamond syndrome had vitamin A and selenium deficiencies despite receiving pancreatic enzyme replacement therapy. Twenty of 21 children in the study received enzyme replacement therapy; in addition, 11 (52%) were taking multivitamin supplements and 2 (10%) were on zinc and selenium supplementation. The report found vitamin A and selenium deficiencies in 16 (76%) and 10 (48%) children, respectively. Other deficiencies included vitamin E (4 patients, 19%), zinc (7 patients, 33%), and copper (5 patients, 24%). [28]

Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia) are common in individuals with Shwachman-Diamond syndrome because of neutropenia/neutrophil migration defects. [6]

As with other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is also observed with Shwachman-Diamond syndrome. The frequency of leukemia in patients with Shwachman-Diamond syndrome, particularly acute myeloid leukemia (AML), is as much as 36% by age 30 years [29] and increases to 71% by age 50 years. [30]  Most of the malignant transformations involve chromosome 7, such as monosomy 7. Isochromosome 7q may be a specific marker of myeloid malignant transformation in association with Shwachman-Diamond syndrome. [31]  Ninety-two percent of such transformations occur in males. Other cancers reported in patients with Shwachman-Diamond syndrome include pancreatic adenocarcinoma, [32] CNS B-cell lymphoma, [33] and breast cancer. [34]

Whether increased angiogenesis in Shwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear, [35] but increased expression of vascular endothelial growth factor-A and other cytokines may play a role. [36] At the genetic level, spindle instability that contributes to bone marrow failure and leukemia development has also been implicated. [37] Spindle instability may also be attributed, at least in part, to the high frequency of acquired chromosomal anomalies found in patients with Shwachman-Diamond syndrome, which may form the basis of malignant transformation in tissues with high mitotic activity. [38]

Additionally, increased apoptosis of nontransformed cells through Fas stimulation leads to a growth advantage in mutated cells. Deficiency in the SBDS gene results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by the Fas ligand, leading to accelerated apoptosis. This finding suggests that the SBDS gene may play an important role in regulating the Fas-mediated apoptosis pathway and may be responsible for the reduced cellularity in the bone marrow and exocrine pancreas of patients with Shwachman-Diamond syndrome. [39, 40]

Death usually occurs from overwhelming sepsis or malignancy. Alter et al report that the projected median survival age is older than 35 years for all patients with Shwachman-Diamond syndrome. [41]

A study by the National Cancer Institute indicated that in patients with one of four types of bone marrow failure syndromes—Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome—the greatest median age for overall survival is associated with Diamond-Blackfan anemia (67 years), with the median survival ages in dyskeratosis congenita, Shwachman-Diamond syndrome, and Fanconi anemia being 51 years, 41 years, and 39 years, respectively. [42]

For patients with Shwachman-Diamond syndrome whose course is complicated by aplastic anemia, the median survival age is 24 years, whereas patients whose course is complicated by leukemia have a median survival age of 10 years.


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