Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Pediatr Res. 2022 Dec;92(6):1671-1680. doi: 10.1038/s41390-022-02009-8. Epub 2022 Mar 23.
Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities.
We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute's (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort.
PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258 + 2T > C and c.183_184TA > CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies.
SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management.
ClinicalTrials.gov Identifier: NCT00027274.
The clinical and genetic spectrum of Shwachman Diamond Syndrome was comprehensively evaluated, and the findings illustrate the importance of a multidisciplinary approach for these complex patients. Our work reveals: 1. a narrow genotypic spectrum in SDS; 2. a low risk of solid tumors in patients with SDS; 3. patients with SDS have clinical manifestations in multiple organ systems.
Shwachman Diamond 综合征（SDS）是一种与胰腺功能不全、中性粒细胞减少和骨骼发育不良相关的遗传性骨髓衰竭综合征（IBMFS）。SBDS 的双等位基因致病性变异（PV）占 SDS 的>90%。我们假设 SDS 表型基于基因型而有所不同，并进行了一项基因型-表型相关性研究，以更好地了解这些复杂性。
我们回顾了美国国家癌症研究所（NCI）IBMFS 研究中所有 SDS 或 SDS 样综合征患者的记录。还回顾了其他已发表的 SDS 队列，并与 NCI 队列进行了比较。
SBDS 的 PV 存在于 32/47（68.1%）参与者中。我们的研究和已发表的队列中最常见的基因型是 SBDS c.258 + 2T > C 和 c.183_184TA > CT 的双等位基因遗传（25/32，78.1%）。大多数患者具有 SDS 的标志性特征，包括中性粒细胞减少（45/45，100%）、胰腺功能不全（41/43，95.3%）和/或骨异常（29/36，80.6%）。发育迟缓很常见（20/34，58.8%）。在 NCI 队列和已发表的研究中都观察到年轻患者血液恶性肿瘤风险增加和实体恶性肿瘤罕见的现象。
SDS 是一种具有狭窄基因型谱的复杂儿童疾病。患者可能首先到初级保健、胃肠病学、矫形和/或血液科就诊。协调多学科护理对诊断和患者管理很重要。
ClinicalTrials.gov 标识符：NCT00027274。
全面评估了 Shwachman Diamond 综合征的临床和遗传谱，研究结果表明了对这些复杂患者采用多学科方法的重要性。我们的工作揭示了：1. SDS 具有狭窄的基因型谱；2. SDS 患者患实体瘤的风险较低；3. SDS 患者具有多个器官系统的临床表现。
