Clinical Features of Shwachman-Diamond Syndrome Patients Lacking Biallelic SBDS Mutation
Authors: Shimamura Akiko , Bolyard Audrey Anna , Chakrabarti Satabdi , Bond Jordan M. , Cole Theresa , Moore Joan , Boxer Laurence A. , Newburger Peter E. , Alter Blanche P , Harris Richard E. , Davies Stella M. , Dale David C. 
Published: October 2019

Abstract
Abstract 4367
Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder defined clinically by marrow failure and exocrine pancreatic dysfunction. Previous research estimates that 90% of patients harbor biallelic mutations in the SBDS gene. The clinical course of patients lacking SBDS mutations has not been examined previously. To address this question, we examined 102 patients referred to the North American Shwachman-Diamond syndrome registry (SDSR) or the Severe Chronic Neutropenia International Registry (SCNIR). Seventy-nine subjects were <18 years of age (median age 8.8, range 2.8–17.6), with a male:female ratio of 1:1.7. Twenty-three subjects were >18 years of age (median 23.6, range 18.2–61.9), with a male:female ratio of 1.6:1. SBDS genetic analyses were available for 75 patients; 48 of 75 have biallelic SBDS mutations. Twenty-seven patients were phenotypically consistent with SDS, as demonstrated by exocrine pancreatic dysfunction and marrow failure, but either lacked SBDS mutations (24 patients) or harbored only one mutant SBDS allele (3 patients). The remaining 27 subjects were indeterminate for SDS or lacked sufficient data. In this study, we compared the hematologic complications of the 75 SDS patients presenting with or without SBDS mutations.
Fifty-two subjects had complete hematological data. Of the 28 patients with SBDS mutations, neutropenia was noted in 21 (6 severe with ANC <500/mm3), thrombocytopenia in 14 (2 severe with platelets <20,000/mm3), macrocytosis in 5, and anemia in 20 (1 transfusion-dependent). Of the 24 subjects lacking biallelic SBDS mutations, 20 had neutropenia (11 severe) and 8 had thrombocytopenia (6 severe), 1 had macrocytosis and 15 had anemia.
Bone marrow reports were available for 47 patients. Of the 21 patients with SBDS mutations, 17 had marrow hypoplasia, 5 had marrow dysplasia. Nine showed clonal abnormalities including del(20q), iso(7q), monosomy 7, trisomy 8, and trisomy 7q21. Of the 26 patients without biallelic mutations, 16 had marrow hypoplasia, 3 had marrow dysplasia and 8 showed clonal abnormalities including del(20q), monosomy 7, del(3q), del (21q), del (7q), and iso(7q).
Three subjects (2 with biallelic SBDS mutations, 1 lacking SBDS mutations) developed MDS. One patient without SBDS mutations developed AML. Three deaths have been reported. All deaths involved patients with clinical SDS lacking SBDS mutations. Causes of death were AML, failure to engraft during bone marrow transplant, and sepsis. Eight patients (4 with biallelic SBDS mutations and 4 lacking SBDS mutations) underwent bone marrow transplant.
These data suggest that patients without mutations in SBDS may be more common than previous estimates. The hematological complications for patients with and without SBDS mutations appear to be similar. These Registries offer important opportunities to study the genetic and pathophysiological mechanisms for SDS.

Disclosures:
Boxer: Amgen: Equity Ownership. Dale:Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.