Shwachman-Diamond syndrome (SDS) is a rare congenital multisystem disorder characterized by exocrine pancreatic insufficiency and bone marrow dysfunction with an increased risk of leukemia or bone marrow aplasia, growth failure, and short stature [1].
The birth prevalence is reported to be 1/153,000-168,000 live births, mostly of autosomal recessive inheritance, with a male/female ratio of 1.7/1. No specific ethnic predilection has been identified [2].
The genetic causes of SDS in 80-90% of cases are mutations in the SBDS gene (7q11.22), which encodes a protein responsible for ribosome biogenesis and mitosis and is expressed in all human tissues [3,4]. In some cases, SDS can also be caused by DNAJC21, EFL1, or SRP54 gene mutations [5,6,7,8]. Of note, SRP54 gene mutations are inherited in an autosomal dominant pattern [9,10].
Clinical symptoms manifest during infancy and early childhood and show wide variability. The most common feature of SDS is moderate, intermittent neutropenia associated with recurrent secondary infections. Mild anemia and thrombocytopenia may also be seen. Exocrine pancreatic insufficiency is characterized by steatorrhea, failure to thrive, and growth retardation. Despite adequate nutrition and pancreatic enzyme replacement, 38% of children with SDS are reported to have height and weight below the third percentile for age and sex [11]. Delayed bone age and maturation with metaphyseal dysplasia result in short stature, pectus carinatum, osteopenia, and abnormal somatic development [12,13]. Other clinical features may also occur, including dental abnormalities, psychomotor retardation, eczema or ichthyosis, and mental retardation (Table 1).
The overall prognosis of SDS depends on the clinical severity of the manifestations and in particular on the development of bone marrow failure. Approximately 1/3 of patients develop bone marrow aplasia and subsequent leukemic transformation requiring bone marrow transplantation. However, the risk of malignant transformation from bone marrow failure to myelodysplastic syndrome in SDS patients is not well defined, although the risk of leukemic transformation seems to increase with age [14].
Diabetes mellitus in SDS patients
Type 1 diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells, resulting in absolute insulin insufficiency. To date, diabetes mellitus and pancreatic endocrine dysfunction have not been associated with SDS. In a case series of 25 genetically proven SDS patients, 26% were affected by at least one endocrine disorder (excluding short stature). Interestingly, there was only one case of manifest type 1 diabetes mellitus (4%), but 5 patients were found to have either impaired fasting glucose or impaired glucose tolerance (fasting glucose >100 mg/dl or postprandial glucose >140 mg/dl in a standard oral glucose tolerance test) [11]. In the Italian national SDS registry, type 1 diabetes was reported in 3.23% (2 of 62) of cases, indicating a significantly increased risk of diabetes in SDS patients compared to the reference population [15]. The authors hypothesize that known defects in immune regulation in SDS may play a role in the pathogenesis of type 1 diabetes mellitus. Furthermore, defective ribosome function in SDS may contribute to impaired insulin secretion and predispose affected patients to the development of dysglycemia [16].
To our knowledge, a total of 11 cases of type 1 diabetes in SDS patients have been reported [17,18,19,20,21,22,23,15,24,13]. It should be noted that only 4 of these 11 patients were reported to have type 1 diabetes with positive autoantibody screening, while the remaining patients had either negative or no measured antibodies. Furthermore, no common pathogenetic mechanism has been identified to account for the potential increased risk of diabetes development in SDS patients.
From an epidemiologic point of view, there is very limited information on possible age peaks at onset. Among the published cases, the youngest was a premature infant with SDS who developed autoantibody-negative diabetes mellitus at the age of three months due to slowly progressive hyperglycemia requiring insulin treatment 12 months later [20]. Another case of neonatal manifestation of diabetes in a patient with SDS was treated with tolbutamide with efficient glucose normalization over the years [17]. Kamoda and coworkers described the case of an infant with SDS with slowly deteriorating glucose homeostasis from 3 weeks of age until the diagnostic criteria for overt diabetes mellitus were met at 15 months, requiring insulin therapy. In this case, hyperglycemia remained mild for the first 12 months, suggesting a slow and gradual decline in beta-cell capacity [21].
There is also a paucity of data on the treatment options used, the metabolic control achieved, and the acute and chronic complications of diabetes mellitus in Shwachman-Diamond patients. One case report showed improved health-related quality of life after initiation of continuous subcutaneous insulin infusion (CSII) in a boy with SDS who developed antibody-negative diabetes at the age of 13 years [24]. Recently, another child with type 1 diabetes and SDS was also reported to be effectively treated with insulin pump therapy (CSII) [13].
Interestingly, severe episodes of symptomatic hypoglycemia in the context of otherwise normal glucose regulation have been reported in a neonatal patient with SDS requiring treatment with diazoxide and in another child with SDS at the age of 2 years [25,26]. According to these case reports, the underlying pathogenesis of recurrent hypoglycemia has not been identified, and the hypoglycemia appears to resolve with age.
Reviewing all reported cases of diabetes mellitus in SDS patients, we hypothesize that SDS-associated diabetes can be divided into two groups: first, cases with a rather mild course of diabetes after manifestation in infancy or early childhood [17,20,21,26], and second, cases in older children or adolescents that rapidly require intensive insulin therapy as in classic type 1 diabetes [24,13].
Other endocrine comorbidities in SDS patients
No consistent endocrine phenotype has been observed in patients with SDS with a genetically confirmed diagnosis [11,13]. Endocrine disorders other than diabetes mellitus that have been described in patients with SDS include growth hormone deficiency, hypothyroidism, congenital hypopituitarism, and post-transplant hypergonadotropic hypogonadism [11]. Systematic data on the incidence of endocrine abnormalities in patients with SDS are not currently available.