Cystic fibrosis (CF) is an autosomal recessive condition caused by defects in the CF transmembrane regulator (CFTR) gene. About 85 % of patients with CF are pancreas insufficient (PI) [16].

Shwachman–Diamond syndrome (SDS) is an autosomal recessive disorder characterized by congenital anomalies, pancreatic insufficiency, bone marrow failure, and predisposition to myelodysplasia and acute myeloid leukemia (AML) [27]. Mutations in the Shwachman–Bodian–Diamond syndrome (SBDS) gene can be found in approximately 90 % of classically presenting patients with SDS [28]. These mutations usually result in reduced, but not absent, protein expression. In mice, targeted deletion of the gene results in embryonic death suggesting that some expression of this gene is necessary for survival [29]. The SBDS gene is involved in ribosomal function [30], and ribosomal subunit assembly is impaired in patients with SDS [31]. The exact mechanism by which this leads to pancreatic insufficiency is unknown . One study found that patients negative for mutations in the SBDS gene may have more severe hematological manifestations while having milder pancreatic disease [32].

The incidence of SDS is 1:76,000 individuals with a male to female ratio of 1.7:1 [33, 34].

The classic presentation of SDS is in infancy with failure to thrive, diarrhea, and neutropenia. SDS infants have an average birth weight at the 25th percentile [34]. Table 39.2 details the criteria for the diagnosis of SDS. Growth failure with malnutrition is common in the first year of life, and height falls and remains below the third percentile in 38–56 % of patients [35, 36]. After diagnosis, and with appropriate therapy, most children show normal growth velocity, and it appears that with current treatment they attain normal body mass indexes (BMIs) [35]. Steatorrhea is caused by decreased secretion of lipolytic and proteolytic enzymes, while ductular fluid and electrolyte secretion of the pancreas remain normal [37, 38] . Pancreatic insufficiency tends to be diagnosed within the first 6 months of life with 90 % of patients being diagnosed in the first year [37]. Spontaneous improvement in pancreatic function can occur in later childhood with 50 % of patients having normal fat absorption by age 4 years and no longer requiring pancreatic enzyme supplementation [37]. The pancreas in SDS exhibits a characteristic fatty replacement which can be visualized on ultrasound, CT scanning, and, perhaps, best by MRI scanning [39] .

Hepatomegaly and raised serum liver enzymes are common in children with SDS [40]. These resolve by the age of 5 years and no long-term consequences have been observed [40].

Neutropenia is the most common cytopenia and can be persistent or intermittent and mild to severe [34]. Anemia with low reticulocyte counts [34] and elevation in fetal hemoglobin is each seen in 80 % of patients [41]. Thrombocytopenia can also be seen. Bone marrow biopsy is usually hypoplastic with increased deposition of fat [41, 42]. Patients with SDS have a propensity to developing infections due to the neutropenia and the occasional functional neutrophil deficits that are seen in SDS [43]. Patients with SDS develop clonal changes in the bone marrow which may or may not be associated with an increased risk of myelodysplasia or AML [23]. Due to the predisposition to myelodysplasia and AML, all patients with SDS should be referred to a pediatric hematologist. Based on data from several registries, the frequency of both myelodysplasia and AML increases with increasing age [32, 44, 45]. In general, early bone marrow transplantation in children with severe cytopenias prior to development of myelodysplasia or AML improves outcome.

The bony dysplasia of SDS manifests as short stature and delayed appearance but subsequent normal development of secondary ossification centers [34]. There is variable metaphyseal widening and irregularity that is most often seen in the ribs in early childhood and femurs later in childhood and adolescence [46]. Rarely, skeletal involvement may be extremely severe and generalized [34]. Usually, these metaphyseal changes become clinically insignificant, but rarely they may lead to limb deformities and fractures [46] .

A characteristic pattern of neurocognitive and behavioral difficulties has been described in SDS [47].

A high degree of suspicion may be needed to diagnose milder cases of SDS. A study of 37 children with SDS found that neutropenia (81 %), diarrhea (58 %), failure to thrive (73 %) lipomatous infiltration of the pancreas (~  90 %), fecal elastase (82 %), skeletal (38 %), and congenital and endocrine malformations (65 %) were all inconsistently present [48].

Serum immunoreactive trypsinogen (IRT) and pancreatic isoamylase concentrations can be useful markers of the pancreatic phenotype in SDS [49]. In healthy children, serum IRT concentrations are at adult levels at birth, while pancreatic isoamylase concentrations are low at birth and reach adult levels by 3 years of age [49]. In contrast, in SDS, young children have low serum IRT concentrations which then rise with age, while serum pancreatic isoamylase activities are low at all ages. Serum IRT is generally low in PI patients with SDS, while a normal value does not rule out pancreatic insufficiency. Serum isoamylase concentrations are not useful in determining pancreatic sufficiency or insufficiency . Hence, when SDS is suspected, a serum IRT should be obtained in children < 3 years of age, while serum pancreatic isoamylase should be obtained in children ≥ 3 years of age [34] .

The diagnosis of SDS is made using the criteria shown in Table 39.3. The combination of exocrine pancreatic dysfunction and hematological abnormalities when other known causes of exocrine pancreatic dysfunction and bone marrow failure are excluded gives rise to a clinical diagnosis of SDS [34]. CF should be ruled out with a sweat test while Pearson marrow-pancreas syndrome can be differentiated by a bone marrow examination and imaging of the pancreas. Cartilage hair hypoplasia which presents with diarrhea (but not with pancreatic insufficiency), cytopenia, and metaphyseal chondrodysplasia is more common in certain populations such as the Amish.

Pearson described a syndrome of refractory, transfusion-dependent sideroblastic anemia with vacuolization of the bone marrow and exocrine pancreatic insufficiency [4] . Other variable features may include hepatic failure, proximal renal tubulopathy, watery diarrhea, patchy erythematous skin lesions, neutropenia, and thrombocytopenia and high serum lactate/pyruvate ratios [50]. This condition should be considered in the differential diagnosis of Shwachman syndrome. In this syndrome, vacuolization of the marrow is seen, while in Shwachman syndrome the bone marrow is dysplastic; the pancreas is fibrotic in Pearson syndrome, while it is fatty in Shwachman syndrome [51]. Pearson syndrome is caused by mitochondrial DNA alterations which are more abundant in the blood than in other tissues [50]. Diagnosis is suspected based on clinical findings and can be confirmed by Southern blot analysis which detects rearrangements of mitochondrial DNA [52]. This syndrome is usually fatal in infancy, but some children who survive past infancy develop severe neurological symptoms suggestive of another mitochondrial DNA disorder, Kearns–Sayre syndrome [53]. In children without multisystem involvement, bone marrow transplantation or unrelated cord blood cell transplantation has been suggested as a mechanism to manage the severe hematological manifestations of this syndrome [52] .