Shwachman-Diamond Syndrome 

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

Overview

Practice Essentials

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities.[1, 2, 3] Diagnosis of the condition requires the presence of exocrine pancreatic insufficiency and bone marrow dysfunction; skeletal abnormalities and gene mutations are not a requirement to confirm the diagnosis. The goals of Shwachman-Diamond syndrome (SDS) treatment include (1) pancreatic enzyme supplementation, (2) prevention or treatment of serious and/or invasive infections with early attention to febrile illnesses, (3) correction of hematologic abnormalities when possible, and (4) prevention of orthopedic deformities.[4]

SDS is the second most common cause of inherited pancreatic insufficiency after cystic fibrosis and the third most common inherited bone marrow failure syndrome after Fanconi anemia and Diamond-Blackfan anemia. In 90% of cases, SDS is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, located on chromosome 7.

In 1964, Shwachman, Diamond, Oski, and Knaw first reported the syndrome in a group of five children participating in a cystic fibrosis (CF) clinic at Harvard Medical School.

Signs and symptoms

Patients with SDS typically present with diarrhea, short stature, weight loss, and dry skin (eczema). Recurrent bacterial infections of the upper respiratory tract, otitis media, sinusitis, pneumonia, osteomyelitis, bacteremia, skin infections, aphthous stomatitis, fungal dermatitis, and paronychia are common because of a neutropenia/neutrophil migration defect.[5, 6, 7, 8]

In addition to short stature, skeletal abnormalities in an individual with SDS may include the following:

  • Clinodactyly

  • Syndactyly

  • Supernumerary metatarsals

  • Coxa vara deformity

  • Genu and cubitus valgus

  • Tooth enamel defects (dental dysplasia)[9]

Along with eczema, dermatologic manifestations in patients with SDS include ichthyosis and petechiae.

As with other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is observed with SDS.

Workup

A complete blood count (CBC) is used to assess neutropenia, anemia, and thrombocytopenia. Other laboratory studies in SDS include the following:

  • Neutrophil function studies

  • Fetal hemoglobin

  • Iron, folate, and vitamin B12 levels

  • Secretin-cholecystokinin quantitative stimulation test

  • Sweat test

  • Glucose tolerance test

  • Urinalysis

  • Serum bicarbonate, PCO2, hydrogen ion concentration (H+), and urinary pH

  • Liver function tests

  • Immunoglobulin levels

  • Growth hormone levels

  • Vitamin A, D, E and K levels

  • Serum calcium and phosphorous

Management

A significant proportion of patients with SDS require pancreatic enzymes, a low-fat diet, multivitamins, and fat-soluble vitamins; however, the needs of these patients may decrease with age.

When patients with SDS experience an acute febrile illness, obtain bacterial cultures because of the increased risk of sepsis from the neutrophil migrational defect with or without neutropenia observed in these patients. Empiric treatment with parenteral, broad-spectrum antibiotics may be indicated. Additionally, prophylactic antibiotics may be necessary to help prevent infection.

Anemia and thrombocytopenia may require repeated transfusions if the patient is symptomatic. Additionally, erythropoietin may be beneficial in the treatment of anemia.

Lymphoproliferative and myeloproliferative malignancies and aplastic marrow observed in patients with Shwachman-Diamond syndrome are usually unresponsive to standard chemotherapy and require allogenic hematopoietic stem cell transplantation.[10, 11]

Pathophysiology

All patients with Shwachman-Diamond syndrome have some degree of pancreatic insufficiency beginning in infancy. This insufficiency is defined as the loss of exocrine function, resulting in the inability to digest and, therefore, an inability to normally assimilate nutrition. Thus, patients typically present in early infancy with malabsorption, steatorrhea, failure to thrive, and deficiencies of fat-soluble vitamins A, D, E, and K.[12, 13]

Symptoms of malnutrition typically develop when more than 98% of pancreatic reserve is lost. In individuals with this condition, pancreatic acinar cells do not develop in utero and are replaced by fatty tissue. In contrast to cystic fibrosis, the pancreatic ductal architecture is spared; thus, an intact anion secretion and fluid flow occurs.[14] Low serum pancreatic trypsinogen and low isoamylase levels are helpful markers for pancreatic insufficiency, depending on the age of the patient. Trypsinogen levels are low in patients younger than 3 years, but this finding becomes less useful as a disease marker in older patients because levels increase to normal range with age. Serum isoamylase levels are low in patients with Shwachman-Diamond syndrome of all ages but use of this test is limited in children younger than 3 years because all children may normally have low circulating isoamylase levels.[14]

Fecal elastase levels and pancreatic enzyme secretion in response to stimulation testing may also be reduced. For reasons yet to be identified, pancreatic lipase secretion increases with age, often improving pancreatic function to normal levels of fat absorption. Approximately 50% of patients with Shwachman-Diamond syndrome become pancreatically sufficient throughout childhood and no longer require enzyme replacement therapy.[15] Pancreatic endocrine functions generally remain intact, although cases of insulin-dependent diabetes mellitus have been reported. Rarely, these patients may present with hypoglycemia, which may be due to severe chronic malabsorption.[15]

Shwachman-Diamond syndrome is considered one of the inherited bone marrow failure syndromes.[16, 17] Another key feature of Shwachman-Diamond syndrome involves ineffective hematopoiesis. Studies to understand the pathophysiology of bone marrow failure are currently underway. A generalized marrow dysfunction with an abnormal bone marrow stroma (in terms of its ability to support and maintain hematopoiesis) is thought to be present in addition to a stem cell defect. Neutropenia is the most common hematologic abnormality seen in patients with Shwachman-Diamond syndrome.[18] Data from a large international cohort study consisting of 88 patients with Shwachman-Diamond syndrome revealed neutropenia in 98% of patients, followed by anemia (42%), thrombocytopenia (34%), and pancytopenia (19%).

More specifically, neutrophils may have defects in mobility, migration, and chemotaxis. These abnormalities might be due to abnormal distribution of concanavalin-A receptors on the neutrophils or a cytoskeletal/microtubular abnormality. Also, Shwachman-Diamond syndrome has been associated with mutations in the SBDS gene, located on chromosome 7. The SBDS gene may not be required for neutrophil maturation but may act to maintain survival of granulocyte precursor cells. The SBDS gene product, the SBDS protein, may play a role in chemotaxis.[19] Recent studies have shown that the neutrophils in Shwachman-Diamond syndrome have aberrant chemoattractant-induced F-actin properties, which may contribute to the neutrophil chemotaxis defects. The SDS neutrophils have a delayed F-actin cytoskeleton polarization and polymerization, which impairs the directed migration of neutrophils.[20]

Fetal hemoglobin levels are elevated in 80% of patients. The elevation of heterogeneously distributed fetal hemoglobin reflects "stress" hematopoiesis, ineffective erythropoiesis related to apoptosis, or both. New data has demonstrated prosurvival properties of the SBDS gene and indicates that accelerated apoptosis occurs through the Fas pathway when SBDS is inhibited. The loss of SBDS is now thought to be sufficient to induce abnormalities in hematopoiesis.

Failure to thrive has been attributed to nutritional deficits (malabsorption), recurrent infections, and skeletal abnormalities as well as decreased or absent growth hormone levels in individuals with Shwachman-Diamond syndrome.

The exact pathophysiology of skeletal anomalies is unknown; however, skeletal anomalies are reported to occur in more than 75% of patients with Shwachman-Diamond syndrome. In addition to skeletal dysplasia, Shwachman-Diamond syndrome is associated with a more generalized bone disease characterized by low bone mass, low bone turnover, and vertebral fragility fractures. Osteoporosis may result from a primary defect in bone metabolism and could be related to the bone marrow dysfunction and neutropenia.

Mild cognitive impairments and variable degrees of development abnormalities may also be seen in patients with Shwachman-Diamond syndrome.[21, 22, 23, 24, 25] These patients have lower performance in most cognitive domains than age-matched controls.[23] Although they do not have gross brain abnormalities, they are frequently found to have significantly reduced brain volumes.[26]

Epidemiology

Frequency

United States

After cystic fibrosis, Shwachman-Diamond syndrome is the second most common cause of pancreatic insufficiency in childhood. Approximately 3% of childhood pancreatic dysfunction is attributed to Shwachman-Diamond syndrome. The incidence of Shwachman-Diamond syndrome has been estimated at 1 case in 77,000 population using comparison cystic fibrosis data.[27]

International

More than 200 cases of Shwachman-Diamond syndrome have been reported in the literature.

Mortality/Morbidity

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.

Race

Shwachman-Diamond syndrome is reported among all racial and ethnic groups.[41]

Sex

The male-to-female ratio is 1.7:1.[8]

Age

Shwachman-Diamond syndrome is usually diagnosed during the newborn period or infancy when patients present with malabsorption and recurrent infections.

 

Presentation

History

See the list below:

  • Patients with Shwachman-Diamond syndrome (SDS) typically present with diarrhea, short stature, weight loss, and dry skin (eczema).

    • They may have fatty stools that usually improve with age.[43]

    • Imperforate anus and Hirschsprung disease have been associated with Shwachman-Diamond syndrome. These associations may delay diagnosis of Shwachman-Diamond syndrome because the presenting symptom is constipation and not diarrhea.

  • Recurrent bacterial infections of the upper respiratory tract, otitis media, sinusitis, pneumonia, osteomyelitis, bacteremia, skin infections, aphthous stomatitis, fungal dermatitis, and paronychia are common because of a neutropenia/neutrophil migration defect.[5, 6, 7, 8]

  • Hearing loss may occur secondary to recurrent otitis media.

  • A history of pallor, easy bruising, epistaxis, melena, hematemesis, or hematuria may be present in individuals with Shwachman-Diamond syndrome.

  • Unlike patients with cystic fibrosis, patients with Shwachman-Diamond syndrome have a paucity of pulmonary symptoms,[44] although some patients may present with recurrent upper and lower respiratory tract infections.

  • Delayed dental development, gingival bleeding upon brushing, and pain with eating (associated with recurrent oral ulcerations) may occur.[45]

  • Saliva production is decreased; however, no significant clinical symptoms are associated with this phenomenon.

  • Patients with Shwachman-Diamond syndrome typically experience delayed puberty.[10]

  • Mild-to-moderate psychomotor and/or developmental delay including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders may be observed in as many as 15% of affected individuals and has been shown to affect quality of life.[24]

Physical

See the list below:

  • Patients with Shwachman-Diamond syndrome may appear emaciated, with abdominal distension accentuated by hypotonia and hepatomegaly.

  • More than 50% of these individuals have short stature with a normal growth velocity.[8] Their height and weight are usually below the third percentile but may occasionally reach the 25th percentile.[10]

  • In addition to short stature, skeletal abnormalities in an individual with Shwachman-Diamond syndrome may include the following:

    • Clinodactyly

    • Syndactyly

    • Supernumerary metatarsals

    • Coxa vara deformity

    • Genu and cubitus valgus

    • Tooth enamel defects (dental dysplasia), including hypomaturation, hypocalcification, and hypoplasia (Dental caries and tooth surface loss are seen in about a third of patients.[9] )

  • Dermatologic manifestations in a person with Shwachman-Diamond syndrome include the following:

    • Eczema

    • Ichthyosis

    • Petechiae

Causes

Shwachman-Diamond syndrome is inherited in an autosomal recessive fashion.[46] See the image below.

Autosomal recessive inheritance. Autosomal recessive inheritance.

In 90% of patients with Shwachman-Diamond syndrome, mutations have been found in the SBDS gene located on chromosome 7q11. The most frequent mutations are due to gene conversion between the SBDS gene and its pseudogene (SBDSP). The SBDS gene contains 5 exons, which encode a 250-amino-acid protein of unknown function.[47] SBDS is a highly conserved protein[48] which is known to play a role in ribosome biosynthesis, mitotic spindle assembly, chemotaxis, and regulation of reactive oxygen species generation.[49, 50, 51, 52, 53]

Experiments reveal that SBDS knockdown affects expression of critical genes involved in brain development and function, bone morphogenesis, blood cell proliferation and differentiation, and cell adhesion.[54] This may be due to its role in ribosome biogenesis or RNA processing, which has been shown in yeast[55] and mammalian cells.[56] One of the SBDS-binding proteins, nucleophosmin (NPM, B23), has a role in ribosome biogenesis and control of cell cycle,[57] and the SBDS proteins facilitate the release of eIF-6 which impairs the association of the 40S and 60S subunits.[51] Interestingly, mutations that affect ribosome assembly or function are associated with other inherited bone marrow failure syndromes,[58] and models of how impairment of ribosomal pathways might affect hematopoiesis and tumorigenesis are currently under investigation.[57]

Burwick et al found that knockdown of eIF-6 expression showed improvement of ribosomal subunit association but did not improve the hematopoietic deficits noted in Shwachman-Diamond syndrome.[59]

A study by Joyce et al indicated that in Shwachman-Diamond syndrome, increased activity in the transforming growth factor-β (TGFβ) pathway triggers hematopoietic dysfunction and bone marrow failure. The investigators found a rise in hematopoietic stem cells and multipotent progenitors in Shwachman-Diamond syndrome patient bone marrow in connection with TGFβ inhibitors. The study also reported higher levels of TGFβ pathway members in the blood plasma of patients with the syndrome.[60]

 

DDx

Diagnostic Considerations

Shwachman-Diamond syndrome (SDS) is differentiated from Pearson syndrome in that Pearson syndrome is characterized by vacuolated erytropoietic precursors, pancreatic fibrosis (rather than fatty replacement of pancreatic tissue), and a lack of skeletal abnormalities.

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • CBC to assess neutropenia, anemia, and thrombocytopenia

    • Cyclic or persistent neutropenia is observed in 88-100% of patients with Shwachman-Diamond syndrome (SDS).[61, 62, 63, 6, 64, 52] Because the neutropenia may be intermittent, CBC counts may need to be repeated biweekly over a 3-week period to document neutropenia.[65]

      • Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/mcL in whites and less than 1200 in blacks. See the Absolute Neutrophil Count calculator.

      • Mild neutropenia is defined as an ANC of 1000-1500/mcL.

      • Moderate neutropenia is defined as an ANC of 500-1000/mcL.

      • Severe neutropenia is defined as an ANC of less than 500/mcL.

    • Anemia is present in more than 50% of patients with Shwachman-Diamond syndrome secondary to iron deficiency and/or bone marrow hypoplasia.

    • Thrombocytopenia is present in more than 25% of patients with Shwachman-Diamond syndrome.

    • A CBC count should also be obtained every 3-6 months or as clinically indicated.[66]

  • Neutrophil function studies: A neutrophil migration defect may be documented.

  • Fetal hemoglobin: This is elevated in approximately 80% of patients with Shwachman-Diamond syndrome.[31]

  • Iron, folate, and vitamin B12 levels: Patients may have associated iron, folate, or vitamin B12 deficiency secondary to malabsorption. Obtain at time of diagnosis and as clinically indicated.[66]

  • A 72-hour fecal fat measurement:

    • An increase in fecal lipids and fatty acids is present in persons with Shwachman-Diamond syndrome.

    • The fecal fat losses vary from 3-60%, and these losses decrease with age. After an individual with Shwachman-Diamond syndrome is aged 8 years, fecal fat losses average 8% of intake.[67] This decrease in fecal fat losses may be related to the patient's increasing pancreatic secretion of lipase coupled with the decreased dietary fat with age.

    • The absence of steatorrhea does not exclude the diagnosis of Shwachman-Diamond syndrome.[10]

  • Secretin-cholecystokinin quantitative stimulation test: Pancreatic insufficiency is evidenced by the absence or decrease of trypsin, lipase, colipase, and amylase activities in pancreatic secretions from less than 2% to approximately 10-14% of the reference range after quantitative stimulation test with intravenous secretin and cholecystokinin.[5] Obtain at time of diagnosis and as clinically indicated.[66]

  • Sweat test: In individuals with Shwachman-Diamond syndrome, this test demonstrates no increase in chloride, in contrast to cystic fibrosis, in which the chloride level is abnormally elevated; however, false positives have been reported.[68, 69] The test should be repeated if there is any doubt regarding the diagnosis.[69]

  • Glucose tolerance test: These findings are generally normal. Rarely, patients with Shwachman-Diamond syndrome may have diabetes mellitus.

  • Urinalysis: In persons with Shwachman-Diamond syndrome, urinalysis reveals inconsistent galactosuria with the presence of reducing substances but without glucosuria.

  • Serum bicarbonate, PCO2, hydrogen ion concentration (H+), and urinary pH: Measured simultaneously, these may suggest renal tubular acidosis.

  • Liver function tests

    • Transaminases (ie, alanine aminotransferase, aspartate aminotransferase) may be elevated in individuals with Shwachman-Diamond syndrome.[70]

    • Alkaline phosphatase may be within the reference range or slightly increased.

    • Findings on coagulation studies are normal, and the serum bilirubin level is within the reference range.

    • Hypoalbuminemia may be present secondary to malabsorption.

    • These should be obtained at time of diagnosis and as clinically indicated.[66]

  • Immunoglobulin levels: Immunoglobulin A (IgA), IgM, and/or immunoglobulin G (IgG) levels may be low. Obtain at time of diagnosis and as clinically indicated.[66]

  • Growth hormone levels: These are often decreased in persons with Shwachman-Diamond syndrome.

  • Vitamin A, D, E and K levels: These may be low due to malabsorption.[63] Obtain vitamin A, D, and E and prothrombin time at time of diagnosis, one month after initiation of pancreatic enzyme therapy, then every 6-12 months.[66]

  • Serum calcium and phosphorous: These levels are within the reference range.

Imaging Studies

The pancreas can be evaluated using ultrasonography, CT, or MRI.

Ultrasonographic findings of the pancreas of an individual with Shwachman-Diamond syndrome reveal increased echogenicity of the pancreatic silhouette.[71]

CT scanning reveals lipomatosis of the pancreas. The size of the pancreas may be normal or atrophic.[72]

MRI may be used to evaluate the pancreatic fat content and can even help confirm the clinical diagnosis of Shwachman-Diamond syndrome.[73] In those who have mutations in the SBDS gene, MRI reveals a characteristic pattern of fat-replaced pancreas, which can differentiate these patients from patients without mutations.[74]

A skeletal survey in a person with Shwachman-Diamond syndrome may reveal some of the following skeletal abnormalities:

  • Delayed bone age (>75%).[5]

  • Thoracic dysostosis consisting of costochondral thickening, short flaring lower ribs, and a narrow thoracic cage that is most obvious when the individual with Shwachman-Diamond syndrome is younger than 2 years (44-60%)[67] and have been reported to cause respiratory failure in newborns.

  • Metaphyseal chondrodysplasia noted in individuals with Shwachman-Diamond syndrome who are older than 6 years, as evidenced by shortening of the extremities, metaphyseal widening, and "cup" deformity of the ribs (40-80%).[75]

  • Abnormal tubulation of the long bones, especially the ulnae, tibia, and first metacarpals (33%).[68, 5]

  • Valgus deformities of the elbows and knees.[68]

  • Slipped femoral epiphysis[76]

  • Kyphosis and scoliosis[76]

  • Osteopenia early on, which improves with age. As many as 45% of patients who become pancreatic sufficient later in childhood have shown complete reversal. However, adults should be screened with densitometry.[66]

MRI of the brain reveals as much as a 23% reduction in overall gray-matter and white-matter volume with resultant increase in ventricular volume when compared with persons without Shwachman-Diamond syndrome. The areas of the brain most affected include the corpus callosum, brain stem, cerebellum, and thalamus. Booij et al's findings indicate that patients with Shwachman-Diamond may have a dysregulated dopaminergic system that can account for ADHD and learning difficulties.[77]

Patients with Shwachman-Diamond syndrome may show diastolic dysfunction at rest and depressed left ventricular contractility during stress on MRI of the heart.[78]

Other Tests

See the list below:

  • A predilection for developing bone marrow failure and leukemic transformation is associated with Shwachman-Diamond syndrome.

    • Isochromosome arm 7q may be a specific marker of myeloid malignant transformation.

    • Bone marrow aspiration and biopsy are indicated at the time of diagnosis and every 1-3 years or as clinically indicated.[79, 41, 66]

  • Diagnosis is confirmed by performing genetic testing for the SBDS gene located on chromosome 7q11, which is present in 90% of patients with Shwachman-Diamond syndrome.

  • Developmental/neuropsychological screening due to risk for developmental delay, ADHD, and autism spectrum disorders. Obtain at time of diagnosis with regular assessment at well child visits with special attention at age 6-8 years, age 11-13 years, and age 15-17 years.[66]

Procedures

See the list below:

  • Duodenal aspiration (performed by a gastroenterologist) in the person with Shwachman-Diamond syndrome reveals a concentration of ductal (bicarbonate) secretions that is within the reference range with significant impairment of acinar (enzyme) secretions without satisfactory response to pancreatic stimulation.

Histologic Findings

See the list below:

  • Biopsy of the pancreas of a person with Shwachman-Diamond syndrome reveals mostly adipose tissue containing the islets of Langerhans with very few elements of exocrine gland structure present.[44] The pancreas of patients with cystic fibrosis usually has fibrosis rather than lipomatosis, as is observed in patients with Shwachman-Diamond syndrome and Johanson-Blizzard syndrome. Routine biopsy of the pancreas is not indicated.

  • Periodically perform bone marrow evaluation studies because of the predilection for developing marrow failure and leukemic transformation (5-33% of patients with Shwachman-Diamond syndrome), including acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia. However, examination of the bone marrow in a person with Shwachman-Diamond syndrome typically reveals hypocellularity, with maturation arrest in the myeloid series and fat infiltration. Megakaryocytes may be within the reference range or decreased in number.[44, 68]

  • The liver of an individual with Shwachman-Diamond syndrome may exhibit periportal fibrosis,[70] periportal mononuclear infiltrate, and fibrous bridging between the portal tract areas. Cirrhosis and steatosis have been reported.

  • Endocardial fibrosis may be exhibited in the heart of a person with Shwachman-Diamond syndrome.

Staging

Diagnostic criteria of Shwachman-Diamond syndrome

According to a consensus at the international conference in 2002, persons diagnosed with Shwachman-Diamond syndrome must fulfill at least two of the following criteria:[80]

  • At least 2 of the following:

    • Chronic cytopenia(s) detected on at least 2 occasions over at least 3 months

    • Reduced marrow progenitors

    • Persistent elevation of hemoglobin F

    • Persistent RBC macrocytosis (not caused by nutritional deficiency)

  • At least one of the following:

    • Evidence of pancreatic lipomatosis

    • Reduced levels of at least 2 pancreatic enzymes adjusted to age

  • Positive genetic testing

  • First degree-family member with Shwachman-Diamond syndrome

 

Treatment

Medical Care

The goals of Shwachman-Diamond syndrome (SDS) treatment include (1) pancreatic enzyme supplementation, (2) prevention or treatment of serious and/or invasive infections with early attention to febrile illnesses, (3) correction of hematologic abnormalities when possible, and (4) prevention of orthopedic deformities.[4]

A significant proportion of patients with Shwachman-Diamond syndrome require pancreatic enzymes, a low-fat diet, multivitamins, and fat-soluble vitamins; however, the needs of these patients may decrease with age. Treatment of pancreatic insufficiency only slightly improves growth.[68, 81]

When patients with Shwachman-Diamond syndrome experience an acute febrile illness, obtain bacterial cultures because of the increased risk of sepsis from the neutrophil migrational defect with or without neutropenia observed in these patients. Empiric treatment with parenteral, broad-spectrum antibiotics may be indicated. Additionally, prophylactic antibiotics may be necessary to help prevent infection.

No therapy has been successful in completely reversing neutropenia, anemia, or thrombocytopenia.[68]

Neutropenia may be treated by granulocyte colony-stimulating factor (GCSF). However, its risk of accelerating the development of myeloproliferative disorders remains to be determined.

Lithium and thiamine were used in the past to improve chemotactic performance;[82, 7, 83] however, their use has fallen out of favor since the advent of recombinant growth factor in the 1990s.

Neutropenia has not been improved by the administration of fresh frozen plasma, vitamin B-12, folic acid, pyridoxine, riboflavin, methionine, prednisolone, anabolic steroids, vitamin A, vitamin E, or pancreatic extract.[44]

Anemia and thrombocytopenia may require repeated transfusions if the patient is symptomatic. Additionally, erythropoietin may be beneficial in the treatment of anemia.

Lymphoproliferative and myeloproliferative malignancies and aplastic marrow observed in patients with Shwachman-Diamond syndrome are usually unresponsive to standard chemotherapy and require allogenic hematopoietic stem cell transplantation.[10, 11] These patients are at high risk for complications after bone marrow transplant. Numerous factors may contribute to this high complication rate. The patients' underlying hematologic abnormalities and high reported rate of nonspecific organ malfunctions may place them at higher risk for the development of toxicities.[84] In an attempt to reduce toxicity, preparative regimens avoiding the combination of busulfan and cyclophosphamide have been tried.[85] Reduced-intensity conditioning was associated with excellent donor cell engraftment and modest morbidity.[86]

Burroughs et al found success in reducing toxicity while maintaining decreased morbidity, utilizing a combination of treosulfan, fludarabine, and thymoglobulin in patients with marrow failure disorders (including Shwachman-Diamond syndrome).[87]  Isaev et al reported the first successful hematopoietic stem cell transplantation for Shwachman-Diamond syndrome that was performed using an unaffected human leukocyte antigen (HLA)–matched sibling donor engendered via preimplantation genetic diagnosis.[88]

Andre et al found that mesenchymal stem cells from patients with Shwachman-Diamond syndrome function normally and may have a positive influence on the success of hematopoietic stem cell transplantation.[89]

Growth hormone has been used to treat children with Shwachman-Diamond syndrome who have growth hormone deficiency. The initial response is good; however, long-term therapy with growth hormone is unsuccessful.[90]

Appropriate orthopedic follow-up of metaphyseal dysplasia may prevent deformities.

Consultations

See the list below:

  • Pediatric gastroenterologist - For management of pancreatic insufficiency

  • Pediatric endocrinologist - For pancreatic insufficiency, short stature, and delayed puberty

  • Pediatric immunologist - For neutropenia, neutrophil migrational defects, and immunoglobulin deficiencies

  • Pediatric oncologist - For routine bone marrow aspirations, which are indicated for early detection of aplasia and lymphoproliferative and myeloproliferative malignancies

  • Pediatric infectious diseases specialist - To help treat unusual infections that may occur from neutropenia and a neutrophil migrational defect

  • Clinical geneticist - For parent counseling and chromosome studies

  • Pediatric orthopedic surgeon - To manage skeletal abnormalities (Special attention is required for metaphyseal dysplasia because of the risk of significant deformities, particularly in knees and hips.) Surgical intervention is considered only if abnormalities poise problems with ambulation.[63]

Diet

A low-fat diet may be necessary depending on the degree of malabsorption.

Activity

No limitations on activity are necessary for individuals with Shwachman-Diamond syndrome, unless thrombocytopenia is observed.

 

Medication

Pancreatic enzymes

Class Summary

These agents are used to replace endogenous pancreatic enzymes.

Pancrelipase (Creon, Ku-Zyme, Pancrease, Viokase, Ultrase)

Assists in digestion of protein, carbohydrates, and fats. Dosage recommendations are only approximations for initial dosages. Actual dose depends on digestive requirement of individual patient.

Colony-stimulating factors

Class Summary

These agents provide red cell line stimulation.

Epoetin alfa (Epogen, Procrit)

FDA approved for treatment of chronic anemia. Stimulates division and differentiation of committed erythroid progenitor cells; induces release of reticulocytes from bone marrow into bloodstream. SC route provides sustained serum levels compared to IV route. Reduce dose when hematocrit reaches target range of 30-36% or hematocrit increases >4 points over any 2-wk period. Hold dose if hematocrit >36%.

Filgrastim (Neupogen)

FDA approved for severe chronic neutropenia.

GCSF activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. If IV route is used and GCSF final concentration is < 15 mcg/mL, add 2 mg of albumin/mL to prevent drug adsorption to administration set.

Vitamins

Class Summary

Vitamins are essential for normal DNA synthesis and cell function.

ADEK vitamins (ADEKS)

PO multinutrient specially formulated for use under medical supervision to provide nutritional supplementation in individuals with malabsorptive conditions. Each dose contains water-miscible forms of fat-soluble vitamins A, D, E, and K plus other nutrients, including vitamin C, B-complex vitamins, biotin, folic acid, and zinc. Available as chewable tab or pediatric drops.

 

Follow-up

Deterrence/Prevention

See the list below:

  • No prevention for Shwachman-Diamond syndrome is known.

  • Advise parents to obtain genetic counseling.

  • A genetic test for carrier status is available. All siblings of patients with Shwachman-Diamond syndrome should undergo genetic testing. Persons who carry a single Shwachman-Diamond syndrome mutation do not have clinical symptoms.

Complications

See the list below:

  • Malabsorption due to pancreatic insufficiency

    • Diarrhea

    • Hypoproteinemia

    • Fat-soluble vitamin deficiencies

  • Failure to thrive[43]

  • Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia); patients at risk for overwhelming sepsis[5]

  • Hearing loss secondary to recurrent otitis media

  • Predilection for developing bone marrow failure and leukemic transformation in 5-33% of patients with Shwachman-Diamond syndrome[84]

    • Frequency increases with age.

    • Acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia have been reported in patients with Shwachman-Diamond syndrome.

  • Hemosiderosis secondary to multiple red cell transfusions

  • Coxa vara deformity

  • Slipped femoral epiphysis[76]

  • Kyphosis and scoliosis[76]

  • Osteopenia, osteoporosis[74]

  • Cirrhosis of the liver

  • ADHD and learning difficulties[77]

  • Diastolic dysfunction and depressed left ventricular contractility during stress[78]

Prognosis

Long-term prognosis for individuals with Shwachman-Diamond syndrome is uncertain and varies.

  • Patients with Shwachman-Diamond syndrome are at an increased risk of infection secondary to neutropenia and a neutrophil migration defect. Sepsis and death may occur.[5]

  • An increased incidence of myelodysplasia and transformation to acute myeloid leukemia is reported. Acute myeloid leukemia is usually unresponsive to conventional chemotherapy and requires allogenic hematopoietic stem cell transplantation.[10, 11] Even after stem cell transplantation, the prognosis in these patients is poor, mainly due to organ toxicity related to treatment (specifically cardiotoxicity).[31] This has led to a new debate regarding whether patients with Shwachman-Diamond syndrome have a predisposed myocardium, through genetic mechanisms, which become clinically significant after stress of treatment with cardiotoxic conditioning regimens such as whole-body radiation and cyclophosphamide.[91]

Patient Education

See the list below:

  • Educate families on all aspects of this disease and the importance of notifying a physician whenever the patient has a fever or is not acting well.