AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by pancreatic insufficiency, bone marrow dysfunction, and short stature. In 1964, Shwachman, Diamond, Oski, and Knaw first reported the syndrome in a group of 5 children participating in a cystic fibrosis (CF) clinic at Harvard Medical School. SDS is the second most common cause of inherited pancreatic insufficiency.

Pathophysiology

All patients with SDS have varying degrees of pancreatic insufficiency, which is defined as the loss of exocrine function resulting in the inability to digest and therefore assimilate nutrition normally. Symptoms of malnutrition typically develop when greater 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 CF, the pancreatic ductal architecture is spared; thus, an intact anion secretion and fluid flow occurs. For reasons as yet unknown, the pancreatic lipase secretion increases slightly with age in patients with SDS, resulting in increased pancreatic function with slowing and decrease in fat excretion.

The definitive pathogenic defect responsible for the associated hematologic abnormalities in persons with SDS is unknown. Almost one half of patients with SDS have pancytopenia; however, some may have variable degrees of anemia, thrombocytopenia, or neutropenia. The absolute neutrophil count (ANC) may be intermittently or persistently low in more than 95% of patients. The neutropenia may be mild, moderate, or severe. Irrespective of the total number of neutrophils, patients with SDS have defective neutrophil chemotaxis.

Defective neutrophil chemotaxis is linked to a defect in chromosome 7. Some patients with SDS have been shown to have a defect in chromosome 7. Mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7 have been found in up to 75% of patients with SDS. An unusual surface distribution of concanavalin A on neutrophils may reflect a cellular cytoskeletal defect. Hematologic abnormalities may be due to a stem cell abnormality because patients with SDS have demonstrated decreased colony-forming unit–granulocyte-macrophage (CFU-GM) and colony-forming unit–erythrocyte (CFU-E) growth potential on culture.

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 SDS.

The exact pathophysiology of skeletal anomalies is unknown; however, skeletal anomalies are reported to occur in more than 75% of patients with SDS.

Frequency

United States

After CF, SDS is the second most common cause of pancreatic insufficiency in childhood. Approximately 3% of childhood pancreatic dysfunction is attributed to SDS, which occurs in 1 in 10,000-200,000 births.

International

More than 200 cases of SDS have been reported in the literature.

Mortality/Morbidity

Prognosis for individuals with the disorder is uncertain. Because SDS was described relatively recently, limited data are available regarding follow-up in these patients.

• Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia) are common in individuals with SDS because of a neutropenia/neutrophil migration defect.
• A predilection for developing bone marrow failure and leukemic transformation appears to exist in persons with SDS. Isochromosome arm 7q may be a specific marker of myeloid malignant transformation. Up to 90% of patients with SDS have mutations in the SBDS gene on chromosome 7q11.
• Death usually occurs from overwhelming sepsis or malignancy.
• Alter et al (1998) report that the projected median survival age is older than 35 years for all patients with SDS. For those patients whose course is complicated by aplastic anemia, the median survival age is 24 years, while those patients whose course is complicated by leukemia have a median survival age of 10 years.

Race

SDS is reported among all racial and ethnic groups.

Sex

The male-to-female ratio is 1.7:1.

Age

SDS is usually diagnosed during the newborn period or infancy when patients present with malabsorption and recurrent infections.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• 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.
  • Imperforate anus and Hirschsprung disease have been associated with SDS. These associations may delay diagnosis of SDS 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.
• 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 SDS.
• Unlike patients with CF, patients with SDS have a paucity of pulmonary symptoms, although some patients may present with recurrent upper and lower respiratory tract infections.
• Saliva production is decreased; however, no significant clinical symptoms are associated with this phenomenon.
• Patients with SDS typically experience delayed puberty.
• Mild-to-moderate psychomotor and/or developmental delay may be observed in up to 15% of affected individuals.

Physical

• Patients with SDS 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. Their height and weight are usually below the third percentile but may occasionally reach the 25th percentile.
• 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
  • Dental abnormalities
• Dermatologic manifestations in a person with SDS include the following:
• • Eczema
  • Ichthyosis
  • Petechiae

Causes

SDS is an autosomal recessive disorder caused by mutations in the SBDS gene located on chromosome 7q11. The SBDS gene contains 5 exons, which encode a 250-amino-acid protein of unknown function. The most frequent mutations are due to gene conversion between the SBDS gene and its pseudogene (SBDSP). However, these mutations have not been found in all patients with SDS. Tada et al (1987) have reported one individual with SDS with increased spontaneous chromosome breakage.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Johanson-Blizzard syndrome
Exocrine pancreatic dysfunction with refractory sideroblastic anemia
Pancreatic agenesis
Congenital rubella with chronic pancreatic insufficiency
Isolated enzyme deficiencies (eg, lipase, lipase/colipase, colipase, trypsin, amylase)
Myelokathexis
Chédiak-Higashi syndrome
Inborn errors of metabolism
Immunologic disorders (eg, hyper–immunoglobulin M [IgM] syndrome)
Congenital aplastic anemias (eg, Fanconi anemia, congenital dyskeratosis, amegakaryocytic purpura, reticular dysgenesis)
Dubowitz syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood cell count to assess neutropenia, anemia, and thrombocytopenia
• • Cyclic or persistent neutropenia is observed in 88-95% of patients with Shwachman-Diamond syndrome (SDS). Because the neutropenia may be intermittent, blood cell counts may need to be repeated biweekly over a 3-week period to document neutropenia.
    • Neutropenia is defined as an ANC of less than 1500 in white people and less than 1200 in black people.
    • Mild neutropenia is defined as an ANC of 1000-1500.
    • Moderate neutropenia is defined as an ANC of 500-1000.
    • Severe neutropenia is defined as an ANC of less than 500.
  • Anemia is present in more than 50% of patients with SDS secondary to iron deficiency and/or bone marrow hypoplasia.
  • Thrombocytopenia is present in more than 25% of patients with SDS.
• Neutrophil function studies: A neutrophil migration defect may be documented.
• Fetal hemoglobin: This is elevated in approximately 75% of patients with SDS.
• Iron studies: Patients may have associated iron deficiency secondary to malabsorption.
• A 72-hour fecal fat measurement:
• • An increase in fecal lipids and fatty acids is present in persons with SDS.
  • The fecal fat losses vary from 3-60%, and these losses decrease with age. After an individual with SDS is aged 8 years, fecal fat losses average 8% of intake. 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 SDS.
• 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.
• Sweat test: In individuals with SDS, this test demonstrates no increase in chloride, in contrast to CF, where the chloride is elevated abnormally.
• Glucose tolerance test: Findings on this test are generally normal. Rarely, patients with SDS may have diabetes mellitus.
• Urinalysis: In persons with SDS, 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 SDS.
  • 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.
• Immunoglobulin levels: Immunoglobulin A (IgA), IgM, and/or immunoglobulin G (IgG) may be low.
• Growth hormone levels: These are often decreased in persons with SDS.
• Serum calcium and phosphorous: These levels are within the reference range.

Imaging Studies

• The pancreas can be evaluated through ultrasonography or CT imaging.
• • Ultrasonographic findings of the pancreas of an individual with SDS show a pancreas of normal size with increased echogenicity of the pancreatic silhouette. In contrast, the size of the pancreas in patients with CF usually is decreased.
  • CT scan reveals lipomatosis of the pancreas.
• A skeletal survey in a person with SDS may show some of the following skeletal abnormalities:
• • Delayed bone age (>75%)
  • Thoracic dysostosis consisting of costochondral thickening, short flaring lower ribs, and a narrow thoracic cage that is most obvious when the individual with SDS is younger than 2 years (44-60%)
  • Metaphyseal chondrodysplasia noted in individuals with SDS who are older than 6 years, as evidenced by shortening of the extremities, metaphyseal widening, and "cup" deformity of the ribs (40-80%)
  • Abnormal tubulation of the long bones, especially the ulnae, tibia, and first metacarpals (33%)
  • Valgus deformities of the elbows and knees
  • Osteopenia early on, which improves with age (Up to 45% of patients who become pancreatic sufficient later in childhood have shown complete reversal.)

Other Tests

• A predilection for developing bone marrow failure and leukemic transformation appears to exist in persons with SDS. Isochromosome arm 7q may be a specific marker of myeloid malignant transformation. Up to 90% of patients with SDS have mutations in the SBDS gene on chromosome 7q11. Therefore, periodic bone marrow evaluation studies may be helpful.

Procedures

• Duodenal aspiration (performed by a gastroenterologist) in the person with SDS 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

Biopsy of the pancreas of a person with SDS reveals mostly adipose tissue containing the islets of Langerhans with very few elements of exocrine gland structure present. The pancreas of patients with CF usually shows fibrosis rather than lipomatosis, observed in patients with SDS and Johanson-Blizzard syndrome. Routine biopsy of the pancreas is not indicated.

Perform bone marrow evaluation studies periodically because of the predilection for developing marrow failure and leukemic transformation (occurs in 5-33% of patients with SDS), including acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia. However, examination of the bone marrow in a person with SDS typically demonstrates hypocellularity with maturation arrest in the myeloid series and fat infiltration. Megakaryocytes may be within the reference range or decreased in number.

The liver of an individual with SDS may exhibit periportal fibrosis, 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 SDS.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

• 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. Treatment of pancreatic insufficiency only slightly improves growth.
• 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.
• No therapy has been successful in completely reversing neutropenia, anemia, or thrombocytopenia.
• 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; 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.
• 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 SDS are usually unresponsive to standard chemotherapy and require allogenic hematopoietic stem cell transplantation. These patients are at high risk for complications after bone marrow transplant. A number of factors may contribute to this high complication rate. Their underlying hematologic abnormalities and high reported rate of nonspecific organ malfunctions may place them at higher risk for the development of toxicities.
• Growth hormone has been used to treat children with SDS who have growth hormone deficiency. The initial response is good; however, long-term therapy with growth hormone is unsuccessful.
• Appropriate orthopedic follow-up of metaphyseal dysplasia may prevent deformities.

Consultations

• 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.)

Diet

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

Activity

No limitations on activity exist for individuals with SDS, unless thrombocytopenia is observed.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Pancreatic enzymes

These agents are used to replace endogenous pancreatic enzymes.

Drug Category: Colony-stimulating factors

These agents provide red cell line stimulation.

Drug Category: Vitamins

Vitamins are essential for normal DNA synthesis and cell function.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• No known prevention for Shwachman-Diamond syndrome (SDS) exists.
• Advise parents to obtain genetic counseling.
• Currently, the medical profession is unable to detect the carrier state of this disease.

Complications

• Malabsorption due to pancreatic insufficiency
• • Diarrhea
  • Hypoproteinemia
  • Fat-soluble vitamin deficiencies
• Failure to thrive
• Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia) common; patients at risk for overwhelming sepsis
• Hearing loss secondary to recurrent otitis media
• Predilection for developing bone marrow failure and leukemic transformation in 5-33% of patients with SDS
• • Frequency increases with age
  • Acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia have been reported in patients with SDS
• Hemosiderosis secondary to multiple red cell transfusions
• Coxa vara deformity
• Osteopenia
• Cirrhosis of the liver

Prognosis

Long-term prognosis for individuals with SDS is uncertain and variable.

• Patients with SDS are at an increased risk of infection secondary to neutropenia and a neutrophil migration defect. Sepsis and death may occur.
• An increased incidence of myelodysplasia and transformation to acute myeloid leukemia exists. Acute myeloid leukemia is usually unresponsive to conventional chemotherapy and requires allogenic hematopoietic stem cell transplantation.

Patient Education

• 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider Shwachman-Diamond syndrome if the patient has pancreatic insufficiency and a negative finding on sweat test
• Failure to avoid underdiagnosis, which is caused by lack of awareness of this condition

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 13, 2006