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eMedicine Specialties > Pediatrics: General Medicine > Hematology

Shwachman-Diamond Syndrome

Antoinette C Spoto-Cannons, MD, FAAP, Associate Professor, Department of Pediatrics, Director, Undergraduate Children's Health Care Education, University of South Florida College of Medicine
Jessica Marie Keshishian, MD, Resident Physician, Department of Pediatrics, University of South Florida; Sarah Syed, University of South Florida College of Medicine; Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine

Updated: Sep 30, 2009

Introduction

Background

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, leukemia predisposition, and skeletal abnormalities. 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. Shwachman-Diamond syndrome 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 Blackfan-Diamond anemia. In most cases, Shwachman-Diamond syndrome is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7.

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.

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.1 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.1

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.2 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.2

Shwachman-Diamond syndrome is considered one of the inherited bone marrow failure syndromes. Another key feature of Shwachman-Diamond syndrome involves ineffective hematopoiesis. The relationship of the genetic defect to the pathophysiology of bone marrow failure is currently unknown. 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. 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.3 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.4

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, Schwachman-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.5,6,7 These patients have lower performance in most cognitive domains than age-matched controls.7 Although they do not have gross brain abnormalities, they are frequently found to have significantly reduced brain volumes.8

Frequency

United States

After cystic fibrosis, Schwachman-Diamond syndrome is the second most common cause of pancreatic insufficiency in childhood. Approximately 3% of childhood pancreatic dysfunction is attributed to Schwachman-Diamond syndrome. The incidence of Schwachman-Diamond syndrome has been estimated at 1 case in 75,000 population using comparison cystic fibrosis data.

International

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

Mortality/Morbidity

Prognosis for individuals with the disorder is uncertain. Because Schwachman-Diamond syndrome 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 Schwachman-Diamond syndrome because of neutropenia/neutrophil migration defects.9

Like other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is also observed with Schwachman-Diamond syndrome. The frequency of leukemia in patients with Schwachman-Diamond syndrome is 5-10%; most cases are acute myeloid leukemia (AML).10 Isochromosome 7q may be a specific marker of myeloid malignant transformation in association with Schwachman-Diamond syndrome.11

Whether increased angiogenesis in Schwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear,12 but increased expression of vascular endothelial growth factor-A and other cytokines may play a role.13 At the genetic level, spindle instability that contributes to bone marrow failure and leukemia development has also been implicated.14 Spindle instability may also be attributed, at least in part, to the high frequency of acquired chromosomal anomalies found in patients with Schwachman-Diamond syndrome, which may form the basis of malignant transformation in tissues with high mitotic activity.15

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.16,17

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 Schwachman-Diamond syndrome.18 For patients 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

Schwachman-Diamond syndrome is reported among all racial and ethnic groups.18

Sex

The male-to-female ratio is 1.7:1.19

Age

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

Clinical

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.20
    • 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.21,9,22,19
  • 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,23 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.24
  • Saliva production is decreased; however, no significant clinical symptoms are associated with this phenomenon.
  • Patients with Shwachman-Diamond syndrome typically experience delayed puberty.25
  • Mild-to-moderate psychomotor and/or developmental delay may be observed in as many as 15% of affected individuals.

Physical

  • 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.19 Their height and weight are usually below the third percentile but may occasionally reach the 25th percentile.25
  • 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.26 )
  • 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.27

    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.28 SBDS is a highly conserved protein.29 In a mouse model, it was demonstrated to be essential for early mammalian development.30
  • 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.31 This may be due to its role in ribosome biogenesis or RNA processing, which has been shown in yeast.32 One of the SBDS-binding proteins, nucleophosmin (NPM, B23), has a role in ribosome biogenesis and control of cell cycle.33 Interestingly, mutations that affect ribosome assembly or function are associated with other inherited bone marrow failure syndromes,34 and models of how impairment of ribosomal pathways might affect hematopoiesis and tumorigenesis are currently under investigation.33

Differential Diagnoses

Cystic Fibrosis
Jeune Syndrome
Pearson Syndrome
Severe Combined Immunodeficiency
Thrombocytopenia-Absent Radius Syndrome

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, several congenital neutropenia)
Dubowitz syndrome
Cartilage-Hair Hypoplasia

Workup

Laboratory Studies

  • CBC 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, CBC counts may need to be repeated biweekly over a 3-week period to document neutropenia.35
      • Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/mcL in whites and less than 1200 in blacks.
      • 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.
  • Neutrophil function studies: A neutrophil migration defect may be documented.
  • Fetal hemoglobin: This is elevated in approximately 80% of patients with Shwachman-Diamond syndrome.11
  • 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 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.36 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.25
  • 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.21
  • 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.37,38 The test should be repeated if there is any doubt regarding the diagnosis.38
  • 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.39
    • 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) levels may be low.
  • Growth hormone levels: These are often decreased in persons with Shwachman-Diamond syndrome.
  • 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.40
    • CT scanning reveals lipomatosis of the pancreas. The size of the pancreas may be normal or atrophic.41
    • MRI may be used to evaluate the pancreatic fat content and can even help confirm the clinical diagnosis of Shwachman-Diamond syndrome.42 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.43
  • A skeletal survey in a person with Shwachman-Diamond syndrome may reveal some of the following skeletal abnormalities:
    • Delayed bone age (>75%)21
    • 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%)36
    • 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%)44
    • Abnormal tubulation of the long bones, especially the ulnae, tibia, and first metacarpals (33%)37,21
    • Valgus deformities of the elbows and knees37
    • Osteopenia early on, which improves with age (As many as 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 is associated with Schwachman-Diamond syndrome.

  • Isochromosome arm 7q may be a specific marker of myeloid malignant transformation.
  • As many as 90% of patients with Schwachman-Diamond syndrome have mutations in the SBDS gene on chromosome 7q11.
  • Annual bone marrow evaluation with cytogenetics may be helpful.45,18

Procedures

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

  • Biopsy of the pancreas of a person with Schwachman-Diamond syndrome reveals mostly adipose tissue containing the islets of Langerhans with very few elements of exocrine gland structure present.23 The pancreas of patients with cystic fibrosis usually has fibrosis rather than lipomatosis, as is observed in patients with Schwachman-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 Schwachman-Diamond syndrome), including acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia. However, examination of the bone marrow in a person with Schwachman-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.23,37
  • The liver of an individual with Schwachman-Diamond syndrome may exhibit periportal fibrosis,39 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 Schwachman-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.

  • A significant proportion of patients with Schwachman-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.37 .
  • When patients with Schwachman-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.37
  • 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;46,22,47 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.23
  • 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 Schwachman-Diamond syndrome are usually unresponsive to standard chemotherapy and require allogenic hematopoietic stem cell transplantation.25,48 These patients are at high risk for complications after bone marrow transplant. Numerous 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.49 In an attempt to reduce toxicity, preparative regimens avoiding the combination of busulfan and cyclophosphamide have been tried.50 Reduced-intensity conditioning was associated with excellent donor cell engraftment and modest morbidity.51
  • Growth hormone has been used to treat children with Schwachman-Diamond syndrome who have growth hormone deficiency. The initial response is good; however, long-term therapy with growth hormone is unsuccessful.52
  • 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 are necessary for individuals with Schwachman-Diamond syndrome, unless thrombocytopenia is observed.

Medication

Pancreatic enzymes

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.

Dosing

Adult

Pediatric

6-12 months: 2000-4000 IU per 120 mL of formula
1-6 years: 4000-8000 IU with meals; 4000 IU with snacks
7-12 years: 4000-12,000 IU with meals and snacks

Interactions

Calcium carbonate and magnesium hydroxide decrease effect of pancreatic enzymes, while H2 antagonists (eg, ranitidine, cimetidine) increase effects of enzymes

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Doses >6000 U/kg per meal may be associated with fibrosing colonopathy, which has been evident in patients with CF who developed strictures of the ascending colon; inactivated by acids (use microencapsulated products whenever possible because these products permit better dissolution of enzymes in the duodenum and protect enzyme preparations from acid degradation in stomach); adverse reactions include nausea, cramps, constipation, diarrhea, lacrimation, sneezing, rash, bronchospasm, and shortness of breath; high doses may cause hyperuricemia and hyperuricosuria

Colony-stimulating factors

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%.

Dosing

Adult

50-150 U/kg IV/SC 3 times per wk

Pediatric

Administer as in adults; individualize to maintain hematocrit within 30-36% of target range; increase 25-50 U/kg 3 times per wk q4-6wk if hematocrit does not increase by 5-6 points after 8 wk of therapy and hematocrit is below target range; increase dose until desired response, not to exceed 300 U/kg 3 times per wk

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled hypertension; neutropenia in newborns

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in porphyria, hypertension, and history of seizures; decrease dose if hematocrit increases >4 U in any 2-wk period; monitor hematocrit, blood pressure, clotting times, platelets, BUN, and serum creatinine levels; prior to and during therapy, evaluate iron stores by obtaining serum iron, ferritin, and total iron-binding capacity; may cause hypertension, seizures, fever, headaches, edema, rash, urticaria, dizziness, fatigue, chest pain, cough, nausea, vomiting, diarrhea, clotted access, arthralgia, weakness, myocardial infarction, stroke, transient ischemic attack, and rarely neutropenia


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.

Dosing

Adult

5 mcg/kg/d SC

Pediatric

5-10 mcg/kg per dose IV/SC qd for 14 d or until ANC reaches acceptable level, which varies from patient to patient; not to exceed 480 mcg/d

Interactions

Do not use 12-24 h before or 24 h after administering cytotoxic chemotherapy because it increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of developing myelodysplastic syndrome or acute myeloid leukemia in certain patients; leukocytosis; possible tumor growth; monitor CBC count, uric acid, and LFTs; caution in patients with malignancies with myeloid characteristics and in patients with gout or psoriasis; may cause bone pain, osteoporosis, fever, rash, pain at injection site, thrombophlebitis, anaphylactic reaction, increased alkaline phosphatase, reversible increase in uric acid and lactate dehydrogenase, splenomegaly, leukocytosis, thrombocytopenia, chest pain, hematuria, proteinuria, headache, weakness, supraventricular arrhythmias, transient decrease in blood pressure, and pericarditis

Vitamins

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.

Dosing

Adult

Pediatric

<12 months: 1 mL PO qd
1-3 years: 2 mL PO qd
4-10 years: 1 tab PO qd
>10 years: 2 tabs PO qd

Interactions

Best administered with supplementary pancreatic enzymes for individuals requiring enzyme therapy for control of steatorrhea or improved fat absorption; vitamin K interferes with actions of anticoagulant drugs

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Do not exceed recommended doses; contraindicated in pregnancy if vitamin A exceeds RDA; exclude pernicious anemia before using because folic acid in doses >0.1 mg/d may mask symptoms; for chewable tab, chew or crush tab thoroughly before swallowing

Follow-up

Deterrence/Prevention

  • No prevention for Shwachman-Diamond syndrome (SDS) is known.
  • 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 thrive20
  • Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia); patients at risk for overwhelming sepsis21
  • Hearing loss secondary to recurrent otitis media
  • Predilection for developing bone marrow failure and leukemic transformation in 5-33% of patients with Schwachman-Diamond syndrome49
    • Frequency increases with age.
    • Acute myeloid leukemia, acute lymphoid leukemia, and juvenile chronic myeloid leukemia have been reported in patients with Schwachman-Diamond syndrome.
  • Hemosiderosis secondary to multiple red cell transfusions
  • Coxa vara deformity
  • Osteopenia, osteoporosis43
  • Cirrhosis of the liver

Prognosis

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

  • Patients with Schwachman-Diamond syndrome are at an increased risk of infection secondary to neutropenia and a neutrophil migration defect. Sepsis and death may occur.21
  • 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.25,48 Even after stem cell transplantation, the prognosis in these patients is poor, mainly due to organ toxicity related to treatment (specifically cardiotoxicity).11 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.53

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

Medicolegal 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

Multimedia

Autosomal recessive inheritance.

Media file 1: Autosomal recessive inheritance.

References

  1. Ip WF, Dupuis A, Ellis L, Beharry S, Morrison J, Stormon MO. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman-Diamond syndrome. J Pediatr. Aug 2002;141(2):259-65. [Medline].

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Keywords

Shwachman-Diamond syndrome, SDS, bone marrow dysfunction, pancreatic insufficiency, short stature, congenital lipomatosis of pancreas, metaphyseal dysplasia, pancreatic hypoplasia, marrow dysfunction, pancreatic hypoplasia, marrow dysfunction, metaphyseal dysplasia, Shwachman-Bodian syndrome, Shwachman-Diamond-Oski-Knaw syndrome, cystic fibrosis, Fanconi anemia, Blackfan-Diamond, skeletal dysplasia, osteoporosis, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia, myelodysplastic syndrome, MDS, leukemia, malabsorption, imperforate anus, Hirschsprung disease, constipation, diarrhea, hearing loss, tooth enamel defects, hypomaturation, hypocalcification, hypoplasia, treatment, diagnosis

Contributor Information and Disclosures

Author

Antoinette C Spoto-Cannons, MD, FAAP, Associate Professor, Department of Pediatrics, Director, Undergraduate Children's Health Care Education, University of South Florida College of Medicine
Antoinette C Spoto-Cannons, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, Council on Medical Student Education in Pediatrics, and Florida Pediatric Society
Disclosure: Nothing to disclose.

Coauthor(s)

Jessica Marie Keshishian, MD, Resident Physician, Department of Pediatrics, University of South Florida
Jessica Marie Keshishian, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Student Association/Foundation, and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Sarah Syed, University of South Florida College of Medicine
Sarah Syed is a member of the following medical societies: American Medical Student Association/Foundation
Disclosure: Nothing to disclose.

Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine
Mudra Kumar, MD, MBBS, MRCP is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MBBS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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