Shwachman-Diamond Syndrome


Article Author:
Samid Farooqui
Hassam Zulfiqar


Article Editor:
Muhammad Aziz


Editors In Chief:
Linda Lindsay


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
6/9/2019 11:49:32 PM

Introduction

Schwachman-Diamond syndrome (SDS) is an autosomal recessive disorder that is the second most common cause of exocrine pancreatic insufficiency after cystic fibrosis. It presents with the common triad of exocrine pancreatic dysfunction, skeletal abnormalities, and bone marrow dysfunction. However, cardiac abnormalities, immune dysfunction, and hematologic disorders are also reported. A mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene on chromosome 7 is found in 90% of the cases.[1][2][3][4]

Etiology

SDS is caused by an SBDS gene mutation on chromosome 7. It codes for the SBDS protein (SBDSP) which is widely expressed, throughout the body, in different organ systems. SBDS gene and SBDSP pseudogene are located in proximity on chromosome 7, and a possible conversion event between the 2 loci result in the mutation.[5][6][7]

Epidemiology

It is a rare disorder with a reported incidence of 1 in 75,000 individuals. Patients generally present in infancy. Life expectancy into the third and fourth decades of life is reported in the literature. There is a higher incidence of males affected with a male to female ratio of 1.7:1.

Pathophysiology

SBDS gene codes for the SBDS protein. The protein is found predominantly in the nucleolus and is implicated in the normal functioning of ribosomes, amplification of the centrosomes, and in leukemogenesis. However, the true function of the SBDS protein is still unknown. In the pancreas, there is the fatty replacement of the acinar cells which results in an exocrine deficiency. Cytopenias result in stress hematopoiesis in the bone marrow which accounts for the elevated levels of hemoglobin F. The exact mechanism behind malignant transformation into acute myelogenous leukemia (AML) is unknown.  The abnormalities in the hematological system may be absent on initial presentation but can manifest later, as part of an evolving process.[8][9][10]

History and Physical

SDS is thought to be underdiagnosed in the general population due to its ambiguous presentation. It can present at any time in life, though most cases present earlier in life. Predominantly, patients present with exocrine pancreatic insufficiency and hematologic abnormalities; other manifestations are less common. Steatorrhea, malabsorption, and deficiency of fat-soluble vitamins are the hallmarks of exocrine pancreatic insufficiency; however, most these symptoms improve with age in most patients.

Hematologic abnormalities are also common in patients with SDS. Leukopenia results in recurrent viral and bacterial infections, including but not limited to sinusitis, pneumonia, osteomyelitis, and septicemia. Patients can present with bleeding, sometimes life-threatening, due to thrombocytopenia. Macrocytic or normocytic anemia is also seen in up to 80% of patients.  

Patients can also present with manifestations of skeletal abnormalities. These include short stature, rib-cage abnormalities, slipped femoral epiphysis, spinal and finger deformities.

Neurological abnormalities, including intellectual disability, depressed attention span, difficulty in executive functioning and impaired visual motor coordination can also be present. Behavioral changes are also reported in children with SDS.

Evaluation

Presence of hematological abnormalities and exocrine pancreatic insufficiency are needed to make a clinical diagnosis of SDS, according to the latest guidelines. However, other causes of bone marrow failure and exocrine pancreatic insufficiency should be excluded.

Patients with suspected exocrine pancreatic insufficiency should have a 72-hour stool fat quantification test performed. Trypsinogen and isoamylase levels aid in the diagnosis; however, trypsinogen levels can only be measured before 3 years of age as levels start increasing after 3 years; whereas, isoamylase levels always remain low. A sweat chloride test is normal in these patients, and this distinguishes between SDS and cystic fibrosis.

Routine blood workup can provide information about cytopenias. Patients with SDS need frequent monitoring of blood for early detection of progression to myelodysplastic syndromes or acute myelogenous leukemia (AML). 

Genetic testing for mutations of the SBDS gene can confirm the diagnosis in 90% of the cases. Upon confirmation of diagnosis, a bone marrow biopsy, aspirate smear, cytological testing and a skeletal survey is recommended.

Referral to a specialist should be made if any neurocognitive deficit is suspected.

Treatment / Management

Upon confirmation of diagnosis, patients should be initiated on a pancreatic enzymatic replacement. This is shown to generate a good response in these patients. Levels of fat-soluble vitamins should also be checked regularly (every 6 to 12 months) and replaced as necessary. The exocrine pancreatic function should be checked as it improves with time and enzymatic replacement may need to be discontinued. Additionally, patients should have dietary counseling provided by a certified dietitian with regular monitoring of growth by serial height and weight measurements.

Transfusions of packed red blood cells (PRBC) and platelets are the mainstay of management for anemia and thrombocytopenia respectively. In patients requiring extensive PRBC transfusions, initiation of iron chelation needs to be considered.

Infections are the feared complication of leukopenia. Prompt treatment with antibiotics is the mainstay of therapy. Granulocyte colony-stimulating factor (G-CSF) can be used to increase the white blood cell (WBC) count. However, it is not needed in most patients. It can be used in patients with severe neutropenia or patients with frequent invasive infections. The goal of G-CSF administration is to reduce the incidence of infections and not to achieve normal laboratory hematological values. There is some concern about G-CSF use causing myelodysplastic and leukemic transformation in the bone marrow, but there is a lack of strong evidence to prove it.

Patients should have routine blood monitoring every 3 to 4 months with a hematologist for detection of marrow failure, myelodysplastic syndrome or Leukemia. Due to the rarity of the disease, there is no particular chemotherapeutic regimen approved for these patients. Chemotherapy only serves to contain the disease process and is not curative in SDS patients with leukemia. Hematopoietic stem cell transplant (HSCT) is the only curative treatment in these patients. The indication for receiving HSCT determines the survival. Patients receiving HSCT for bone marrow failure (e.g., aplastic anemia) have been reported to fare better than patients receiving HSCT for leukemia.

Patients with SDS are more likely to have complications from chemotherapy and HSCT than patients with isolated hematological problems requiring similar treatments. These include infections, persistent aplasia, cardiotoxicity and renal failure.

Follow-up of the skeletal system is determined by the findings of the initial skeletal survey performed at the time of diagnosis. Patients with SDS should be monitored for osteoporosis. Vitamin D levels should be checked and maintained within normal limits.

Patients with SDS should have regular developmental neuropsychological evaluations from ages 5 to 18 to assess for adequate brain maturation.

Differential Diagnosis

  • Cystic fibrosis 
  • Pearson syndrome 
  • Pancreatic agenesis 
  • Johanson-Blizzard syndrome 
  • Cartilage-hair hypoplasia

Consultations

  • Hematology/Oncology 
  • Gastroenterology 
  • Orthopedic surgery 
  • Psychologist

Enhancing Healthcare Team Outcomes

SDS is a rare blood disorder associated with pancreatic insufficiency. It is best managed by a multidisciplinary team that includes hematology nurses. There is no cure for this disorder and treatment is required in most patients. Unfortunately, the treatments do have adverse effects which are not well tolerated. Once a diagnosis of SDS is made, a genetic consult should be made for the rest of the family, 

The outcomes for patients with SDS are guarded.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Shwachman-Diamond Syndrome - Questions

Take a quiz of the questions on this article.

Take Quiz
What is the second most common cause of exocrine pancreas insufficiency in children?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following findings is least likely in a patient with Shwachman-Diamond syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 4 month old child is noted to have poor weight gain despite a large intake of formula. The parents report greasy, foul smelling stools. The infant is small, thin, and pale. CBC shows leukopenia and anemia. Sweat chloride test is negative. An x-ray shows metaphyseal dysostosis. Select the most probable diagnosis.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the definitive treatment for Myelodysplastic Syndrome (MDS) in patients with Shwachman-Diamond syndrome (SDS)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Shwachman-Diamond Syndrome - References

References

Tan S,Kermasson L,Hoslin A,Jaako P,Faille A,Acevedo-Arozena A,Lengline E,Ranta D,Poirée M,Fenneteau O,Ducou le Pointe H,Fumagalli S,Beaupain B,Nitschké P,Bôle-Feysot C,de Villartay JP,Bellanné-Chantelot C,Donadieu J,Kannengiesser C,Warren AJ,Revy P, EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome. Blood. 2019 May 31;     [PubMed]
Szabo CE,Man OI,Şerban RS,Kiss E,Lazăr CF, Bruising as the first sign of exocrine pancreatic insufficiency in infancy. Medicine and pharmacy reports. 2019 Apr;     [PubMed]
Jensen LT,Phyu T,Jain A,Kaewwanna C,Jensen AN, Decreased accumulation of superoxide dismutase 2 within mitochondria in the yeast model of Shwachman-Diamond syndrome. Journal of cellular biochemistry. 2019 Apr 2;     [PubMed]
Cipolli M,Tridello G,Micheletto A,Perobelli S,Pintani E,Cesaro S,Maserati E,Nicolis E,Danesino C, Normative growth charts for Shwachman-Diamond syndrome from Italian cohort of 0-8 years old. BMJ open. 2019 Jan 17;     [PubMed]
Kallen ME,Dulau-Florea A,Wang W,Calvo KR, Acquired and germline predisposition to bone marrow failure: Diagnostic features and clinical implications. Seminars in hematology. 2019 Jan;     [PubMed]
Bezzerri V,Cipolli M, Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives. Molecular diagnosis     [PubMed]
Nelson AS,Myers KC, Diagnosis, Treatment, and Molecular Pathology of Shwachman-Diamond Syndrome. Hematology/oncology clinics of North America. 2018 Aug;     [PubMed]
Ong SY,Li ST,Wong GC,Ho AYL,Nagarajan C,Ngeow J, Delayed diagnosis of Shwachman diamond syndrome with short telomeres and a review of cases in Asia. Leukemia research reports. 2018;     [PubMed]
Farooqui SM,Aziz M, Shwachman-Diamond Syndrome 2019 Jan;     [PubMed]
Nelson A,Myers K, Shwachman-Diamond Syndrome 1993;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of NP-Genetics. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for NP-Genetics, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in NP-Genetics, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of NP-Genetics. When it is time for the NP-Genetics board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study NP-Genetics.