Shwachman-Diamond Syndrome

What is Pancytopenia? 

Reduction in peripheral blood concentration of all three lineages, i.e., RBCs, leukocytes, and platelets. Pancytopenia words stand for the reduction in circulating levels of all cells.

Pancytopenia with Hypocellular or Acellular Bone Marrow

Inherited BM failure syndromes e.g. Fanconi's anemia and DKC (Dyskeratosis Congenita). It also includes the categories of acquired aplastic anemia and the hypoplastic variant of myelodysplastic syndrome

Pancytopenia with Cellular BM

• It can be seen due to acute leukemia. It can also happen in autoimmune conditions, particularly SLE. It can be seen in hypersplenism, where the increased splenic function is responsible for pancytopenia. It can also be seen in sarcoidosis and severe infections. It can also be seen in nutritional causes. The two important nutritional causes are vitamin B12 and folate deficiency.
• The sub-category included in pancytopenia with Cellular BM is:
  • Pancytopenia with bone marrow infiltration will be seen in bone marrow metastasis.
  • It is seen in storage disorders. The typical storage disorders are gaucher's disease and nieman pick disease.
  • It can be seen in myelofibrosis and osteopetrosis.

Inherited Bone Marrow Failure Syndromes

They comprise about 30% of the cases of pediatric BM failure. Most of them are monogenic disorders and show Mendelian inheritance. It may begin as a uni/bilineage disorder and later evolves into pancytopenia. The most common type of IBMFS is Fanconi's anemia.

Important IBMFSs

• Fanconi's anemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• Cartilage-hair hypoplasia syndrome
• Pearson marrow pancreas syndrome
• Diamond-blackfan anemia
• Hyper IgM syndrome
• Congenital amegakaryocytic thrombocytopenia
• Nijmegen breakage syndrome
• Seckel syndrome
• Dubowitz syndrome

Shwachman-Diamond syndrome

A BMFS with extra-hematological manifestation different from FA and shows no enhanced chromosomal fragility in response to DEB or MMC. It is considered to be a ribosomopathy (there is a problem in the assembly of ribosomes). Most of them are inherited and show the autosomal recessive inheritance. Genes Implicated: SBDS gene 7q11 (80 to 90%). Rare genes are the DNAJC21 gene and EFL-1 (10%). The product of SBDS gene plays a role in pre-60s ribosome subunit maturation. The protein binds to the EFL1 GTPase and facilitates the release of eIF6 to enable 80S monosomes formation. Late stage of ribosomes assembly.

Clinical Feature

Almost 80% of patients with SDS are found to have reduced formation of pancreatic acini and increased fibrofatty infiltration in pancreas, which will produce pancreatic insufficiency and decreased pancreatic enzyme, although many of these children are diagnosed in the 1st yr of the life. These pancreatic features are prominent in 1st 3-4 yrs of life and as the child gets older and survives the features improve. Exocrine pancreatic insufficiency, they tend to improve with time.

Growth retardation skeletal defects. BM failure changes due to either dysfunctional hematopoietic stem cells or they arise due to apoptosis of progenitor cells. It is found that most of these individual neutropenia is virtually always present, anemia and thrombocytopenia may be present but neutropenia will be present in the majority of these patients. Growth retardation includes short stature as well as decreased body weight. The classic skeletal defects can be in the form of metaphyseal dysplasia. In addition osteopenia can also be found in patients.

Rare Manifestations

• Hepatomegaly and raised liver enzymes
• Dental abnormalities
• Neurocognitive problems and poor social skills

Laboratory Findings

Tests for pancreatic insufficiency and fat malabsorption. Pancreatic enzymes- serum trypsinogen, pancreatic isoamylase are low but their age adjusted values need to be checked. Low fecal elastase will be present. Prothrombin time is elevated due to Vitamin K deficiency. Serum vit A and 25 (OH) vitamin D levels are low. USG/CT scan shows fatty replacement of pancreatic tissue. Stool for fat globules and 72 hour stool fat assay. Blood test:

• Neutropenia is seen in 70% at presentation and almost 100% on follow-up.
• Neutrophil function also affected
• Anemia seen in 40-66% of patients.
• Thrombocytopenia seen in 40-60% of patients.
• Pancytopenia seen in 21-44% of patients.

BM studies; hypocellular BM with decreased progenitor cell. Immune defects: low IgG or subclasses, low Ig production, low B cells or NK cells or T cells, less in vitro B and T cell proliferation.

Diagnosis 

• Based on BMFS + pancreatic dysfunction diagnosis can be done.
• Pancreatic dysfunction may be missing in 20% of cases.
• Genetic testing is the gold standard.

Complications

• High risk of developing MDS or Acute leukemias
• 25% develop by 18 years of age.
• 33% develop by 30 years of age.
• Risk of MDS/leukemia is low in i7q and del 20q
• Patients need CBC every 3 monthly and BM studies every 1-3 yearly.

Treatment

• Pancreatic enzymes supplementation orally
• Replacement of fat soluble vitamins
• Daily G-CSF given subcutaneously
• Transfusions can be done
• A trail of steroid + androgens can be given
• Allogeneic HSCT - use reduced-intensity conditioning regimens that incorporates Fludarabine

Prognosis

• Median survival is average 35 years of age
• Almost 50% patients show spontaneous improvement in pancreatic function as age increase
• HSCT has increased a survival rate to 50-70%
• Those developing MDS or acute leukemia have a poor prognosis

Also read: NEET SS Pediatric Neonatology Important Topics

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