Severe Shwachman-Diamond syndrome and associated CF carrier mutations

1. Introduction 

Shwachman-Diamond syndrome (SDS) is autosomal recessive presenting in infancy with exocrine pancreatic insufficiency, bone marrow failure, growth and skeletal abnormalities such as thoracic dystrophy and failure to thrive (FTT).1, 2 It affects 1 in 75,000.3 In 90% of patients with SDS the genetic mutations have been localized to chromosome 7(7p10–7q11).3, 4

The mean age for diagnosis of SDS is 1 year with projected survival of most patients into adult years.5 During infancy the main causes of increased morbidity and mortality are malabsorption, infections and thoracic dystrophy (rib cage abnormalities with shortened ribs and a narrow rib cage).2, 5 The leading causes of morbidity and mortality later in life are hematological abnormalities and treatment of the hematological complications.5 Children with SDS have an increased risk for developing myelodysplastic syndrome and acute myeloid leukemia (AML) with poor prognosis.3

Cystic fibrosis (CF) is an autosomal recessive disease common among Caucasians of European descent. The defective gene isolated is on the long arm of chromosome 7. Delta F508 is the most common mutation among Caucasians and I1027T has been studied as a delta F508-I1027 haplotype consisting of a cis-association of the two mutations.6, 7 Cystic fibrosis carriers do not show any manifestations of the disease.8 Our case report is unique with a very early age of diagnosis due to severe morbidity not usually seen. Our hypothesis is that the combination of SDS genetic mutations and CF carrier mutations led to the severe morbidity and early mortality of our case.

2. Case report 

ZM was born at 42 weeks gestation with profound hypotonia, poor suckling and leukopenia with subsequent pancytopenia. Birth weight was 2.6kg (∼5th percentile). Family history was notable for a half-brother with septo-optic dysplasia. No family history of consanguinity.

At three months of age, he was hospitalized for four weeks with respiratory insufficiency and hypoxia, persistent steatorrhea and FTT. Genetic testing for SDS and CF identified two separate mutations for SDS: C.258 2T-to-C and C.258 1G-to-C (compound heterozygote for SDS) leading to the diagnosis of SDS and two genetic mutations for CF (delta F508 and I1027T) identified were determined to be of maternal origin. Sweat chloride test was negative. Low fecal elastase demonstrated severe pancreatic insufficiency. He had severe FTT despite pancreatic enzyme supplementation.

He was rehospitalized at five months of age for worsening hypoxia and respiratory distress secondary to RSV bronchiolitis. He developed respiratory failure requiring mechanical ventilation, pneumothorax and septic shock. He was eventually weaned to oxygen via nasal cannula. He continued to have respiratory distress, severe FTT (up 205g from birth weight) and cyclic pancytopenia. He was transferred to our hospital after three weeks for further work up and management.

Throughout the six-week hospitalization he was persistently tachypneic (respiratory rates 60–80s). Chest X-rays demonstrated hypoplastic thorax and short ribs. High resolution CT of the chest and abdomen revealed bilateral atelectasis, thoracic rib cage dysostosis, and fatty infiltrate of the pancreas. He was kept on intravenous (IV) total parental nutrition due to poor wound healing of G Tube site. Episodes of cyclic pancytopenia were often associated with fever and multiple infections with methicillin resistant Staph epidermidis and Staph aureus and Pseudomonas aeruginosa. He received numerous platelet and packed RBC transfusions. Bone marrow biopsy demonstrated 46 XY with hypocellularity, depressed white cell lineages without clonal or leukemic abnormalities. He had two subsequent admissions for recurrence of fever and diarrhea and was treated with antibiotics.

He was readmitted at eight months of age within a day of discharge, with fever, respiratory distress and worsening hypoxia. He was not considered for bone marrow transplant due to poor nutrition, worsening hypoxia and severe restrictive lung disease. He succumbed at eight months of age due to respiratory failure, acidosis, persistent fever and a precipitous anemia.

3. Discussion 

SDS is an autosomal recessive syndrome with median survival of 35 years.5 Although genetic mutation is identifiable in up to 90% of patients, a correlation between genotype and phenotype or disease severity has not been found.9 Management for patients with SDS is pancreatic enzyme replacement, monitoring of white counts, management of neutropenia with granulocyte colony stimulating factor, management of anemia and thrombocytopenia with red blood cell and platelet transfusions. Hemopoetic stem cell transplantation is currently the only treatment for bone marrow failure.10 Our patient died in infancy, despite aggressive management secondary to severe restrictive lung disease, profound neutropenia, anemia, recurrent infections and poor nutritional status. The severity of his SDS is striking complicated by compound CF carrier status. We hypothesize that the two mutations of cystic fibrosis that were present on the 7th chromosome exon 10 site found in close proximity to the SDS mutations at chromosome 7q11, may have contributed to the severity of his SDS course. This is the first report that documents a case with severe SDS and 2 mutations for CF that are originating from one parent.

Conflict of interest statement 

None of the authors have a conflict of interest to declare in relationship to this work.