Shwachman-Diamond Syndrome in a Child with Severe Failure to Thrive and Gastrointestinal Symptoms, in Pakistan
Introduction
Shwachman-Diamond syndrome (SDS)
is a rare multiorgan, autosomal recessive genetic disorder with only a few
hundred cases reported. More than 90% of cases are caused by compound
heterozygous or homozygous Shwachman-Bodian- Diamond syndrome (SBDS) gene mutations
on chromosome 7q11 [1]. Its clinical presentation mainly comprises pancreatic
exocrine insufficiency, skeletal abnormalities, and hematological abnormalities
due to bone marrow dysfunction, possibly leading to a higher risk for malignant
transformation [2]. Other common features of SDS include diarrhea, failure to
thrive in infancy, elevation in fetal hemoglobin, anemia, neutropenia
associated with bone marrow hypoplasia, and normal sweat electrolytes [3].
Rarely, immunological and cardiac abnormalities have been reported as well [4].
Herein, we report a case of SDS for the first time in Pakistan. The patient
presented with severe failure to thrive alongside chronic diarrhea and
vomiting.
Case Presentation
General information
A 2-year-old male child
presented to the Out-Patient Department of Liaquat National Hospital, Karachi,
Pakistan, with complaints of severe failure to thrive and unexplained diarrhea
since birth. He had food intolerance and on-off vomiting for the past 1 year.
He was delivered on term through a C-section due to meconium aspiration but did
not require intensive care. His birth weight was 2.6kg [5th Percentile]. There
were no other complications during or after pregnancy. He was a result of
non-consanguineous marriage. He reached all developmental milestones timely.
The baby started passing loose stools as soon as he started feeding. The loose
stools started off as 3-5 episodes per day but gradually progressed to 20- 25
episodes per day. They were watery in consistency and variable in color. All
lab tests were normal and didn’t show signs of infection or any underlying
pathology. At 1 year of age, the child started vomiting, which started off as
1-2 episodes per day, but progressed to 3-4 episodes per day. The vomiting was
usually spontaneous but was often associated with food intake. At the time of
presentation, he looked wasted and was very irritable. His height was normal at
84cm but weight was 8kg, indicating severe failure to thrive. He had maxillary
prominence and peg shaped teeth with poor enamel (picture1). There was no
hepatomegaly, splenomegaly or localized or generalized lymphadenopathy.
His behavior, appetite and sleep
habits had been disturbed for the entire duration. He had an extremely poor
oral food intake on account of his vomiting. There were no urinary or
respiratory complaints. He had an elaborate work-up to rule out malnutrition,
tuberculosis, cystic fibrosis, celiac disease and infections. Eventually, he
was tested positive for stool elastase deficiency which in combination of
skeletal and hematological abnormalities led to the diagnosis of SDS.
Treatment
After confirmed diagnosis, the
patient underwent a percutaneous endoscopic gastrostomy (PEG) procedure for
medication and feeding on account of his poor oral food intake, chronic history
of vomiting and failure to thrive. Furthermore, the patient was administered
Pancreatic enzyme replacement as 1000 units prior to every meal times a day
along with fat-soluble vitamin supplementation (vitamins A,D,E,K) 1ml daily and
iron supplementation (iron polymaltose drops) once daily.
Discussion
SDS is a rare autosomal
recessive hereditary condition, with 90% of the patients having changes in the
SBDS quality on chromosome 7q11; the most widely known mutations are
c.258+2T> C and c.183–184TA> CT [2,5], which makes the SBDS protein
truncated. The SBDS gene is responsible for synthesis of various proteins
liable for microtubule stabilization and actin polymerization, additionally
known to play part in bone marrow proliferation, mitosis and the matrix
microenvironment [6]. Our patient could not undergo genetic testing due to
unavailability of the test at the health facility and financial limitations on
account of the patient. SDS is a diverse disorder involving multiple organs,
mainly the pancreas, liver, bones, blood system, immune system and teeth, and
some less common associations include skin disorders. The main clinical
manifestations involve pancreatic exocrine insufficiency, hematological
abnormalities and skeletal deformities, usually occurring in infants and young
children [6]. (Table 1.1) shows drastic hematological changes in our patient
over a period of 5 months. He developed a macrocytic anemia as evident by his
low hemoglobin levels, low hematocrit, low RBC levels and high MCV. He also developed
moderate to severe neutropenia and lymphocytosis (Table 1.1: Section 1).
SDS is the second most common
cause of pancreatic insufficiency after cystic fibrosis. Therefore, considering
the pancreatic dysfunction is of great importance in ruling out other
differentials. (Table 1.1 Section 4) shows a negative sweat test in our patient,
ruling out cystic fibrosis. Celiac disease was also ruled out with a negative
ANTI-TTG IgG (ELISA) test (Table 1.1: Section 4). A normal metabolic profile
further ruled out causes of malnutrition and malabsorption. SDS presents with
exocrine pancreatic insufficiency in infants usually in the primary year of
life. About 15% of the patients show signs of hepatomegaly, which may be due to
fat deposition as well, hence a ‘fatty liver’. Furthermore, 60% of the patients
have shown elevated liver enzymes (transaminases) [4]. The main presenting
manifestations to confirm diagnosis include decreased pancreatic elastase
levels, decline in fat soluble vitamin content (A,D,E,K) and increasing fecal
fatty content(steatorrhea), all of which indicate severe pancreatic
dysfunction. Our patient was diagnosed with SDS on account of his severely low
pancreatic elastase levels (Table 1.1: Section 4), inevitably pointing towards
severe pancreatic insufficiency. This resulted in a fat-soluble vitamin
deficiency as well, further contributing to his failure to thrive.
Figure 1.
Monitoring the levels of fat
soluble vitamins and vitamin K dependent prothrombin time in patients with
untreated pancreatic insufficiency holds great importance for excluding other
differentials because some studies have shown resolution of hepatic symptoms
like hepatomegaly and elevated transaminases by the age of 5 in SDS patients
[2,7]. Our patient had mildly elevated AST and ALP levels, but ALT levels were
normal, indicating mild hepatic dysfunction (Table 1.1: Section 2). Skeletal
abnormalities are also common in SDS patients, such as stunted growth,
spondylolisthesis, Spinal and thoracic abnormalities etc., all of which may
occur secondary to malabsorption of vitamin D and K which require pancreatic
juice for absorption, resulting in increased risks of getting fractures in
extremities and spine [5]. Our patient showed tooth enamel defects, including
hypo maturation, dental hypoplasia and dysplasia, and hypocalcification (Figure
1.1). He also had enlarged maxillary prominences, possibly pointing towards
extramedullary hematopoiesis. There were no other skeletal abnormalities found.
A few cases additionally show critical neurological changes, these patients have extreme intellectual and behavioral disabilities which render huge hindrances to academic performance, intellectual reasoning, advanced verbal skills and visual motor skills [2]. Along with some structural changes as well, brain MRI of SDS patients with neurological deficits have shown reluctance with smaller posterior fossa and associated structures like corpus callosum, brain stem, and cerebellar vermis [8]. Our patient, however, did not show any signs of neurological impairment.
Follow us for more Articles on: https://biomedres01.blogspot.com/
https://scholar.google.com/citations?user=OFtUOZYAAAAJ&hl=en
https://www.base-search.net/Search/Results?lookfor=Biomed+Journal+of+Scientific+%26+Technical+Research&l=en&refid=dcsuggesten
https://citefactor.org/journal/2574-1241/biomedical-journal-of-scientific-technical-research
https://ideas.repec.org/s/abf/journl.html
https://econpapers.repec.org/article/abfjournl/
https://www.ncbi.nlm.nih.gov/nlmcatalog/101723284
https://bjstr.org/
https://bjstr.org/about.php
https://biomedres.us/reprints.php
https://biomedres.net/submit-manuscript.php
https://independent.academia.edu/BJSTRAngelaRoy
