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Shwachman-Diamond syndrome

in a child presenting with cystic


fibrosis-type symptoms and a
false-positive sweat test
SMN Brown
1
+ R Buchdahl
1,2
1
Department of Paediatrics, Hillingdon Hospital NHSTrust, London, UK
2
Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHSTrust, London, UK
Correspondence to: Sarah Brown. E-mail: sarahbrownmay@doctors.org.uk
Introduction
A six-month-old Caucasian boy was referred by
his general practitioner with concerns regarding
poor weight gain and poor feeding. He was the
second child of unrelated parents. His mother was
Italian and his father English. His older brother,
aged 5 years, was known to be egg allergic but well
in other respects. There was no other family his-
tory of note. He was born following a normal preg-
nancy and there were no initial neonatal concerns.
Birth weight was 3.86 kg (75th centile). He was
breast-fed for the first four months, after which he
was fed on standard formula. From 14 weeks of
age his weight started to falter from the 75th to the
9th centile. He hadonly receivedhis first immuniz-
ation at two months of age due to parental con-
cerns regarding his health. There had been no
developmental concerns.
On his first reviewhe had appeared quite irrita-
ble on feeding and the question of cows milk pro-
tein intolerance was raised. His feed was therefore
changed to a hydrolysed formula and a dietitian
reviewed him. On reviewthree weeks later he was
found to be chesty and wheezy, but with no chest
deformity. He was pale and thin. His stools were
noted to be fatty, loose and offensive and his
weight gain had not significantly improved. From
his initial blood tests he was noted to have a raised
alanine aminotransferase (ALT) concentration of
73 U/L (reference range 045 U/L) and a border-
line low neutrophil count of 1.9 10
9
/L (reference
range 1.58 10
9
/L). The results of other initial
investigations, performed as part of a failure-to-
thrive screen, were unremarkable, including
immunoglobulin E (IgE), radioallergosorbent test
(RAST) to cows milk protein, thyroid function
tests, urine andfaecal microbiology, coeliac screen,
faecal reducing substances and amino and organic
acids. Abdominal ultrasound scan was also nor-
mal. Given the concerns regarding his poor weight
gain, loose offensive stools and malabsorption, a
sweat test and faecal elastase level were requested.
His sweat test was reported as positive (chlo-
ride 75 mmol/L). Sodium levels were not
measured. Sweat volume of at least 30 L was
collected using the Macroduct sweat collection
system. Faecal elastase level was significantly low
(<15 IU). His chest X ray was normal. A diagnosis
was made of cystic fibrosis (CF) with pancreatic
insufficiency. His parents were counselled regard-
ing the diagnosis and he was started on prophylac-
tic amoxicillin and clavulanic acid, as well as
pancreatic enzyme and vitamin supplementation.
Genotyping was requested and he was referred to
a tertiary centre for joint care.
Over the next weeks he started to gain weight,
although not as much as would have been
expected. His stools were less oily. Genotyping
failed to show any CF mutations both on routine
analysis and on extended testing.
His parents became increasingly concerned that
the diagnosis was incorrect. Their concerns were
initially raisedas they felt he didnot taste salty, but
were compounded by the fact that a mutation was
not isolated. A repeat sweat test was sent and
reported as negative (chloride 5 mmol/L). A third
sweat test was also negative (8 mmol/L). Repeat
faecal elastase level was still <15 IU/g, confirming
pancreatic insufficiency.
Following these two negative sweat tests an
alternative diagnosis was sought, in particular
Shwachman-Diamond syndrome (SDS). Genotyp-
ing was requested and he was found to be
homozygous for 258+2T>2C, the genetic mutation
for SDS. His parents were both heterozygous. A
final diagnosis was therefore made of SDS and he
was referred to a tertiary centre for further man-
agement.
Why was the initial sweat test
positive?
The sweat tests were performed using the Macrod-
uct sweat collection system. At least 30 L of sweat
DECLARATIONS
Competing interests
None declared
Funding
None
Ethical approval
Not applicable
Guarantor
SMNB
Contributorship
Both authors
contributed equally
Acknowledgements
None
SUPPLEMENT
J R Soc Med 2008: 101: S39S43. DOI 10.1258/jrsm.2008.s18009 S39
was collected for each test. Chloride level only was
analysed by our laboratory following national
guidelines.
1
Sodium levels were not analysed. The
childs arm was cleaned before each test with dis-
tilled water and all other quality controls were
met.
The laboratory commented that before the
second and third sweat tests the mother had
cleanedthe childs armwith holy water fromLour-
des. They therefore queried whether she had also
cleaned the child with the same water before the
initial sweat test, and whether this water had a
high chloride level, thus affecting the results. A
sample of the water was taken for analysis and
found not to contain any chloride ions, therefore
disproving this theory. The laboratory felt that the
only possible area of error was if the childs arm
was not cleaned adequately on the first test. They
were unable to provide an alternative explanation.
There is a well-recognized list of causes of false-
positive sweat test results in the literature.
2
How-
ever, the evidence for these is limited. The most
important of these causes are technical failure and
operator error, eczema and other skin conditions
where it is often difficult to obtain enough sweat,
and underlying blood electrolyte abnormalities
which may cause misleading results. To our
knowledge there are no cases reportedof SDS itself
causing a false-positive sweat test, although con-
ceivably any underlying illness which causes mal-
nutrition may cause misleadingly positive results.
3
This particular case scenario is clearly not par-
ticularly common and hopefully with the advent
of national neonatal screening for CF the situation
will become even less likely. It does, however,
highlight some important points, including
remembering other causes of malabsorption and
failure to thrive in children. This case serves as a
reminder to always repeat a sweat test if there is
any doubt regarding the diagnosis. In this particu-
lar case, the presence of pancreatic insufficiency
and convincing clinical features, along with a posi-
tive sweat test, resulted in a diagnosis of CF being
confirmed on the basis of one sweat test. Recom-
mended practice is to repeat the sweat test up to
three times in an attempt to eliminate error.
4
While it is unusual not to find a CF genotype in
Caucasian patients, this family were initially reas-
suredthat the failure to isolate a genotype is some-
times encountered in patients with CF. While this
is certainly not incorrect information, it serves as a
reminder that even with convincing clinical fea-
tures, if a genotype has not been isolated it is
worth reconsidering whether the diagnosis is
indeed correct.
Finally, this is a valuable lesson in taking heed
of parental concerns. They may not always be cor-
rect and may have great difficulty in accepting a
diagnosis such as CF or any other life-limiting
condition, but their concerns should always be
listened to.
Shwachman-Diamond syndrome
SDS is an autosomal recessive condition affecting
between 1:100,000 and 1:200,000 live births. The
majority of patients have compound heterozygous
mutations of the Shwachman-Diamond-Bodian
syndrome (SBDS) gene on chromosome 7 (7q11).
This gene was identified in 2002 and is thought to
encode a protein of 250 amino acids. There is an
adjacent pseudogene on 7q11 which appears to
recombine with the SDBS gene during meiosis,
thus making it dysfunctional.
5
SDS was first
described in the early 1960s by Nezelof and
Watchi, initially as a syndrome encompassing pan-
creatic exocrine insufficiency and neutropenia.
6
Shwachman et al. further described the condition
as pancreatic insufficiency with bone marrowdys-
function in 1964.
7
Skeletal dysplasias were
observed to be associated with SDS in the late
1960s.
8
Subsequently other organs have been
noted to be involved in children with SDS, with a
wide variety of phenotypes.
SDS is the second most common inherited cause
of pancreatic exocrine insufficiency after CF, and
should therefore be included in the differential
diagnosis of children presenting with malabsorp-
tion or CF-type symptoms. Usually the two con-
ditions can be differentiated on the basis of a sweat
test, and this should form part of the initial inves-
tigations. Other rarer causes of pancreatic exocrine
insufficiency include severe malnutrition, Pearson
syndrome, Johanson-Blizzard syndrome and
Jeune syndrome.
Clinical features
Exocrine pancreatic insufficiency
Pancreatic insufficiency in SDS presents with stea-
torrhoea and malabsorption in the first months of
life. These children have poor growth and often
initially present due to failure to thrive. A pro-
portion of children will still be pancreatic suf-
ficient, as it is necessary to lose over 98%pancreatic
exocrine function before clinical malabsorption
becomes apparent. Children may also be deficient
in the fat-soluble vitamins A, D, E and K due to fat
malabsorption.
Journal of the Royal Society of Medicine
J R Soc Med 2008: 101: S39S43. DOI 10.1258/jrsm.2008.s18009 S40
Unlike CF, pancreatic exocrine function in SDS
improves over time in 4060% of patients.
9
This
can make diagnosis in older children more diffi-
cult, as they may appear pancreatic sufficient.
Since the isolation of the SDS gene and successful
molecular genetics, it is now possible to make a
diagnosis of SDS in most children.
The underlying pathophysiology of pancreatic
insufficiency in SDS is thought to be due to
replacement of the pancreatic exocrine acini with
fat. This is different to CF where pancreatic insuf-
ficiency is due to obstruction by thickened secre-
tions. In SDS there is preservation of the endocrine
activity as the islets of Langerhans and ductal
structure are spared. Fatty pancreatic infiltration
can be seen on imaging such as ultrasound scan or
abdominal computed tomography.
10
Pancreatic insufficiency and fat malabsorption
can be assessed by a number of means. Direct
pancreatic stimulation is considered the gold stan-
dard, but is rarely used due to the invasiveness of
the test. Three-day faecal fat measurement is also
considered by many to be a definitive test. How-
ever, this is unpleasant for the family and is
becoming less available as a laboratory investi-
gation. Spot measurements of excessive numbers
of fat globules in stool can be useful as a basic
screening test where other investigations are not
available, but this can only provide limited infor-
mation.
Many centres rely on faecal elastase measure-
ment as an assessment of exocrine sufficiency.
This has been shown overall to be a reliable
marker of pancreatic function. However, low lev-
els can also be seen in patients with malabsorption
from a primary intestinal cause, rather than pan-
creatic insufficiency.
11
Serumpancreatic enzymes
(iso-amylase and trypsinogen) should also be
assayed and will be low in SDS. Similarly,
immune reactive trypsinogen (IRT) levels will be
normal or low.
12
This is as a contrast to CF, where
IRT levels will be high due to ductal obstruction.
13
In normal subjects, serum trypsinogen levels are
present at birth and through infancy. This is in
contrast to serum iso-amylase levels, which are
naturally low at birth and in infancy, making
interpretation of levels in children <3 years old
more difficult. Serum trypsinogen levels will rise
with improving pancreatic function in some
patients, with approximately 20% having normal
levels by the age of 34.
14
It is therefore important
to stress that apparently normal pancreatic func-
tion suspected by the absence of steatorrhoea or
normal pancreatic enzyme levels does not exclude
a diagnosis of SDS.
As well as infiltration of the pancreas with fat,
children may also develop fatty liver. Around 60%
of children will have raised liver transaminases
and hepatomegaly, although generally no other
features of hepatic dysfunction. Over time
transaminase concentrations and liver size return
to normal.
15
Haematological abnormalities
A number of different haematological abnormali-
ties have been described in SDS. It is generally
agreed that the development of haematological
abnormalities in SDS is related to low numbers of
CD34+ progenitor cells and a faulty marrow
microenvironment.
16
There does not appear to be a
genotypephenotype correlation for haematologi-
cal disorders in patients with SDS.
17
The most
common abnormality seen is neutropenia, which
can be continuous but more commonly varies over
time.
18
The neutrophils that are present are usually
functionally impaired, thus exacerbating suscepti-
bility to bacterial infections. SDS neutrophils retain
the ability to migrate to areas of infections, but lack
the ability to localize and kill pathogens. Patients
are susceptible to a wide variety of infections,
including pneumonia, which may initially confuse
the clinical picture with CF. Particular pathogens
which SDS patients are susceptible to include Sta-
phylococcus aureus, Haemophilus influenzae and
Gram-negative pathogens including Pseu-
domonas species. Many will require prophylactic
antibiotic therapy to try to prevent the develop-
ment of bacterial infections.
19
Granulocyte colony-
stimulating factor has been used to stimulate
neutrophil levels in some patients, although con-
cern has been raised that this therapy could
increase the risk of acute myeloid leukaemia
(AML).
18
Patients with SDS should be monitored by rou-
tine blood testing and bone marrow assessment
at diagnosis andthroughout life for bone marrow
failure, myelodysplasia and malignant change, in
particular AML. Around 2033% of patients will
develop myelodysplasia, with 1225% developing
leukaemia.
20
Treatment of myelodysplasia or
AML with chemotherapy is often unsuccessful.
Bone marrow transplantation is seen as an option
in some patients with severe haematological
abnormalities, with varying success.
20
SDS patients may have isolated cytopenias
other than neutropenia, including anaemia and
thrombocytopenia, and a significant proportion
develop aplastic anaemia.
Shwachman-Diamond syndrome in a child presenting with cystic fibrosis-type symptoms
J R Soc Med 2008: 101: S39S43. DOI 10.1258/jrsm.2008.s18009 S41
Skeletal and growth abnormalities
Most patients with SDS are growth restricted, and
this is often present at birth. This suggests that not
only does malabsorption have a significant impact
on growth and development, but that there is also
an inherent abnormality of growth in these
patients. Most patients will remain small through-
out their lives, with associated pubertal delay.
21
There are a number of skeletal abnormalities
present in patients with SDS, but their pathogen-
esis is unclear. Metaphyseal dysostosis is com-
monly found (4080% of patients), particularly in
the femoral head, hips, spine andknees. Rib abnor-
malities occur in around 50% of patients, with
chostochondral thickening of shortened ribs.
Abnormalities of the digits have also been
described.
13
Patients with SDS are also at risk of defects of
bone mineralization due to deficiencies in vitamin
D secondary to malabsorption.
Psychological abnormalities
Since the first description of SDS it has become clear
that many children with SDS have learning difficul-
ties and developmental delay, as well as some
behavioural problems. Studies have suggested that
these are of a neurological rather than social aeti-
ology, and are part of the disease process.
22
Other abnormalities
Since the original description of SDS, a wide var-
iety of other abnormalities and organ involve-
ments have been described. These include dental
abnormalities, dermatological conditions such as
severe eczema and ichthyosis, facial abnormalities,
myocardial fibrosis, renal calculi and renal tract
abnormalities.
23
Management of children with
Shwachman-Diamond syndrome
As with all chronic conditions, a multi-disciplinary
approach to management is appropriate. Children
require pancreatic enzyme and fat-soluble vitamin
supplementation, with particular attention given
to their nutritional status, growth and develop-
ment. Involvement of a paediatric dietician is para-
mount, as is the involvement of a paediatric
gastroenterologist. Many patients develop
improving pancreatic function, and enzyme sup-
plementation requirements may therefore reduce
over time.
24
Routine monitoring of the patients haemato-
logical status is required at diagnosis and through-
out life. This includes bone marrow assessment.
Patients with febrile neutropenia should receive
intensive broad-spectrum antibiotic cover. Those
with cytopenias may require blood and platelet
transfusions.
Appropriate specialities should be involved in
the management of other clinical manifestations of
the disease.
Life expectancy of patients with SDS is expected
to be >35 years.
13
However, those with significant
haematological abnormalities, including AML,
have significant morbidity and mortality and sub-
sequently reduced life expectancy.
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J R Soc Med 2008: 101: S39S43. DOI 10.1258/jrsm.2008.s18009 S43