Abstract
Introduction
A six-month-old Caucasian boy, the son of unrelated parents of European origin, was referred by his general practitioner with concerns regarding poor weight gain and poor feeding. He was born following a normal pregnancy 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 had only received his first immunization at two months of age due to parental concerns regarding his health. There had been no developmental concerns.
DECLARATIONS
None declared
None
Not applicable
SMNB
Both authors contributed equally
On his first review he had appeared quite irritable on feeding and the question of cow's milk protein intolerance was raised. His feed was therefore changed to a hydrolysed formula and a dietitian reviewed him. On review three 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 0-45 U/L) and a borderline low neutrophil count of 1.9 × 10 9 /L (reference range 1.5-8 × 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 cow's milk protein, thyroid function tests, urine and faecal microbiology, coeliac screen, faecal reducing substances and amino and organic acids. Abdominal ultrasound scan was also normal. 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 (chloride 75 mmol/L). Sodium levels were not measured. Sweat volume of at least 30 μL 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 regarding the diagnosis and he was started on prophylactic 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 raised as they felt he did not 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). Genotyping was requested and he was found to be homozygous for 258+2T>C, 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 management.
Why was the initial sweat test positive?
The sweat tests were performed using the Macroduct sweat collection system. At least 30 μL of sweat was collected for each test. Chloride level only was analysed by our laboratory following national guidelines. 1 Sodium levels were not analysed. The child's arm was cleaned before each test with distilled water and all other quality controls were met.
There is a well-recognized list of causes of false-positive sweat test results in the literature. 2 However, 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 reported of SDS itself causing a false-positive sweat test, although conceivably any underlying illness which causes malnutrition may cause misleadingly positive results. 3
This particular case scenario is clearly not particularly 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 particular case, the presence of pancreatic insufficiency and convincing clinical features, along with a positive sweat test, resulted in a diagnosis of CF being confirmed on the basis of one sweat test. Recommended 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 reassured that the failure to isolate a genotype is sometimes encountered in patients with CF. While this is certainly not incorrect information, it serves as a reminder that even with convincing clinical features, 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 correct 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 pancreatic exocrine insufficiency and neutropenia. 6 Shwachman et al. further described the condition as pancreatic insufficiency with bone marrow dysfunction 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 malabsorption or CF-type symptoms. Usually the two conditions can be differentiated on the basis of a sweat test, and this should form part of the initial investigations. 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 steatorrhoea and malabsorption in the first months of life. These children have poor growth and often initially present due to failure to thrive. A proportion of children will still be pancreatic sufficient, 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.
Unlike CF, pancreatic exocrine function in SDS improves over time in 40-60% of patients. 9 This can make diagnosis in older children more difficult, 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 insufficiency is due to obstruction by thickened secretions. 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 standard, 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. However, this is unpleasant for the family and is becoming less available as a laboratory investigation. 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 information.
Many centres rely on faecal elastase measurement as an assessment of exocrine sufficiency. This has been shown overall to be a reliable marker of pancreatic function. However, low levels can also be seen in patients with malabsorption from a primary intestinal cause, rather than pancreatic insufficiency. 11 Serum pancreatic 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 3-4. 14 It is therefore important to stress that apparently normal pancreatic function 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 abnormalities 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 mi-croenvironment. 16 There does not appear to be a genotype-phenotype correlation for haematological 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 susceptibility 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 Staphylococcus aureus, Haemophilus influenzae and Gram-negative pathogens including Pseudo-monas species. Many will require prophylactic antibiotic therapy to try to prevent the development of bacterial infections. 19 Granulocyte colony-stimulating factor has been used to stimulate neutrophil levels in some patients, although concern has been raised that this therapy could increase the risk of acute myeloid leukaemia (AML). 18
Patients with SDS should be monitored by routine blood testing and bone marrow assessment -at diagnosis and throughout life - for bone marrow failure, myelodysplasia and malignant change, in particular AML. Around 20-33% of patients will develop myelodysplasia, with 12-25% 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.
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 throughout their lives, with associated pubertal delay. 21
There are a number of skeletal abnormalities present in patients with SDS, but their pathogenesis is unclear. Metaphyseal dysostosis is commonly found (40-80% of patients), particularly in the femoral head, hips, spine and knees. Rib abnormalities 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 difficulties and developmental delay, as well as some behavioural problems. Studies have suggested that these are of a neurological rather than social aetiology, and are part of the disease process. 22
Other abnormalities
Since the original description of SDS, a wide variety of other abnormalities and organ involvements 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 development. Involvement of a paediatric dietician is paramount, as is the involvement of a paediatric gastroenterologist. Many patients develop improving pancreatic function, and enzyme supplementation requirements may therefore reduce over time. 24
Routine monitoring of the patient's haematological status is required at diagnosis and throughout 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 subsequently reduced life expectancy.
Footnotes
Acknowledgements
None