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Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. more...

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Clinical Features

This syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormalities and growth retardation. Neutropenia may be intermittent or persistent and is the most common haematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia. Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients. More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients), and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographs from 15 patients indicated that all of them had at least one skeletal anomaly, though many were sub-clinical.


Initially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded with a normal sweat chloride test result. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either malabsorption, or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The gene responsible for the disease has been identified and genetic testing is now available. Though useful in diagnostics, a genetic test does not surmount the need for careful clinical assessment and monitoring of all patients.


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Evaluating the child with chronic diarrhea
From American Family Physician, 2/1/96 by Alexander K.C. leung

The term "diarrhea" refers to an increase in the frequency, fluidity or volume of bowel movements, relative to the usual habit of an individual.[1-3] This bowel problem may be considered chronic if it persists for 14 or more days.[4]

Chronic diarrhea in children is a common problem with numerous causes. Although most of these causes are benign, serious illnesses may present as chronic diarrhea. This article reviews the etiology of chronic diarrhea and outlines an approach to the investigation of this problem.

Causes and Clinical Manifestations

The causes of chronic diarrhea in children are listed in Table 1.


Gastrointestinal infection is by far the most common cause of chronic diarrhea in children.[1] The major bacterial pathogens include enteropathogenic and enterohemorrhagic Escherichia coli, Salmonella species, Shigella species, Yersinia enterocolitica and Campylobacter jejuni.[1] Major parasitic causes of chronic diarrhea include Giardia lamblia, Entamoeba histolytica and Cryptosporidium species.[5] Common viral agents include rotavirus, adenovirus, Norwalk virus and the enteroviruses.

Acute infectious gastroenteritis may be complicated by postenteritis diarrhea occurring after damage to the small intestinal mucosa, with resulting secondary disaccharidase deficiency and carbohydrate intolerance. Typically, patients with postenteritis diarrhea relapse with diarrhea when lactose-containing foods are reintroduced into the diet. In infants and young children, systemic infections, such as a urinary tract infection, may occasionally be associated with chronic diarrhea.[6]


Protein intolerance, especially to cow's milk or soy protein, is a common cause of chronic diarrhea. Symptoms usually occur before six months of age. Associated manifestations include bloody diarrhea, anemia, protein-losing enteropathy and extraintestinal manifestations of allergy, such as eczema, hives or asthma.[7]


Chronic nonspecific diarrhea of childhood is one of the most common causes of chronic diarrhea. This benign, self-limited disorder usually presents in children between the ages of six months and three years.8,9 The male to female ratio is 2:1.

The syndrome is characterized by persistent or recurrent episodes of voluminous loose stools, usually with six or more stools per day. Undigested food particles may be noted in the stools. Nocturnal diarrhea is absent. Despite having diarrhea, children with this disorder thrive and appear healthy.[9]

The exact etiology of chronic nonspecific diarrhea of childhood is not clear. The syndrome may occur after a viral infection or the institution of dietary restrictions, such as the elimination of milk and dairy products.[8] In one study,[10] the mouth-to-anus transit time of food in children with chronic nonspecific diarrhea was found to be shorter than in age-matched control subjects. Emotional stress and excessive ingestion of cold or hyperosmolar fluid (fruit juice) have also been implicated as possible causative factors.[8,9]


Excessive intake of fluids, especially hyperosmolar fruit juice, may cause chronic diarrhea.[10,11] Osmotic diarrhea can be caused by common dietary sugars such as sorbitol and fructose. Sorbitol is found in significant concentrations in prunes, pears, peaches, apple juice and sugar-free gum. Fructose is found in honey, dried figs, dried dates, prunes and some soft drinks.[8] In children with diarrhea resulting from excess hyperosmolar fluid intake, the first stools of the day are usually formed.[12]


Primary deficiencies of disaccharidase (i.e., lactase, sucrase or isomaltase) are rare. However, secondary disaccharidase deficiencies are common, and they are associated with other gastrointestinal disorders, including infection, bacterial over-growth and untreated celiac disease.[8]

Diarrhea caused by carbohydrate loss may be the result of osmotic or fermentative mechanisms.[13] In fermentation, malabsorbed sugars are broken down by colonic bacteria into osmotically active organic acids with associated hydrogen production.[7]

Typically, diarrhea resulting from disaccharidase deficiency is explosive and watery. Other symptoms include abdominal pain, bloating and flatulence.


Primary monosaccharide malabsorption is rare and is inherited as an autosomal recessive trait. The characteristic defect is an impairment in the ability of cells in the intestinal mucosa to actively transport glucose and galactose, so that only about 10 percent of the ingested glucose and galactose can be absorbed.[13] This absorption disorder, which usually presents in neonates, is characterized by watery diarrhea with an acidic stool.


Celiac disease is associated with villous atrophy of the proximal small intestine. This condition is the result of a permanent intolerance to the gliadin fraction of gluten protein. Celiac disease has a strong association with histocompatibihty-type human leukocyte antigens (HLAs), such as HLA-B8 and class II HLA-DR3, HLA-DR7, HLA-DQ, HLA-W2 and HLA-DR4.[7,14]

Symptoms can develop any time after gluten (e.g., wheat, barley, rye) is introduced into the diet. Most children with celiac disease present at six to 24 months of age. Major manifestations include chronic diarrhea, anorexia, failure to thrive, muscle wasting, irritability and abdominal distention. Characteristically, the stools are pale, loose, bulky and oily, and they have a pungent odor.[14]


Cystic fibrosis, the most common pancreatic disorder causing chronic diarrhea, is inherited as an autosomal recessive trait. The gene responsible for cystic fibrosis has been localized to the long arm of chromosome 7.

The triad of pancreatic exocrine deficiency, chronic obstructive pulmonary disease and an abnormally high level of chloride in the sweat is present in most patients.[1] Clinically, the disease may manifest as steatorrhea (fat-containing stools) with malabsorption, meconium inspissation in the neonatal period, prolonged neonatal jaundice, growth retardation, anasarca, recurrent or chronic chest infections, nasal polyps, rectal prolapse or digital clubbing. Even though they have voracious appetites, most children with cystic fibrosis remain malnourished.[14]

Shwachman-Diamond syndrome is characterized by neutropenia and pancreatic insufficiency. Other features include short stature and skeletal abnormalities. The disease is usually inherited as an autosomal recessive trait, but an autosomal dominant mode of inheritance has also been reported. Shwachman-diamond syndrome may be differentiated from cystic fibrosis by the presence of normal levels of sweat chloride and the absence of pulmonary disease.[13]


Inflammatory bowel disease frequently develops in late childhood or during adolescence. This disorder is characterized by unpredictable remissions and exacerbations. The etiology of inflammatory bowel disease is unknown, but genetic factors appear to make persons with this disorder more vulnerable to an immunologically related inflammatory reaction.[14]

Ulcerative colitis is an inflammatory disease that most commonly involves the mucosa of the colon and rectum. Predominant symptoms include bloody diarrhea, lower abdominal cramps and tenesmus. Anorexia, malaise, weight loss and growth failure occur as the disease progresses. Older children may have extraintestinal manifestations, including arthritis, erythema nodosum, pyoderma gangrenosum, iritis, hepatitis, digital clubbing and intermittent fever.

Crohn's disease is a segmental transmural inflammatory disease that may affect one or more segments of the gastrointestinal tract, from the mouth to the anus. The distal ileum and colon are the bowel segments most commonly affected. The classic symptom triad includes bloody diarrhea, abdominal pain and weight loss. Stomatitis and chronic perianal lesions, such as fissures, fistulas and abscesses, may be present bullous and eczematous lesions symmetrically distributed in the perioral, acral and perineal areas.[13]


In children with intestinal lymphangiectasia, rupture of the intestinal mucosal lacteals may result in massive gastrointestinal loss of fat and protein. Consequently, lymph may leak into the bowel lumen. Children with this condition typically have steatorrhea, protein-losing enteropathy, anemia, malnutrition and growth retardation.[20]


Abetalipoproteinemia is a disorder resulting from the inability to form chylomicrons in the intestinal mucosa.[13] Typically, children with this rare autosomal recessive disorder present with diarrhea, failure to thrive, acanthocytosis, retinitis pigmentosa and cerebellar ataxia.


Chronic diarrhea may occur because of the absence of a normal ileal mechanism for active absorption of chloride in exchange for bicarbonate. Typically, this congenital problem presents in neonates and is characterized by watery diarrhea and metabolic alkalosis.[13]

Clinical Evaluation

A thorough history (Table 2) and a complete physical examination (Table 3) are important in the evaluation of chronic diarrhea.

Laboratory Evaluation

Certain basic laboratory studies can be helpful in many patients with chronic diarrhea. The stool should be analyzed for pH, reducing substances, occult blood, fatty acid crystals, fat globules, red blood cells, white blood cells, and ova and parasites. The stool culture may also yield important information. Other potentially useful tests include a complete blood count with differential and peripheral smear, an erythrocyte sedimentation rate, serum electrolyte concentrations, total protein and albumin levels, and a serum carotene level.

The presence of reducing substances in a stool with a pH less than 6 suggests carbohydrate malabsorption.[2] A positive stool guaiac test indicates intestinal mucosal breakdown, which may be caused by gastrointestinal infection, protein intolerance or inflammatory bowel disease.[22] The guaiac test may also be positive if the diet contains meat.[7]

Fat globules in the stool may be normal in the first few months of life.[7,22] In an older child, the presence of fat globules suggests steatorrhea. Lubricants used during a digital examination to obtain a stool specimen may give a false-positive result for stool fat.[21] Refractile fatty-acid crystals suggest a mucosal problem such as celiac disease.[21]

A fresh stool sample should be examined microscopically. The presence of a large number of neutrophils or red blood cells indicates bacterial gastroenteritis or inflammatory bowel disease. The presence of eosinophils suggests protein intolerance or parasitic infestation. Mobile parasites (G. lamblia or E. histolytica), cysts (protozoa or nematodes) and ova (nematodes and trematodes) may be seen. Stool cultures for specific organisms should also be performed.

A complete blood count is often helpful. Neutrophilia and an increased number of band forms or toxic granulations are suggestive of bacterial infection. Neutropenia may be present in some immunodeficiency disorders, while eosinophilia may occur in parasitic infestation or protein intolerance. Hypochromic microcytic anemia suggests chronic gastrointestinal blood loss or malabsorption of iron. Acanthocytes in the peripheral smear suggest abetalipoproteinemia, while macrocytosis suggests vitamin [B.sub.12] or folate deficiency.[22] An elevated erythrocyte sedimentation rate suggests active infection or inflammatory bowel disease.

In malnutrition, the serum albumin and globulin levels are decreased proportionally In contrast, protein-losing enteropathy is characterized by a greater loss of albumin and therefore a disproportionately depressed serum albumin level.[22] The serum carotene level is an inexpensive and simple marker for fat malabsorption, assuming dietary carotene intake is adequate.[23]

In watery diarrhea, calculation of the stool osmotic gap may help to differentiate diarrhea caused by osmotic agents such as sugars from diarrhea caused by abnormalities in the ionic transport of electrolytes. The stool osmotic gap is calculated by the following formula: stool osmolality - [2 x (stool sodium + stool potassium)]. If the stool osmotic gap is increased, the diarrhea may be caused by an osmotically active agent, such as a sugar. If there is no osmolar gap, the diarrhea is more likely the result of impairment of the ionic transport of an electrolyte, which is common in infectious gastroenteritis, bile salt malabsorption, bacterial overgrowth, laxative abuse and short-bowel syndrome.[20] Other tests that should be performed when indicated include serum immunoglobulin levels for immunodeficiency, a hydrogen breath test for carbohydrate malabsorption, a 72-hour fecal fat test for fat malabsorption, a sweat chloride test for cystic fibrosis, an upper gastrointestinal series with small-bowel follow-through for anatomic abnormalities and Crohn's disease, a barium enema for Hirschsprung's disease and inflammatory bowel disease, sigmoidoscopy for inflammatory bowel disease and pseudomembranous colitis, a stool assay for giardiasis and a jejunal biopsy for celiac disease.

The authors thank Kathy Campbell-Brown and Paula Pang for their excellent secretarial assistance and Sulakhan Chopra of the University of Calgary medical library for his assistance in the preparation of the manuscript.


[1.] Baldassano RN, Liacouras CA. Chronic diarrhea. A practical approach for the pediatrician. Pediatr Clin North Am 1991;38:667-86. [2.] Fitzgerald JF, Clark JH. Chronic diarrhea. Pediatr Clin North Am 1982;29:221-31. [3.] Leung AK, Taylor PG, Geoffrey L, Darling P. Efficacy and safety of two oral solutions as maintenance therapy for acute diarrhea. A double-blind, randomized, multicenter trial. Clin Pediatr 1988;27:359-64. [4.] Ament ME, Barclay GN. Chronic diarrhea. Pediatr Ann 1982;11:124-31. [5.] Phillips AD, Thomas AG, Walker-Smith JA. Cryptosporidium, chronic diarrhea and the proximal small intestinal mucosa. Gut 1992;33:1057-61. [6.] Leung AK, Robson WL. Urinary tract infection in infancy and childhood. Adv Pediatr 1991;38:257-85. [7.] Lo CW, Walker WA. Chronic protracted diarrhea of infancy: a nutritional disease. Pediatrics 1983;72: 786-800. [8.] Treem WR. Chronic nonspecific diarrhea of childhood. Clin Pediatr 1992;31:413-20. [9.] Leung AK. Chronic nonspecific diarrhea of childhood (irritable colon syndrome). Contemp Pediatr 1987;3(2):10-3. [10.] Lifshitz F, Ament ME, Kleinman RE, Klish W, Lebenthal E, Perman J, et al. Role of juice carbohydrate malabsorption in chronic nonspecific diarrhea in children. J, Pediatr 1992;120:825-9. [11.] Leung AK, Robson WL. Acute diarrhea in children. What to do and what not to do. Postgrad Med 1989;86(8):161-4,167-74. [12.] Greene HL, Ghishan FK. Excessive fluid intake as a cause of chronic diarrhea in young children. J Pediatr 1983;102:836-40. [13.] Gryboski JD. Chronic diarrhea. Curr Probl Pediatr 1979;9(5):1-52. [14.] Hamilton JR. Inflammatory bowel disease. In: Behrman RE, Kliegman RM, Nelson WE, Vaughan VC 3d, eds. Nelson Textbook of pediatrics. 14th ed. Philadelphia: Saunders, 1992:966-79. [15.] Andres JM. Advances in understanding the pathogenesis of persistent diarrhea in young children. Adv Pediatr 1988;35:483-95. [16.] Sutphen JL, Grand RJ, Flores A, Chang TW, Bartlett JG. Chronic diarrhea associated with Clostridium difficile in children. Am J Dis Child 1983;137:275-8. [17.] Keusch GT, Thea DM, Kamenga M, Kakanda K, Mbala M, Brown C, et al. Persistent diarrhea associated with AIDS. Acta Paediatr 1992;381(Suppl):45-8. [18.] Yolken RH, Hart W, Oung I, Shiff C, Greenson J, Perman JA. Gastrointestinal dysfunction and disaccharide intolerance in children infected with human immunodeficiency virus. J Pediatr 1991;118:359-63. [19.] Poley JR. Chronic diarrhea in infants and children. Part II. South Med J 1973;66:1133-41. [20.] Poley JR. Chronic diarrhea in infants and children. Part I. South Med J 1973;66:1035-49. [21.] Patrick M, Gall DG. Clues to chronic diarrhea in children. Diagnosis 1987;4(5):127-31. [22.] George DE. Chronic diarrhea in infants and children. Am Fam Physician 1984;29(5):280-8. [23.] Leung AK, Siu TO, Chiu AS, Robson WL, Larsen TE. Serum carotene concentrations in normal infants and children. Clin Pediatr 1990;29:575-8.

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