Síndrome de Shwachman

 

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What is Shwachman Syndrome ?

 

The syndrome is a rare genetic condition named after the clinician who first described in 1964. The primary features of the syndrome can include neutropenia. This can lead to reduced ability to fight general illness and mouth ulcers, gum disease, tooth decay, ear infections etc. Other primary features can include inability to produce enough enzymes to digest food sufficiently, bone abnormalities and growth retardation. Some children also have developmental delay although many catch up by school age. A minority have severe learning difficulties. Most have normal IQs. Because of its relative "newness" and rarity clinicians are more likely not to recognise children with the syndrome during their careers. There is a risk that children may be inappropriately treated and cared for. Consequently the primary purpose of this site is to help facilitate and co-ordinate information exchange between support groups, clinical professionals and families in similar circumstances. It is also hoped that it will help clinicians identify the signs and symptoms, diagnose promptly and develop appropriate multi-disciplinary treatment regimes.

Also known as: Lipomatosis of Pancrease, Congenital; Shwachman-Bodian Syndrome; Pancreatic Insufficiency and Bone Marrow Dysfunction; Shwachman Diamond Syndrome. Other spellings .... Schwachmann .... Schwachman ... Shwachmann.... (any other?)

 

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Disease information

 

First described in 1964, Shwachman-Diamond Syndrome is a rare disease which mainly involves the pancreas, bone marrow and skeleton, but other organs may also be affected. Next to Cystic Fibrosis, it is the most common cause of pancreatic insufficiency in children. Because of this reason, it is sometimes confused with Cystic Fibrosis; but in children with Shwachman-Diamond Syndrome the sweat test is normal. People with Shwachman-Diamond Syndrome usually have a decreased ability to digest food because the cells of the pancreas, in which digestive enzymes are produced, do not work properly. Additionally, there is usually a decreased number of at least one kind of blood cells. In some patients, there is a decrease in all kinds of blood cells. Most frequently, this decrease occurs in the number of neutrophils, the blood cell that is necessary to fight bacteria infections.

CAUSE

Shwachman-Diamond syndrome is genetic, most likely an autosomal recessive condition. The genetic defect is unknown at present. The inheritance is supported by the presence of more than one effect patient in a family. Males and females are effected with equal frequency. However, the factors which lead to multisystem diseases are unknown.

GENERAL FEATURES

Infants often become ill with symptoms by the age of four or six months old. Early problems include failure to thrive, feeding problems and recurrent infections. Growth soon slows and remains below normal; only a few children show growth beyond the third percentile. Infections are present early in at least 85% of children. These occasionally lead to death. Diagnosis is generally made in the first few years of life, although occasionally diagnosis is delayed.

SPECIFIC FEATURES

Digestive

Diarrhea is almost always present in infancy. Stools contain an excessive amount of fat and are foul smelling and greasy in appearance. Improvement in stools are seen after enzymes replacement therapy is begun. Although weight gain is noted, growth does not seem to improve. Some older patients are able to discontinue enzyme replacement with no clinical consequences.

Bone Marrow

As a result of dysfunction of the bone marrow, patients may have a decrease in any or all types of blood cells. There may be decreased numbers of neutrophils (the white blood cell that helps fight infection), platelets( the blood cell that helps clot the blood), or red blood cells. Blood cell counts should be monitored regularly. Shwachman-Diamond Syndrome patients have apropensity to myelodysplasia or leukemic transformation, for this reason bone marrow aspirates and biopsies are recommended.

Neutropenia

Neutropenia is present when the counts are lower than 1500 per microliter. Neutrophils are a type of white blood cell important in fighting bacteria infections. Neutropenia is seen, at sometime during the course of the disease, in virtually all patients. Many patients are prone to repeated bacterial infection. Some of these infections may be life threatening. Close attention should be paid to infection, with appropriate treatment instituted as quickly as possible.

Thrombocytopenia

The blood also contains cells called platelets. It is their function to clot the blood when bleeding occurs. Normally, platelet counts are above 150,000 per microliter. In about 35% of patients with Shwachman-Diamond syndrome this count is below that number; this is called thrombocytopenia. Easy bruisability is one indication of thrombocytopenia, but severe bleeding is unusual. Precautions may be required before dental work or surgery, and platelet transfusions or medications may be necessary to diminish the risk of abnormal bleeding.

Anemia

Anemia occurs when the hemoglobin level is under 10gm/dl, and has been observed in up to 40% of patients with Shwachman-Diamond Syndrome. Anemia is usually mild and does not respond well to treatment with iron, folic acid and vitamin B-12.

Skeleton

Bone lesions have been reported in 10 to 15% of patients. The bone abnormalities are called metaphyseal chondrodysplasia. X-ray changes are most commonly seen in the hip, femur, tibia (leg bone) and ribs. These changes can be severe enough to require surgical correction.

Liver

Abnormalities in the structure of the liver and in function are not uncommon. Hepatomegaly (enlarged liver) occurs in about 2/3 of patients under the age of five years of age, but is less frequent in older children. Serum liver enzymes are elevated in 50 to 75% of cases, again most often in young children and tending to fall with age. Chronic liver disease has been reported.

Other Involvements

Less frequently reported conditions include cardiac lesions, developmental and intellectual delays, behavior and eating problems, lung disease, renal tubular malfunction, abnormal pulmonary function tests, testicular fibrosis, dental problems, diabetes mellitus and pubertal delays.

Prognosis

Mortalities have been reported. Full growth may not be obtained despite aggressive therapy, particularly if hip disease is severe. The other features of the disease may persist into adulthood.

Treatment

If the pancreas is not working properly, enzyme replacement should be begun immediately. Guidelines for enzyme use are similar to those for Cystic Fibrosis. Enzyme replacement should decrease diarrhea and foul, greasy stools. This may not, however, improve growth. Multivitamins and supplemental fat-soluble vitamins (vitamins A,D,E,and K) should be given daily. The diet should provide protein and energy adequate for nutritional needs and may require supplementation with high calorie foods or prepared supplements. Infections should be treated vigorously with appropriate antibiotics. Bleeding problems and anemia may require blood and platelet transfusions or other intervention (such as DDAVP). Hip disease should be monitored closely and may require surgical intervention. Developmental delays may be helped by physical and speech therapy.

This article is general information for educational purposes.

Please consult a qualified physician for diagnosis and treatment

 

 

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Shwachman- diagnostic Checklist Guide

Probability

Extremely rare

why rare:

Inherited disorder - probable that affected person has inherited one defective gene from each parent (autosomal recessive genetic trait). Difficult to be very precise but the probabilities are circa the following:

Probability of meeting partner with same genetic defect - odds are incalculable (has anyone worked it out?). For example at this point in time there are about 40 families in the UK who are known to have a child with the syndrome- out of a total population of 56 million. Even if the level of under-reporting was very significant the odds of meeting a partner with the same defective gene can be seen to be very very slim ........

Probability of having a child with the syndrome if both partners have defective genes is one in four or 25%

Probablity of passing on one of the two defective genes to child but not both defective genes is one in two or 50% (but the child should not exhibit any signs of having the syndrome - they would be the same as their parents). If this did occur the child would have to meet a partner with the other defective gene to run a one in four chance of having a child with the syndrome

Probability of a child with the syndrome passing it on to their children if they have a partner with no defective genes .......... can anyone point to any research that identifies what this is?????

Probability of not inheriting any of the two defective genes from either parent is one in four or 25% - in other words there is then no risk that the child will, in turn, have children with the syndrome

Probability of each child not having the syndrome is three in four or 75%

Note that the odds are the same for each child the partners have. The odds do not get better or worse with each child the couple have. Each time the risk is one in four that the couple will have a child with the syndrome - or to put it another way there is a three in four chance that they won't.

Tests

As far as we know there is no test that can be carried out during pregnancy that can determine whether the unborn child has the syndrome. Because there is no pre-natal test there is no way a couple can make an informed decision with their first child in the same way that can be done for say Downs Syndrome and go for an abortion. Even if there was, the cost of such a test would make it unlikely that any commercial organisation would deem it cost effective to develop and market. For a couple with a Shwachman child the chances of the next child getting Shwachman's is one in four. .

Cure?

Given that this is a genetic condition there is no cure to mend the defective genes that cause the problems. But there are treatments available that deal with many the signs and symptoms and help to manage the condition effectively. Who knows.......... one day gene therapy may work (where "genetic fixes" are "injected" into a patient which repairs the abnormal genes permanently) and if so a cure would then be available for anyone with the syndrome. IDENTIFYING THE GENES THAT CAUSE SHWACHMAN SYNDROME IS THE VERY FIRST STEP ALONG THAT ROAD. This could be many many years away........... if anyone disagrees please tell me.

Characteristics

Multiple and varied manifestations - many variations, can be a wide degree of variation among those with the syndrome

Signs & Symptoms

Thanks go to Peter Drurie, MD, FRCPC, from The Hospital for Sick Children, Toronto, Canada -- figures/% shown below were taken from a 1996 study of 25 patients diagnosed as having Shwachman Syndrome conducted by Dr P Durie.

Malabsorption (in most cases)

Abnormal bone development (abnormal ossification)

Improper functioning of bone marrow (bone marrow dysfunction)

for example:

Neutropenia occured in 22 out of 25 patients studied.

Severe neutropenia occured in 15 out of 25 patients studied.

Leukopenia occured in 13 out of 25 patients studied.

Anemia occured in 14 out of 25 patients studied.

Thrombocytopenia occured in 15 out of 25 cases studied.

Leukemia occured in 3 out of 25 patients studied.

Approx 40% of patients had abnormalities affecting all three cell lines (red cells, white cells and platelets).

other:

 

 

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Bibliography

 

Shwachman Syndrome Bibliography Alphabetic listing on publication title:

Key reference:

Shwachman Syndrome: Understanding the Disease. Peter Durie, The Hospital for Sick Children,Toronto, Ontario, Canada.

"In 1964, DR. Harry Shwachman first described children who had exocrine pancreatic and hematologic abnormalities. Identical observations were made by Dr. Bodian the same year. These reports recognised that Shwachman Syndrome was probably an inherited condition affecting multiple organs in the body. Additional reports of a larger number of patients have allowed us to develop a more detailed understanding of the clinical manifestations of Shwachman Syndrome. The two largest series to date were reports of 21 cases by Dr Aggett in 1980 and in 1996 a report of 25 cases by our group."

A Case of Shwachman's syndrome: evaluation of hemopoietic disorder by in vitro culture technique. Ikuta K. Sasaki H. Koiso Y. Kawashima T. Ohnishi S. Matsuyama S. Japanese Journal of Clinical Hematology. 21. 1989-1991. 1980.

A case of Shwachman Syndrome with increased spontaneous chromosome breakage. Tada H et al. Hum Genet Nov 1987 77(3) Pp 289-91.

A randomised controlled Phase III trial of Rh-GCSF for treatment of severe chronic neutropenia. Dale D et al. Blood 81:2496-2502, 1993.

A review of 125 cases to determine the risk of myelodysplasia and leukemia in pediatric neutropenic patients after treatment with recombinant human granulocyte-stimulating factor. Imashuku S et al. Blood 81: 2380, 1994.

Aberrant phagocyte function in Shwachman Syndrome. Repo H et al. Clin Exp Immunol 69:204-212, 1987.

Acute leukemia complicating bone marrow hypoplasia in an adult with Shwachman Syndrome. Seymour JF, Escudier SM. Leukemia and Lymphoma. 12: 131-135, 1993.

Allogenic Bone Marrow Transplantation in a patient with Shwachman-Diamond Syndrome. Arseniev L et al. Ann Hematol Feb 1996 72(2) Pp 83-84

An inherited defect of neutrophil mobility in Shwachman Syndrome. Aggett PJ et al. J Pediatr 94:391-394,1979.

Aplastic anemia, acquired and inherited. Young N, Alter B, Ch 17, pp.340-346, Saunders, Philadelphia, 1994.

Aplastic anemia associated with the Shwachman Syndrome: in vivo and in vitro observations. Woods WG. Krivit W. Lubin BH. Ramsay NKC. Am J of Pediatr Hematology/Oncology 3 347-351. 1981a

Association of Pancreatic Insufficiency and Chronic Neutropenia in Childhood. Burke V et al. Arch Dis Child 42: 147-157, 1967 .

Bone marrow transplant in Shwachman Diamond Syndrome. Barrios NJ, Kirkpatrick DV. British Journal of Haematology, 79, 337-338.

Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Luna-Fineman S, Shannon KM, Lange BJ. Blood 85:1985-1999. 1995

Computed tomography and ultrasonographic findings for an adult with Shwachman Syndrome and pancreatic lipomatosis. MacMaster SA, Cummings TM. Can Assoc Radio J 1993:44:301-304.

Congenital hypoplasia of the exocrine pancreas. Bodian M, Sheldon W, Lightwood R. Acta Paediatr 1964; 53:282-293

Congenital Neutropenia and the risk of leukemia. Boxer L, Dale D. J Pediatr 130:335, 1997.

Constant defect in neutrophils locomotion but with age decreasing susceptibility to infection in Shwachman Syndrome. Ruutu P. Savilahti E, Repo H Kosunen TU. Clin Exp Immunol 1984: 57: 249-255.

Correction of defective chemotaxis with thiamine in Shwachman Diamiond Syndrome. Szuts P et al. Lancet 1:1072-1073, 1984.

Fatal cyclophosphamide-induced congestive heart failure in a 10 year old boy with Shwachman-Diamond Syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation. Tsai PH. Sahdev I, Herry A, Lipton JM. Am J of Pediatr Hematology/Oncology 3. 347-351. 1990

Fatty Iniltration of the pancreas in Shwachman's Syndrome: Computerised tomography demonstration. Kurdziel et al. Eur J Radiol 1984 4 Pp 202-04

Frequent myocardial lesions in Shwachman's Syndrome - eight fatal cases among 16 Finish patients. Savilahti E, Rapola J, Acta Paediatrica Scandinavia 73, 642. 1984

G-CSF and congenital neutropenia-risk of leukemia? Corey SJ, Deshpande R. J Pediatr 129:187, 1996.

Granulopoiesis in Shwachman Syndrome. Saunders EF et al. Pediatrics 64:515-519, 1979.

Haematological abnormalities in Shwachman Diamond Syndrome. Smith OP (National Children's Hospital Dublin), Hann IM, Chessells, Reeves RB, Milla P, Departments of Haematology and Gasteroenterology, Great Ormond St Hospital for Children, London and Institute of Child Health, London.Brit J Haematol 94: 279-284, 1996.

........concluded that patients with Shwachman Diamind Syndrome ....."should be considered to be very high risk for development of acuter leukaemia, and we would suggest that they should have a regular bone marrow cytogenic analysis pervformed. If a clonal cytogenetic abnormality is detected, then early bone marrow transplantation should be considered."

Hemopoietic colony-forming cells in Shwachman's Syndrome. Suda T et al. Am J Ped Hem Onc 4:129-133, 1982.

Hereditary and childhood disorders of the pancreas, in Gastrointestinal Disease. Lopez MJ, Grand RJ. 6th Edition, Sleisenger MH and Fortdtran, JS (editors) Philadelphia, WB Saunders & CO, 1997.

Hereditory disorders of the pancreas. Gaskin KJ et al. Ped Gastrointestinal disease, Volume 2 Philadelphia: BC Decker, 1991: 1198-1202.

Hormonal control of growth and the impact on chronic disease. Hintz RL. Inflamm Bowel Dis 1995: 1:313-330

Human Granulocyte Colony -stimulating factor (rHuG-CSF) for treatment of neutropenia in Shwachman- Syndrome. Ventura A et al. Haematologica (May-June 1995) 80(3) Pp 227-29

Hypothesis: Shwachman Syndrome of exocrine pancreatic insufficiency may be caused by neonatal copper deficiency. Paterson CR, Wormsley KG. Ann Nutr Metab 1988: 32 127-132.

In vitro restoration by Lithium of defective chemotaxis in Shwachman-Diamond Syndrome. Azzara A et al. Br. J Haematol 4:502. 1988.

In vivo effectiveness of lithium on impaired neutrophil chemotaxis in Shwachman-Diamiond Syndrome. Azzara A et al. Acta Haematool 85:100-102, 1991. -

Increased whole blood chemiluminescence in patients with Shwachman Syndrome: therapy trial with thiamine and alpha-tocopherol. Ristola M et al. Eur J Pediatr 150: 173-178, 1991.

Investigation and management of pancreatic disease in children. Pncreatic disease in Clinical Practice. Milla PJ. (ed by Mitchell CJ and Kelleher J) Ch 19 pp 291-308 Pitman Medical, Tunbribge Wells, England.

Is Shwachman Syndrome a chromosomal breakage syndrome? Koiffman CP, Gonzales CH, Souza DH, Romani EG, Kim CA, Wajntal A. Human Genetics 87 106-107. 1991

Late presentation of Shwachman's Syndrome. Hislop WS et al. Acta Paediatry

Long term safety of treatment with recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.Bonilla MA, Dale D, Zeidler C, Last L, Reiter A, Ruggeiro M, Davis M , Koci B, Hammond W, Gillio A, Welte K. British Journal of Haematology 88 723-730. 1994

Metaphyseal Chrondrodysplasia, Neutropenia and Pancreatic Insufficiency Prersenting with Respiratory Distress in the Neonatla Period. Danks DM et al. Arch Dis Child 51: 697-701, 1976.

Metaphyseal Chondrodysplasia and Dwarfism, Pancreatic Insufficiency, and Neutropenia. Stanley P and Sutcliffe J. Pediatr Radiol 1:119-226, 1973.

Metaphyseal Dysostosis and the Associated Syndrome of Pancreatic Insufficiency and Blood Disorders. Taybi H, Mitchell A and Friedman G. Radiology 93:563-571. 1969

Monsomy 7 and activating RAS mutations accompanying malignant transformation in patients with congenital neutropenia. Kalra R et al. Blood 86: 4579-4586, 1995.

Nephrocalcinosis in Shwachman's Syndrome. D'Angio CT et al. Arch Dis Child (Apr 1989 6494) Pp 614-615.

Nutritional regulation of IGF-1 and 1GFBPs. Underwood LE. J Pediatr Endocrinol Metab 1996: 9(suppl 3): 303-312.

Orthopedic Aspects of Shwachman Syndrome. Perry L Schoenecker, MD Chief of Staff, St Loius Children's Hospital & Professor, Orthopedic Surgery, Washingtion University School of Medicine

Orthopedic Features of Shwachman Syndrome. Dhar S and Anderton JM. J Bone Joint Surg 76A:278-282, 1994

Pathogenesis, Biology and management of myelodysplastic syndrome in children. Haas O, Gadner H. Semin Hematol 33:225-235, 1996

Phase III randomised multicenter trial of G-CSF vs observation for myelodydplastic syndrome. Greenberg P et al. Blood 82 (10, S1:769), 196a, 1993 -

Psychological characteristics of children with Shwachman Syndrome, Kent A et al. Archives of Diseases in Childhood (1990; 65) Pp 1349-52.

Recombinant human G-CSF in treatment of patients with neutropenia. Boxer L, Hutchinson R, Emerson S.Clin Immunol Immunopathol 62:S39-S46, 1992.

Respiratory Aspects of Shwachmans Syndrome in Adults. Wiggins J et al; Eur Respir J (Mar 1989 2(3) Pp 285-288

RHG-CSF for Shwachman's Syndrome. Adachi N, Tsuchiya H. Nunol H. Higuchi S, Akaboshi I. Chikazowa W. Lancet 336. 1139. 1990

Shwachman Diamond Syndrome presenting as hepatosplenomegaly. Wilschanski M et al. J Pedaitr Gastroenterol Nutr 1994: 19:111-113.

Shwachman-Diamond Syndrome and matched unrelated donor BMT. Smith OP, Chan MY, Evans JP, Veys P. Bone Marrow Transplantation. 16. 717-718. 1995

Shwachman-Diamond Syndrome: Clinical, Radiological, and Sonographic findings. Berrocal T et al. Pediatr Radiol 1995 25(5) Pp 356-59. and 25(4) Pp 289-92

Shwachman's Syndrome and acute lymphoblastic leukaemia, Stevens MJ, Lileyman JS, Williams RB. British Medical Journal. II 18-20. 1978 -

Shwachman Syndrome and Chromosone Breakage. Fraccaro M et al. Human Genetics 1988 79 p194

Shwachman Syndrome and leukaemia. Caselitz J. Kloppel G, Delling G, Grutter R, Holdoff U, Stern M. Virchows Archives (A), 385, 109-112.

Shwachman Syndrome: CT and MR Diagnosis. Bom EP et al. J Comput Assist Tomogr 1993: 17: 474-476.

Shwachman's Syndrome - a review of 21 cases. Aggett PJ, Cavanagh NPC, Matthew DJ Pincott JR, Sutcliffe J, Harries JT. Arch Dis Child 1980; 55: 331-347

Shwachman Syndrome: Exocrine pancreatic dysfunction and variable pheotypic expression. Mack DR, Forstner GG, Wilschanki M, Freedman MH, Durie PR. Gastroenterology 1996; 111:1593-1602

Shwachman Syndrome - Online Mendelian Inheritance of Man (OHIM) McKusick VA, Editor John Hopkins University Entry no 260400, 557000

Shwachman Syndrome - The Broad Spectrum of Bony Abnormalities. McLennan TW and Steinbach HL. Radiology 112:167-173, 1974.

Shwachman Syndrome transformed into leukaemia. Gretillat F, Delepine N, Taillard F, Desbois JC,, Misset JL. Presse Medicale, 14, 45-48.

Some clinical observations on the Shwachman Syndrome. Shwachman H, Holsclaw D. Birth Defects: 8:46-49, 1972.

Steatorrhea and pancreatic insufficiency in Shwachman Syndrome. Hill RE, Durie PR, Gaskin KJ, Davidson GP, Forstner GG. Arch Dis Child 1982; 83:22-27.

Successful cyclosporin A treatment of aplastic anemia in Shwachman-Diamond Syndrome. Barrios NJ, Kirkpatrick DV . British Journal of Haematology, 74, 540-541.

Syndrome of Shwachman and Leukaemia. Huijgens PC et al. Scand J Haematol 18:20-24, 1977.

The cyclical nature of prepubertal growth. Butler GE, McKie M, Ratcliffe SG. Ann Human Biol 1990. 177-198.

The occurence of leukemia in patients with Shwachman Syndrome. Woods W et al. J Pediatr 99:425-428, 1981.

The syndrome of pancreatic insufficiency and bone marrow dysfunction. Harry Shwachman, Diamond LK, Oski FA, Khaw KT. J Pediatr 1964; 65:645-663

The syndrome of neonatal copper deficiency. Ashkenazi A. Levin S. Djaldetti M. Fishel E, Benvenisti D. Pediatrics 52: 525-33

Treatment of neutropenia in Shwachman Syndrome with granulocyte growth factor (G-CSF). Grill J, Bernaudin F, Dresch C, Lemerie S, Reinert P. Arch Fr Pediatr 1993: 50: 331-333

Unusual surface distribution of concanavalin A reflects a cytoskeletal defect in neutrophils in Shwachman's Syndrome. Rothbaum R, Williams D, Daugherty C. Lancet 2:800-801. 1982.