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Shwachman syndrome

This is part of Rare diseases.

Diagnosis: Shwachman syndrome

Synonyms: Shwachman-Diamond syndrome, SDS

Innehåll


Date of publication: 2009-04-06
Version: 2.1

The disease

Shwachman syndrome is a hereditary disease characterised mainly by impaired pancreas function (pancreatic insufficiency) and bone marrow dysfunction. Individuals with Shwachman syndrome are susceptible to infection and have an elevated risk of leukaemia, skeletal abnormalities, and liver enlargement.

The syndrome was first described by French physicians Christian Nezelof and J.M. Wachti in 1961, but the condition was named after American paediatrician Harry Shwachman, a prominent specialist in the field of cystic fibrosis (CF). In 1964, Harry Shwachman, Louis Klein Diamond and co-workers published a case report describing siblings with pancreatic insufficiency, growth delay, and bone marrow abnormalities.

Occurrence

Shwachman syndrome is a very rare condition. The exact incidence has not been determined, but it is estimated that one in 300,000 babies is born with the syndrome. In Sweden this corresponds to one child being born with the syndrome every three years. It is slightly more common in boys than girls.

Although very few Swedish cases are known, the condition is probably under-diagnosed, as the clinical presentation varies widely.

Cause

The majority of individuals with the syndrome have mutations in the SBDS gene on chromosome 7. SBDS is a regulatory gene affecting the growth and function of multiple tissues and organs.

The full function of the SBDS protein remains unclear, but it is known to be necessary for the formation of ribosomes. The ribosomes are small structures in the cell which function as “factories” for the production of different proteins. Genes in the cell nucleus translate the genetic code (DNA) into RNA molecules, which can leave the nucleus and bind with proteins to form the ribosomes.

Heredity

The inheritance pattern of Shwachman syndrome is autosomal recessive. This means that two copies of the mutated gene are needed in order to develop the disease. If both parents have only one copy of the mutated gene they are called healthy carriers. Their children will have a 25 per cent risk of inheriting two mutated genes and developing the disease. In 50 per cent of the cases the child will inherit only one copy of the mutated gene and become a healthy carrier. In 25 per cent of the cases the child will inherit two normal genes and will neither develop the disease nor pass it down.

Figure. Autosomal recessive inheritance of genetic traits

If one parent is not a carrier, but the other has an inherited autosomal recessive disorder (and thus has two copies of the mutated gene), the children will all be carriers of the mutation but the condition will not affect them. If an individual with an autosomal recessive disorder has a child with a healthy carrier, who has one copy of the mutated gene, there is a 50 per cent risk that the child will develop the condition, while in 50 per cent of the cases the child will be a healthy carrier.

Symptoms

As Shwachman syndrome affects several organs, the expression and severity of the condition varies significantly, ranging from mild pancreatic insufficiency to severe blood disease with risk of leukaemia. The syndrome usually presents as a combination of pancreatic insufficiency, low concentrations of neutrophil granulocytes (a type of white blood cell), and short stature.

The pancreas

Shwachman syndrome is associated with exocrine pancreatic insufficiency, a condition in which the pancreas does not produce sufficient amounts of enzymes to digest food in the intestines.

Early signs that a child is affected include loose, fatty stools and failure to thrive. Loss of exocrine function impairs fat digestion (fat malabsorption) and leads to poor uptake of fat-soluble vitamins A, D, E, and K. Essential fatty acid and vitamin deficiencies weaken the immune system and may cause night blindness, eczema, and coagulation disturbances, which can cause internal haemorrhages. If left untreated, severe organ damage may result.

The pancreas also produces insulin, which is released into the blood stream. Insulin is essential to the blood sugar metabolism. Children with low insulin levels secondary to pancreatic insufficiency will present with symptoms similar to insulin-dependent diabetes mellitus type I (IDDM). However, insulin deficiency in Shwachman syndrome is relatively rare.

Pancreatic exocrine insufficiency often improves over the years. Almost 50 per cent of adults with the syndrome have normal pancreatic function and no symptoms of fat malabsorption.

Bone marrow

The main function of the bone marrow is to produce red blood cells, white blood cells, and thrombocytes (blood platelets). Red blood cells are responsible for oxygen transport, white blood cells are part of the immune system, and thrombocytes are required for blood coagulation.

Although all three blood cell types may be affected, the most characteristic sign of Shwachman syndrome is low neutrophil granulocyte (white blood cell) count, a condition known as neutropenia. Agranulocytosis is a severe and rare variant of neutropenia, in which the individual has no neutrophil granulocytes. Symptoms of neutropenia include recurrent bacterial infections in the skin, mucous membranes (the oral cavity and gums), and respiratory tract (ears, sinuses, and lungs). More serious infections, such as sepsis (blood infection) and osteomyolitis (bone infection), may also occur. The risk of developing a serious infection is strongly correlated with the level of neutrophils. Over time, many patients become less prone to infections.

Approximately half of all children with the syndrome are anaemic and have a low thrombocyte count (thrombocytopenia). Symptoms include pallor, fatigue, and abnormal bleeding tendency. Pancytopenia, shortage of all blood cell types, is rare in Shwachman syndrome. Children with pancytopenia present with all the symptoms listed above.

Some children develop a bone marrow disorder known as myelodysplastic syndrome (pre-leukaemia) or a type of leukaemia (blood cancer) known as acute myeloid leukaemia. For unknown reasons, bone marrow dysfunction is more severe in boys than in girls with the syndrome.

Skeletal growth

Short stature is often evident even in newborns with the syndrome, and growth remains slow. Poor growth may be explained by anomalies in the long bone growth zones (the arms and legs). Ribs that fail to develop normally may result in an unusual chest shape.

The liver

Enlarged liver and liver function abnormalities are common symptoms, but as a rule they are only temporary. Most adults with the syndrome have normal liver function.

Other symptoms

Most children with the syndrome have normal intellectual development. Learning difficulties are common, however, and some children have mild intellectual disability.

Less common symptoms include asthma, cleft lip or palate, feeding difficulties, tooth enamel defects, and strabismus (squinting).

Kidney stones caused by urinary tract malformations can sometimes occur.

Diagnosis

Owing to the wide variation in clinical expression, Shwachman syndrome is difficult to diagnose. In children with a mild form of the disease, early symptoms such as failure to thrive and digestive problems may be mistaken for cystic fibrosis (CF). A simple test of the salt concentration in sweat, performed at most paediatric clinics, can be used to exclude CF. Shwachman syndrome should be suspected in children with exocrine pancreatic insufficiency and low granulocyte count, possibly in combination with short stature.

Pancreatic function

Pancreatic function is evaluated with a faecal test (faecal elastase).Testing should be performed at regular intervals, as pancreas function is restored in approximately 50 per cent of all adults with the syndrome and treatment may no longer be required. The test can be carried out by the chemistry laboratory of most university hospital clinics.

Owing to the risk of insulin deficiency, Shwachman syndrome patients should have their fasting blood sugar (FBS) and morning urine checked regularly.

Blood and bone marrow evaluation

A white blood cell count should be carried out on repeated occasions, as granulocytopenia (granulocyte deficiency) is sometimes intermittent. Neutrophil concentrations may be particularly low (neutropenia), and fail to increase in response to bacterial infection. Red blood cell and thrombocyte counts should also be assessed regularly.

The bone marrow is always evaluated in suspected cases of Shwachman syndrome. Whether bone marrow evaluation should be implemented on an annual basis, for early detection of myelodysplastic syndrome and leukaemia, is an issue currently under debate.

Other symptoms

Skeletal abnormalities should be checked for with a normal X-ray.

Blood tests and ultrasonography are used to examine liver function and appearance. In some cases liver biopsy is required (fine needle aspiration of liver tissue examined under a microscope).

The majority of individuals with the syndrome have SBDS mutations. On suspicion of Shwachman syndrome, DNA testing can be used to confirm the diagnosis. Prenatal diagnosis is possible if the familial mutation is known.

Treatment/interventions

There is no cure for Shwachman syndrome, but a great deal can be done to alleviate symptoms. As multiple organs are affected, several specialists cooperate to ensure the best care, such as sufficient nourishment, healthy blood status, and early detection of infections. A paediatric immunologist should be part of the treatment team, together with a dietician, a social worker, a psychologist, and a nurse. Early recognition and treatment of new symptoms are essential for prevention of serious infections.

Enzyme treatment and diet

Dietary therapy is essential, and a dietician should be involved in treatment as early as possible. Despite medical treatment, children with the syndrome cannot absorb fat as well as if they had normal pancreatic function, and therefore need considerably more calories than other children of the same age.

Pancreatic enzymes are administered to normalise stools. The doses are tailored to meet the needs of the individual child. Children should pass 1-2 solid, flushable stools every day. The calorie-rich diet should be supplemented with polyunsaturated fatty acids and vitamins (A, D, E, and K).

If feeding is a problem, nutritional fluids can be administered through a feeding tube from the nose to the stomach. If tube feeding is required for extended periods, a gastrostomy may be performed in which paediatric surgeons access the stomach through the abdominal wall. After a few months, the tube is replaced by a skin level device, a “button” (percutaneous endoscopic gastrostomy). The button may be used to supplement the child’s daytime diet with nutritional fluids administered during the night. Both parents and children often find this a relief, as feeding can be a demanding task.

The child’s growth should be carefully monitored, and blood tests to evaluate essential fatty acids and vitamin levels should be performed annually. Enzyme and vitamin doses often need to be adjusted as the child grows.

Neutropenia, infection, anaemia, and bleeding treatments

The immune system may be strengthened by administering granulocyte colony-stimulating factor (G-CSF), a medicine that stimulates the production of neutrophil granulocytes in the bone marrow.

Prophylactic antibiotics may be prescribed to help prevent infection. If this preventive measure is not taken, antibiotics should be administered immediately on suspicion of bacterial infection. It is important that children with Shwachman syndrome are vaccinated according to the recommended vaccine schedule.

Iron therapy is used for treatment of anaemia. In rare cases of severe thrombocytopenia and bleeding tendency, the patient is given thrombocyte infusions. However, as improvement is temporary, thrombocyte infusions are only administered in cases of severe bleeding and before surgery.

If possible, large gatherings of people in public spaces should be avoided owing to the risk of infection. As even apparently healthy young children often carry bacteria causing respiratory tract infections, large groups of children, for example at a day care centre, should also be avoided.

Pronounced neutropenia can cause oral inflammation and increases the risk of tooth loss (periodontal disease). A dental hygienist should be consulted for prophylactic dental care and advice on how to maintain oral health.

A complete blood count should be carried out regularly. On suspicion of myelodysplastic syndrome or leukaemia, a bone marrow evaluation should be performed.

Leukaemia treatment

Acute leukaemia is treated by administering large doses of chemotherapeutic drugs (cytostatic agents) over a short period of time. This demanding treatment aims to induce a state of remission by removing leukaemic cells from the bone marrow, thus enabling normal blood cell production. In Shwachman syndrome, chemotherapy needs to be supplemented with haematopoietic stem cell transplantation (HSCT).

Haematopoietic stem cell transplantation (HSCT)

Haematopoietic stem cell transplantation (commonly referred to as “bone marrow transplantation”) is often successful in Shwachman syndrome patients with leukaemia in remission, myelodysplastic syndrome, or pancytopenia.

Haematopoietic stem cells, usually retrieved from bone marrow or from umbilical cord blood, have the potential to differentiate into various blood cells. Transplantation makes it possible to use stem cells from a donor to replace diseased stem cells. For the new stem cells to engraft, the recipient’s tissue type must be compatible with the donor’s.

To optimise the chances of successful transplantation, the recipient should preferably be free from infection and in as good physical condition as possible. The intervention itself is fairly simple, but the preparations, aftercare, and major risks involved make it a highly demanding procedure. The stem cells are administered through an intravenous catheter, and make their own way into the bone cavities of the recipient. The new stem cells grow as the recipient’s immune system slowly recovers, a process that takes at least one year.

Other interventions

Skeletal abnormalities should be evaluated by a paediatric orthopaedic specialist who will assess the need for surgery or other treatment.

Apart from early specialist treatment, the child and the family may require assistance from a paediatric habilitation centre. The degree of functional limitation determines the need for interventions.

Having a child who is susceptible to infections may be demanding for the parents and there is a risk of social isolation. The whole family should be offered psychological and social support. Contact with other families in a similar situation may be valuable. The family may also require assistance in coordinating interventions.

Practical advice

Be attentive to hand hygiene. Avoid places that are smoky or dusty, as well as large crowds during times of infections.

Particular attention must be paid to food and hygiene when travelling, especially abroad, as foreign travel often brings the affected individual into contact with new types of bacteria. Consult your doctor about which medications you should take with you.

Air humidifiers easily spread bacteria and fungus. If it is necessary to use air humidifiers they should be cleaned regularly with a bleach solution.

National and regional resources in Sweden

Department of Paediatric Immunology, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel +46 31 343 40 00.

Resource personnel

Professor Anders Fasth, Department of Paediatric Immunology, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel +46 31 343 40 00, fax +46 31 84 30 10, email: anders.fasth@gu.se.

Associate Professor Marie Johannesson, Uppsala University, SE-751 22 Uppsala, Sweden. Tel +46 18 471 61 95, email: marie.johannesson@pubcare.uu.se.

Professor Taco W. Kuijpers, Academic Medical Center, Amsterdam, The Netherlands. Email: t.w.kuijpers@amc.uva.nl.

Courses, exchanges of experience, recreation

PIO, The Primary Immunodeficiency Organisation in Sweden, regularly organises lectures and information meetings about immunodeficiency at their annual meeting. There is a yearly weekend gathering arranged by PIO for children and adolescents with CVID. PIO and other Nordic immunodeficiency associations also arrange joint meetings providing members with the opportunity to exchange information and experience. These meetings are excellent opportunities to learn more and exchange experience. For further information contact PIO, see under “Organizations for the disabled/patient associations.”

IPOPI, the International Patient Organisation for Patients with Primary Immunodeficiencies, of which PIO is an affiliate, arranges a conference in conjunction with a biennial international medical conference on immunodeficiency. IPOPI’s conferences are conducted in English. For further information contact PIO, see under “Organizations for the disabled/patient associations.”

Organizations for the disabled/patient associations

PIO, The Primary Immunodeficiency Organisation in Sweden, Mellringevägen 120 B, SE-703 53 Örebro, Sweden. Tel +46 19 673 21 24, email: pio@telia.com, Internet: www.pio.nu.

Courses, exchanges of experience for personnel

SLIPI - The Swedish Physicians’ Association for Primary Immunodeficiencies, arranges meetings and symposia. Chair: Professor Janne Björkander, Unit of Pulmonary Medicine and Allergy, Ryhov County Hospital, SE-551 85 Jönköping, Sweden. Tel +46 36 32 10 00, fax +46 36 32 21 58, email: janne.bjorkander@lj.se, Internet: www.slipi.nu.

SISSI - The Swedish Nursing Group for Immunodeficiencies, publishes a newsletter and arranges members’ conferences. These are held in collaboration with ESID, IPOPI, and INGID every second year. Chair: Bengt Steger, Pulmonary/Allergy Unit, Falu Hospital, SE-791 82 Falun, Sweden. Tel +46 23 49 04 47, email: bengt.steger@ltdalarna.se, Internet: www.sissi.nu.

ESID - The European Society for Immunodeficiencies, organises conferences and summer schools for physicians and researchers. Chair: Jean-Laurent Casanova, Necker Medical School, Rue de Vaugirard 156, FR-75015 Paris, France. Internet: www.esid.org.

INGID - The International Nursing Group for Immunodeficiencies, arranges international meetings in collaboration with ESID and the international patient organisation IPOPI. Chair: Gaby Strotmann, Klinikum Innenstadt der Lugwig-Maximilians Universität, Immunologische Tagesklinik, Lindwurmstrasse 4-80337, München, Germany 80337. Tel +49 89 5160 3931, fax +49 89 5160 3964, email: gstrotma@med.uni-muenchen.de, Internet: www.ingid.org.

Research and development (R&D)

Research on Shwachman syndrome is ongoing at different centres, such as the Academic Medical Center in Amsterdam, The Netherlands, and The Hospital for Sick Children in Toronto, Canada.

Information material

An information booklet on Shwachman syndrome, which summarises the information in this database text, is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2006-12-201). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The information material listed below may be ordered from PIO, The Swedish Primary Immunodeficiency Organisation (see under “Organizations for the disabled/patient associations”):

  • “Primär immunbrist hos barn och vuxna.” Information folder about primary immunodeficiency from PIO, 8th ed., 2005. (In Swedish only).
  • “Så mår immunförsvaret bättre. Praktisk livsföring vid primär immunbrist - några råd,” 1999. (Advice about living with primary immunodeficiency. In Swedish only).
    The Story of Primary Immunodeficiency, 1999.
  • “En skola för alla. Praktiska råd för en bättre skolmiljö vid primär immunbrist.” 2nd ed., 2007. (Practical advice about schooling for children with primary immunodeficiency, separate information for parents and for schools. In Swedish only.)
  • “Studera med primär immunbrist. Praktiska tips för universitets/högskolestudier vid primär immunbrist.” 1st ed., 2008. (Practical advice about studying at university or college with primary immunodeficiency, one folder intended for students and one for schools. In Swedish only.)

Patient and Family Handbook for the Primary Immune Deficiency Diseases. IDF, The Immune Deficiency Foundation, 4th ed., USA 2007. The book can be downloaded as a PDF at the website: www.primaryimmune.org/publications/book_pats/book_pats.htm.

“ALPI-studien. Att Leva med Primär Immunbrist.” A study from Karolinska Institutet, by Professor Ann Gardulf et al. Three reports (in Swedish only) have been published on the website of Karolinska Institutet: http://ki.se/ki/jsp/polopoly.jsp?d=16775&l=en.

Literature

Calhoun DA, Christensen RD. Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate. Curr Opin Hematol 1998; 5: 37-41.

Cesaro S, Oneto R, Messina C, Gibson BE, Buzyn A, Steward C et al. EBMT Severe Aplastic Anaemia and Paediatric Diseases Working Party. Haematopoietic stem cell transplantation for Shwachman-Diamond disease: a study from the European Group for blood and marrow transplantation. Br J Haematol 2005; 131: 231-236.

Cipolli M, D’Orazio C, Delmarco A, Marchesini C, Miano A, Mastella G. Shwachman syndrome: Pathomorphosis and Long-term Outcome. J Ped Gastroenterol 1999; 29: 265-272.

Donadieu J, Michel G, Merlin E, Bordigoni P, Monteux B, Beaupain B et al. Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry. Bone Marrow Transplant 2005; 36: 787-792.

Ganapathi KA, Shimamura A. Ribosomal dysfunction and inherited marrow failure. Br J Haematol 2008; 141: 376-87.

Ginzberg H, Shin J, Ellis L, Morrison J, Ip W, Dror Y et al. Shwachman syndrome: phenotypic manifestations of siblings sets and isolated cases in a large patient cohort are similar. J Pediatr 1999; 135: 81-88.

Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR et al. Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Genet 2001; 68: 1048-1054.

Kamoda T, Saito T, Kinugasa H, Iwasaki N, Sumazaki R, Mouri Y et al. A case of Shwachman-Diamond syndrome presenting with diabetes from early infancy. Diabetes Care 2005; 28: 1508-1509.

Kent A, Murphy GH, Milla P. Psychological characteristics of children with Shwachman syndrome. Arch Dis Child 1990; 65: 1349-1352.

Shwachman-Diamond syndrome: the clinical imitator of cystic fibrosis. PR Health Sci J 1995; 14: 275-277.

Mäkitie O, Ellis L, Durie PR, Morrison JA, Sochett EB, Rommens JM et al. Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. Clin Genet 2004; 65: 101-112.

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

Smith OP, Chan MY, Evans J, Veys P. Shwachmann-Diamond syndrome and matched unrelated donor BMT. Bone Marrow Transpl 1995; 16: 717-718.

Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Hematological abnormalities in Shwachman-Diamond syndrome. Brit J Haemat 1996; 94: 279-284.

Toivainen-Salo S, Mäkitie O, Mannerkoski M, Hämäläinen J, Valanne L, Autti T. Shwachman-Diamond syndrome is associated with structural brain alterations on MRI. Am J Med Genet 2008, 146A: 1558-1564.

Woloszynek JR, Rothbaum RJ, Rawls AS, Minx PJ, Wilson RK, Mason PJ et al. Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood 2004; 104: 3588-3590.

Database references

OMIM (Online Mendelian Inheritance in Man).
Internet: http://www.ncbi.nlm.nih.gov/omim
Search: shwachman syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Marie Johannesson, Uppsala University, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2009-04-06
Version: 2.1
Publication date of the original Swedish version:
2008-12-01

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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