- Email: [email protected]
Shwachman-Diamond Syndrome in a Mexican Family
Archives of Medical Research 32 (2001) 318–323
CASE REPORT
Shwachman-Diamond Syndrome in a Mexican Family Jaime Belkind-Gerson,* Patricia Ontiveros-Nevares,** Valeria Ocampo-Roosens** and Daniel Sandoval-Juárez*** *Departamentos de Gastroenterología, **Patología, y ***Hematología-Oncología, Hospital del Niño Morelense Macaria Than de Rivapalacio, Cuernavaca, Morelos, Mexico Received for publication August 31, 2000; accepted March 9, 2001 (00/127).
Shwachman-Diamond Syndrome (SDS) is an inherited condition with multisystemic abnormalities including pancreatic exocrine dysfunction, neutropenia, short stature, and skeletal abnormalities. In this report, we describe the case of a 14-year-old female with a history of neutropenia, pancreatic exocrine insufficiency and pancreatic endocrine sufficiency, pancreatic lipomatosis (10), and the development of myeloid leukemia. Postmortem examination revealed a high probability of SDS. We also describe the clinical findings in the patient’s six siblings, suggesting this as a familial form of SDS. Because the gene(s) responsible for this syndrome have not yet been identified, genetic confirmation is not yet possible. This is the first report in the literature of a Mexican family with probable SDS. © 2001 IMSS. Published by Elsevier Science Inc. Key Words: Shwachman-Diamond syndrome, Pancreatic insufficiency, Neutropenia, Leukemia.
Introduction Shwachman-Diamond syndrome (SDS) was first identified in 1964 (1) and is the second most common inherited cause of exocrine pancreatic dysfunction (2). In addition to pancreatic exocrine hypoplasia, SDS is characterized by short stature, bone marrow dysfunction, skeletal abnormalities, the development of myeloid leukemia, and other less common findings (3–6). Mack et al. (7) reported a series of 25 patients in whom pancreatic exocrine function was evaluated by fat balance studies, serum cationic trypsinogen, and by a quantitative pancreatic stimulation test. Severe fat maldigestion was present in early life and persistent deficits of enzyme secretion continued; nonetheless, 45% of patients had moderate age-related improvements leading to pancreatic sufficiency. In this same series, neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequent. Three patients died of acute myelogenous leukemia. Although growth velocity improved after 6 months of age, average growth was below the fifth percentile with wide variability in growth percentiles. Address reprint requests to: Dr. Jaime Belkind-Gerson, Hospital del Niño Morelense, Calle Gustavo Gómez Azcárate #205, Col. Lomas de la Selva, 62270, Cuernavaca, Morelos, México. Phone and FAX: (52) (7) 311-1150; E-mail: [email protected]
The disease may present as an isolated case or in a familial form. Segregation ratios have suggested that mode of inheritance is autosomally recessive (8); however, the abnormal gene(s) involved in its pathogenesis have not yet been identified. Ginzberg et al. (9) studied 63 patients with SDS with no familial involvement and 25 affected siblings from 12 multiplex families and concluded that similarities in phenotype among isolated cases and affected siblings support the hypothesis that Shwachman syndrome is a single disease entity.
Methods In this report, we describe a case of a child seen at our institution. This patient presented with clinical and autopsy findings that strongly suggested a diagnosis of SDS. After obtaining informed consent, the patient’s siblings underwent examination by a pediatric gastroenterologist, an orthopedist, and a geneticist. A serum sample was obtained for pancreatic cationic immunoreactive trypsin and isoamylase determinations. X-ray surveillance of skeletal malformations and weekly complete blood counts during a period of 1 month were also performed, in order to screen for hematologic abnormalities. We present the findings of our work-up.
0188-4409/01 $–see front matter. Copyright © 2001 IMSS. Published by Elsevier Science Inc. PII S0188-4409(01)00 2 9 3 - 4
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323 Table 1. Autopsy findings Organ or system Pancreas
Lymphoid Bone marrow
Lower extremities Liver and spleen
Probable cause of death
Finding Fatty infiltration and extensive fibrosis of more than 90% of the exocrine component Endocrine component normal (Figures 1 and 2). Calcification of the muscle layer of the pancreatic artery (Figure 3) Extreme involution of thymus and lymphoid tissue Acute myeloid leukemia with greater than 30% blasts in bone marrow (Figure 4). Blast infiltration to adrenals and liver Cellulitis in lower extremities with gasforming organisms Macro- and micro-vesicular hepatic steatosis. Abscesses in liver and spleen and postmortem changes including cavities from gas-producing bacteria (Figures 1 and 5) Septic shock
Description of the Case Our patient was a 14-year-old female from a rural Mexican community with poor access to medical services. At arrival at our institution, the patient was gravely ill. Her illness became manifest 6 years earlier with a non-quantified weight loss that progressed, resulting in the cachexia with which she was admitted. Her past medical history also included episodes of intermittent diarrhea, some of which lasted several weeks, petechiae and ecchymosis that had worsened 1 week prior to admission, edema of the lower extremities
319
that worsened 4 days prior to admission, and fever for the previous 3–4 days. Her past medical records from a different institution contained studies obtained during a hospital admission 3 years earlier for diarrhea and weight loss. At that time, she had a large amount of fat in her stools in several different specimens with a normal D-xylose, small intestinal biopsy, normal electrolytes in sweat, and an undetectable trypsin activity in stool. Serum glucoses were normal, as had been an HIV determination and serum immunoglobulins. Anemia and neutropenia had also been noted. An abdominal computed tomography (CT) scan was reported with findings of a small pancreas with no cysts and heterogeneous liver parenchyma. A liver biopsy showed an infiltrate of mononuclear cells with moderate portal fibrosis. A trial of pancreatic enzyme supplementation had been attempted with some apparent improvement in diarrhea and weight gain over 3 months. Unfortunately, the patient stopped taking the enzymes because the family could not afford these and the patient was lost to follow-up. The patient lived in a small wooden shack with two rooms where she, her parents, and six other siblings aged 1–10 years of age resided. The family had received little or no medical attention in the past. Upon admission to our institution, a weight of 18 kg was recorded, her pulse was 120, respiration rate was 24, temperature was 36C, and blood pressure was 90/60 mmHg. She complained of pain in her lower extremities and of being very cold despite blankets and warming lights. She had periods of consciousness but appeared disoriented and frequently drifted off to sleep. The patient had partial alopecia with brittle, discolored, thin hair. Her oral hygiene was poor
Figure 1. Macroscopic appearance of pancreas, biliary system, and liver. The liver has multiple orifices due to gas-producing bacteria. The pancreas has a fatty appearance.
320
Belkind-Gerson et al./ Archives of Medical Research 32 (2001) 318–323
Figure 2. Microscopic appearance of pancreas with residual ducts and acini; the remainder of the pancreas has been replaced by fibrous tissue (20).
and her gums were swollen and bleeding; halitosis was also noted. Her pupils were normal. No fundoscopic exam was performed. No adenomegaly was noted. A chest and heart exam revealed clear lungs and a regular cardiac rhythm with a 2/6 stage systolic murmur. Her abdomen was soft with faint bowel sounds and no hepatosplenomegaly or masses were palpated. Examination of the extremities revealed very
thin arms and legs with poor muscle mass. Her lower extremities had pitting edema up to mid-tibia and purpuric discoloration of the lower third of the legs with bulous lesions, which drained serohematic fluid. There was exquisite pain on palpation of the lower extremities. Laboratory tests showed normal clotting times and serum glucose and urine analysis. The patient’s sodium was 138, potassium 2.6, chloride 113,
Figure 3. Microscopic appearance of pancreas. Note the calcification of the muscle layer of the pancreatic artery (60).
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323
321
Figure 4. Microscopic appearance of bone marrow. Note the abundant myeloid blast cells (40).
magnesium 2.8, total calcium 8, total protein 4.8, albumin 2.7, and amylase, 66.5. A complete blood count revealed hemoglobin of 13, hematocrit 38.5, 2,400 leukocytes, with a differential count of 65% segmented, 2% bands, 30% lymphocytes, 1% monocytes, and 2% eosinophils. Her platelet count was 44,000. Blood, urine, stool, and vesicle fluid cultures were obtained. The patient was admitted to the intensive care unit
where fluid and electrolyte replacement as well as broadspectrum antibiotics were begun. A few hours after admission and previous to any culture data, the patient experienced deteriorating mental status with subsequent hypotensive episodes. She was intubated and given aggressive fluid, followed by pressor management; however, septic shock ensued. The patient died from irreversible cardiac arrest
Figure 5. Microscopic appearance of the liver with macro- and micro-vesicular steatosis and multiple orifices by gas-producing organisms (20).
322
Belkind-Gerson et al./ Archives of Medical Research 32 (2001) 318–323
Table 2. Clinical, radiologic, and laboratory findings in all siblings Gender/age (years) F/14a F/1.3 M/3 M/6 F/7 F/8.8 M/9.8
Serum trypsinogen
Serum isoamylase
Neutropenia
Anemia
Thrombocytes
Skeletal abdomenc
Heightd
NA Normal Low Low Normal Borderline Low
NA Lowb Low Normal Normal Normal Low
NA 3rd p. 3rd p. 3rd p. 3rd p. 3rd p. 3rd p.
a Index case; bAlthough value was very low, this may represent developmental changes due to the patient’s age; cskeletal malformations included metaphyseal dysostosis of long bones and thoracic cage abnormalities; dpercentiles according to the Ramos-Galván growth chart for Mexican children.
12 h after admission. Autopsy findings are summarized in Table 1 (see also Figures 1–5). Findings in siblings. The patient’s siblings were studied in an attempt to diagnose SDS early, if any were affected. Because the family lives in a remote area that is difficult to reach, after obtaining signed consent the family members were brought to our institution on one occasion where examinations by a pediatric gastroenterologist, an orthopedist, and a geneticist were performed. At this initial visit, we obtained a whole blood sample for complete blood count determination and a serum sample for pancreatic cationic immunoreactive trypsin and isoamylase determinations. X-ray surveillance of skeletal malformations was also obtained. The family refused, however, to come back to our institution for further work-up, as this meant time lost from work. The family did agree to be visited by a phlebotomist on three more visits for a weekly complete blood count determination. Three of the six siblings had an abnormal serum trypsinogen result and one was borderline; two also had low serum isoamylase levels (Table 2). The remainder of the clinical and laboratory findings is also summarized in Table 2. Discussion The case described in this report with pancreatic exocrine insufficiency and with pancreatic endocrine sufficiency (2,5), with pancreatic lipomatosis (10), and the development of myeloid leukemia (11–13) strongly suggests the diagnosis of SDS. The lower-than-expected serum calcium level relative to serum albumin found at admission to our institution was probably due to electrolyte imbalances caused by the septic process. However, hypoparathyroidism cannot be ruled out because due to lack of time, a parathyroid hormone level was not obtained before death and thus the Pearson bone marrow pancreas syndrome cannot be excluded. This is, however, unlikely as no sideroblastic anemia or vacuolization of erythroid and myeloid precursors was ever found (14). Because the family members live in a remote area, we were able to perform only a limited work-up on the siblings. Three of the patient’s siblings had low levels of serum immunoreactive trypsin; two additionally had a low level of
serum immunoreactive isoamylase. It is uncommon to have exocrine pancreatic insufficiency secondary to malnutrition. In fact, the immunoreactive pancreatic cationic trypsinogen usually rises in acute and chronic malnutrition, as reported by Durie et al. and Cleghorn et al., a finding thought to be due to pancreatic acinar damage (15,16). An earlier report by Fedail et al., however, described very low levels of serum trypsinogen in chronic malnutrition (17). Measurement for height recorded in all siblings was less than the third percentile, according to the Ramos-Galván growth chart for Mexican children (18). Short stature is not likely due to malnutrition, as weight plotted vs. height was between the 25th and 50th percentiles in all siblings, suggesting a genetic rather than a nutritional basis. Thus, although the effect of chronic malnutrition cannot be completely ruled out, growth abnormalities (6) and pancreatic exocrine insufficiency are suggestive of SDS. The skeletal malformations observed may be found in SDS; however, unlike Mack et al. (7) we did not find hematologic abnormalities in the patient’s siblings. This may be due to a different phenotypic expression in this family, or more likely to the short follow-up time, as neutropenia is often cyclic. Unfortunately, the gene mutation(s) responsible for the development of this disease have not yet been identified; in this manner, the diagnosis of SDS is clinical, because it is not yet possible to confirm the diagnosis through genetic testing. Due to this and because of the limited work-up of family members, we can only conclude that the findings suggest SDS; nevertheless, we cannot be certain of the diagnosis at present. To the best of our knowledge, this is the first Mexican family reported in the literature with a probable diagnosis of SDS. Pediatricians, internists, and sub-specialists in Mexico need to be aware of this syndrome for early diagnosis and treatment. These findings suggest that the Shwachman-Diamond syndrome may be present in a subset of Mexican patients with maldigestion, growth abnormalities, and/or hematologic disturbances.
Acknowledgments The authors wish to thank Dr. Peter Durie and his staff at the Toronto Hospital for Sick Children for their help with the processing of pancreatic enzyme serum samples and their clinical expertise.
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323
References 1. Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr 1964;65:645. 2. Durie PR. Inherited and congenital disorders of the exocrine pancreas. Gastroenterologist 1996;4(3):169. 3. Berrocal T, Simón MJ, al-Assir I, Prieto C, Pastor I, de Pablo L, Lama R. Shwachman-Diamond syndrome: clinical, radiological and sonographic findings. Pediatr Radiol 1995;25(5):356. 4. Durie PR. Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction. Med Clin North Am 2000;84(3):609 [ix.]. 5. Hill RE, Durie PR, Gaskin KJ, Davidson GP, Forstner GG. Steatorrhea and pancreatic insufficiency in Shwachman syndrome. Gastroenterology 1982;83(1 Pt 1):22. 6. Kornfeld SJ, Kratz J, Diamond F, Day NK, Good RA. Shwachman-Diamond syndrome associated with hypogammaglobulinemia and growth hormone deficiency. J Allergy Clin Immunol 1995;96(2):247. 7. Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology 1996;111(6):1593. 8. Ginzberg HJ, Shin J, Ellis S, Goobie J, Morrison M, Corey M, Durie PR, Rommens JM. Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance. Am J Hum Genet 2000;66(4):1413. 9. Ginzberg H, Shin J, Ellis L, Morrison J, Ip W, Dror Y, Freedman M, Heitlinger LA, Belt MA, Corey M, Rommens JM, Durie PR. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr 1999;135(1):81.
323
10. Robberecht EP, Nachtegaele P, Van Rattinghe R, Afschrift M, Kunnen M, Verhaaren R. Pancreatic lipomatosis in the Shwachman-Diamond syndrome. Identification by sonography and CT-scan. Pediatr Radiol 1985;15(5):348. 11. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999;94(9):3048. 12. Huijgens PC, van der Veen EA, Meijer S, Muntinghe OG. Syndrome of Shwachman and leukaemia. Scand J Haematol 1977;18(1):20. 13. Woods WG, Roloff JS, Lukens JN, Krivit W. The occurrence of leukemia in patients with the Shwachman syndrome. J Pediatr 1981;99(3):425. 14. Sansone G, Masera G, Terzoli S, Cantú-Rajnoldi A. Congenital refractory anaemia with vacuolisation of bone marrow precursors, sideroblastosis and growth failure in a girl with normal endocrine pancreatic function. Haematologica 1989;74(6):587. 15. Durie PR, Forstner GG, Gaskin KJ, Weizman Z, Kopelman HR, Ellis L, Largman C. Elevated serum immunoreactive pancreatic cationic trypsinogen in acute malnutrition: evidence of pancreatic damage. J Pediatr 1985;106(2):233. 16. Cleghorn G, Erlich GJ, Bowling FG, Forrest FG, Greer Y, Holt R, Shepherd R. Exocrine pancreatic dysfunction in malnourished Australian aboriginal children. W Med J Aust 1991;154(1):45. 17. Fedail SS, Karar ZA, Harvey RF, Read AE. Serum trypsin as measure of pancreatic exocrine function in children with protein calorie malnutrition (Letter). Lancet 1980;2(8190):374. 18. Vásquez-Garibay EM, Sandoval-Galindo DM, Kumazawa-Ichikawa MR, Romero-Velarde E, Nápoles-Rodríguez F. Estado de nutrición del niño que ingresa al Nuevo Hospital Civil de Guadalajara. Bol Med Hosp Infant Mex 1993;50(6):383.
CASE REPORT
Shwachman-Diamond Syndrome in a Mexican Family Jaime Belkind-Gerson,* Patricia Ontiveros-Nevares,** Valeria Ocampo-Roosens** and Daniel Sandoval-Juárez*** *Departamentos de Gastroenterología, **Patología, y ***Hematología-Oncología, Hospital del Niño Morelense Macaria Than de Rivapalacio, Cuernavaca, Morelos, Mexico Received for publication August 31, 2000; accepted March 9, 2001 (00/127).
Shwachman-Diamond Syndrome (SDS) is an inherited condition with multisystemic abnormalities including pancreatic exocrine dysfunction, neutropenia, short stature, and skeletal abnormalities. In this report, we describe the case of a 14-year-old female with a history of neutropenia, pancreatic exocrine insufficiency and pancreatic endocrine sufficiency, pancreatic lipomatosis (10), and the development of myeloid leukemia. Postmortem examination revealed a high probability of SDS. We also describe the clinical findings in the patient’s six siblings, suggesting this as a familial form of SDS. Because the gene(s) responsible for this syndrome have not yet been identified, genetic confirmation is not yet possible. This is the first report in the literature of a Mexican family with probable SDS. © 2001 IMSS. Published by Elsevier Science Inc. Key Words: Shwachman-Diamond syndrome, Pancreatic insufficiency, Neutropenia, Leukemia.
Introduction Shwachman-Diamond syndrome (SDS) was first identified in 1964 (1) and is the second most common inherited cause of exocrine pancreatic dysfunction (2). In addition to pancreatic exocrine hypoplasia, SDS is characterized by short stature, bone marrow dysfunction, skeletal abnormalities, the development of myeloid leukemia, and other less common findings (3–6). Mack et al. (7) reported a series of 25 patients in whom pancreatic exocrine function was evaluated by fat balance studies, serum cationic trypsinogen, and by a quantitative pancreatic stimulation test. Severe fat maldigestion was present in early life and persistent deficits of enzyme secretion continued; nonetheless, 45% of patients had moderate age-related improvements leading to pancreatic sufficiency. In this same series, neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequent. Three patients died of acute myelogenous leukemia. Although growth velocity improved after 6 months of age, average growth was below the fifth percentile with wide variability in growth percentiles. Address reprint requests to: Dr. Jaime Belkind-Gerson, Hospital del Niño Morelense, Calle Gustavo Gómez Azcárate #205, Col. Lomas de la Selva, 62270, Cuernavaca, Morelos, México. Phone and FAX: (52) (7) 311-1150; E-mail: [email protected]
The disease may present as an isolated case or in a familial form. Segregation ratios have suggested that mode of inheritance is autosomally recessive (8); however, the abnormal gene(s) involved in its pathogenesis have not yet been identified. Ginzberg et al. (9) studied 63 patients with SDS with no familial involvement and 25 affected siblings from 12 multiplex families and concluded that similarities in phenotype among isolated cases and affected siblings support the hypothesis that Shwachman syndrome is a single disease entity.
Methods In this report, we describe a case of a child seen at our institution. This patient presented with clinical and autopsy findings that strongly suggested a diagnosis of SDS. After obtaining informed consent, the patient’s siblings underwent examination by a pediatric gastroenterologist, an orthopedist, and a geneticist. A serum sample was obtained for pancreatic cationic immunoreactive trypsin and isoamylase determinations. X-ray surveillance of skeletal malformations and weekly complete blood counts during a period of 1 month were also performed, in order to screen for hematologic abnormalities. We present the findings of our work-up.
0188-4409/01 $–see front matter. Copyright © 2001 IMSS. Published by Elsevier Science Inc. PII S0188-4409(01)00 2 9 3 - 4
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323 Table 1. Autopsy findings Organ or system Pancreas
Lymphoid Bone marrow
Lower extremities Liver and spleen
Probable cause of death
Finding Fatty infiltration and extensive fibrosis of more than 90% of the exocrine component Endocrine component normal (Figures 1 and 2). Calcification of the muscle layer of the pancreatic artery (Figure 3) Extreme involution of thymus and lymphoid tissue Acute myeloid leukemia with greater than 30% blasts in bone marrow (Figure 4). Blast infiltration to adrenals and liver Cellulitis in lower extremities with gasforming organisms Macro- and micro-vesicular hepatic steatosis. Abscesses in liver and spleen and postmortem changes including cavities from gas-producing bacteria (Figures 1 and 5) Septic shock
Description of the Case Our patient was a 14-year-old female from a rural Mexican community with poor access to medical services. At arrival at our institution, the patient was gravely ill. Her illness became manifest 6 years earlier with a non-quantified weight loss that progressed, resulting in the cachexia with which she was admitted. Her past medical history also included episodes of intermittent diarrhea, some of which lasted several weeks, petechiae and ecchymosis that had worsened 1 week prior to admission, edema of the lower extremities
319
that worsened 4 days prior to admission, and fever for the previous 3–4 days. Her past medical records from a different institution contained studies obtained during a hospital admission 3 years earlier for diarrhea and weight loss. At that time, she had a large amount of fat in her stools in several different specimens with a normal D-xylose, small intestinal biopsy, normal electrolytes in sweat, and an undetectable trypsin activity in stool. Serum glucoses were normal, as had been an HIV determination and serum immunoglobulins. Anemia and neutropenia had also been noted. An abdominal computed tomography (CT) scan was reported with findings of a small pancreas with no cysts and heterogeneous liver parenchyma. A liver biopsy showed an infiltrate of mononuclear cells with moderate portal fibrosis. A trial of pancreatic enzyme supplementation had been attempted with some apparent improvement in diarrhea and weight gain over 3 months. Unfortunately, the patient stopped taking the enzymes because the family could not afford these and the patient was lost to follow-up. The patient lived in a small wooden shack with two rooms where she, her parents, and six other siblings aged 1–10 years of age resided. The family had received little or no medical attention in the past. Upon admission to our institution, a weight of 18 kg was recorded, her pulse was 120, respiration rate was 24, temperature was 36C, and blood pressure was 90/60 mmHg. She complained of pain in her lower extremities and of being very cold despite blankets and warming lights. She had periods of consciousness but appeared disoriented and frequently drifted off to sleep. The patient had partial alopecia with brittle, discolored, thin hair. Her oral hygiene was poor
Figure 1. Macroscopic appearance of pancreas, biliary system, and liver. The liver has multiple orifices due to gas-producing bacteria. The pancreas has a fatty appearance.
320
Belkind-Gerson et al./ Archives of Medical Research 32 (2001) 318–323
Figure 2. Microscopic appearance of pancreas with residual ducts and acini; the remainder of the pancreas has been replaced by fibrous tissue (20).
and her gums were swollen and bleeding; halitosis was also noted. Her pupils were normal. No fundoscopic exam was performed. No adenomegaly was noted. A chest and heart exam revealed clear lungs and a regular cardiac rhythm with a 2/6 stage systolic murmur. Her abdomen was soft with faint bowel sounds and no hepatosplenomegaly or masses were palpated. Examination of the extremities revealed very
thin arms and legs with poor muscle mass. Her lower extremities had pitting edema up to mid-tibia and purpuric discoloration of the lower third of the legs with bulous lesions, which drained serohematic fluid. There was exquisite pain on palpation of the lower extremities. Laboratory tests showed normal clotting times and serum glucose and urine analysis. The patient’s sodium was 138, potassium 2.6, chloride 113,
Figure 3. Microscopic appearance of pancreas. Note the calcification of the muscle layer of the pancreatic artery (60).
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323
321
Figure 4. Microscopic appearance of bone marrow. Note the abundant myeloid blast cells (40).
magnesium 2.8, total calcium 8, total protein 4.8, albumin 2.7, and amylase, 66.5. A complete blood count revealed hemoglobin of 13, hematocrit 38.5, 2,400 leukocytes, with a differential count of 65% segmented, 2% bands, 30% lymphocytes, 1% monocytes, and 2% eosinophils. Her platelet count was 44,000. Blood, urine, stool, and vesicle fluid cultures were obtained. The patient was admitted to the intensive care unit
where fluid and electrolyte replacement as well as broadspectrum antibiotics were begun. A few hours after admission and previous to any culture data, the patient experienced deteriorating mental status with subsequent hypotensive episodes. She was intubated and given aggressive fluid, followed by pressor management; however, septic shock ensued. The patient died from irreversible cardiac arrest
Figure 5. Microscopic appearance of the liver with macro- and micro-vesicular steatosis and multiple orifices by gas-producing organisms (20).
322
Belkind-Gerson et al./ Archives of Medical Research 32 (2001) 318–323
Table 2. Clinical, radiologic, and laboratory findings in all siblings Gender/age (years) F/14a F/1.3 M/3 M/6 F/7 F/8.8 M/9.8
Serum trypsinogen
Serum isoamylase
Neutropenia
Anemia
Thrombocytes
Skeletal abdomenc
Heightd
NA Normal Low Low Normal Borderline Low
NA Lowb Low Normal Normal Normal Low
NA 3rd p. 3rd p. 3rd p. 3rd p. 3rd p. 3rd p.
a Index case; bAlthough value was very low, this may represent developmental changes due to the patient’s age; cskeletal malformations included metaphyseal dysostosis of long bones and thoracic cage abnormalities; dpercentiles according to the Ramos-Galván growth chart for Mexican children.
12 h after admission. Autopsy findings are summarized in Table 1 (see also Figures 1–5). Findings in siblings. The patient’s siblings were studied in an attempt to diagnose SDS early, if any were affected. Because the family lives in a remote area that is difficult to reach, after obtaining signed consent the family members were brought to our institution on one occasion where examinations by a pediatric gastroenterologist, an orthopedist, and a geneticist were performed. At this initial visit, we obtained a whole blood sample for complete blood count determination and a serum sample for pancreatic cationic immunoreactive trypsin and isoamylase determinations. X-ray surveillance of skeletal malformations was also obtained. The family refused, however, to come back to our institution for further work-up, as this meant time lost from work. The family did agree to be visited by a phlebotomist on three more visits for a weekly complete blood count determination. Three of the six siblings had an abnormal serum trypsinogen result and one was borderline; two also had low serum isoamylase levels (Table 2). The remainder of the clinical and laboratory findings is also summarized in Table 2. Discussion The case described in this report with pancreatic exocrine insufficiency and with pancreatic endocrine sufficiency (2,5), with pancreatic lipomatosis (10), and the development of myeloid leukemia (11–13) strongly suggests the diagnosis of SDS. The lower-than-expected serum calcium level relative to serum albumin found at admission to our institution was probably due to electrolyte imbalances caused by the septic process. However, hypoparathyroidism cannot be ruled out because due to lack of time, a parathyroid hormone level was not obtained before death and thus the Pearson bone marrow pancreas syndrome cannot be excluded. This is, however, unlikely as no sideroblastic anemia or vacuolization of erythroid and myeloid precursors was ever found (14). Because the family members live in a remote area, we were able to perform only a limited work-up on the siblings. Three of the patient’s siblings had low levels of serum immunoreactive trypsin; two additionally had a low level of
serum immunoreactive isoamylase. It is uncommon to have exocrine pancreatic insufficiency secondary to malnutrition. In fact, the immunoreactive pancreatic cationic trypsinogen usually rises in acute and chronic malnutrition, as reported by Durie et al. and Cleghorn et al., a finding thought to be due to pancreatic acinar damage (15,16). An earlier report by Fedail et al., however, described very low levels of serum trypsinogen in chronic malnutrition (17). Measurement for height recorded in all siblings was less than the third percentile, according to the Ramos-Galván growth chart for Mexican children (18). Short stature is not likely due to malnutrition, as weight plotted vs. height was between the 25th and 50th percentiles in all siblings, suggesting a genetic rather than a nutritional basis. Thus, although the effect of chronic malnutrition cannot be completely ruled out, growth abnormalities (6) and pancreatic exocrine insufficiency are suggestive of SDS. The skeletal malformations observed may be found in SDS; however, unlike Mack et al. (7) we did not find hematologic abnormalities in the patient’s siblings. This may be due to a different phenotypic expression in this family, or more likely to the short follow-up time, as neutropenia is often cyclic. Unfortunately, the gene mutation(s) responsible for the development of this disease have not yet been identified; in this manner, the diagnosis of SDS is clinical, because it is not yet possible to confirm the diagnosis through genetic testing. Due to this and because of the limited work-up of family members, we can only conclude that the findings suggest SDS; nevertheless, we cannot be certain of the diagnosis at present. To the best of our knowledge, this is the first Mexican family reported in the literature with a probable diagnosis of SDS. Pediatricians, internists, and sub-specialists in Mexico need to be aware of this syndrome for early diagnosis and treatment. These findings suggest that the Shwachman-Diamond syndrome may be present in a subset of Mexican patients with maldigestion, growth abnormalities, and/or hematologic disturbances.
Acknowledgments The authors wish to thank Dr. Peter Durie and his staff at the Toronto Hospital for Sick Children for their help with the processing of pancreatic enzyme serum samples and their clinical expertise.
Belkind-Gerson et al. / Archives of Medical Research 32 (2001) 318–323
References 1. Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr 1964;65:645. 2. Durie PR. Inherited and congenital disorders of the exocrine pancreas. Gastroenterologist 1996;4(3):169. 3. Berrocal T, Simón MJ, al-Assir I, Prieto C, Pastor I, de Pablo L, Lama R. Shwachman-Diamond syndrome: clinical, radiological and sonographic findings. Pediatr Radiol 1995;25(5):356. 4. Durie PR. Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction. Med Clin North Am 2000;84(3):609 [ix.]. 5. Hill RE, Durie PR, Gaskin KJ, Davidson GP, Forstner GG. Steatorrhea and pancreatic insufficiency in Shwachman syndrome. Gastroenterology 1982;83(1 Pt 1):22. 6. Kornfeld SJ, Kratz J, Diamond F, Day NK, Good RA. Shwachman-Diamond syndrome associated with hypogammaglobulinemia and growth hormone deficiency. J Allergy Clin Immunol 1995;96(2):247. 7. Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology 1996;111(6):1593. 8. Ginzberg HJ, Shin J, Ellis S, Goobie J, Morrison M, Corey M, Durie PR, Rommens JM. Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance. Am J Hum Genet 2000;66(4):1413. 9. Ginzberg H, Shin J, Ellis L, Morrison J, Ip W, Dror Y, Freedman M, Heitlinger LA, Belt MA, Corey M, Rommens JM, Durie PR. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr 1999;135(1):81.
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