J Korean Med Sci.  2008 Feb;23(1):142-145. 10.3346/jkms.2008.23.1.142.

A Case of Shwachman-Diamond Syndrome Confirmed with Genetic Analysis in a Korean Child

• Lee JH
• Bae SH
• Yu JJ
• Lee R
• Yun YM
• Song EY

• KMID: 1786862
• DOI: http://doi.org/10.3346/jkms.2008.23.1.142

Abstract

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disorder, consisting of exocrine pancreatic insufficiency, chronic neutropenia, neutrophil chemotaxis defects, metaphyseal dysostosis, short stature, dental caries, and multiple organ involvements. Although SDS is the second most common hereditary abnormality of exocrine pancreas following cystic fibrosis in the Western countries, it has rarely been reported in Asia. We diagnosed a case of SDS in a 42-month-old girl, and genetic analysis including the relatives of the patient confirmed the diagnosis for the first time in Korea. She had short stature, steatorrhea, dental caries, and recurrent prulent otitis media and pneumonias. Laboratory studies revealed cyclic neutropenia, and serum levels of trypsin, amylase, and lipase were decreased. Simple radiography revealed metaphyseal sclerotic changes at the distal femur. A CT scan demonstrated a fatty infiltration and atrophy of the pancreas. On direct sequencing analysis of Shwachman-Bodian-Diamond Syndrome gene exon 2 region, the patient was homozygous for the c.258+2T>C mutation and heterozygous for the c.183_184TA>CT mutation and c.201A>G single nucleotide polymorphism. Treatment with pancreatic enzyme replacement, multivitamin supplementation, and regular to high fat diet improved her weight gain and steatorrhea.

Keyword

Shwachman-Diamond Syndrome; Mutation; Korea

MeSH Terms

Child, Preschool
Dental Caries/*genetics
Dysostoses/*genetics
Exocrine Pancreatic Insufficiency/*genetics
Female
Humans
*Mutation
Neutropenia/*genetics
Pedigree
Syndrome

Figure

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  Fig. 1 CT scanning shows low-attenuated pancreas, suggesting fatty infiltration.

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  Fig. 2 Mutations in SBDS causing SDS. (A) Map of SBDS (coding regions in light blue, non-coding regions in dark blue) and sequence alignment of the exon 2 region of SBDS and SBDSP, with genetic-specific (green) and pseudogene-specific (red) sequences indicated. The sequence differences in SBDSP present at position 141, 183, 201, 258+2, 258+124, and 258+126. (B) Electropherogram for direct sequencing from the exon 2 region of SBDS showed sequence changes (arrow) in proband with SDS that was derived from gene mutation (c.258+2T>C homozygous mutation). (C) On direct sequencing analysis of SBDS exon 2 region of the the patient's relatives revealed c.183_184TA>CT mutation and c.201A>G single nucleotide polymorphism (SNP) in addition to c.258+2T>C mutation.

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  Fig. 3 The pedigree of the family is shown with the proband affected with SDS indicated by black symbol. On direct sequencing analysis of SBDS exon 2 region, the proband were shown to be homozygous for the c.258+2T>C mutation and heterozygous for the c.183_184TA> CT mutation and c.201A>G single nucleotide polymorphism (SNP). Her father and paternal grandmother were heterozygous for the c.183_184TA>CT; 258+2T>C mutations and c.201A>G SNP. Her mother was heterozygous for the c.258+2T>C mutation. Her twin brothers, grandfather, and paternal aunt had no mutations in the exon 2 region of the SBDS gene. Numbers represent sequence of genomic DNA . Nt, nucleotide.

Reference

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

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

3. Aggett PJ, Cavanagh NP, Matthew DJ, Pincott JR, Sutcliffe J, Harries JT. Shwachman's syndrome: a review of 21 cases. Arch Dis Child. 1980. 55:331–347.

4. Kwak JW, Kim S, Lim YT. A case of Shwachman-Diamond syndrome. Korean J Pediatr. 2004. 47:900–903.

5. Park SY, Chae MB, Kwack YG, Lee MH, Kim IH, Kim YS, Kim CS. Allogenic bone marrow transplantation in Shwachman-Diamond syndrome with malignant myeloid transformation: a case report. Korean J Intern Med. 2002. 17:204–206.

6. Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003. 33:97–101.

7. Nicolis E, Bonizzato A, Assael BM, Cipolli M. Identification of novel mutations in patients with Shwachman-Diamond syndrome. Hum Mutat. 2005. 25:410–417.

8. Woods WG, Roloff JS, Lukens JN, Krivit W. The occurrence of leukemia in patients with the Shwachman syndrome. J Pediatr. 1981. 99:425–428.

9. Dror Y, Freedman MH. Shwachman-Diamond syndrome. Br J Haematol. 2002. 118:701–713.

10. Vibhakar R, Radhi M, Rumelhart S, Tatman D, Goldman F. Successful unrelated umbilical cord blood transplantation in children with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2005. 36:855–861.

11. Mitsui T, Kawakami T, Sendo D, Katsuura M, Shimizu Y, Hayasaka K. Successful unrelated donor bone marrow transplantation for Shwachman-Diamond syndrome with leukemia. Int J Hematol. 2004. 79:189–192.

12. Kawakami T, Mitsui T, Kanai M, Shirahata E, Sendo D, Kanno M, Noro M, Endoh M, Hama A, Tono C, Ito E, Tsuchiya S, Igarashi Y, Abukawa D, Hayasaka K. Genetic analysis of Shwachman-Diamond syndrome: phenotypic heterogeneity in patients carrying identical SBDS mutations. Tohoku J Exp Med. 2005. 206:253–259.

13. Nakashima E, Mabuchi A, Makita Y, Masuno M, Ohashi H, Nishimura G, Ikegawa S. Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome. Hum Genet. 2004. 114:345–348.