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A case showing an association between type 1 diabetes mellitus and Kabuki syndrome
Diabetes Research and Clinical Practice 60 (2003) 25 /31 www.elsevier.com/locate/diabres
A case showing an association between type 1 diabetes mellitus and Kabuki syndrome Midori Fujishiro a, Takehide Ogihara a, Katsunori Tsukuda a, Nobuhiro Shojima a, Yasushi Fukushima a, Satoshi Kimura a, Yoshitomo Oka b, Tomoichiro Asano a,* a
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan b Department of Internal Medicine, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai 980-8574, Japan Received 24 May 2002; received in revised form 5 November 2002; accepted 18 November 2002
Abstract The case of a 31-year-old female suffering from type 1 diabetes mellitus (DM) and Kabuki syndrome is presented. The patient was diagnosed as having impaired glucose tolerance (IGT) at age 18; secondary amenorrhea occurred at age 20, following acute body weight loss. Extensive examination revealed the patient to have a slowly progressive form of type 1 DM and, based on the physical findings, including her facial features, she was diagnosed as also having congenital Kabuki syndrome. Since then, this patient has experienced several episodes of diabetic ketoacidosis, all of which were brought about by prolonged bronchial infection. Although it is perhaps reasonable at present to consider this case to represent a chance association, further clinical investigations will be carried out to clarify whether or not Kabuki syndrome and type 1 DM have any common pathogenic features. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Type 1 diabetes; Kabuki syndrome; Immunodeficiency; Autoimmune diseases; Congenital diseases
1. Introduction First described by Niikawa [1] and Kuroki [2] in 1981, Kabuki syndrome is a congenital disorder that, in some cases, is associated with the chromosomal abnormalities, ring chromosome X and * Corresponding author. Tel.: /81-3-3815-5411x33133; fax: /81-3-5803-1874 E-mail address: [email protected] (T. Asano).
paracentric inversion of 4p (46XX inv(4)/p12pten) [3 /5]. Its clinical features include moderate to severe mental retardation, postnatal growth retardation, unusual facial features, fingertip pads and minor skeletal, dermatoglyphic, urogenital and cardiac abnormalities [3]. Typical facial anomalies involve arched eyebrows with sparse or dispersed lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes and large, prominent ears. To date, more than 90 Japanese
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and 90 non-Japanese individuals have been reported with this syndrome [6 /9]. On the other hand, type 1 diabetes mellitus (DM) is a metabolic disorder characterized by diminished insulin production caused by the destruction of pancreatic b cells [10,11]. In most cases, an abnormal immunoresponse is involved in the pathogenesis of type 1 DM and autoimmune antibodies are often detectable. Recently, several congenital diseases were identified as being associated with the occurrence of DM [12], including Down’s syndrome [13] and Wolframs syndrome [14]. In this report, we introduce a patient with Kabuki syndrome who developed type 1 DM and we discuss the possibility of an association between Kabuki syndrome and type 1 DM.
2. Case report The patient was the second child of nonconsanguineous Japanese parents, delivered at a birth weight of 2.7 kg following an uneventful 38week pregnancy. Her parents and brothers were all healthy, of normal height and exhibited no anomalies. When she was 5 months of age, it was noted that the patient had both mental and growth retardation. In 1984 (age 15), she began regular menstruation. In 1987 (age 18), urinary glucose was 3/ and a 75-g oral glucose tolerance test (OGTT) revealed impaired glucose tolerance (IGT). In 1989 (age 20), the patient experienced a significant loss of weight (10 kg in 1 year) together with amenorrhea, but no symptoms of infection and was hospitalized for further examination. At that time, her height was 139 cm, her weight was 32 kg (BMI /16.6 kg/m2) and it was noted that she had arched eyebrows with sparse lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes, large and prominent ears, a low posterior hair line (Fig. 1) and mild lumber scoliosis. Her fingers were stubby with clinodactyly of the bilateral fifth fingers (Fig. 2) and the second toes were bilaterally hypoplastic. Fingertip pads were found on all fingers. Her intelligence quotient was estimated to be 48. She had no pneumonia, otitis media or urinary tract infections.
Laboratory studies showed the patient’s casual serum glucose to be 400 mg/dl, serum C-peptide immunoreactivity was 1.3 ng/ml, urinary C-peptide was 20 mg per day and she was positive for islet cell autoantibodies (ICA). As soon as type 1 DM was diagnosed, insulin therapy (28 U per day) was started. Additional analyses revealed mild anemia (Hb, 10.3 g/dl), moderate liver dysfunction (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and g-glutamyl transpeptidase (g-GTP) were 37, 117, 237 and 62 IU/l, respectively), a somewhat low serum IgA level (57 g/dl) and that the patient was positive for anti-nucleic antibody (speckled pattern 40 times). An LH /RH test suggested slight hypothalamic pituitary dysfunction (maximum LH was 15 mIU/ml). Hormone replacement treatment, i.e. Holmstrom therapy (dydrogesterone, 10 mg per day for 7 days starting on day 21 of the menstrual cycle) was initiated and effective. Other laboratory data are shown in Tables 1 /3. A liver biopsy was nearly normal. Roentgenograms showed mild lumbar scoliosis. Abdominal computed tomography showed a horseshoe kidney. Ultrasound cardiography showed no heart abnormalities and G-banding analysis of the karyotypes of cultured peripheral blood lymphocytes also showed no abnormalities. Despite frequent infusions of rapid insulin combined with NPH insulin, the patient’s diabetes has not been well controlled (HbA1c was currently at :/9%). At age 27, she contracted a common cold that resulted in her developing bronchitis. When admitted to the hospital because of drowsiness, she was diagnosed as having diabetic ketoacidosis based on the following parameters: serum glucose 600 mg/dl, urinary ketotic body 3/, pH 7.160, PO2 135 mEq/l, PCO2 9.2 mEq/l, HCO3 3.3 mEq/l and O2Sat 98%. Given hydration and intensive insulin therapy, her condition improved within a few days. In 1998, the patient was determined to be positive for anti-glutamic acid decarboxylase (GAD65) antibody (49,700 U/ml; normal range B/1.4 by RIA) and her ability to secrete insulin has steadily declined by 2000, serum C-peptide was 0.1 ng/ml and urinary C-peptide was 0.2 mg per day. She experienced similar episodes of diabetic ketoacidosis induced by bron-
M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
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Fig. 1. The patient exhibited the typical facial abnormalities of Kabuki syndrome: arched eyebrows with sparse lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes and large, prominent ears.
chitis at ages 29, 30 and 31 (in 1998, 1999 and 2000, respectively).
3. Discussion
Fig. 2. Right hand of this patient shows the short, stubby, inwardly curved fifth fingers frequently seen in patients with Kabuki syndrome.
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. The vast majority of diabetes cases fall into two broad etiopathogenetic categories termed ‘type 1’ and ‘type 2’ [12]. In type 1 DM, the cause is an absolute deficiency of insulin secretion, usually resulting from cell-mediated autoimmune destruction of the b-cells of the pancreas. This autoimmune response is often indicated by the presence of ICA, autoantibodies to insulin (IAAs) and/or autoantibodies to GAD65. In addition, this disease has strong human leukocyte antigen (HLA) associations, with linkage to specific HLA-DR/DQ alleles. Still, some forms of type 1 DM have unknown etiologies with no associations with HLAs, and in some cases, infection with certain viruses, including Coxsackie-virus B [15 / 18], cytomegalovirus [19 /21], adenovirus [18,22]
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Table 1 Clinical data at admission in 1989
Table 2 Immunological examination
CBC WBC RBC Hb Ht Plt
Serum IgA 57 g/dl IgG 1171 g/dl IgM 296 g/dl CH50 49 U/ml C3 61 mg/dl C4 28 mg/dl Anti nucleic antibody Speckled type; 40 times Islet cell autoantibodies Positive (ICA) Anti dsDNA antibody Negative Anti ssDNA Negative Anti SS-A antibody Negative Anti SS-B antibody Negative Anti Scl 70 antibody Negative Rheumatoid factor Negative Anti cardiolipin antibody Negative Anti mitochondrial antibody Negative Anti TSH receptor antibody Negative Coombs tests Negative Anti HCV antibody Negative Anti HBs antigen Negative Anti Hepes Zoster virus Less than four times antibody (CF) Anti Cytomegalovirus antiLess than four times body (CF) Anti Rubella virus antibody 16 times (HI) Anti Coxsackie-virus B 1-6 All of them less than four times (CF) VCA-IgG 160 times VCA-IgM Less than ten times Anti early antigen-IgG Less than ten times Anti EBNA antibody Less than ten times
Biochemistry TP Alb T-Bil AST ALT LDH CPK ALP g-GTP LAP ChE Amy TTT ZTT BUN Cre UA Na K Cl Ca P T-Cho TG Glucose HbA1c Blood gas analysis (room air) pH PO2 PCO2 HCO3 BE Urinalysis Gravity pH Protein Sugar Ketone body ESR CRP
3800/ml 474 /104/ml 10.3 g/dl 33.4% 22.9 /104/ml 6.5 g/dl 3.8 g/dl 0.3 g/dl 37 IU/l 117 IU/l 119 IU/l 29 IU/l 237 IU/l 62 IU/l 60 IU/l 538 IU/l 103 mg/dl 0.8 U 2.2 U 16 mg/dl 0.4 mg/dl 2.7 mg/dl 140 mEq/l 3.5 mEq/l 100 mEq/l 8.3 mg/dl 3.0 mg/dl 100 mg/dl 74 mg/dl 237 mg/dl 15.1%
HLA typing 7.363 106.2 mmHg 30.3 mmHg 17.0 mmol/l /7.2 1.030 7.0 85 mg/day 113.8 g/day / 17 mm/h 0.3 mg/dl
A2, A26(10) B60(40), B62(15) CW3 DR4, DR12(5)
Table 3 Endocrinological examination TSH Free T4 Growth hormone Cortisol Somatomedin C FSH LH PRL Estradiol
2.7 mU/ml 0.9 ng/dl 2.8 ng/ml 52 mg/dl 22 ng/ml 7.7 mIU/ml 1.7 mIU/ml 2.0 ng/ml 0.8 pg/ml
M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
and mumps [23,24], has been implicated in its pathogenesis. On the other hand, a diagnosis of Kabuki syndrome is made on the basis of mental retardation, developmental delay and characteristic facial and skeletal abnormalities [3]. The incidence of Kabuki syndrome among Japanese newborns is estimated to be 1 in 32,000 and no consistent causal factors have yet been identified. With the exception of five families in which it runs as an autosomal dominant trait [25 /28], the reported cases of Kabuki syndrome have been sporadic. Furthermore, although chromosomal abnormalities are reportedly associated with Kabuki syndrome in some cases [3 /5], no such chromosomal abnormality was seen in our case. As this is the first report, to our knowledge, of an association between Kabuki syndrome and type 1 DM, it is reasonable to consider this case to represent a chance association. In addition, the fact that this patient has HLA-DR4, one of the susceptible DR allele in Japanese type 1 DM, may support an occurrence of type 1 DM independent from that of Kabuki syndrome. On the other hand, if we assume that a common pathogenesis is present in the co-occurrence of type 1 DM and Kabuki syndrome, two possible mechanisms can be considered. The first involves the increased susceptibility to infection seen in Kabuki syndrome patients [3,29]. Indeed, recurrent otitis media and frequent upper respiratory infections are often reported in patients with Kabuki syndrome; in our case, prolonged bronchial infection preceded the patient’s diabetic ketoacidosis on all occasions. It is unclear whether structural anomalies of organs or immune dysfunction is involved in the increased susceptibility to infection. On the other hand, as mentioned above, infection with some viruses can induce or at least trigger type 1 DM. Such viruses might therefore be the link between Kabuki syndrome and the occurrence of type 1 DM. However, our case had no apparent evidence of viral infections as a trigger of type 1 DM, which indicates lack of a viral infectionmediated association between these two diseases. Furthermore, since there is little evidence indicating that immunodeficient subjects tend to develop type 1 DM, this possibility may be rather unlikely.
29
Alternatively, we can speculate that selective IgA deficiency [30 /32], one of the immunological manifestations of Kabuki syndrome [3], could be related to the occurrence of type 1 DM. Indeed, it has been reported that subjects with IgA deficiency have a significantly higher frequency of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatic arthritis and type 1 DM [33 / 39]. HLA-DQB1 alleles encoding non-Asp residues at position 57 are associated with susceptibility to both type 1 DM and selective IgA deficiency, providing a possible basis for increased co-occurrence of the two diseases [32,34,35,40 /43]. Although DQB1 genotype in our patient has not been typed, her serum IgA was somewhat low. In this regard, IgA deficiency may be one of the factors connecting Kabuki syndrome and type 1 DM. The second possibility involves autoimmune diseases themselves actually contributing to a link between Kabuki syndrome and type 1 DM. Certain autoimmune diseases, such as Hashimoto disease, a form of autoimmune thyroiditis [44], idiopathic thrombocytopenic purpura [45] and autoimmune hemolytic anemia [9], have been reported to be co-exist with Kabuki syndrome, though the frequency of autoimmune diseases being associated with Kabuki syndrome is not particularly high. Taken these observations together, it is difficult to identify the background factor(s) possibly contributing to the association between Kabuki syndrome and type 1 DM and at present, we must consider our case as perhaps representing a chance association. However, we cannot rule out the possibility that type 1 DM is an autoimmune disease that tends to co-occur with Kabuki syndrome. Thus, we advocate further clinical investigations regarding the coexistence of autoimmune diseases, including type 1 DM, with Kabuki syndrome.
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[17] A.B. Jenson, H.S. Rosenberg, A.L. Notkins, Pancreatic islet-cell damage in children with fatal viral infections, Lancet 2 (1980) 354 /358. [18] D.B. Jones, I. Crosby, Proliferative lymphocyte responses to virus antigens homologous to GAD65 in IDDM, Diabetologia 39 (1996) 1318 /1324. [19] K.P. Ward, W.H. Galloway, I.A. Auchterlonie, Congenital cytomegalovirus infection and diabetes, Lancet 1 (1979) 497. [20] C.Y. Pak, H.M. Eun, R.G. McArthur, J.W. Yoon, Association of cytomegalovirus infection with autoimmune type 1 diabetes, Lancet 2 (1988) 1 /4. [21] N. Yasumoto, M. Hara, Y. Kitamoto, M. Nakayama, T. Sato, Cytomegalovirus infection associated with acute pancreatitis, rhabdomyolysis and renal failure, Intern. Med. 31 (1992) 426 /430. [22] H.M. Surcel, J. Ilonen, M.L. Kaar, H. Hyoty, P. Leinikki, Infection by multiple viruses and lymphocyte abnormalities at the diagnosis of diabetes, Acta Paediatr. Scand. 77 (1988) 471 /474. [23] K. Helmke, A. Otten, W. Willems, Islet cell antibodies in children with mumps infection, Lancet 2 (1980) 211 /212. [24] D.R. Gamble, Relation of antecedent illness to development of diabetes in children, Br. Med. J. 281 (1980) 99 / 101. [25] F. Halal, R. Gledhill, A. Dudkiewicz, Autosomal dominant inheritance of the Kabuki make-up (Niikawa-Kuroki) syndrome, Am. J. Med. Genet. 33 (1989) 376 /381. [26] O. Kobayashi, N. Sakuragawa, Inheritance in Kabuki make-up (Niikawa-Kuroki) syndrome, Am. J. Med. Genet. 61 (1996) 92 /93. [27] M. Silengo, M. Lerone, M. Seri, G. Romeo, Inheritance of Niikawa-Kuroki (Kabuki makeup) syndrome, Am. J. Med. Genet. 66 (1996) 368. [28] M. Tsukahara, Y. Kuroki, K. Imaizumi, Y. Miyazawa, K. Matsuo, Dominant inheritance of Kabuki make-up syndrome, Am. J. Med. Genet. 73 (1997) 19 /23. [29] K.H. Chrzanowska, M. Krajewska-Walasek, J. Kus, et al., Kabuki (Niikawa-Kuroki) syndrome associated with immunodeficiency, Clin. Genet. 53 (1998) 308 /312. [30] A.J. Burks, R.W. Steele, Selective IgA deficiency, Ann. Allergy 57 (1986) 3 /13. [31] M. Fiore, C. Pera, L. Delfino, I. Scotese, G.B. Ferrara, C. Pignata, DNA typing of DQ and DR alleles in IgAdeficient subjects, Eur. J. Immunogenet. 22 (1995) 403 / 411. [32] O. Olerup, C.I. Smith, L. Hammarstrom, Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency, Nature 347 (1990) 289 /290. [33] R.S. Liblau, S. Caillat-Zucman, A.M. Fischer, J.F. Bach, C. Boitard, The prevalence of selective IgA deficiency in type 1 diabetes mellitus, APMIS 100 (1992) 709 /712. [34] W.J. Smith, B.S. Rabin, A. Huellmantel, D.H. Van Thiel, A. Drash, Immunopathology of juvenile-onset diabetes mellitus. I. IgA deficiency and juvenile diabetes, Diabetes 27 (1978) 1092 /1097.
M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31 [35] S. Hoddinott, J. Dornan, J.C. Bear, N.R. Farid, Immunoglobulin levels, immunodeficiency and HLA in type 1 (insulin-dependent) diabetes mellitus, Diabetologia 23 (1982) 326 /329. [36] M. Ambrus, E. Hernadi, G. Bajtai, Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency, Clin. Immunol. Immunopathol. 7 (1977) 311 /314. [37] F. Perez-Jimenez, P.B. Lopez, E.P. Tallo, J.R. Guzman, J.S. Molina, J.A. Pereperez, Selective IgA deficiency and the HLA-B8 antigen. Report of two cases with familial data, Arch. Intern. Med. 141 (1981) 509 /510. [38] D.H. Van Thiel, W.I. Smith, Jr, B.S. Rabin, S.E. Fisher, R. Lester, A syndrome of immunoglobulin A deficiency, diabetes mellitus, malabsorption, a common HLA haplotype. Immunologic and genetic studies of forty-three family members, Ann. Intern. Med. 86 (1977) 10 /19. [39] G.A. Hagen, R.M. Bolman, III, J.P. Frank, Atypical adrenal insufficiency with failure of the pituitary feedback receptor. A case with associated diabetes mellitus and selective IgA deficiency with steatorrhea, Am. J. Med. 59 (1975) 882 /888.
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[40] J.A. Todd, J.I. Bell, H.O. McDevitt, HLA-DQ beta gene contributes to susceptibility and resistance to insulindependent diabetes mellitus, Nature 329 (1987) 599 /604. [41] J.A. Todd, Genetic control of autoimmunity in type 1 diabetes, Immunol. Today 11 (1990) 122 /129. [42] G.T. Horn, T.L. Bugawan, C.M. Long, H.A. Erlich, Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility, Proc. Natl. Acad. Sci. USA 85 (1988) 6012 /6016. [43] K.S. Ronningen, T. Iwe, T.S. Halstensen, A. Spurkland, E. Thorsby, The amino acid at position 57 of the HLA-DQ beta chain and susceptibility to develop insulin-dependent diabetes mellitus, Hum. Immunol. 26 (1989) 215 /225. [44] A. Ewart-Toland, G.M. Enns, V.A. Cox, G.C. Mohan, P. Rosenthal, M. Golabi, Severe congenital anomalies requiring transplantation in children with Kabuki syndrome, Am. J. Med. Genet. 80 (1998) 362 /367. [45] T. Watanabe, M. Miyakawa, M. Satoh, T. Abe, Y. Oda, Kabuki make-up syndrome associated with chronic idiopathic thrombocytopenic purpura, Acta Paediatr. Jpn. 36 (1994) 727 /729.
A case showing an association between type 1 diabetes mellitus and Kabuki syndrome Midori Fujishiro a, Takehide Ogihara a, Katsunori Tsukuda a, Nobuhiro Shojima a, Yasushi Fukushima a, Satoshi Kimura a, Yoshitomo Oka b, Tomoichiro Asano a,* a
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan b Department of Internal Medicine, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai 980-8574, Japan Received 24 May 2002; received in revised form 5 November 2002; accepted 18 November 2002
Abstract The case of a 31-year-old female suffering from type 1 diabetes mellitus (DM) and Kabuki syndrome is presented. The patient was diagnosed as having impaired glucose tolerance (IGT) at age 18; secondary amenorrhea occurred at age 20, following acute body weight loss. Extensive examination revealed the patient to have a slowly progressive form of type 1 DM and, based on the physical findings, including her facial features, she was diagnosed as also having congenital Kabuki syndrome. Since then, this patient has experienced several episodes of diabetic ketoacidosis, all of which were brought about by prolonged bronchial infection. Although it is perhaps reasonable at present to consider this case to represent a chance association, further clinical investigations will be carried out to clarify whether or not Kabuki syndrome and type 1 DM have any common pathogenic features. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Type 1 diabetes; Kabuki syndrome; Immunodeficiency; Autoimmune diseases; Congenital diseases
1. Introduction First described by Niikawa [1] and Kuroki [2] in 1981, Kabuki syndrome is a congenital disorder that, in some cases, is associated with the chromosomal abnormalities, ring chromosome X and * Corresponding author. Tel.: /81-3-3815-5411x33133; fax: /81-3-5803-1874 E-mail address: [email protected] (T. Asano).
paracentric inversion of 4p (46XX inv(4)/p12pten) [3 /5]. Its clinical features include moderate to severe mental retardation, postnatal growth retardation, unusual facial features, fingertip pads and minor skeletal, dermatoglyphic, urogenital and cardiac abnormalities [3]. Typical facial anomalies involve arched eyebrows with sparse or dispersed lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes and large, prominent ears. To date, more than 90 Japanese
0168-8227/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 2 ) 0 0 2 7 6 - 0
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M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
and 90 non-Japanese individuals have been reported with this syndrome [6 /9]. On the other hand, type 1 diabetes mellitus (DM) is a metabolic disorder characterized by diminished insulin production caused by the destruction of pancreatic b cells [10,11]. In most cases, an abnormal immunoresponse is involved in the pathogenesis of type 1 DM and autoimmune antibodies are often detectable. Recently, several congenital diseases were identified as being associated with the occurrence of DM [12], including Down’s syndrome [13] and Wolframs syndrome [14]. In this report, we introduce a patient with Kabuki syndrome who developed type 1 DM and we discuss the possibility of an association between Kabuki syndrome and type 1 DM.
2. Case report The patient was the second child of nonconsanguineous Japanese parents, delivered at a birth weight of 2.7 kg following an uneventful 38week pregnancy. Her parents and brothers were all healthy, of normal height and exhibited no anomalies. When she was 5 months of age, it was noted that the patient had both mental and growth retardation. In 1984 (age 15), she began regular menstruation. In 1987 (age 18), urinary glucose was 3/ and a 75-g oral glucose tolerance test (OGTT) revealed impaired glucose tolerance (IGT). In 1989 (age 20), the patient experienced a significant loss of weight (10 kg in 1 year) together with amenorrhea, but no symptoms of infection and was hospitalized for further examination. At that time, her height was 139 cm, her weight was 32 kg (BMI /16.6 kg/m2) and it was noted that she had arched eyebrows with sparse lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes, large and prominent ears, a low posterior hair line (Fig. 1) and mild lumber scoliosis. Her fingers were stubby with clinodactyly of the bilateral fifth fingers (Fig. 2) and the second toes were bilaterally hypoplastic. Fingertip pads were found on all fingers. Her intelligence quotient was estimated to be 48. She had no pneumonia, otitis media or urinary tract infections.
Laboratory studies showed the patient’s casual serum glucose to be 400 mg/dl, serum C-peptide immunoreactivity was 1.3 ng/ml, urinary C-peptide was 20 mg per day and she was positive for islet cell autoantibodies (ICA). As soon as type 1 DM was diagnosed, insulin therapy (28 U per day) was started. Additional analyses revealed mild anemia (Hb, 10.3 g/dl), moderate liver dysfunction (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and g-glutamyl transpeptidase (g-GTP) were 37, 117, 237 and 62 IU/l, respectively), a somewhat low serum IgA level (57 g/dl) and that the patient was positive for anti-nucleic antibody (speckled pattern 40 times). An LH /RH test suggested slight hypothalamic pituitary dysfunction (maximum LH was 15 mIU/ml). Hormone replacement treatment, i.e. Holmstrom therapy (dydrogesterone, 10 mg per day for 7 days starting on day 21 of the menstrual cycle) was initiated and effective. Other laboratory data are shown in Tables 1 /3. A liver biopsy was nearly normal. Roentgenograms showed mild lumbar scoliosis. Abdominal computed tomography showed a horseshoe kidney. Ultrasound cardiography showed no heart abnormalities and G-banding analysis of the karyotypes of cultured peripheral blood lymphocytes also showed no abnormalities. Despite frequent infusions of rapid insulin combined with NPH insulin, the patient’s diabetes has not been well controlled (HbA1c was currently at :/9%). At age 27, she contracted a common cold that resulted in her developing bronchitis. When admitted to the hospital because of drowsiness, she was diagnosed as having diabetic ketoacidosis based on the following parameters: serum glucose 600 mg/dl, urinary ketotic body 3/, pH 7.160, PO2 135 mEq/l, PCO2 9.2 mEq/l, HCO3 3.3 mEq/l and O2Sat 98%. Given hydration and intensive insulin therapy, her condition improved within a few days. In 1998, the patient was determined to be positive for anti-glutamic acid decarboxylase (GAD65) antibody (49,700 U/ml; normal range B/1.4 by RIA) and her ability to secrete insulin has steadily declined by 2000, serum C-peptide was 0.1 ng/ml and urinary C-peptide was 0.2 mg per day. She experienced similar episodes of diabetic ketoacidosis induced by bron-
M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
27
Fig. 1. The patient exhibited the typical facial abnormalities of Kabuki syndrome: arched eyebrows with sparse lateral halves, long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes and large, prominent ears.
chitis at ages 29, 30 and 31 (in 1998, 1999 and 2000, respectively).
3. Discussion
Fig. 2. Right hand of this patient shows the short, stubby, inwardly curved fifth fingers frequently seen in patients with Kabuki syndrome.
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. The vast majority of diabetes cases fall into two broad etiopathogenetic categories termed ‘type 1’ and ‘type 2’ [12]. In type 1 DM, the cause is an absolute deficiency of insulin secretion, usually resulting from cell-mediated autoimmune destruction of the b-cells of the pancreas. This autoimmune response is often indicated by the presence of ICA, autoantibodies to insulin (IAAs) and/or autoantibodies to GAD65. In addition, this disease has strong human leukocyte antigen (HLA) associations, with linkage to specific HLA-DR/DQ alleles. Still, some forms of type 1 DM have unknown etiologies with no associations with HLAs, and in some cases, infection with certain viruses, including Coxsackie-virus B [15 / 18], cytomegalovirus [19 /21], adenovirus [18,22]
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M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
Table 1 Clinical data at admission in 1989
Table 2 Immunological examination
CBC WBC RBC Hb Ht Plt
Serum IgA 57 g/dl IgG 1171 g/dl IgM 296 g/dl CH50 49 U/ml C3 61 mg/dl C4 28 mg/dl Anti nucleic antibody Speckled type; 40 times Islet cell autoantibodies Positive (ICA) Anti dsDNA antibody Negative Anti ssDNA Negative Anti SS-A antibody Negative Anti SS-B antibody Negative Anti Scl 70 antibody Negative Rheumatoid factor Negative Anti cardiolipin antibody Negative Anti mitochondrial antibody Negative Anti TSH receptor antibody Negative Coombs tests Negative Anti HCV antibody Negative Anti HBs antigen Negative Anti Hepes Zoster virus Less than four times antibody (CF) Anti Cytomegalovirus antiLess than four times body (CF) Anti Rubella virus antibody 16 times (HI) Anti Coxsackie-virus B 1-6 All of them less than four times (CF) VCA-IgG 160 times VCA-IgM Less than ten times Anti early antigen-IgG Less than ten times Anti EBNA antibody Less than ten times
Biochemistry TP Alb T-Bil AST ALT LDH CPK ALP g-GTP LAP ChE Amy TTT ZTT BUN Cre UA Na K Cl Ca P T-Cho TG Glucose HbA1c Blood gas analysis (room air) pH PO2 PCO2 HCO3 BE Urinalysis Gravity pH Protein Sugar Ketone body ESR CRP
3800/ml 474 /104/ml 10.3 g/dl 33.4% 22.9 /104/ml 6.5 g/dl 3.8 g/dl 0.3 g/dl 37 IU/l 117 IU/l 119 IU/l 29 IU/l 237 IU/l 62 IU/l 60 IU/l 538 IU/l 103 mg/dl 0.8 U 2.2 U 16 mg/dl 0.4 mg/dl 2.7 mg/dl 140 mEq/l 3.5 mEq/l 100 mEq/l 8.3 mg/dl 3.0 mg/dl 100 mg/dl 74 mg/dl 237 mg/dl 15.1%
HLA typing 7.363 106.2 mmHg 30.3 mmHg 17.0 mmol/l /7.2 1.030 7.0 85 mg/day 113.8 g/day / 17 mm/h 0.3 mg/dl
A2, A26(10) B60(40), B62(15) CW3 DR4, DR12(5)
Table 3 Endocrinological examination TSH Free T4 Growth hormone Cortisol Somatomedin C FSH LH PRL Estradiol
2.7 mU/ml 0.9 ng/dl 2.8 ng/ml 52 mg/dl 22 ng/ml 7.7 mIU/ml 1.7 mIU/ml 2.0 ng/ml 0.8 pg/ml
M. Fujishiro et al. / Diabetes Research and Clinical Practice 60 (2003) 25 /31
and mumps [23,24], has been implicated in its pathogenesis. On the other hand, a diagnosis of Kabuki syndrome is made on the basis of mental retardation, developmental delay and characteristic facial and skeletal abnormalities [3]. The incidence of Kabuki syndrome among Japanese newborns is estimated to be 1 in 32,000 and no consistent causal factors have yet been identified. With the exception of five families in which it runs as an autosomal dominant trait [25 /28], the reported cases of Kabuki syndrome have been sporadic. Furthermore, although chromosomal abnormalities are reportedly associated with Kabuki syndrome in some cases [3 /5], no such chromosomal abnormality was seen in our case. As this is the first report, to our knowledge, of an association between Kabuki syndrome and type 1 DM, it is reasonable to consider this case to represent a chance association. In addition, the fact that this patient has HLA-DR4, one of the susceptible DR allele in Japanese type 1 DM, may support an occurrence of type 1 DM independent from that of Kabuki syndrome. On the other hand, if we assume that a common pathogenesis is present in the co-occurrence of type 1 DM and Kabuki syndrome, two possible mechanisms can be considered. The first involves the increased susceptibility to infection seen in Kabuki syndrome patients [3,29]. Indeed, recurrent otitis media and frequent upper respiratory infections are often reported in patients with Kabuki syndrome; in our case, prolonged bronchial infection preceded the patient’s diabetic ketoacidosis on all occasions. It is unclear whether structural anomalies of organs or immune dysfunction is involved in the increased susceptibility to infection. On the other hand, as mentioned above, infection with some viruses can induce or at least trigger type 1 DM. Such viruses might therefore be the link between Kabuki syndrome and the occurrence of type 1 DM. However, our case had no apparent evidence of viral infections as a trigger of type 1 DM, which indicates lack of a viral infectionmediated association between these two diseases. Furthermore, since there is little evidence indicating that immunodeficient subjects tend to develop type 1 DM, this possibility may be rather unlikely.
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Alternatively, we can speculate that selective IgA deficiency [30 /32], one of the immunological manifestations of Kabuki syndrome [3], could be related to the occurrence of type 1 DM. Indeed, it has been reported that subjects with IgA deficiency have a significantly higher frequency of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatic arthritis and type 1 DM [33 / 39]. HLA-DQB1 alleles encoding non-Asp residues at position 57 are associated with susceptibility to both type 1 DM and selective IgA deficiency, providing a possible basis for increased co-occurrence of the two diseases [32,34,35,40 /43]. Although DQB1 genotype in our patient has not been typed, her serum IgA was somewhat low. In this regard, IgA deficiency may be one of the factors connecting Kabuki syndrome and type 1 DM. The second possibility involves autoimmune diseases themselves actually contributing to a link between Kabuki syndrome and type 1 DM. Certain autoimmune diseases, such as Hashimoto disease, a form of autoimmune thyroiditis [44], idiopathic thrombocytopenic purpura [45] and autoimmune hemolytic anemia [9], have been reported to be co-exist with Kabuki syndrome, though the frequency of autoimmune diseases being associated with Kabuki syndrome is not particularly high. Taken these observations together, it is difficult to identify the background factor(s) possibly contributing to the association between Kabuki syndrome and type 1 DM and at present, we must consider our case as perhaps representing a chance association. However, we cannot rule out the possibility that type 1 DM is an autoimmune disease that tends to co-occur with Kabuki syndrome. Thus, we advocate further clinical investigations regarding the coexistence of autoimmune diseases, including type 1 DM, with Kabuki syndrome.
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