J Clin Immunol DOI 10.1007/s10875-014-9999-1
LETTER TO EDITOR
Dursun Syndrome Due to G6PC3 Gene Defect has a Fluctuating Pattern in All Blood Cell Lines Rıza Köksal Özgül & Didem Yücel-Yılmaz & Ali Dursun
Received: 28 October 2013 / Accepted: 12 February 2014 # Springer Science+Business Media New York 2014
To the Editor, Alangari et al. reported four patients with cyclic neutropenia (CyN) due to G6PC3 gene mutation (c.974 T>G, p.Leu325Arg). In the article, four patients presented clearly with CyN associated with thrombocytopenia [1]. They concluded that their cases were the first report of a homozygous mutation in G6PC3 resulting in a phenotype compatible with CyN in addition to the classical phenotype of Severe Congenital Neutropenia (SCN) [1]. We would like to draw attention to the gradually widening clinical spectrum and allelic heterogeneity due to G6PC3 gene defects. G6PC3 gene defect results in three major clinical spectra; Dursun syndrome (OMIM 613034 and 612541), syndromic severe congenital neutropenia 4 (SCN4), and nonsyndromic SCN4 [2–5]. Major findings of Dursun syndrome are primary pulmonary hypertension (PPH) developed in newborn period which is one of the most remarkable finding differentiating it from other types of SCN4, secundum type ASD, in addition to neutropenia, thrombocytopenia, anemia, monocytosis all of which show a fluctuating pattern, dysplasia in all cell lines in bone marrow, and hypoplasia of the thymus associated with severe lymphopenia. Minor findings of the syndrome are proximal localization of the first phalanx, completeincomplete simian line, broad nasal bridge, undescended testis, pectus carinatum and high palatal arch. The mutation in the original cases with Dursun syndrome was c.346A>G; p.Met116Val [3]. Until now, 57 cases due to G6PC3 deficiency have been reported and only two of them are siblings with Dursun syndrome. It seems that the similarities in CyN/SCN
and Dursun syndrome might be attributable to the G6PC3 mutations and the least partly, the differences can be explained by modifiers and residual enzyme activity. Recently two new patients with different sex were diagnosed in our department who mainly presented cyclic neutropenia and pulmonary hypertension developed in newborn period. These two patients also presented minor findings of Dursun syndrome such as proximal localization of thumb, simian line, broad nasal bridge, and undescended testis in the male patient. In these newly diagnosed patients, mutation screening for G6PC3 gene revealed two different homozygous mutations respectively, c.765_766delAG; p.Ala257fs [6] and c.175T>C; p.Trp59Arg (manuscript in preparation). In our original article [2], we especially emphasized cyclic pattern of neutropenia every one or two weeks. In addition, we would like to take attention that other blood cell lines including lymphocyte, monocyte, and thrombocyte have similar fluctuating pattern. The newest two patients with Dursun syndrome also clearly presented a fluctuating pattern in neutropenia similar to original cases every one or two weeks. In a conclusion, clinical symptoms in G6PC3 deficiency are gradually expanding, however, care should be taken when considering the “new” symptoms, whether they can be attributed to G6PC3 deficiency primarily or they simply appear secondary to complications of the disorder. In addition, we would like to stress that rare diseases such as Dursun syndrome are quite valuable to improve our understanding of disease mechanisms as well as interaction of different biochemical pathways.
R. K. Özgül Institute of Child Health, Metabolism Unit, Hacettepe University, Ankara, Turkey
References
R. K. Özgül : D. Yücel-Yılmaz : A. Dursun (*) Faculty of Medicine, Department of Pediatrics, Metabolism Unit, Hacettepe University, Sihhiye, 06100 Ankara, Turkey e-mail: [email protected]
1. Alangari AA, Alsultan A, Osman ME, Anazi S, Alkuraya FS. A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family. J Clin Immunol. 2013;33:1403–6.
J Clin Immunol 2. Dursun A, Ozgul RK, Soydas A, Tugrul T, Gurgey A, Celiker A. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement. Clin Dysmorphol. 2009;18(1):19–23. 3. Banka S, Newman WG, Ozgül RK, Dursun A. Mutations in the G6PC3 gene cause Dursun syndrome. Am J Med Genet A. 2010;152A(10):2609–11.
4. Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32–43. 5. Banka S, Wynn R, Byers H, Arkwright PD, Newman WG. G6PC3 mutations cause non-syndromic severe congenital neutropenia. Mol Genet Metab. 2013;108(2):138–41. 6. Dursun A, Yilmaz-Yucel D, Sagiroğlu MS, Erguner B, Smiths G, Vilain C, et al. JIMD. 2013;36(2):239. P-484.
LETTER TO EDITOR
Dursun Syndrome Due to G6PC3 Gene Defect has a Fluctuating Pattern in All Blood Cell Lines Rıza Köksal Özgül & Didem Yücel-Yılmaz & Ali Dursun
Received: 28 October 2013 / Accepted: 12 February 2014 # Springer Science+Business Media New York 2014
To the Editor, Alangari et al. reported four patients with cyclic neutropenia (CyN) due to G6PC3 gene mutation (c.974 T>G, p.Leu325Arg). In the article, four patients presented clearly with CyN associated with thrombocytopenia [1]. They concluded that their cases were the first report of a homozygous mutation in G6PC3 resulting in a phenotype compatible with CyN in addition to the classical phenotype of Severe Congenital Neutropenia (SCN) [1]. We would like to draw attention to the gradually widening clinical spectrum and allelic heterogeneity due to G6PC3 gene defects. G6PC3 gene defect results in three major clinical spectra; Dursun syndrome (OMIM 613034 and 612541), syndromic severe congenital neutropenia 4 (SCN4), and nonsyndromic SCN4 [2–5]. Major findings of Dursun syndrome are primary pulmonary hypertension (PPH) developed in newborn period which is one of the most remarkable finding differentiating it from other types of SCN4, secundum type ASD, in addition to neutropenia, thrombocytopenia, anemia, monocytosis all of which show a fluctuating pattern, dysplasia in all cell lines in bone marrow, and hypoplasia of the thymus associated with severe lymphopenia. Minor findings of the syndrome are proximal localization of the first phalanx, completeincomplete simian line, broad nasal bridge, undescended testis, pectus carinatum and high palatal arch. The mutation in the original cases with Dursun syndrome was c.346A>G; p.Met116Val [3]. Until now, 57 cases due to G6PC3 deficiency have been reported and only two of them are siblings with Dursun syndrome. It seems that the similarities in CyN/SCN
and Dursun syndrome might be attributable to the G6PC3 mutations and the least partly, the differences can be explained by modifiers and residual enzyme activity. Recently two new patients with different sex were diagnosed in our department who mainly presented cyclic neutropenia and pulmonary hypertension developed in newborn period. These two patients also presented minor findings of Dursun syndrome such as proximal localization of thumb, simian line, broad nasal bridge, and undescended testis in the male patient. In these newly diagnosed patients, mutation screening for G6PC3 gene revealed two different homozygous mutations respectively, c.765_766delAG; p.Ala257fs [6] and c.175T>C; p.Trp59Arg (manuscript in preparation). In our original article [2], we especially emphasized cyclic pattern of neutropenia every one or two weeks. In addition, we would like to take attention that other blood cell lines including lymphocyte, monocyte, and thrombocyte have similar fluctuating pattern. The newest two patients with Dursun syndrome also clearly presented a fluctuating pattern in neutropenia similar to original cases every one or two weeks. In a conclusion, clinical symptoms in G6PC3 deficiency are gradually expanding, however, care should be taken when considering the “new” symptoms, whether they can be attributed to G6PC3 deficiency primarily or they simply appear secondary to complications of the disorder. In addition, we would like to stress that rare diseases such as Dursun syndrome are quite valuable to improve our understanding of disease mechanisms as well as interaction of different biochemical pathways.
R. K. Özgül Institute of Child Health, Metabolism Unit, Hacettepe University, Ankara, Turkey
References
R. K. Özgül : D. Yücel-Yılmaz : A. Dursun (*) Faculty of Medicine, Department of Pediatrics, Metabolism Unit, Hacettepe University, Sihhiye, 06100 Ankara, Turkey e-mail: [email protected]
1. Alangari AA, Alsultan A, Osman ME, Anazi S, Alkuraya FS. A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family. J Clin Immunol. 2013;33:1403–6.
J Clin Immunol 2. Dursun A, Ozgul RK, Soydas A, Tugrul T, Gurgey A, Celiker A. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement. Clin Dysmorphol. 2009;18(1):19–23. 3. Banka S, Newman WG, Ozgül RK, Dursun A. Mutations in the G6PC3 gene cause Dursun syndrome. Am J Med Genet A. 2010;152A(10):2609–11.
4. Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32–43. 5. Banka S, Wynn R, Byers H, Arkwright PD, Newman WG. G6PC3 mutations cause non-syndromic severe congenital neutropenia. Mol Genet Metab. 2013;108(2):138–41. 6. Dursun A, Yilmaz-Yucel D, Sagiroğlu MS, Erguner B, Smiths G, Vilain C, et al. JIMD. 2013;36(2):239. P-484.
