A Syndrome with Congenital Neutropenia and Mutations in<i>G6PC3</i>

Boztuğ, Kaan; Appaswamy, Giridharan; Ashikov, Angel; Schäffer, Alejandro A.; Salzer, Ulrich; Diestelhorst, Jana; Germeshausen, Manuela; Brandes, Gudrun; Lee-Gossler, Jacqueline; Noyan, Fatih; Gatzke, Anna-Katherina; Minkov, Milen; Greil, Johann; Kratz, Christian P.; Petropoulou, Theoni; Pellier, Isabelle; Bellanné‐Chantelot, Christine; Rezaei, Nima; Mönkemöller, Kirsten; Irani-Hakimeh, Noha; Bakker, Hans; Gerardy‐Schahn, Rita; Zeidler, Cornelia; Grimbacher, Bodo; Welte, Karl; Klein, Christoph

doi:10.1056/nejmoa0805051

Cited by 330 publications

(394 citation statements)

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“…Cryptorchidism, micropenis, and ambiguous genitalia, as detected in our patient, are common features in patients with G6PC3 mutations, documented in up to 44% of patients, and were considered as structural urogenital abnormalities (2,11,16,17). These findings on physical examination are usually the result of either undervirilization in a male or overvirilization in a female.…”

Section: Discussionsupporting

confidence: 50%

“…Sequencing of the G6PC3 from the patient's genomic DNA was performed as previously described (2). The Institutional Review Board (Sheba Medical Center, Tel Hashomer) approved this study, and written informed consent was obtained from the patient's parents.…”

Section: Genetic Work-upmentioning

confidence: 99%

“…A typical example for the latter is glucose-6-phosphatase-β (G6PC3) deficiency that is characterized by congenital neutropenia and variable developmental disorders. The variable phenotype of individuals with G6PC3 deficiency may include cardiovascular malformations, such as atrial septal defect, patent ductus arteriosus, and pulmonary vascular abnormality (which leads to pulmonary hypertension), as well as urogenital disorders (e.g., hydronephrosis, urachal fistulations, and cryptorchidism), inflammatory bowel disease, and a peculiar visibility of subcutaneous veins (2)(3)(4)(5). The latter was recently described as the most consistent, nonhematologic feature of G6PC3 deficiency.…”

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Testicular failure in a patient with G6PC3 deficiency

et al. 2014

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Background: Glucose-6-phosphatase-β (G6PC3) deficiency is characterized by congenital neutropenia and variable developmental disorders, including those of the cardiovascular system and the urogenital system (e.g., cryptorchidism) and a peculiar visibility of subcutaneous veins. Methods: A patient with clinical findings suggestive of G6PC3 deficiency was investigated. Genetic, hematopathologic, immunologic, and endocrine work-up were performed. results: The reported patient had binucleotide deletion mutation in G6PC3 and displayed the full spectrum of clinical manifestations associated with G6PC3 deficiency including neutropenia. The reported patient had normal bone marrow cellularity without increased apoptosis, and his neutrophils displayed normal respiratory burst activity. Endocrine workup revealed low testosterone levels, which did not respond to human chorionic gonadotropin stimulation, extremely elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and undetectable anti-Müllerian hormone, all of which are suggestive of testicular failure or anorchia. conclusion: Our report extends the knowledge about this syndrome and suggests a role for G6PC3 in testicular differentiation and formation. Urogenital dysmorphism could indeed be unrelated to G6PC3 and secondary to consanguinity. However, given the similar description of urogenital anomalies in previous reports of this syndrome, the dysmorphism in our patient is likely related.

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Section: Discussionsupporting

confidence: 50%

Section: Genetic Work-upmentioning

confidence: 99%

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Testicular failure in a patient with G6PC3 deficiency

et al. 2014

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“…If marrow morphology shows maturation arrest at the stage of pro-myelocyte/myelocyte AE the presence of a cytogenetic clone, then the diagnosis of severe congenital neutropenia (SCN) is considered as appropriate (EO, 8.6, B) and the study of ELA2 and HAX-1 [12,[50][51][52] mutations, as the most frequently involved genes, were recommended by the panel (EO, 8.6, B). In presence of genital-cardiac malformations the lesion of G6PC3 gene has to be considered [53]. Activating mutations in the WAS gene have been found to be responsible for some cases of X-linked-SNC [54,55] (EO, IV, V, 8.1, B).…”

Section: (Eo 9 A)mentioning

confidence: 99%

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

Fioredda

Calvillo

Bonanomi

et al. 2011

Pediatric Blood & Cancer

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Congenital and acquired neutropenia are rare disorders whose frequency in pediatric age may be underestimated due to remarkable differences in definition or misdiagnosed because of the lack of common practice guidelines. Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document which includes a classification of neutropenia and a comprehensive guideline on diagnosis of neutropenia. Pediatr Blood Cancer 2011;57:10–17. © 2011 Wiley‐Liss, Inc.

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“…Severe congenital neutropenia is caused by loss-of-function mutations in a variety of proteins including the genes encoding neutrophil elastase, HAX1, and the recently identified glucose-6-phosphatase catalytic subunit 3 (Ancliff, 2003;Klein et al, 2007;Boztug et al, 2009). The XLN-WASP mutations (L270P, S272P, and I294T) add to the genetic complexity of the disease (Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009).…”

Section: Br Ief Definitive Repor Tmentioning

confidence: 99%