Extended Spectrum of Human Glucose-6-Phosphatase Catalytic Subunit 3 Deficiency: Novel Genotypes and Phenotypic Variability in Severe Congenital Neutropenia

Boztuğ, Kaan; Rosenberg, Philip S.; Dorda, Marie; Banka, Siddharth; Moulton, Thomas; Curtin, Julie; Rezaei, Nima; Corns, John S.; Innis, Jeffrey W.; Avcı, Zekai; Tran, Hung C.; Pellier, Isabelle; Pierani, Paolo; Fruge, Rachel; Parvaneh, Nima; Mamishi, Setareh; Mody, Rajen; Darbyshire, P; Jayashree, Muralidharan; Murray, Jennie; Buchanan, George R.; Newman, William G.; Alter, Blanche P.; Boxer, Laurence A.; Donadieu, Jean; Welte, Karl; Klein, Christoph

doi:10.1016/j.jpeds.2011.09.019

Cited by 75 publications

(77 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: Discussionmentioning

confidence: 50%

“…G6PC3 deficiency causes severe neutropenia and multiple nonhematological abnormalities (11). We reported here about a patient with binucleotide deletion in the G6PC3 gene, which led to a putative frameshift that presumably produced a severely altered and nonfunctional protein product due to a premature stop codon.…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies of adult patients with G6PC3 deficiency reported males with clinical hypogonadism, which included delayed puberty and gynecomastia. In contrast, females had a slight delay of puberty with normal menarche and menses, which continued during adult life (11,16). No endocrine work-up was reported to have been carried out, and the mechanism of pubertal delay was not explained.…”

Section: Discussionmentioning

confidence: 98%

“…Their neutrophils exhibit impaired respiratory burst, chemotaxis, and calcium flux, mimicking the immune phenotype seen in other human neutrophil defects (10). The spectrum of urogenital structural aberrations is wider than previously appreciated with cryptorchidism being the most frequent one (11). Cryptorchidism is an anatomical abnormality, which can be the result of a developmental failure.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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Testicular failure in a patient with G6PC3 deficiency

et al. 2014

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“…Thrombocytopenia, increased TSH and uric acid, decreased HDL and growth hormone deficiency have been observed in some patients in addition to neutropenia as laboratory findings (6). It has been emphasized that the risk of development of myelodysplastic syndrome and acute myeloid leukemia might be lower in these patients compared to other SCN types (14). Most of the thirty one patients defined until the present time originated from the middle-east (Turkey, Iran, Lebanon).…”

Section: Discussionmentioning

confidence: 84%

Doğuştan ağır nötropenide fenotip-genotip ilişkisi

...

2012

Tpa

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Aim:Severe congenital neutropenia is a rare hereditary disease presenting with infections such as sepsis, abscess, omphalitis and gingivitis in early life. We evaluated the association between clinical findings and mutations in our patients with severe congenital neutropenia. Material and Method:The clinical and laboratory findings of six patients with severe congenital neutropenia were obtained and the diagnosis was confirmed by mutation analysis in all family members (parents and children). Results: The most common clinical presentation included formation of abscess and presence of otitis and gingivitis. The mutation analysis by DNA sequencing revealed HAX-1 mutation in four and G6PC3 mutation in two patients. Prominent superficial veins, inverted nipple and triangular face were observed in patients with G6PC3 mutation. In addition, developmental delay, convulsion, inability to speak and learning difficulties were observed in two patients with HAX1 mutation. Conclusions: In patients with severe, recurrent infections, assessment of neutrophil count and consideration of various presentations of severe congenital neutropenia are critical for establishing early diagnosis and for successful treatment of the disease. Additionally, genetic counseling and mutation analysis should be offered to these patients. (Turk Arch Ped 2012; 47: 268-273)

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Neutropenia

Dale

2015

Encyclopedia of Life Sciences

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Neutropenia is a decrease in the number of neutrophilic leucocytes in the blood. Neutropenia is defined as an absolute neutrophil count or ANC (total white blood cells per litre multiplied by the percentage of neutrophils) more than two standard deviations below the normal mean. The ANC is usually more than 2.0 × 10 9 L −1 . Neutropenia is graded as mild, moderate or severe; severe is less than 0.5 × 10 9 L −1 . Severe neutropenia predisposes to a high risk of bacterial and fungal infections. Neutropenia occurs both as an acquired and as an inherited disorder. Drugs and autoimmune diseases are the common causes of acquired neutropenia. There are many hereditary causes of neutropenia; all of these are rare conditions, but some are quite severe. Proper treatment depends on understanding the cause of neutropenia and its expected duration. Short periods of neutropenia can be managed with careful observation or antibiotics. Patients with severe chronic neutropenia benefit from long‐term treatment with granulocyte colony‐stimulating factor (G‐CSF). Key Concepts Neutrophils are critical for normal defence from infections by bacteria on body surfaces. Blood neutrophil levels below normal, that is, neutropenia, predispose to bacterial and fungal infections. The bone marrow produces neutrophils from haematopoietic stem cells through an orderly process that takes about 10–14 days. Neutropenia is usually due to acquired or intrinsic/hereditary disorders affecting bone marrow production of these cells. When neutrophil production is interrupted by drugs or diseases recovery often takes several days. The risk of infection in patients with neutropenia depends on the severity of neutropenia and its duration. With a brief period, that is, 1–3 days, the risk is relatively low. Severe neutropenia lasting longer is associated with a steadily increasing risk of severe infection and even death. Proper management of neutropenia requires understanding its cause and the expected duration of neutropenia. When it is due to drugs, either cancer chemotherapy or as an idiosyncratic reaction to other drugs, the duration is usually relatively brief and can be managed with observation or antibiotics. Neutropenia lasting more than about 5–7 days and more chronic neutropenia predispose patients to a much higher risk of bacterial and fungal infections. These patients benefit from treatment with granulocyte colony‐stimulating factor (G‐CSF). It is now possible to identify the genetic cause for severe chronic neutropenia in many patients through deoxyribonucleic acid (DNA) sequencing studies. Understanding of the molecular and cellular basis for these disorders is growing rapidly.

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Extended Spectrum of Human Glucose-6-Phosphatase Catalytic Subunit 3 Deficiency: Novel Genotypes and Phenotypic Variability in Severe Congenital Neutropenia

Cited by 75 publications

References 31 publications

Testicular failure in a patient with G6PC3 deficiency

Testicular failure in a patient with G6PC3 deficiency

Doğuştan ağır nötropenide fenotip-genotip ilişkisi

Neutropenia

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