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Dursun Syndrome

Pulmonary Arterial Hypertension - Leukopenia - Atrial Septal Defect

Dursun syndrome (DS) is a rare congenital disorder caused by mutations of the G6PC3 gene. The clinical hallmarks of DS are atrial septal defect, pulmonary arterial hypertension, and leukopenia. Only two patients have been described so far. DS is allelic to severe congenital neutropenia type 4 (SCN4), where immunodeficiency and recurrent infections dominate the clinical picture. Whether DS is an entity truly distinct from severe congenital neutropenia or merely an extension of its phenotypic spectrum remains to be clarified.


Presentation

In general, DS interferes with postnatal development and weight gain. Patients may be born with a normal birth weight after an uneventful pregnancy, but poor growth becomes apparent within the first few months of life. The clinical examination of DS patients may reveal hepatomegaly [1].

Cardiovascular disorders, namely ostium secundum atrial septal defect and pulmonary arterial hypertension, have been observed in both DS patients reported so far [1]. While atrial septal defects are frequently observed in SCN4 patients, pulmonary arterial hypertension is not generally listed as a characteristic feature of that disease. Nevertheless, it has been detected in at least one patient diagnosed with SCN4 [2]. The children described by Dursun and colleagues developed respiratory distress on the second day of life. Auscultation revealed mild systolic murmurs in both cases [1].

Oxygen supply is additionally hampered by anemia, one of several manifestations of an extensive impairment of hematopoiesis. Accordingly, DS patients also present with leukopenia and thrombocytopenia. Leukopenia with neutropenia and lymphopenia causes severe immunodeficiency and predisposes to infections. Increased susceptibility to infections is the clinical hallmark of SCN4, so DS patients may be expected to develop recurrent infections of the skin, ear, respiratory or gastrointestinal tract, too. However, normoglobulinemia has been found in both patients described so far, and neither of them was plagued by severe infections [1]. DS is related to - presumably reactive - monocytosis [2]. With regard to thrombocytopenia, this condition may induce a hemorrhagic diathesis, but hemorrhages have not yet been described in DS patients.

Beyond the aforementioned symptoms, a variety of skeletal anomalies may be observed. Facial dysmorphism with hypertelorism, a broad nasal bridge and a high-arched palate, malformations of the hand with long fingers, proximally placed thumbs and a single palmar crease, and pectus carinatum have been reported [1]. Male patients seem to be at risk for inguinal hernias and cryptorchidism, conditions previously related to SCN4 [2].

Increased Susceptibility to Infections
  • Increased susceptibility to infections is the clinical hallmark of SCN4, so DS patients may be expected to develop recurrent infections of the skin, ear, respiratory or gastrointestinal tract, too.[symptoma.com]
Aspiration
  • Bone marrow specimens have to be obtained by aspiration, and the quantities and qualities of individual cell populations have to be assessed. DS is related to bone marrow dysplasia and hypocellularity but a normal distribution of all lineages.[symptoma.com]
  • Bone marrow aspiration, performed at another institution, revealed delayed granulocyte maturation. No mutations were found in the ELANE and HAX1 genes.[ijponline.biomedcentral.com]
High Arched Palate
  • Facial dysmorphism with hypertelorism, a broad nasal bridge and a high-arched palate, malformations of the hand with long fingers, proximally placed thumbs and a single palmar crease, and pectus carinatum have been reported.[symptoma.com]
Heart Disease
  • While non-syndromic severe congenital neutropenia is characterized by anomalies of the myeloid lineages only, patients suffering from SCN4 may also present with congenital heart disease and urogenital malformations, namely cryptorchidism.[symptoma.com]
  • ., Remington, G.. (2004) Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome. Canadian Journal of Psychiatry, 49, 753- 760.[airitilibrary.com]
Systolic Murmur
  • Auscultation revealed mild systolic murmurs in both cases. Oxygen supply is additionally hampered by anemia, one of several manifestations of an extensive impairment of hematopoiesis.[symptoma.com]
Hepatomegaly
  • The clinical examination of DS patients may reveal hepatomegaly. Cardiovascular disorders, namely ostium secundum atrial septal defect and pulmonary arterial hypertension, have been observed in both DS patients reported so far.[symptoma.com]
Long Arm
  • This gene is located on the long arm of chromosome 17 and encodes for the catalytic subunit of glucose-6-phosphatase, an enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in gluconeogenesis and glycogenolysis.[symptoma.com]
Broad Nasal Bridge
  • Facial dysmorphism with hypertelorism, a broad nasal bridge and a high-arched palate, malformations of the hand with long fingers, proximally placed thumbs and a single palmar crease, and pectus carinatum have been reported.[symptoma.com]
Hypertelorism
  • Facial dysmorphism with hypertelorism, a broad nasal bridge and a high-arched palate, malformations of the hand with long fingers, proximally placed thumbs and a single palmar crease, and pectus carinatum have been reported.[symptoma.com]
Cryptorchidism
  • Male patients seem to be at risk for inguinal hernias and cryptorchidism, conditions previously related to SCN4.[symptoma.com]

Workup

Although the triad of secundum-type atrial septal defect, pulmonary arterial hypertension, and leukopenia may suggest DS, this rare entity is unlikely to be considered in the early workup of an infant with multiple congenital anomalies. What's more, the diagnosis of pulmonary arterial hypertension isn't easily obtained. A precise measurement of pulmonary arterial pressure requires right heart catheterization or, at the very least, Doppler echocardiography [3]. Pulmonary arterial pressures of up to 80 mmHg have been noted in infants suffering from DS. The aforementioned techniques are also helpful to confirm the presence of an atrial septal defect, and they should be complemented by electrocardiography and diagnostic imaging of the thorax. In DS patients, electrocardiography may reveal right axis deviation, and images may show a prominent pulmonary conus and enlargement of the right ventricle and atrium. Tricuspid regurgitation may be expected, but has not yet been described in affected individuals. Furthermore, X-ray examinations or computed tomography scans may allow for the diagnosis of thymus hypoplasia [1].

Intermittent anemia, leukopenia, and thrombocytopenia, as well as persistent monocytosis, are diagnosed by repeated analyses of peripheral blood. Neutrophils may present dysplastic changes and vacuolated cytoplasm, while basophilic stippling, hypochromasia, anisocytosis, and polychromasia have been described with regards to red blood cells. If not explainable otherwise, these findings warrant the examination of the bone marrow. Bone marrow specimens have to be obtained by aspiration, and the quantities and qualities of individual cell populations have to be assessed. DS is related to bone marrow dysplasia and hypocellularity but a normal distribution of all lineages [1]. Megaloblastic changes in both myeloid and erythroid lineages may be noted as well as severe vacuolization of myeloid cells [1] [2].

Finally, the diagnosis of DS requires the identification of the underlying mutation. Molecular biological studies have to be carried out to determine whether the patient carries G6PC3 missense mutation c.346A>G or another, as-of-yet undescribed sequence anomaly.

Right Axis Deviation
  • In DS patients, electrocardiography may reveal right axis deviation, and images may show a prominent pulmonary conus and enlargement of the right ventricle and atrium.[symptoma.com]
Anisocytosis
  • Neutrophils may present dysplastic changes and vacuolated cytoplasm, while basophilic stippling, hypochromasia, anisocytosis, and polychromasia have been described with regards to red blood cells.[symptoma.com]

Treatment

Only symptomatic treatment can be provided. Hematopoeitic stem cell transplantation has not yet been carried out in DS patients but may constitute an alternative treatment strategy [4] [5].

  • The complexity of DS-related cardiovascular disorders may complicate the management of atrial septal defects and pulmonary arterial hypertension. Closure of an isolated ostium secundum atrial septal defect is generally recommended at the age of 4 to 5 years, but an earlier intervention may be required in symptomatic infants [6]. Those suffering from DS will be symptomatic and may need surgery within their first year of life, but no such intervention has yet been performed in affected individuals. The risk of aggravating pulmonary arterial hypertension should be considered before making this decision [1]. Pulmonary arterial hypertension itself may be treated surgically, e.g., by pulmonary artery banding, or pharmacologically. Phosphodiesterase-5 inhibitors, prostacyclin analogs, or endothelin receptor antagonists are most commonly administered to this end [7].
  • Transfusions may be required to control anemia and thrombocytopenia, and granulocyte colony-stimulating factor may be applied to augment the pool of mature, functional neutrophils. Fevers and infections require prompt treatment with antibiotics [8].
  • Additional measures may be taken to correct malformations and to alleviate other symptoms.

It shall be pointed out that little is known about the safety and efficacy of the aforementioned treatments in DS. Therapeutic regimens that significantly improve the outcome in other cases may have detrimental side effects in those suffering from DS. Dursun et al. described that the administration of granulocyte colony-stimulating factor provoked severe dysplastic changes in the granulocytes and thrombocytes of one of their patients, which haven't been listed as adverse events of such treatment [1] [9].

Prognosis

Both children described by Dursun and colleagues died during their second year of life. They presented with severe respiratory distress and presumably succumbed to right heart failure [1]. Life-threatening complications may also arise from immunodeficiency, but when neutropenia is treated, the risk of severe infections can be reduced significantly [8]. No statements can yet be made regarding the likelihood of malignant transformation in DS patients. Transformation to myelodysplastic syndrome/acute myeloid leukemia is a dreaded complication of severe congenital neutropenia but has not yet been described in patients with glucose-6-phosphatase deficiency [10].

Etiology

DS has been related to mutations of the G6PC3 gene. This gene is located on the long arm of chromosome 17 and encodes for the catalytic subunit of glucose-6-phosphatase, an enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in gluconeogenesis and glycogenolysis. There are three isoforms of glucose-6-phosphate, and they show different tissue expression patterns. Accordingly, mutations of the genes encoding for each of the isoforms cause distinct diseases. While G6PC3 is ubiquitously expressed, highest levels of expression have been reported for skeletal and heart muscle cells, brain, pancreas, spleen, colon, and kidney.

G6PC3 mutation c.346A>G has been identified in one of the two DS patients reported so far, while DNA from the second patient could not be examined. Mutation c.346A>G results in an exchange of methionine for valine at position 116 of the amino acid chain, which is highly conserved across species. In almost 100 ethnically matched controls, mutations affecting this methionine residue have not been detected. By contrast, both parents of the affected children proved to be heterozygous for missense mutation c.346A>G of G6PC3. DS has thus been suggested to be inherited in an autosomal recessive manner, as is SCN4, a hereditary disease that had previously been associated with mutations of G6PC3.

Several truncating and missense mutations of the G6PC3 gene have been identified in SCN4 patients, and involvement of the methionine residue at position 116 has been demonstrated in at least one of them [11] [12]. Furthermore, DS shows significant clinical overlap with its allelic disorder SCN4, as patients suffering from either disease present with myeloid hypoplasia and cardiovascular disorders. No consensus has been reached on whether or not DS should be considered a rare variant of SCN4: Additional chromosomal or gene aberrations may contribute to the DS phenotype, rendering it a distinct entity, but the Turkish scientists who have worked with the affected infants have proposed to consider DS a subset of SCN4 with pulmonary arterial hypertension as an important clinical feature [2] [8]. In this context, distinct degrees of residual enzyme activity have been proposed as a potential cause of differences in the severity of the disease, but evidence to support this hypothesis has yet to be provided [13].

Epidemiology

To date, DS has only been diagnosed in two siblings of different sex who were born to non-consanguineous Turkish parents. Both children manifested first symptoms on their second day of life and lived to the age of 18 months [1]. If DS is considered a rare manifestation of glucose-6-phosphatase deficiency, there is no reason to expect an increase of case numbers: Glucose-6-phosphatase deficiency has been molecularly proven in <100 individuals worldwide [8]. In populations with founder mutations and those practicing consanguineous marriage, the re-occurrence of DS is somewhat more likely. This may be the case in Israel, Turkey, and Pakistan [14] [15].

Sex distribution
Age distribution

Pathophysiology

DS is caused by glucose-6-phosphatase deficiency. This enzyme is located in the endoplasmic reticulum and catalyzes the removal of phosphate from glucose-6-phosphate. It is assumed to be required for the development of myeloid precursors and the function of neutrophils. In these cells, glucose-6-phosphatase deficiency has been shown to favor apoptosis, presumably via endoplasmatic reticulum stress and reduced levels of intracellular glucose [2] [10].

Little is known about the mechanisms underlying cardiovascular disease in DS patients.

Prevention

Affected families may benefit from genetic counseling. Relatives at risk should be offered a verification of their carrier status, and prenatal testing is recommended for pregnancies if pathogenic variants of G6PC3 have been identified in the family [8]. To date, only missense mutation c.346A>G has been related to DS, which may argue for a straightforward approach [2]. If it doesn't produce the expected results, the possibility of other mutations should be considered.

Summary

DS is a rare congenital disease that has first been described in 2009, by Dursun et al. [1]. The Turkish scientists reported two siblings suffering from disorders of hematopoiesis and consequent susceptibility to infection, from complex cardiovascular malformations and minor skeletal anomalies. To date, additional case reports have been announced but not been published [13].

In 2010, a missense mutation of the G6PC3 gene has been identified in DNA obtained from one of the Turkish siblings [2]. Consequently, DS has been proposed to be part of the phenotypic spectrum of glucose-6-phosphatase deficiency. This spectrum may range from non-syndromic severe congenital neutropenia to SCN4, the classical type of the disease, to DS. While non-syndromic severe congenital neutropenia is characterized by anomalies of the myeloid lineages only, patients suffering from SCN4 may also present with congenital heart disease and urogenital malformations, namely cryptorchidism. In DS, hematopoietic impairment extends to non-myeloid lineages, resulting in lymphopenia and thymic hypoplasia, and cardiovascular disorders include pulmonary arterial hypertension [8]. It should be considered, though, that additional sequence anomalies may contribute to the severe phenotype of DS. At present, digenic or even polygenic inheritance of DS cannot be ruled out.

Patient Information

Dursun syndrome (DS) is a very rare congenital disorder. Only two patients have been described so far. The affected infants were of Turkish descent and developed respiratory distress on their second day of life. Further examinations revealed they had an atrial septal defect and pulmonary arterial hypertension. Both conditions interfere with the supply of oxygen to the body's organs and tissues. Furthermore, laboratory analyses of blood samples showed low counts of red and white blood cells and platelets. While anemia is likely to aggravate the lack of oxygen supply, leukopenia predisposes to infections. Thrombocytopenia, in turn, may render the patients propense to bleed. However, recurrent infections and hemorrhages have not been observed in the Turkish siblings, who succumbed to the disease during their second year of life.

References

Article

  1. Dursun A, Ozgül RK, Soydas A, et al. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement. Clin Dysmorphol. 2009; 18(1):19-23.
  2. Banka S, Newman WG, Ozgul RK, Dursun A. Mutations in the G6PC3 gene cause Dursun syndrome. Am J Med Genet A. 2010; 152a(10):2609-2611.
  3. Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004; 25(24):2243-2278.
  4. Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia. Curr Opin Hematol. 2012; 19(1):44-51.
  5. Fioredda F, Iacobelli S, van Biezen A, et al. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation. Blood. 2015; 126(16):1885-1892; quiz 1970.
  6. Lammers A, Hager A, Eicken A, Lange R, Hauser M, Hess J. Need for closure of secundum atrial septal defect in infancy. J Thorac Cardiovasc Surg. 2005; 129(6):1353-1357.
  7. Stringham R, Shah NR. Pulmonary arterial hypertension: an update on diagnosis and treatment. Am Fam Physician. 2010; 82(4):370-377.
  8. Banka S. G6PC3 Deficiency. 2015 Apr 16 In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
  9. D'Souza A, Jaiyesimi I, Trainor L, Venuturumili P. Granulocyte colony-stimulating factor administration: adverse events. Transfus Med Rev. 2008; 22(4):280-290.
  10. Banka S, Newman WG. A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations. Orphanet J Rare Dis. 2013; 8:84.
  11. Desplantes C, Fremond ML, Beaupain B, et al. Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry. Orphanet J Rare Dis. 2014; 9:183.
  12. Germeshausen M, Zeidler C, Stuhrmann M, Lanciotti M, Ballmaier M, Welte K. Digenic mutations in severe congenital neutropenia. Haematologica. 2010; 95(7):1207-1210.
  13. Ozgül RK, Yücel-Yilmaz D, Dursun A. Dursun syndrome due to G6PC3 gene defect has a fluctuating pattern in all blood cell lines. J Clin Immunol. 2014; 34(3):265-266.
  14. Lebel A, Yacobovich J, Krasnov T, et al. Genetic analysis and clinical picture of severe congenital neutropenia in Israel. Pediatr Blood Cancer. 2015; 62(1):103-108.
  15. Smith BN, Evans C, Ali A, et al. Phenotypic heterogeneity and evidence of a founder effect associated with G6PC3 mutations in patients with severe congenital neutropenia. Br J Haematol. 2012; 158(1):146-149.

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Last updated: 2018-06-22 09:42