Bernard Soulier syndrome in pregnancy: a systematic review

Summary. Bernard Soulier syndrome (BSS) is a rare disorder of platelets, inherited mainly as an autosomal recessive trait. It is characterised by qualitative and quantitative defects of the platelet membrane glycoprotein (GP) Ib‐IX‐V complex. The main clinical characteristics are thrombocytopenia, prolonged bleeding time and the presence of giant platelets. Data on the clinical course and outcome of pregnancy in women with Bernard Soulier syndrome is scattered in individual case reports. In this paper, we performed a systematic review of literature and identified 16 relevant articles; all case reports that included 30 pregnancies among 18 women. Primary postpartum haemorrhage was reported in 10 (33%) and secondary in 12 (40%) of pregnancies, requiring blood transfusion in 15 pregnancies. Two women had an emergency obstetric hysterectomy. Alloimmune thrombocytopenia was reported in 6 neonates, with one intrauterine death and one neonatal death. Bernard Soulier syndrome in pregnancy is associated with a high risk of serious bleeding for the mother and the neonate. A multidisciplinary team approach and individualised management plan for such women are required to minimise these risks. An international registry is recommended to obtain further knowledge in managing women with this rare disorder.     

Twin pregnancy and parturition in a patient with the Bernard Soulier syndrome

A patient with the Bernard Soulier Syndrome was successfully delivered of twins. The pregnancy was complicated by slight bleeding from the uterus during the first 8 weeks, by cord prolapse necessitating emergency caesarean section, and by moderate post partum haemorrhage. The management of pregnancy in the Bernard Soulier Syndrome is discussed.     

Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder caused by a defect in the glycoprotein (GP)Ib/IX/V complex. A patient with a bleeding problem was diagnosed as having BSS based on the prolonged bleeding time, the absence of ristocetin induced platelet aggregations, thrombocytopenia and the presence of giant platelets. Analysis of the platelets of the propositus, a 39-year-old Belgian female, by flow cytometry revealed a decreased expression of the GPIb/IX polypeptides. Western blotting confirmed these results and showed moreover that there was a decreased disulfide bridge formation between GPIb f and GPIb g . After sequence analysis of the GPIb f , GPIb g and GPIX genes, only a mutation in the GPIX gene at position 1826 (A M G) was identified, changing Asn45 M Ser. Restriction analysis with Fnu 4H1 demonstrated that the patient was homozygous for this mutation. As this Asn45 M Ser mutation in the GPIX gene was already found in four unrelated families, i.e. in a British, Austrian, Swedish and Finnish one, the occurrence of this mutation in a Belgian patient supports the hypothesis of Koskela et al . (1999) that the Asn45Ser mutation in GPIX appears to be an ancient mutation shared by northern and central European populations. Our present observation of a decreased disulfide bridge formation between GPIb f and GPIb g shows that GPIX is not only needed for the correct assembly of the complex but might also be needed for the disulfide bridge formation between GPIb f and GPIb g .     

Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder caused by a defect in the glycoprotein (GP)Ib/IX/V complex. A patient with a bleeding problem was diagnosed as having BSS based on the prolonged bleeding time, the absence of ristocetin induced platelet aggregations, thrombocytopenia and the presence of giant platelets. Analysis of the platelets of the propositus, a 39-year-old Belgian female, by flow cytometry revealed a decreased expression of the GPIb/IX polypeptides. Western blotting confirmed these results and showed moreover that there was a decreased disulfide bridge formation between GPIb alpha and GPIb beta. After sequence analysis of the GPIb alpha, GPIb beta and GPIX genes, only a mutation in the GPIX gene at position 1826 (A-->G) was identified, changing Asn45-->Ser. Restriction analysis with Fnu4H1 demonstrated that the patient was homozygous for this mutation. As this Asn45-->Ser mutation in the GPIX gene was already found in four unrelated families, i.e. in a British, Austrian, Swedish and Finnish one, the occurrence of this mutation in a Belgian patient supports the hypothesis of Koskela et al. (1999) that the Asn45Ser mutation in GPIX appears to be an ancient mutation shared by northern and central European populations. Our present observation of a decreased disulfide bridge formation between GPIb alpha and GPIb beta shows that GPIX is not only needed for the correct assembly of the complex but might also be needed for the disulfide bridge formation between GPIb alpha and GPIb beta.     

The same genetic defect in three Tunisian families with Bernard Soulier syndrome: a probable founder Stop mutation in GPIbbeta

GPIbα, GPIbβ, and GPIX are three candidate genes for a rare genetic bleeding disorder named Bernard Soulier syndrome (BSS). These genes are unique in the genome and encode for glycoprotein subunits of the GPIb-IX complex. Quantitative or qualitative deficiency in this complex is often associated with BSS. Here, we report the novel variant of BSS in which Ser23 of GPIbβ is substituted by a Stop codon causing a premature termination of translation, recently described in one family. This genetic defect is revealed in three unrelated BSS patients. The pedigree was determined for two families (F1 and F2) and revealed the homozygosity of the mutation in the two patients and its heterozygosity in parents. In the third family, the patient DNA was heterozygote with the same Ser23 Stop mutation in addition to two missense heterozygote mutations (Asp 51 Gly) and (Ala 55 to Pro). We studied the effect of the Ser23 Stop mutation on the expression of the complex. Our findings confirm that the identified GPIbβ mutation is responsible for the BSS phenotype and hampers the GPIb-IX complex to form on the platelets’ surface. Regarding the scarcity of the BSS syndrome, the occurrence of the same mutation in three unrelated families would suggest a BSS founder mutation in Tunisia.     

How we treat the platelet glycoprotein defects; Glanzmann thrombasthenia and Bernard Soulier syndrome in children and adults

The inherited platelet glycoprotein deficiencies, Glanzmann thrombasthenia (GT) and Bernard Soulier syndrome (BSS) are rare but important long‐term bleeding disorders. Once diagnosed, affected patients should be referred to a specialist centre for bleeding disorders for general advice and ongoing management. Patients do not require prophylactic treatment and so the management of GT and BSS focuses around prophylactic treatment prior to high risk procedures and treatment in response to non‐surgical bleeding events and, in women, the management of menorrhagia and pregnancy. There is no consistent approach to the treatment or prevention of bleeding complications. Management must be tailored for each individual and the approach may not be the same for different events, even for the same patient, depending on the type of accident or invasive procedure, the extent of bleeding and the presence or not of platelet refractoriness.     

Molecular genetics of Marfan syndrome

PURPOSE OF REVIEW: Marfan syndrome, the founding member of connective tissue disorders, is characterized by involvement of three major systems (skeletal, ocular, and cardiovascular) due to alteration in microfibrils. FBN1 at 15q21.1 was found to cause Marfan syndrome in 1991, and in 2004 TGFBR2 at 3p24.1 was newly identified as the Marfan syndrome type II gene. Several studies implied that fibrillin-1 and transforming growth factor-beta (TGF-beta) signaling are functionally related in extracellular matrix. Identification of TGFBR2 mutations in Marfan syndrome type II provided the direct evidence of the relation in humans. RECENT FINDINGS: More than 500 FBN1 mutations have been found in Marfan syndrome, tentative genotype - phenotype correlations have emerged, and mouse models are providing insight into pathogenic mechanisms. TGFBR2 mutations are still limited, however, in 2005 were also reported to cause a new aneurysm syndrome. Functional association between fibrillin-1 and TGF-beta signaling in extracellular matrix has been presented. SUMMARY: This review focuses on recent molecular genetics advances in Marfan syndrome and overlapping connective tissue disorders. Mutation spectrum of FBN1 and TGFBR2 in relation to phenotype is presented. Functional relation between fibrillin-1 and TGF-beta signaling is discussed. Future prospects in the study of Marfan syndrome are presented.     

Bernard–Soulier syndrome in pregnancy

Bernard–Soulier syndrome (BSS) is a rare autosomal recessively inherited bleeding disorder. Pregnancy in patients with BSS is characterized by ante‐, intra‐, or postpartum haemorrhage, which may be delayed and severe. There is no consensus in the management of BSS in pregnancy and so far only 16 pregnancies in nine patients have been described. We report a further three pregnancies in two women with the syndrome. We also outline our management of pregnant patients with BSS.     

预激综合征的分子遗传学与电生理学研究进展

预激综合征包括家族性和散发性,以散发性为主,家族性预激综合征为常染色体显性遗传疾病.目前其分子遗传学研究热点为编码AMP活化蛋白激酶γ2调节亚单位的基因(PRKAG2)突变,电生理学研究主要为旁道的定位和电生理特性.     

Molecular genetics and age-related disease.

Maintenance and repair processes are crucial to the pathogenesis of ageing and late-onset disease. Thus, there is increasing recognition of the importance of genetic factors in the development of late-onset conditions such as stroke, Parkinson's disease and osteoporosis, and accumulating evidence for a genetic component in the development of chronic obstructive pulmonary disease. We review the approaches and problems in the genetic investigation of complex disorders in old age, taking chronic obstructive pulmonary disease as an example.     

Paris-Trousseau syndrome platelets in a child with Jacobsen's syndrome

The thrombocytopenia in an infant with clinical features of Jacobsen's syndrome characterized by multiple congenital anomalies, cardiac defects, psychomotor retardation, and deletion of chromosome 11 at 11q23.3 has been evaluated. Study of his platelets in the electron microscope revealed giant alpha granules in his cells identical in appearance to those reported in the family with Paris-Trousseau syndrome. As a result, the Paris-Trousseau syndrome appears to be a variant of the Jacobsen syndrome, and the thrombocytopenia observed in all cases of chromosome 11q23.3 deletion due to dysmegakaryopoieses. Giant alpha granules are frequently observed in normal platelets during long-term storage and may form in Jacobsen and Paris-Trousseau platelets during prolonged residence in the bone marrow.     

Glanzmann thrombasthenia and Bernard–Soulier syndrome in south Iran

Glanzmann thrombasthenia (GT) and Bernard–Soulier syndrome (BSS) are two rare inherited disorders of platelet function. In this study, we report the demographic, clinical and biological characteristics of 23 patients with GT and of seven patients with BSS from southern Iran who had been followed for many years but fully characterized only recently, when platelet aggregation tests and flow cytometric studies became available for the first time in the country. We found a high prevalence of both diseases that can be explained by the high rate of consanguineous marriages in south Iran. Patients affected by GT and BSS suffer mainly from mucocutaneous bleedings causing anemia and transfusion requirements.     

Opsoclonus-myoclonus syndrome in a child with neuroborreliosis

Opsoclonus-myoclonus is a rare neurological syndrome affecting children and adults. In children it occurs as a parainfectious process or a paraneoplastic syndrome in association with neuroblastoma. Here we report it presenting as an unusual neurological manifestation of Lyme borreliosis. To our knowledge, this is the first report which describes recovery from this syndrome in a child.     

Brugada syndrome with monomorphic ventricular tachycardia in a one-year-old child.

A one-year-old child with a structurally normal heart presented with monomorphic ventricular tachycardia. Electrocardiogram in sinus rhythm showed right bundle branch block with ST segment elevation suggesting a diagnosis of Brugada syndrome. At a later date, when the ST segment was isoelectric. intravenous procainamide caused ST elevation typical of Brugada syndrome.     

Giant platelet granules in a child with the Chediak-Higashi syndrome.

Previous ultrastructural investigation have not identified abnormal lysosomes in platelets obtained from humans or animals with the Chediak-Higashi Syndrome. We report here a patient whose megakaryocytes and platelets were found to contain giant granules when viewed by light and electron microscopy. The granules measured up to 1.5 micrometer in diameter, contained either homogeneous or heterogeneous material, were acid phosphatase positive, and were present in approximately 30% of bone marrow megakaryocytes and 5% of circulating platelets. A decrease was observed in serotonin containing dense granules, serotonin uptake and serotonin release as reported previously. Microtubules in platelets and megakaryocytes were intact and no other morphologic abnormalities were identified. No clinical evidence of bleeding was observed in this patient and platelet counts have been normal. The lack of giant platelet lysosomes in other reported cases of Chediak-Higashi Syndrome attests to significant heterogeneity in this disease with a spectrum of clinical and laboratory findings.