Umran Caliskan

Spectrum of the Mutations in Bernard–Soulier Syndrome

Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb‐IX‐V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER)

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received freshfrozen plasma. Prophylactic schedules clustered into “frequent” courses (three times weekly, n=23) and “infrequent” courses (≤2 times weekly, n=15). Excluding courses for menorrhagia, “frequent” and “infrequent” courses produced 18/23 (78%) and 5/12 (41%) “excellent” outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on “frequent” administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency (clinicaltrials.gov: NCT01269138).

Variable presentation of primary immune deficiency: Two cases with CD3 gamma deficiency presenting with only autoimmunity

CD3 chain expression defects including CD3 gamma, epsilon, delta, and zeta chain subunits, are autosomal recessive inherited severe combined immunodeficiencies (SCID). The phenotype is usually T‐B+NK+ SCID with lymphopenia where the clinical findings may be mild (CD3γ) or severe (CD3δ, ε, ζ) owing to the underlying molecular defect. There is limited information about the disease in literature.

Diminished Platelet Aggregation in Patients with Iron Deficiency Anemia

To evaluate platelet function in iron deficiency anemia, using impedance (in whole blood) and optic (in plate let-rich plasma methods, platelet aggregation analyses were performed in 42 children with iron deficiency anemia at the time of diagnosis and after iron therapy. Collagen-induced platelet aggregation was decreased in patients before therapy compared to after therapy and control levels as indicated by the two methods while adenosine diphosphate (ADP)-induced platelet aggregation was decreased only by the whole blood method. Platelet aggregation with epinephrine, performed only by the optic method, was not altered in patients with iron de ficiency anemia. Platelet counts were found to be increased in patients with iron deficiency anemia, and decreased with therapy. These results indicate that some platelet functions are decreased in patients with iron deficiency anemia. These de creased functions may be compensated by increased platelet numbers.

Hepatoblastoma in a child with neurofibromatosis type I.

A major hallmark of NF1 is the development of benign tumors, including peripheral neurofibromas, plexiform neurofibromas, gliomas of the optic tract, other low grade gliomas, and pheochromocytomas. Hepatoblastoma have not been previously reported in patients with neurofibromatosis type 1. We present a case of a 9‐month‐old boy diagnosed with both hepatoblastoma and neurofibromatosis type 1. Hepatoblastoma occurs in association with several well‐described cancer predisposition syndromes, including familial adenomatous polyposis, Beckwith–Wiedemann syndrome, Li‐Fraumeni syndrome, trisomy 18, and glycogen storage disease type I. This paper describes a case of hepatoblastoma diagnosed in association with neurofibromatosis type 1. Pediatr Blood Cancer 2007;49:357–359.

Successful prophylactic use of recombinant activated factor VII (rFVIIa) in a patient with congenital FVII deficiency and inhibitors to FVII.

organ failure. However, it seems that the use of rFVIIa in newborn presenting with severe vital distress and massive cord haematoma should be considered to limit bleeding. Composite heterozygous FVII deficiency can be responsible for very severe bleedings even in the first hours of life, including massive spontaneous cord haematoma. Without clear relationship between genotype and phenotype, it is very difficult to forecast the severity of bleedings. We consider that the FVII gene analysis could be beneficial in every situation where factor VII deficiency is found to be responsible for severe bleeding symptoms to assert the diagnosis and to better analyse the correlation between phenotype and genotype. In the case of our patient, the gene analysis of the family allowed for genetic counselling.

Conn syndrome in a child, caused by adrenal adenoma

Hyperaldosteronism owing to aldosterone-producing adenoma (Conn syndrome) is a rare but potentially curable form of pediatric hypertension. The authors report on a 5-year-old girl who had symptoms of polyuria, polydipsia, and fatigue, and for whom the diagnosis of hyperaldosteronemia was suggested by a low serum potassium level and persistent hypertension. The diagnosis was confirmed by increased levels of plasma aldosterone and decreased levels of plasma renin. The tumor was localized with ultrasonography and computed tomography, which showed a 2-cm mass in the left adrenal gland. The left adrenal gland was excised, and pathological assessment showed an adenoma. Only 14 other pediatric cases (< 16 years of age) have been reported in the English-language literature.

CD3G Gene Defects in Familial Autoimmune Thyroiditis

The patients with CD3γ deficiency can present with different clinical findings despite having the same homozygous mutation. We report three new CD3gamma‐deficient siblings from a consanguineous family with a combined T−B+NK+ immunodeficiency and their variable clinical and cellular phenotypes despite the same homozygous mutation of the CD3G gene (c.80‐1G>C). We also re‐evaluate a previously reported non‐consanguineous family with two CD3gamma‐deficient siblings with the same mutation. The median age at diagnosis was 11 years (14 months–20 years). We found all five patients to display autoimmunity: autoimmune thyroiditis (n = 5), autoimmune haemolytic anaemia (n = 2), immune thrombocytopenia (n = 1), autoimmune hepatitis (n = 1), minimal change nephrotic syndrome (n = 1), vitiligo (n = 1) and positive antinuclear antibodies (n = 3) as well as high IgE (n = 2) and atopic eczema (n = 2). While CD3+TCRαβ+T cell percentages were low in all patients, only one had lymphopenia and 3 had CD3+T cell lymphopenia. Strikingly, we report frequent and multiple autoimmunity in tested heterozygous carriers in both families (n = 6; in 67%), and frequent autoimmunity in family members not available for testing (n = 5, in 80%). The results suggest that CD3G should be studied as a candidate gene for autoimmunity and that CD3gamma deficiency should be considered among other primary immunodeficiencies with predominantly autoimmune manifestations.

DYSGERMINOMA IN A CHILD WITH ATAXIA–TELANGIECTASIA

Ataxia–telangiectasia is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, high incidence of cancer, and increased sensitivity to ionizing radiation. The authors report a case of dysgerminoma in a child with high α-fetoprotein, CA125 and β-human chorionic gonadotropin, who has been followed-up for ataxia–telangiectasia for 2 years.

Unexpected result in the etiological approaching to an anemic case: A leech infestation

One of the causes of the childhood anemia is gastrointestinal system bleeding, which rarely results from parasites. The authors report on a 3-year-old boy with severe anemia and a history of hematemesis. While they were investigating the cause of the anemia and the hematemesis, a leech showing itself in the nasal passage led to a quick and exact treatment. Leeches should be considered for differential diagnosis of anemia and gastrointestinal system bleeding in the children.