Anna Jakubiuk-Tomaszuk

Hepatoblastoma as a result of APC gene mutation.

H epatoblastoma is a rare early childhood neoplasm occurring in patients with genetic disorders, such as trisomies of chromosomes 18, or inherited predispositions to some neoplastic diseases, including Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP) (1). The observed increase in the risk of hepatoblastoma in APC (adenomatous polyposis coli) gene mutation carriers is low, not exceeding 1%, which is associated with APC gene mutation located in the region of codons 459 to 1309, where most mutations identified in families affected by FAP in Poland are found. Tissues obtained from patients with hepatoblastoma but without the diagnosis of FAP show loss of heterozygocity at the locus of APC or MCC (mutated in colorectal cancers) genes. Hepatoblastoma growth is the result of the sequence of changes in genetic material. A major role can be ascribed to the Wnt pathway where somatic mutations have been observed in the genes of B-cathenin (CTNNB1, Cathenin [cadherin-associated protein], b-1.88 kD), and AXIN1 (axis inhibitor 1) (2,3). We present a case of familial hepatoblastoma in a 3-month-old infant with a constitutional mutation in the APC gene. A female infant ages 3 months (Fig. 1. IV, 4) was admitted to the department for the diagnosis and treatment of abdominal tumor. The index case was born after an uneventful pregnancy with routine antenatal scanning carried out during the pregnancy, which was unremarkable. Parents are healthy and unrelated. This was her mother’s fourth pregnancy; the first and third pregnancies ended with miscarriages in 1st trimester (Fig. 1. IV, 1 and 3). Second pregnancy resulted in a girl born at 36th week who died at age 14 months with the diagnosis of multiple congenital defects: congenital hydrocephalus, spina bifida, anorectal malformations, and cardiac anomaly. Her chromosomal analysis was normal: 46, XX (Fig. 1. IV, 2). On admission, the physical examination revealed a large hard tumor, bulging in the whole abdominal cavity. Additional tests found thrombocythemia (701 10 /mL) and elevated levels of a-fetoproteins (331.000 ng/mL) and b-human chorionic gonadotropin (75.81 mU/mL). The ophthalmic examination showed congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the eye fundus. Computed tomography scan visualized a pathological 120 95 74-mm mass, visible from the left dome of the

Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF gene

Cardio-facio-cutaneous (CFC) syndrome is characterized by a variable degree of developmental delay and congenital anomalies, including characteristic facial, cardiac, and ectodermal abnormalities. It is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. In, however, approximately 10%-30% of individuals with a clinical diagnosis of CFCS, no mutation of the causative gene is found. Therefore, clinical studies in patients with the CFCS spectrum are valuable. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting genes encoding serine/threonine kinases, a group of 15 children and young adults with a diagnosis of CFCS was screened. We documented three novel mutations in the BRAF gene and correlated clinical findings with causative mutations in the BRAF or MEK1/MEK2 genes.

Decrease of interleukin (IL)17A gene expression in leucocytes and in the amount of IL-17A protein in CD4+ T cells in children with Down Syndrome

BACKGROUND Down Syndrome is by far the most common and best known chromosomal disorder in humans. It expresses multiple systemic complications with both structural and functional defects as part of the clinical manifestation. The mechanisms of immune changes occurring in Down Syndrome are complex and include an extra gene copy of chromosome 21 and secondary dysregulation of numerous intercellular interactions. Recent studies suggest a role of interleukin 17A (IL-17A), a pro-inflammatory cytokine located on 6p12 chromosome, in the pathogenesis of inflammatory and autoimmune diseases. We aimed to analyze IL17A gene expression in peripheral white cells and IL-17A intracellular expression on CD4+ T-cells. METHODS The research was carried out on a group of 58 children aged 6-12 years including a group of 30 children with Down Syndrome (simple trisomy of chromosome 21 only) and a reference group of 28 healthy children. We evaluated gene IL17A expression using real-time PCR and intracellular IL-17A analyzed by flow cytometry. RESULTS We found significantly decreased gene expression in white cells and significantly decreased expression of IL-17A levels on CD4+ T-cells in Down Syndrome. CONCLUSIONS Our data indicate that decreased IL-17A expression may play a significant role in the etiology of infections in Down Syndrome. Moreover, we demonstrated that in Down Syndrome the other gene located outside the extra chromosome 21 is also affected.

Expanding the phenotype associated with missense mutations of the ARX gene

The Aristaless-related homeobox gene (ARX, OMIM# 300382)located in chromosome Xp21.3 belongs to a family of homeobox genes that encode transcription factors playing a crucial role during early embryogenesis. In the brain, ARX is involved in cerebral development and patterning. Mutations in ARX have been shown to cause different forms of intellectual disability, which are classified as a malformation and a nonmalformation group of phenotypes. The latter involves mainly expansions of the trinucleotide repeats coding the second and first polyalanine tracts (polyA). Only few missense mutations in ARX have been reported in nonmalformed patients to date [Shoubridge et al., 2010; Sartori et al., 2011]. Here, we report on a large family with recurrence of intellectual disability and dystonia due to a novel missense mutation in ARX. There were nine affected males over two generations and there was an X-linked pattern of inheritance (Fig. 1). Patient cognitive and social skills were assessed by means of the Wechsler Intelligence Scale for Children (WISC-R) and Edgar Doll’s Vineland Social Maturity Scale (VSMS)

Mutations spectrum in hereditary disorders predisposing to occurrence of intestine polyposis in Poland

The term polyp refers to any overgrowth of tissue from the surface of mucous membranes. Intestinal polyps grow out of the lining of the small and large bowels. The polyps that arise as a result of proliferative dysplasia are termed as adenomatous polyps or adenomas. They are true neoplastic lesions and are precursors of carcinoma. The hamartomatous polyps are formed as a result of abnormal mucosal maturation. They are non-neoplastic and do not have malignant potential. There are several hereditary diseases that produce large numbers of intestinal polyps. These disorders include: familial adenomatous polyposis of the colon (MIM 175100), familial adenomatous polyposis type 2(MIM 608456), Lynchs syndrome (MIM 120435), Peutz-Jeghers syndrome (MIM 175200), Juvenile polyposis syndrome (MIM 174900) PTEN Hamartoma Tumor Syndrome (PHTS) PHTS Includes: Bannayan-Riley-Ruvalcaba Syndrome (MIM 153480), Cowden Syndrome (MIM 153480), PTEN-Related Proteus Syndrome, Proteus-Like Syndrome. Here we present spectrum of mutation detected in over six hundred Polish families with intestinal polyposis. The studies have encompassed over 30 families with Juvenile polyposis syndrome and PHTS, over 40 families with Peutz-Jeghers syndrome and almost 600 families with familial adenomatous polyposis of the colon. The study was in part financed by the Ministry of Education and Science, Poland, grant number N402 481537, N401 331936.

The case of the youngest infant with hepatoblastoma with APC gene mutation

Hepatoblastoma is a rare early malignant liver neoplasm occurring in infants and children. Some cases of hepatoblastoma are associated with genetic conditions such as trisomies of chromosomes 18, Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP). The observed increase in the risk of hepatoblastoma in APC (adenomatous polyposis coli) gene mutation carriers is low, not exceeding 1%, which is associated with APC gene mutation located in the region of codons 459-1309, where most mutations identified in families affected by FAP in Poland are found. Tissues obtained from patients with hepatoblastoma but without the diagnosis of FAP show loss of heterozygocity at the locus of APC or MCC (mutated in colorectal cancers) genes. Hepatoblastoma growth is the result of the sequence of changes in genetic material. However, a major role can be ascribed to the Wnt pathway where somatic mutations have been observed in the genes of Bcathenin (CTNNB1, Cathenin (cadherin-associated protein), beta 1.88kD) and AXIN1 (Axis inhibitor 1). We present a case of familial hepatoblastoma in a 3-month-old infant with a constitutional mutation in the APC gene.