Chimeric genes in acute leukemias

In this thesis the genetic analysis of two types of acute leukemia characterized by translocations will be described. Both translocations generate chimeric genes which are specific for these subtypes of leukemia. The non-random changes that occur at the molecular level can be used in addition to karyotyping to diagnose the presence of tumor cells. The linkage of specific subtypes of acute myeloid leukemia with t(6;9) to a consistent rearrangement involving the ~-gene on chromosome 6 and the g.n-gene on chromosome 9 will be shown (Chapters III.2 and ill.3). This is of clinical importance since a correct diagnosis and subclassification indicates the prognosis of the diaease and helps to choose the right therapy, thereby improving the prognosis for a patient. The second type of acute leukemia that will be discussed is the acute lymphoblastic leukemia associated with the t(9;22). Here, rearrangement of genes results in a chimeric bcr-abl gene on the Philadelphia chromosome. A variant of this chimeric gene was found and analyzed (Chapter II.3). The study of altered genes in leukemia provides us with a multitude of questions conceroing their function and role in the origin of the tumor. However, unusual variants of tumor-specific products may help to solve parts of the mystery of tumor formation

Pfeiffer syndrome

Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet. Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows, abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic testing is important to confirm the diagnosis. Management includes multiple-staged surgery of craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial hypoplasia

KBG syndrome

KBG syndrome is a rare condition characterised by a typical facial dysmorphism, macrodontia of the upper central incisors, skeletal (mainly costovertebral) anomalies and developmental delay. To date, KBG syndrome has been reported in 45 patients. Clinical features observed in more than half of patients that may support the diagnosis are short stature, electroencephalogram (EEG) anomalies (with or without seizures) and abnormal hair implantation. Cutaneous syndactyly, webbed short neck, cryptorchidism, hearing loss, palatal defects, strabismus and congenital heart defects are less common findings. Autosomal dominant transmission has been observed in some families, and it is predominantly the mother, often showing a milder clinical picture, that transmits the disease. The diagnosis is currently based solely on clinical findings as the aetiology is unknown. The final diagnosis is generally achieved after the eruption of upper permanent central incisors at 7–8 years of age when the management of possible congenital anomalies should have been already planned. A full developmental assessment should be done at diagnosis and, if delays are noted, an infant stimulation program should be initiated. Subsequent management and follow-up should include an EEG, complete orthodontic evaluation, skeletal investigation with particular regard to spine curvatures and limb asymmetry, hearing testing and ophthalmologic assessment

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms

VARIABLE EXPRESSION OF THE POPLITEAL PTERYGIUM SYNDROME IN 2 3-GENERATION FAMILIES

Three successive generations in two families affected with the popliteal pterygium syndrome are reported. While expression of the syndrome was relatively mild in the first and second generation, the patients in the third generation showed the full-blown syndrome. Differential diagnosis between mildly affected patients with the popliteal pterygium syndrome and those with Van der Woude syndrome is difficult and may even be impossible. The present observations further support the hypothesis that both syndromes may in fact represent variants of the same condition