Macrocephaly with multiple epiphyseal dysplasia: a second example of Al Gazali-Bakalinova syndrome?

Four individuals from one consanguineous family affected with macrocephaly, multiple epiphyseal dysplasia and distinctive facies were presented by Al Gazali and Bakalinova in 1998 (1) as a distinct clinical entity. To the best of our knowledge, no other similarly affected family has been presented in the literature. Here, we present an affected macrocephalic male, from a consanguineous family, with facial anomalies, cranial MRI findings and multiple epiphyseal dysplasia findings. We believe this is the second family with a similar clinical spectrum and the same inheritance pattern as those of the family presented by Al Gazali and Bakalinova. Pectus carinatum, hip dislocation and a history of prenatal polyhydramnios have been noted as additional findings in our patient.

New phenotype with generalized platyspondyly, large mandible, hypoplastic teeth, strabismus, hyperopia and low cholesterol levels.

A sporadic, adult male patient with generalized platyspondyly, large mandible, hypoplastic teeth, strabismus, and low serum cholesterol levels is presented. Some of the patient's features resemble brachyolmia, Spondylo-epiphyseal dysplasia tarda, Kenny-Caffey and Stickler syndromes. Based on literature review, possible diagnoses are discussed. In conclusion, this patient can have a variant of brachyolmia or Spondylo-epiphyseal dysplasia tarda. However, we cannot exclude that this constellation of clinical features may represent a new syndrome.

Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders affecting approximately 1/3500 individuals in all ethnic groups. It is characterized by cutaneous and plexiform neurofibromas, café-au-lait spots, Lisch nodules, freckling in axillary and inguinal regions, optic gliomas and an increased risk of malignancy. The mutation rate of NF1 is one of the highest known for human disorders: approximately 50% of all affected individuals carry de novo mutations. Detection of disease causing mutations in the NF1 gene allows presymptomatic and prenatal diagnosis, but is complex and time-consuming due to the large size of the gene, the existence of pseudogenes, the lack of clustering of the mutations in a particular region of the gene, and the variability of clinical findings. Because the time for investigations in prenatal diagnosis is restricted, detection of disease-associated NF1 alleles is more rapid and useful especially for familial cases. Therefore, genetic diagnosis of NF1 is frequently performed by linkage analysis. In our laboratory, 37 families were characterized with this method, of which two requested prenatal diagnosis. One fetus was found to be under NF1 risk. However, parents elected to continue pregnancy: the child is now 2.5 years old and has NF1 features. The phenotypic variability and the absence of genotype-phenotype correlation create difficulties in reproductive decisions for NF1 families, underlining the importance of appropriate counseling and detailed discussion of possible outcomes before genetic testing of the fetus.

A breast cancer patient with pelvic and gastric malignancy after adjuvant tamoxifen treatment for breast cancer.

As is known, tamoxifen therapy is related to endometrial proliferation, hyperplasia, polyp formation, invasive carcinoma and uterine sarcoma. In this study, we present a 75-year-old woman who had five children. Gastric tumor, endometrial carcinoma and cervical adenocarcinoma in situ were detected after treatment with tamoxifen for breast cancer. It seems that being aware of the undesirable affects of tamoxifen treatment during the chemotherapy and post-chemotherapy period is very important.

Magnetic resonance cholangiopancreatography in cholestatic diseases.

BACKGROUND/AIMS: To evaluate the usefulness of magnetic resonance cholangiopancreatography in cholestasis. METHODOLOGY: Sixty-seven patients with cholestasis underwent ultrasound and magnetic resonance cholangiopancreatography, subsequently. The results of ultrasound and magnetic resonance cholangiopancreatography were interpreted by two independent radiologists. RESULTS: According to ultrasonographic findings intra- and extrahepatic cholestasis were diagnosed in 62.7% and 37.3% of patients, respectively. Magnetic resonance cholangiopancreatography revealed intra- and extrahepatic cholestasis in 52.2% and 47.8% of patients at the same group, respectively (p=0.016, kappa=0.789). Endoscopic retrograde cholangiopancreatography was indicated in 37.3% of patients (22.4% diagnostic, 14.9% therapeutic) according to ultrasonographic findings. However, 41.8% of patients had indication for endoscopic retrograde cholangiopancreatography following magnetic resonance cholangiopancreatography in the same group. In 20% of patients who needed diagnostic endoscopic retrograde cholangiopancreatography according to ultrasonographic findings, endoscopic retrograde cholangiopancreatography wasn't indicated after magnetic resonance cholangiopancreatography. Similarly, 8.9% of patients who didn't have indication for endoscopic retrograde cholangiopancreatography according to ultrasonographic findings underwent endoscopic retrograde cholangiopancreatography (p=0.508, kappa=0.72). CONCLUSIONS: Magnetic resonance cholangiopancreatography is valuable in diagnosis of extrahepatic cholestasis in patients suspected with intrahepatic cholestasis according to ultrasonographic findings. Magnetic resonance cholangiopancreatography does not prevent endoscopic retrograde cholangiopancreatography requirement significantly in patients who need diagnostic endoscopic retrograde cholangiopancreatography following ultrasonography.

A chronic myeloid leukemia-like syndrome case with del (12) (p12) in a Li-Fraumeni syndrome family.

Li-Fraumeni syndrome is a familial cancer syndrome characterized by different tumors and hereditary p53 mutations. Here, a chronic myeloid leukemia-like syndrome case in a Li-Fraumeni syndrome family with del (12) (p12) cytogenetic abnormality was presented. A hereditary p53 mutation (pro309ser) supported the Li-Fraumeni syndrome diagnosis in this family. This syndrome was characterized by the clonal myeloproliferative accumulation in bone marrow and peripheral blood with negative bcr/abl gene rearrangement finding. The etiology of this rare syndrome is still unclear. This is the only chronic myeloid leukemia-like syndrome case reported in a Li-Fraumeni syndrome family. Del (12)(p12) was observed in leukemias except chronic myeloid leukemia-like syndrome. The deletion in chromosome 12p12 with hereditary p53 mutation should have a critical role in chronic myeloid leukemia-like syndrome etiology in our case.

Chronic myelomonocytic leukemia developed 2 years after the onset of immune thrombocytopenic purpura like syndrome.

An 80-year old man was diagnosed as having immune thrombocytopenic purpura based on epistaxis, purpura and by the platelet count 8 x 10(9)/l. Prednisolone and gamma globulin were administered and the platelet count had been kept around 50 x 10(9)/l during his follow up. Two years from the onset of immune thrombocytopenic purpura he was admitted because of leukocytosis (79 x 10(9)/l with 79% monocytes), anemia and thrombocytopenia. Hypercellular bone marrow with dysplasia of three lineages was observed. In the bone marrow cytogenic analysis, a -6, clonal cytogenic abnormality was observed. 45XY, der(6), t(6;6)(q16;q23). He was diagnosed as having chronic myelomonocytic leukemia. This is a difficult case in which it was diagnosed as refractory thrombocytopenia as a subgroup of myelodysplastic syndrome, rather than immune thrombocytopenic purpura. which might have preceded the development of chronic myelomonocytic leukemia.

A DIDMOAD syndrome family with juvenile glaucoma and myopia findings.

We present here two DIDMOAD syndrome cases (Diabetes Mellitus, Diabetes Insipidus, Optic Atrophy, Deafness) in a Turkish family. In the examination of the propositus who had consanguineous parents, diabetes mellitus, diabetes insipidus, optic atrophy, and deafness were observed in addition to myopia, juvenile glaucoma, posterior polar cataract, and dilatation of the urinary tract. Diabetes mellitus, diabetes inspidus, optic atrophy, deafness, myopia, and ventricular septal defect were observed in his elder brother. Juvenile onset diabetes mellitus, congenital glaucoma, deafness, and heart disease were the other remarkable findings observed in relatives to this family. Juvenile glaucoma, posterior polar cataract observed in our propositus, and myopia in both our DIDMOAD syndrome cases are the first ophthalmic manifestations described in the DIDMOAD syndrome.

Association of sets of alleles of genes encoding beta3-adrenoreceptor, uncoupling protein 1 and lipoprotein lipase with increased risk of metabolic complications in obesity.

OBJECTIVE: To investigate the relationship between the polymorphisms of the beta3-AR (Trp64Arg), UCP1 (A-->G) and LPL (HindIII and PvuII) loci and the metabolic complications associated with obesity in a Turkish population. SUBJECTS: 271 unrelated individuals of Turkish origin including obese (body mass index, BMI>30 kg¿m2) and lean (BMI< or =25 kg¿m2) subjects. MEASUREMENTS: Anthropometric (weight, height and blood pressure) and metabolic measurements (plasma levels of glucose, cholesterol and triglycerides), and determination of beta3-AR, UCP1 and LPL genotypes by polymerase chain reaction followed by enzymatic digestion. RESULTS: The distributions of genotypes for each candidate gene (beta3-AR, UCP1 and LPL) were similar between the obese and the lean subjects. The Arg64 allele of the beta3-AR gene was absent from massively obese men. GG carriers of the A-->G variant of the UCP1 gene showed BMI-associated increases of cholesterol levels which were more marked than both AA (P=0.027) and AG (P=0.039) carriers. Obese P+ carriers of the LPL PvuII variant had significantly higher levels of glucose than non-carriers (P=0.011), whereas obese P+P+ carriers did not have significantly different levels of triglycerides than non-carriers (P=0.087). Moreover, carriers of both alleles (G&P+) had higher levels of glucose than non-carriers (P=0.048), but did not have significantly different levels of triglycerides than non-carriers (P=0.125). However, the BMI-associated increase of triglycerides of P+&G carriers was significantly more marked than that of P+ carriers (P=0.0085). CONCLUSION: Our data support the idea that alleles of specific genes (UCP1, LPL and beta3-AR) might play a role in the development of certain metabolic complications of obesity and might have additive effects when combined with each other (as in the case of UCP1 and LPL). International Journal of Obesity (2000)24, 93-100

Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family.

Li-Fraumeni syndrome is an autosomal dominant disorder that is characterized by various types of cancer in childhood and adult cases. Although hereditary TP53 mutation is very rare in different human cancers, it has been frequently reported in Li-Fraumeni syndrome. On the other hand, hereditary mutations of TP57KIP2, P15INK4B, and P16INK4A, which affect the cell cycle similar to TP53, were observed in some types of cancer. In a Turkish family with the diagnosis of Li-Fraumeni syndrome, we analyzed the mutation pattern of TP53, P57KIP2, P15INK4B, and P16INK4A in the peripheral blood, and loss of heterozygosity (homo/hemizygous deletion) pattern of TP53 and P15INK4B/P16INK4A in two tumor tissues. The propositus had a seminoma, his daughter a medulloblastoma, and one of his healthy cousins, a TP53 codon 292 missense point mutation (AAA-->ATA; Lys-->Ile) in the peripheral blood cells. Tumor tissue obtained from the propositus with the seminoma revealed loss of heterozygosity in the TP53 gene. In the analyses of tumor tissues from the propositus and his daughter, a P16INK4A codon 94 missense point mutation (GCG-->GAG; Ala-->Glu) was observed with the hereditary TP53 mutation. P16INK4A codon 94 mutation observed in our family is a novel mutation in Li-Fraumeni syndrome. No other gene alteration in TP53, P57KIP2, P15INK4B, and P16INK4A was observed. Existence of the P16INK4A mutation and the hereditary TP53 mutation with or without loss of heterozygosity in the TP53 gene (seminoma/medulloblastoma) may be evidence for a common mechanism involved in tumorogenesis. The gene alterations in TP53 and P16INK4A genes may be used as tumor markers in our family.

Cumulation of TP53 mutations and p16INK4A/p15INK4B homozygous deletions in human papilloma virus type 16 positive scrotal cancer.

Scrotal cancer is the first described occupational cancer. The frequency of occupation-related scrotal cancer is very rare because of better hygiene and protective clothing. Human papilloma viruses (oncogenic types 16 and 18) were reported as the causative agents in the pathogenesis of scrotal cancers. E5, E6, and E7 proteins, expressed by human papilloma virus type 16, affect the cell cycle at the G1 checkpoint. TP53, p16INK4A, and p15INK4B were reported as the transcription factors that regulate the cell cycle on the same pathway. Here, the mutation pattern of TP53, p16INK4A, and p15INK4B genes and the homo/hemizygous deletion patterns of p16INK4A/p15INK4B genes are presented in four scrotal carcinoma cases. The results were correlated with the findings of oncogenic human papilloma viruses (types 16 and 18) in this panel. In two of four case, human papilloma virus type 16 was observed. Homozygous deletion in p16INK4A/p15INK4B genes and a codon 259 missense point mutation (GAC-->TAC; Asp-->Tyr) in the TP53 gene were observed in one human papilloma positive scrotal carcinoma case. The homozygous deletion in p16INK4A/p15INK4B genes was observed in another human papilloma positive scrotal carcinoma case. The cumulation of TP53 mutations and p16INK4A/p15INK4B homozygous deletions in human papilloma virus type 16 positive scrotal carcinoma cases indicate that the alterations of TP53, p16INK4A, and p15INK4B genes have an important role in the progression of scrotal cancers, as well as other factors. The survival rate for the two human papilloma virus type 16 positive patients who had a TP53 mutation or p16INK4A/p15INK4B homozygous deletion or both was lower than that for the human papilloma virus type 16 negative cases who had no TP53, p16INK4A, and p15INK4B mutation. The molecular alteration of TP53, p16INK4A, and p15INK4B genes may be useful as a prognostic marker in scrotal cancer.

p53 and p16INK4A mutations during the progression of glomus tumor.

Glomus tumors are significantly rare tumors of carotid body. The great majority of these tumors are benign in character. Here we present two brothers with hereditary glomus jugulare tumor who had consanguineous parents. Radiotherapy was applied approximately 8 and 10 years ago for treatment in both cases. Eight years later, one of these cases came to our notice due to relapse. The mutation pattern of p53, p57KIP2, p16INK4A and p15NK4B genes which have roles in the cell cycle, was analyzed in tumor samples obtained from the two affected cases in the initial phase and from one of these cases at relapse. The DNA sample obtained from the case in initial diagnosis phase revealed no p53, p57KIP2, p16INK4A or p15INK4B mutation. He is still in remission phase. Despite the lack of p53, p57KIP2, p16INK4A and p15INK4B mutation at initial diagnosis the tumor DNA of the other case in relapse revealed p53 codon 243 (ATG-->ATC; met-->ile) and p16 codon 97 (GAC-->AAC; asp-->asn) missense point mutations. No loss of heterozygosity in p53 and p16INK4A was observed by microsatellite analysis of tumoral tissues in these cases. P53 and p16INK4A mutations observed in relapse phase were in conserved regions of both genes. No previous reports have been published with these mutations in glomus tumor during progression. The mutation observed in this case may due to radiotherapy. In spite of this possibility, the missense point mutations in conserved region of p53 and p16INK4A genes may indicate the role of p53 and p16INK4A in tumor progression of glomus tumors.

The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe.

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co-receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delta ccr5 allele was investigated in 18 European populations. A North to South gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%). Highly polymorphic microsatellites (IRI3.1, D3S4579 and IRI3.2, D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant. A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3.1 and IRI3.2 microsatellites: >95% of the Delta ccr5 chromosomes carried the IRI3.1-0 allele, while 88% carried the IRI3.2-0 allele. These alleles were found respectively in only 2 or 1.5% of the chromosomes carrying a wild-type CCR5 gene. From these data, it was inferred that most, if not all Delta ccr5 alleles originate from a single mutation event, and that this mutation event probably took place a few thousand years ago in Northeastern Europe. The high frequency of the Delta ccr5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with homo- or heterozygous carriers of the Delta ccr5 allele.

P53, p15INK4B, p16INK4A and p57KIP2 mutations during the progression of chronic myeloid leukemia.

The occurrence of acute transformation during the treatment of chronic myeloid leukemia (CML) is still a poorly understood mechanism. In this disease p53, p16INK4A, p15INK4B, p57KIP2 mutations and p15INK4B/p16INK4A homo/hemizygous deletions were analyzed in the initial diagnosis phase and during the treatment phase of twelve CML cases, in order to establish whether there was a consistent molecular genetic alteration in its progression. During the treatment period, four of twelve cases had blastic crisis. All the mutations observed in p53, p16INK4A and p15INK4B cumulated in three out of four CML cases who had blastic crises. In one case, p53 codon 282 mutation (CGG-->TGG; arg-->trp) were observed in initial diagnosis. Seven months later, G-->C transition in the 3' side of p15 cDNA (778. nucleotide) was observed in the accelerated phase with the same p53 codon 282 mutation. Thirteen months later, this patient died as a result of blastic crisis. The patient in blastic crises in the initial diagnosis phase had a mis-sense point mutation in p16 codon 69 (ACT-->AGT; thr-->ser) and a polymorphism in codon 68 (GCC-->GCG). Six months later, this patient also died. In one case, p53 codon 237 mutation (ATG-->ATA; met-->ile) were observed in the initial diagnosis phase. Then months later, the patient died as a result of blastic crises. No p15INK4B/p16INK4A homo/hemizygous deletion and p57KIP2 gene mutation which was described in the same pathway were observed in CML progression. These results indicate that p15INK4B and p16INK4A gene alterations may have an affect on the progression of CML-like p53 mutation. A correlation was found with the progression of CML and p53, p15INK4B and p16INK4A somatic mutations. Finding p15INK4B and p16INK4A gene alteration as well as p53 mutations may be a prognostic marker in patients with CML.

Application of the 'Apt test' in prenatal diagnosis to evaluate the fetal origin of blood obtained by cordocentesis: results of 30 pregnancies.

This study aimed to set up a practical lab-side approach to discriminate fetal from maternal blood in samples obtained by cordocentesis. To determine the fetal origin of the blood, a modified Apt test was applied to 30 cases of prenatal diagnosis. A change of colour of the fetal and adult blood during the procedure was the hallmark to assess fetal origin. At the end of 60 s of the test, fetal blood yielded a pink colour whereas adult blood was dark green-brown. The test was repeated in mixtures of fetal and adult blood. The results suggest that the modified Apt test is a practical, quick, inexpensive, and efficient test to determine the origin of blood samples obtained by cordocentesis. However, it should be kept in mind that samples containing a mixture of both fetal and adult blood could also yield a fetal blood reaction. When maternal contamination is suspected, we propose that at least 30 metaphases from different slides should be counted. This could yield fetal as well as maternal chromosomes.

A digital splenoportography: more sensitive method of detecting spontaneous splenorenal shunt.

Splenoportography was performed upon 195 pediatric patients, including 137 by conventional technique and 58 by digital subtraction technique. The results obtained were compared, and it was found that the percentage of diagnosis of spontaneous splenorenal shunt was higher with digital than with conventional technique. In conclusion digital technique is a more sensitive and safer method than the conventional method.

Pericardiac extravasation during intravenous digital subtraction angiography: a case report.

The authors reported a case, pericardiac extravasation of contract medium during an intravenous angiographic (IV DSA) procedure. To their knowledge this is the first such case in the literature. They suggest modifications of the IV DSA method to avoid this complication.

A high incidence of spontaneous splenorenal shunting shown by digital splenoportography.

The technique of digital splenoportography with thin flexible needles and small amounts of dilute contrast medium is described as one particularly suitable for use in paediatric patients. The authors report a high incidence of spontaneous splenorenal shunting revealed in their patients by this technique.