Cenani–Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways

Cenani–Lenz (C–L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features. Most cases are caused by homozygous and compound heterozygous missense and splice mutations of the LRP4 gene. Currently, the syndrome carries one OMIM number (212780). However, C–L syndrome‐like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1‐FMN1 locus, as well as FMN1 mutations. Surprisingly, patients with C–L syndrome‐like phenotype caused by APC truncating mutations have no polyposis despite the increased levels of β catenin. The LRP4 and APC proteins act on the WNT (wingless‐type integration site family) canonical pathway, whereas the GREM‐1 and FMN1 proteins act on the bone morphogenetic protein (BMP) pathway. In this review, we discuss the different mutations associated with C–L syndrome, classify its clinical features, review familial adenomatous polyposis caused by truncating APC mutations and compare these mutations to the splicing APC mutation associated with syndactyly, and finally, explore the pathophysiology through a review of the cross talks between the WNT canonical and the BMP antagonistic pathways.     

Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects

Background

Hemihyperplasia (hemihypertrophy) is defined as asymmetric body overgrowth of one or more body parts. Hemihyperplasia can be isolated or be part of well-defined syndromes such as in the case of Beckwith-Wiedemann syndrome (BWS). Isolated hemihyperplasia is usually sporadic, but a number of familial occurrences have been described.

Case presentation

We describe a Tunisian family in which three maternal cousins and their maternal grandfather present with isolated hemihyperplasia.

Conclusions

The etiology of isolated hemihyperplasia is unknown although in BWS, genomic imprinting has been shown to play a role in the asymmetric overgrowth. Given the similarity between these two conditions, it is possible that both may share a common pathogenesis. We also discuss the possible genetic mechanisms leading to the production of hemihyperplasia in this family.     

Role of Periductal and Ductular Epithelial Cells of the Adult Rat Pancreas in Pancreatic Hepatocyte Lineage: A Change in the Differentiation Commitment

Development of pancreatic hepatocytes in adult rats maintained on copper deficient diet containing 0.6% trien (CuDT) has been reported recently. To elucidate the histogenesis of hepatocytes a sequential study was undertaken using morphologic, histochemical, immunochemical, in situ hybridization, and Northern blot analysis. Male F-344 rats weighing 80 to 90 g were fed CuDT for 8 weeks and returned to normal rat chow. Beginning from 4 weeks of copper depletion, there was a progressive loss of acinar cells and by 8 weeks more than 90% of the acinar tissue was lost. During this period, there was an increase in the number of adipocytes in the interstitium, and in the number of interstitial and ductular cells. Morphologic observations were confirmed by immunoblot and Northern blot analysis, in which the amount of pancreatic proteins and their mRNAs decreased between 5 and 8 weeks. During this period, a progressive increase in the level of albumin mRNA was observed. In situ hybridization, performed at 7 weeks of copper deficiency, showed localization of albumin mRNA over interstitial and ductular cells. Pancreatic hepatocytes were identified immediately after the rats were returned to a normal diet and gradually increased in number. The hepatocytes occupied almost 60% of the pancreatic volume by 8 weeks. During the early recovery phase, hepatocytes were identified in ductules as well as in the interstitium. Based on these studies, it is concluded that both the ductular cells and interstitial cells, which resemble oval cells of liver, are capable of transforming into pancreatic hepatocytes and these cells may be considered stem-cell equivalent.     

Intraspecific density-dependent effects on growth and fecundity of <Emphasis Type="Italic">Diplosentis nudus</Emphasis> (Harada, 1938) Pichelin et Cribb, 2001 (Acanthocephala,Cavisomidae)

During June and July of 2007, a total of 130 specimens of the fish Rastrelliger kanagurta Cuvier (Teleostei, Scombridae), ranging between 19–31 cm in total length, were caught in the Red Sea off the coast of Sharm El-Sheikh, South Sinai, Egypt, and examined for infections by acanthocephalans (65 fish/month). Of this number, 29 (22.30%) were slightly or heavily parasitized by the acanthocephalan Diplosentis nudus (Harada, 1938) Pichelin et Cribb, 2001 (Cavisomidae); no other helminth parasites were found in the intestine of R. kanagurta. Twenty-nine infrapopulations of D. nudus, ranging from 23–218 individuals were collected from the infected fishes. These infrapopulations were distributed in a well-defined fundamental niche along the intestine of R. kanagurta, where the distribution of male worms was not random with respect to female worms size and position and suggests that the male-male competition for access to female may be intense and may select for large males. No correlation between fish size and infrapopulation size was observed. Correlations between female-to-male sex ratio and infrapopulation size, numbers of females and their mean lengths, numbers of males and their mean lengths, mean female length and mean male length within infrapopulation were very strong, and clearly suggest that as the infrapopulation size increased, the number of females and their mean lengths decreased and the number of males and their mean lengths increased. Combination of these results strongly suggests density-dependent effects and competition between male worms. The relationship between the mean female length or size and the number of eggs within its pseudocoel was strongly positive; egg production by female worm significantly decreases as the infrapopulation size increases, suggesting density-dependent reduction in female worm fecundity. Tendency for the variability in male testes size was not significant in infrapopulations of D. nudus. All of these results are discussed.     

Kenny–Caffey syndrome: an Arab variant?

We describe 2 unrelated Bedouin girls who met the criteria for the diagnosis of Kenny-Caffey syndrome. The girls had some unusual features--microcephaly and psychomotor retardation--that distinguish the Kenny-Caffey syndrome profile in Arab children from the classical Kenny-Caffey syndrome phenotype characterized by macrocephaly and normal intelligence. The 2 girls did not harbor the 22q11 microdeletion (the hallmark of the DiGeorge cluster of diseases) that we previously reported in another Bedouin family with the Kenny-Caffey syndrome (Sabry et al. J Med Genet 1998: 35(1): 31-36). This indicates considerable genetic heterogeneity for this syndrome. We also review previously reported 44 Arab/Bedouin patients with the same profile of hypoparathyroidism, short stature, seizures, mental retardation and microcephaly. Our results suggest that these patients represent an Arab variant of Kenny-Caffey syndrome with characteristic microcephaly and psychomotor retardation. We suggest that all patients with Kenny-Caffey syndrome should be investigated for the 22q11 microdeletion. Other possible genetic causes for the Kenny-Caffey syndrome or its Arab variant include chromosome 10p abnormalities.     

Novel 5-flucytosine-resistant clade of Candida dubliniensis from Saudi Arabia and Egypt identified by Cd25 fingerprinting

DNA fingerprinting of Candida dubliniensis isolates using the species-specific probe Cd25 previously showed that this species consists of two distinct groups, termed Cd25 group I and Cd25 group II. The present study investigated the population structure of 30 C. dubliniensis oral isolates from Saudi Arabia and Egypt using Cd25 fingerprinting and rRNA gene internal transcribed spacer region-based genotyping. Cd25 fingerprinting analysis of these isolates revealed two distinct populations, the first of which consisted of 10 closely related genotype 1 isolates (average similarity coefficient [S(AB)] value, 0.86). The second population of 20 isolates was much more heterogeneous (average S(AB) value, 0.35) and consisted of two distinct subpopulations, one of which consisted of genotype 3 isolates (n = 13) and the other of genotype 4 isolates (n = 7). A mixed dendrogram generated from the fingerprint data from the 30 Saudi Arabian and Egyptian isolates, 5 Israeli isolates, and 51 previously characterized international isolates (32 of Cd25 group I and 19 of Cd25 group II) revealed the presence of three distinct main clades. The first corresponded to the previously described Cd25 group I and contained all the Saudi Arabian, Egyptian, and Israeli genotype 1 isolates mixed with international isolates. The second clade corresponded to the previously described Cd25 group II and contained three Israeli isolates, one genotype 2 isolate, one genotype 3 isolate, and a genotype 4 variant isolate, which were mixed with international isolates. The third clade has not been described before and consisted solely of the 20 Saudi Arabian and Egyptian genotype 3 and 4 isolates identified in this study and a previously described genotype 4 Israeli isolate. All 20 Cd25 group III isolates exhibited high-level resistance to 5-flucytosine (MIC > or = 128 microg/ml), whereas all Cd25 group I and Cd25 group II isolates tested (10 Saudi Arabian and Egyptian, 16 Israeli, and 24 international) were susceptible to 5-flucytosine (MIC < or = 0.125 microg/ml). The results of this study show for the first time the presence of a novel 5-flucytosine-resistant clade of C. dubliniensis (Cd25 group III) that is predominant among isolates from Saudi Arabia and Egypt and absent from a previously characterized international collection of 98 isolates from 15 countries.     

Transposon content of nonconjugative plasmids ofEscherichia coli

Department of Biology and General Genetics, Patrice Lumumba Peoples' Friendship University, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Prozorovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 106, No. 12, 711–714, December, 1988.     

Unique demographic situation in the United Arab Emirates

A method which optimizes on global properties of sample recordings is proposed for the definition of and the discrimination between electroencephalogram (EEG) classes. The sample was drawn from students at the University of Heidelberg from 1974 to 1978 and consists of 15 healthy index cases clinically ascertained as belonging to the low voltage EEG group. In addition, the three clinically defined groups: diffuse β (18 index cases), borderline α (12 index cases) and monomorphous α (18 index cases) have been included in the study, as well as the first degree relatives of the index cases, thus providing a clinical classification into four groups. The proposed method provides an automatic and reliable classification algorithm using discriminant and cluster analysis. The relation between such an automatized classification and clinical classification schemes is investigated. In particular, the inheritance of the low voltage, EEG, the question on sex differences and the question of a simple Mendelian mechanism had been examined. The method of random splittings had been applied for discriminant and cluster analysis. Our findings can be summarized as follows: (1) except for the monomorphous α EEG group, the clinical classification shows rather marginal separation (discriminating performance 60% to 75%), while a new and more reliable grouping scheme improves the discriminating performance up to 87% to 91%. The latter scheme leads to the concept of personal channel pattern (PCP) and was compared to the clinical classification scheme by means of contingency tables; (2) only a weak correlation between the clinically and PCP-based groups could be found (Cramér Index: 0.27). Accordingly, we continued to investigate the extent to which the proposed EEG classification scheme can nevertheless explain the genetic mechanisms apparently involved in the low voltage EEG. We thus considered the role of sex differences manifest in our proposed new grouping scheme; (3) males occurred more frequently in the new group 3 and females more frequently in the new group 1. In this regard, a much better correlation of the new groups between mothers and children than between fathers and children was observed; and (4) with help of our new PCP scheme, we have been able to reproduce a simple two gene Mendelian scheme to explain inheritance of the clinical low voltage EEG group. In this PCP-based scheme, the low voltage property does not occur when dominance of a certain gene (called gene A) is absent. © 1996 Wiley-Liss, Inc.     

Circulating immune complexes in patients with cryptogenic fibrosing alveolitis.

Increased Clq binding levels have been obtained in serum from twenty-one (50%) of forty-two patients with cryptogenic fibrosing alveolitis (CFA) suggesting the presence of circulating immune complexes. There was a low frequency of positive results using a number of other tests for circulating immune complexes. The increased Clq binding levels were observed in six (35%) out of seventeen patients with lone lung involvement and in fifteen (60%) out of twenty-five patients with extrapulmonary connective tissue disorders. There was an especially close correlation between arthritis and elevated Clq binding. A strong correlation between Clq binding levels and levels of circulating rheumatoid factor (RF) and IgG, and enhancement in macrophage radiobioassay tests using RF-containing sera, suggested that RF might be involved in the circulating immune complexes in these patients. DNAase pre-treatment of sera did not influence the findings, and there was no correlation between Clq binding and levels of immunofluorescent ANA, C-reactive protein levels, or platelet counts. A weak correlation between Clq binding and erythrocyte sedimentation rates, and slightly lower binding levels in treated than untreated patients with 'lone' CFA suggested that binding levels may give some indication of disease activity and may in some instances be influenced by treatment.