Adenoid hypoplasia in the velo-cardio-facial syndrome

The velo-cardio-facial syndrome is one of the most comprehensively studied congenital malformation syndromes of clefting. More than 20 features have been described to date. The purpose of this investigation is to report evidence for congenital hypoplasia of the adenoids in over 80% of the cases studied. Radiographic and nasopharyngoscopic studies of 30 children with velo-cardio-facial syndrome were reviewed along with 30 age- and sex-matched children with nonsyndromic cleft palate to determine the size of their adenoid masses. Eighty-three percent of the subjects with velo-cardio-facial syndrome were found to have small or absent adenoids, whereas only 20% of the controls were found to have small adenoids. None of the control sample had total adenoid absence. These findings may have significant implications for the hypernasal speech patterns often found in individuals with velo-cardio-facial syndrome and may also be related to histories of frequent upper respiratory illnesses in this group.     

Male-to-male transmission of the velo-cardio-facial syndrome: a case report and review of 60 cases

The velo-cardio-facial syndrome is one of the most common syndromes of clefting. Previous reports have shown vertical pedigree transmission, but in all cases the gene was maternally transmitted. The genetics of this syndrome had been suspected as autosomal dominant, but X-linked dominant inheritance could not be ruled out. This report describes an instance of male-to-male transmission of the velo-cardio-facial syndrome. In addition, the clinical findings in 60 cases are reported to further delineate the phenotypic spectrum of the syndrome.     

Association of generalized aggressive periodontitis and ectrodactyly-ectodermal dysplasia-cleft syndrome

Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is an autosomal dominant disorder characterized by the triad of ectrodactyly, ectodermal dysplasia, and facial clefting. Even though literature has documented the association of various genetic disorders with aggressive periodontitis, the periodontal manifestations in patients with EEC syndrome have never been addressed. This case report presents the periodontal status of three patients in a family with EEC syndrome. The presence of generalized aggressive periodontitis was noticed in these patients. EEC syndrome could be a new addition to the group of genetic disorders associated with aggressive periodontitis.     

Split hand and foot deformity and the syndrome of ectrodactyly,ectodermal dysplasia,and clefting (EEC)

Summary Five new cases of ectrodactyly are described. Two patients have the syndrome of ectrodactyly, extodermal dysplasia, and clefting (EEC). In one patient with the EEC syndrome, the disorder seems to represent a new mutation. One woman with isolated ectrodactyly has a daughter with the EEC syndrome. The variation in the clinical expression of this disorder among affected members of the same family makes it difficult to determine whether there may be several mutant alleles responsible for ectrodactyly and its related manifestations.     

Isolation and characterization of a novel gene containing WD40 repeats from the region deleted in velo-cardio-facial/DiGeorge syndrome on chromosome 22q11

Three congenital disorders, cat-eye syndrome (CES), der(22) syndrome, and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), result from tetrasomy, trisomy, and monosomy, respectively, of part of 22q11. They share a 1.5-Mb region of overlap, which contains 24 known genes. Although the region has been sequenced and extensively analyzed, it is expected to contain additional genes, which have thus far escaped identification. To understand completely the molecular etiology of VCFS/DGS, der(22) syndrome, and CES, it is essential to isolate all genes in the interval. We have identified and characterized a novel human gene, located within the 1.5-Mb region deleted in VCFS/DGS, trisomic in der(22) syndrome and tetrasomic in CES. The deduced amino acid sequence of the human gene and its mouse homologue contain several WD40 repeats, but lack homology to known proteins. We termed this gene WDR14 (WD40 repeat-containing gene deleted in VCFS). It is expressed in a variety of human and mouse adult and fetal tissues with substantial expression levels in the adult thymus, an organ hypoplastic in VCFS/DGS.     

Genetic syndromes caused by mutations in epigenetic genes

The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein–Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.     

Linkage of Van der Woude syndrome (VWS) to REN and exclusion of the candidate gene TGFB2 from the disease locus in a large pedigree

Van der Woude syndrome (VWS) is an autosomal dominant disorder associated with one or more of the following features: clefting of the primary or secondary palate, hypodontia or lower lip pits. It has been estimated to account for 2% of all cases of cleft lip and palate. VWS is one of the rare disorders in which clefting of the primary and secondary palate may be seen to segregate as components associated with the same gene. Because of its autosomal dominant inheritance, VWS is readily accessable to linkage analysis as a preliminary step in the identification of the molecular abnormality underlying the clefting effect in the primary and secondary palate. A reported linkage between REN and VWS has promoted us to use pHRnX3.6 (REN) and several markers surrounding REN for a linkage analysis in a large Swiss family. In a second step, linkage analysis was performed to study restriction fragment length polymorphisms for the candidate gene TGFB2 and other loci recently mapped to the candidate region 1q32–1q41. Evidence for linkage ( = 0.00, lod score = 3.01) between REN and VWS could be confirmed in this pedigree. TGFB2 demonstrated recombination with the disease locus and is unlikely to be causative in VWS. The results of a multipoint linkage analysis showed that VWS was flanked by D1S65 and TGFB2 at a maximum location score of 20.3.     

Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor.     

Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27.

We report on a large Dutch family with a syndrome characterized by severe hand and/or foot anomalies, and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal-duct atresia, nail dysplasia, hypohydrosis, hypodontia, and cleft palate with or without bifid uvula. This combination of symptoms has not been reported previously, although there is overlap with the ulnar mammary syndrome (UMS) and with ectrodactyly, ectodermal dysplasia, and clefting syndrome. Allelism with UMS and other related syndromes was excluded by linkage studies with markers from the relevant chromosomal regions. A genomewide screening with polymorphic markers allowed the localization of the genetic defect to the subtelomeric region of chromosome 3q. Haplotype analysis reduced the critical region to a 3-cM interval of chromosome 3q27. This chromosomal segment has not been implicated previously in disorders with defective development of limbs and/or mammary tissue. Therefore, we propose to call this apparently new disorder "limb mammary syndrome" (LMS). The SOX2 gene at 3q27 might be considered an excellent candidate gene for LMS because the corresponding protein stimulates expression of FGF4, an important signaling molecule during limb outgrowth and development. However, no mutations were found in the SOX2 open reading frame, thus excluding its involvement in LMS.     

Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.     

Development of the diarthrodial joints in the rat embryo

The development of appendicular synovial joints of both legs was studied with histological and histochemical techniques in 43 rat embryos aged 12 to 21 days. From this and previous studies, it appears that joints develop by a sequence of cellular events leading to a full expression of the phenotypic characteristics. The classically described stages: cell condensation, three layered mesenchyme, vascular invasion and joint clefting, were chronologically recorded in all joints. The observations relevant to the intra-articular structures, such as joint capsule, menisci and ligaments, were also presented. Previously unreported, cellular aspects were described during joint morphogenesis and their biological significance was discussed. Among these cellular aspects, of particular interest are: a. an early wave of cell necrosis occurring immediately after differentiation of the interzone. Disappearance of necrotic cells is thought to prevent chondrification of this tissue by clearing up the cells with chondroblastic potentialities; and b. a morphologically peculiar type of cells that differentiate alongside, and by the time of, clefting and seem to be related to this process. Thus, the joint clefting appears also to result from a cell-tissue related phenomenon, acting in conjunction with the joint motion, the importance of which has been previously demonstrated.     

Language cannot be reduced to biology: Perspectives from neuro-developmental disorders affecting language learning

The study of language knowledge guided by a purely biological perspective prioritizes the study of syntax. The essential process of syntax is recursion — the ability to generate an infinite array of expressions from a limited set of elements. Researchers working within the biological perspective argue that this ability is possible only because of an innately specified genetic makeup that is specific to human beings. Such a view of language knowledge may be fully justified in discussions on biolinguistics, and in evolutionary biology. However, it is grossly inadequate in understanding language-learning problems, particularly those experienced by children with neurodevelopmental disorders such as developmental dyslexia, Williams syndrome, specific language impairment and autism spectrum disorders. Specifically, syntax-centered definitions of language knowledge completely ignore certain crucial aspects of language learning and use, namely, that language is embedded in a social context; that the role of envrironmental triggering as a learning mechanism is grossly underestimated; that a considerable extent of visuo-spatial information accompanies speech in day-to-day communication; that the developmental process itself lies at the heart of knowledge acquisition; and that there is a tremendous variation in the orthographic systems associated with different languages. All these (socio-cultural) factors can influence the rate and quality of spoken and written language acquisition resulting in much variation in phenotypes associated with disorders known to have a genetic component. Delineation of such phenotypic variability requires inputs from varied disciplines such as neurobiology, neuropsychology, linguistics and communication disorders. In this paper, I discuss published research that questions cognitive modularity and emphasises the role of the environment for understanding linguistic capabilities of children with neuro-developmental disorders. The discussion pertains to two specific disorders, developmental dyslexia and Williams syndrome.     

Expanding the mutation spectrum for Fraser syndrome: Identification of a novel heterozygous deletion in FRAS1

Fraser syndrome (FS) is a rare autosomal recessive inherited disorder characterized by cryptophthalmos, laryngeal defects and oral clefting, mental retardation, syndactyly, and urogenital defects. To date, 250 patients have been described in the literature. Mutations in the FRAS1 gene on chromosome 4 have been identified in patients with Fraser syndrome. So far, 26 mutations have been identified, most of them are truncating mutations. The mutational spectrum includes nucleotide substitutions, splicing defects, a large insertion, and small deletions/insertions. Moreover, single heterozygous missense mutations in FRAS1 seem to be responsible for non-syndromic unilateral renal agenesis.     

UFD1L and CDC45L: a role in DiGeorge syndrome and related phenotypes?

Molecular genetics is contributing to the understanding of normal and abnormal cardiovascular development and morphogenesis. Deletions of chromosome 22q11.2 have been associated with distinct phenotypes that result from a failure to form derivatives of third and fourth branchial arches, including DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). The biochemical mechanisms underlying these phenotypes remain undetermined. A recent study provides new insight into the mechanism by which gene deletions produce the DGS and VCFS phenotypes.     

A new case of Martsolf syndrome

Martsolf syndrome is an autosomal recessive syndrome characterized by microcephaly, mental retardation, cataract, hypogonadism and short stature. A seven-year-old boy was admitted to the hospital with growth retardation and difficulties in walking. His parents were first cousins. Bilateral lens extraction was performed during infancy because of congenital cataract. On physical examination he had short stature, microcephaly, micropthalmia, hypogonadism, mental retardation. Brain magnetic resonance imaging revealed alterations in the white matter. Up to date very few cases with this syndrome have been reported. This is the first case described in the Turkish population and may add valuable information to the literature.     

Craniofacial morphology in the velo-cardio-facial syndrome

The velo -cardio-facial syndrome is a recently delineated congenital malformation syndrome, probably of autosomal dominant inheritance. Previous reports have concentrated on facial, oropharyngeal, cardiac, speech, language, and psychological features of this fairly common syndrome. To date, no radiographic data have been presented which might help to further delineate the syndrome, nor has there been an explanation of the characteristic facial appearance seen in this syndrome. This current study reports on cephalometric evidence of platybasia (obtuse angulation of the cranial base) in the velo -cardio-facial syndrome. The finding of platybasia adds one more phenotypic feature to the syndrome and also may help to explain the facial features of retrognathia, malar flatness, and prominence of the nasal root.     

Cohesinopathies: One ring, many obligations

Over 75 years ago, two human genetic disorders were initially described and named for their founding physicians: Cornelia de Lange (CdLS) and Roberts syndrome (RBS)/SC Phocomelia (SC). In the past 4 years, genetic studies of patients have revealed the primary genes involved in these disorders are the essential, evolutionarily conserved components of the cohesin pathway. This pathway serves to facilitate cohesion between replicated sister chromatids, thereby enabling proper chromosome segregation. As a result of these findings, these disorders now represent a novel class of human genetic disorders known as cohesinopathies. Over 60% of CdLS patients examined have de novo mutations in either: SCC2/NIPBL, SMC1, or SMC3, whereas the causative gene in Roberts syndrome and SC Phocomelia has been identified as ESCO2. Now modern genetic, biochemical, and cell biological approaches may be applied to determine the underlying mechanism of these genetic disorders.     

A human gene similar to Drosophila melanogaster peanut maps to the DiGeorge syndrome region of 22q11

A Drosophila-related expressed sequence tag (DRES) with sequence similarity to the peanut gene has previously been localized to human chromosome 22q11. We have isolated the cDNA corresponding to this DRES and show that it is a novel member of the family of septin genes, which encode proteins with GTPase activity thought to interact during cytokinesis. The predicted protein has P-loop nucleotide binding and GTPase motifs. The gene, which we call PNUTL1, maps to the region of 22q11.2 frequently deleted in DiGeorge and velo-cardio-facial syndromes and is particularly highly expressed in the brain. The mouse homologue, Pnutl1, maps to MMU16 adding to the growing number of genes from the DiGeorge syndrome region that map to this chromosome.     

X-linked dominant inherited diseases with lethality in hemizygous males

Summary X-linked dominant inheritance with lethality in hemizygous males is a rare mode of inheritance. The three best-known disorders which seem to be inherited in this way, are incontinentia pigmenti (IP) Bloch-Sulzberger, oral-facial-digital I (OFD I) syndrome, and focal dermal hypoplasia (FDH syndrome, Goltz syndrome). It is the purpose of this article to give a review of the clinical and genetic aspects of the abovementioned diseases and to add those disorders in which this mode of inheritance is discussed. These disorders are: X-linked chondrodysplasia punctata (CP), cervico-oculo-acusticus syndrome (Wildervanck syndrome, COA), congenital cataract with microcornea or slight microphthalmia, muscular dystrophy-hemizygous lethal, partial lipodystrophy with lipatrophic diabetes and hyperlipidemia, Aicardi syndrome, coxo-auricular syndrome, and Johanson-Blizzard syndrome. OTC defiency is included in the study, although there is no lethality in utero, only in the neonatal period.A critical evaluation of the current literature is carried out.