Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia.

Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive. Approximately 70% of CL/P cases are non-syndromic (MIM 119530), but CL/P also occurs in many single-gene syndromes, each affecting a protein critical for orofacial development. Here we describe positional cloning of the gene responsible for an autosomal recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (HveC; ref. 7), and the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might result from resistance of heterozygotes to infection by these viruses.

Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly.

Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, hypotelorism, microcephaly, or other craniofacial findings that can be present with or without associated brain malformations. The aetiology of HPE is extremely heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the causal involvement of specific teratogens acting at the earliest stages of neurulation. The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE. A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients. We describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation breakpoints in 2p21 are less than 200 kb from the 5' end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE. We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans.

Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination.

Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants). HPE is aetiologically heterogeneous, with both environmental and genetic causes. So far, three human HPE genes are known: SHH at chromosome region 7q36 (ref. 6); ZIC2 at 13q32 (ref. 7); and SIX3 at 2p21 (ref. 8). In animal models, genes in the Nodal signalling pathway, such as those mutated in the zebrafish mutants cyclops (refs 9,10), squint (ref. 11) and one-eyed pinhead (oep; ref. 12), cause HPE. Mice heterozygous for null alleles of both Nodal and Smad2 have cyclopia. Here we describe the involvement of the TG-interacting factor (TGIF), a homeodomain protein, in human HPE. We mapped TGIF to the HPE minimal critical region in 18p11.3. Heterozygous mutations in individuals with HPE affect the transcriptional repression domain of TGIF, the DNA-binding domain or the domain that interacts with SMAD2. (The latter is an effector in the signalling pathway of the neural axis developmental factor NODAL, a member of the transforming growth factor-beta (TGF-beta) family.) Several of these mutations cause a loss of TGIF function. Thus, TGIF links the NODAL signalling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures.

Clinical findings in patients with GLI2 mutations--phenotypic variability.

Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, panhypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly. Subsequently, anophthalmia plus orbital anomalies, heminasal aplasia, branchial arch anomalies and polydactyly have also been incorporated into the general phenotype. Here we described six Brazilian patients with phenotypic manifestations that range from isolated cleft lip/palate with polydactyly, branchial arch anomalies to semi-lobar holoprosencephaly. Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint (TMJ), a new clinical finding observed with mutations of this gene. Clinical, molecular and genetic aspects are discussed.

Possible new syndrome: Left ventricular noncompaction, partial agenesis of the corpus callosum, and developmental delay in a Brazilian child.

We report on the clinical, neuropsychological and language characteristics of a boy with left ventricular noncompaction cardiomyopathy (LVNC), agenesis of the splenium of the corpus callosum, minor anomalies of face and limbs, mild mental retardation, and speech and language disabilities. The occurrence of pilomatricoma (calcifying epithelioma) may be part of the clinical spectrum or a fortuitous finding. Compared to other related conditions with LVNC suggests that this is a "new" unique pattern MCA/MR syndrome.

Tooth abnormalities and soft tissue alterations in patients with G/BBB syndrome.

OBJECTIVE: The G/BBB syndrome is an X-linked recessive disorder characterized by eye anomalies, laryngotracheoesophageal cleft, congenital heart disease, genitourinary anomalies and gastrointestinal disorders. Patients may also present cleft lip and palate, high-arched palate and thin upper lip. This study aimed to investigate the occurrence of tooth abnormalities and soft tissue changes in patients with G/BBB syndrome. DESIGN: Cross-sectional. SUBJECTS AND METHODS: Twenty-one patients with G/BBB syndrome were analyzed as to the presence of tooth abnormalities and soft tissue alterations. MAIN OUTCOME MEASURES: The prevalence of tooth agenesis and supernumerary teeth was compared to patients without morphofunctional alterations, matched for gender and age. RESULTS: All patients had complete cleft lip and palate; 95.23% of patients presented tooth abnormalities, mainly hypoplastic alterations, with predominance of alterations of number, followed by alterations of structure, shape and position. The frequency of tooth agenesis and supernumerary teeth was significantly higher compared with the control group; 11 patients presented incisiform supernumerary teeth in the mandibular anterior region. Ankyloglossia was observed in 11 of 21 patients. CONCLUSION: The presence of mandibular anterior supernumerary teeth and ankyloglossia should be investigated in the clinical evaluation of patients with suspected diagnosis of the G/BBB syndrome.

Pai syndrome: report of seven South American patients.

Frontonasal dysplasia is etiologically heterogeneous and various subsets are known. Pai syndrome is one subset, which is characterized by mild hypertelorism, midline cleft lip, nasal and facial polyps, pericallosal lipoma, ocular anomalies, and normal neuropsychological development. Here, we report seven South American patients and review earlier reported cases. The phenotype is clinically variable and five reported patients were severely affected. The cause of Pai syndrome is unknown to date. Several literature findings have been noted: nondiagnostic and discordant minor signs in a parent of two separate families with an affected child; discordant phenotype in monozygotic twins in one instance; and a de novo reciprocal translocation, 46,X,t(X;16)(q28;q11.2) in one instance.

High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes.

Twenty-eight families with a clinical diagnosis of Treacher Collins syndrome were screened for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported so far for this disease (93%) and bringing the number of known disease-causing mutations from 35 to 51. This is the first report to describe clustering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually high rate of single-nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterogeneity for this condition, as we identified two families with no apparent pathogenic mutation in the gene. Furthermore, our data confirm the absence of genotype-phenotype correlation and reinforce that the apparent anticipation often observed in TCS families is due to ascertainment bias.

Antecubital pterygium and cleft lip/palate presenting as signs of the nail-patella syndrome: report of a Brazilian family.

We report on 4 persons in a 3-generation Brazilian family presenting the nail-patella syndrome. Cleft lip/palate in one patient and antecubital pterygium in 3 of the reported patients are unusual findings related to this condition.

Tibial hemimelia-cleft lip/palate in a Brazilian child born to consanguineous parents.

We report on a Brazilian boy with widely cleft lip and palate and bilateral tibial hemimelia. Normal consanguineous parents, unremarkable gestational antecedents, and normal peripheral lymphocytes and chromosomes suggest autosomal recessive inheritance.

Autosomal recessive short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfeet in male patients.

We report on 2 unrelated Brazilian boys with the syndrome of autosomal recessive short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfeet. This is the first report of male patients.

Short stature, abnormal ears, monodactylous tetraectrodactyly, cleft palate in a Brazilian boy.

We report on a Brazilian boy presenting short stature, small ears with mild overfolding of the helices, monodactylous tetraectrodactyly and cleft palate. We suspect that he has a previously undescribed syndrome of presently unknown cause.

Short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot: a new autosomal recessive syndrome.

We report on 5 unrelated Brazilian children with short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot. Genetic aspects and phenotypic manifestations are compared with those of previous reports of acrofacial dysostoses and with other Robin sequence syndromes. We suspect that these patients present a previously undescribed autosomal recessive syndrome.

Oblique facial clefts: report on 4 Brazilian patients. Evidence for clinical variability and genetic heterogeneity.

Oblique facial clefts are rare and include types 2-6 of Tessier's classification. Here we report on 4 patients with oblique facial clefts and a strikingly similar facial appearance. The pattern of facial involvement, the presence of consanguinity in 3 of them, as well as the entire clinical picture, suggest a unique dysmorphogenetic process which could represent, in some instances, an oculomaxillofacial dysostosis.

Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome.

We report on 3 Brazilian brothers born to normal consanguineous parents (F = 1/16) and presenting ectodermal dysplasia, cleft lip/palate, mental retardation, syndactyly of fingers 2-3, accessory nipples, and ear anomalies. The similarities of these 3 brothers to previously reported cases and the pattern of inheritance are discussed.

EEC syndrome: report on 20 new patients, clinical and genetic considerations.

We report on 20 Brazilian patients (11 sporadic and 9 familial cases) with the ectrodactyly, ectodermal dysplasia, clefting syndrome (EEC syndrome). Genetic aspects, clinical manifestations, and differential diagnosis of the syndromes involving ectodermal dysplasia/limb anomalies and cleft lip/palate are discussed.

Mental retardation, structural anomalies of the central nervous system, anophthalmia and abnormal nares: a new MCA/MR syndrome of unknown cause.

We report on 2 unrelated Brazilian girls, born to nonconsanguineous parents, and presenting structural central nervous system defects, hydrocephaly, macrocephaly, craniosynostosis, prominent forehead, anophthalmia, and abnormal nares. These patients may have a previously undescribed recurrent-pattern cerebro-oculo-nasal syndrome.

Postaxial acrofacial dysostosis: report of a Brazilian patient.

We report on a Brazilian child with postaxial acrofacial dysostosis (AFD)-type Genée-Wiedemann. Clinical and genetic aspects of the postaxial acrofacial dysostoses are discussed.

Atypical postaxial acrofacial dysostosis (AFD): diabetic embryopathy or a new AFD syndrome?

We report on a Brazilian girl, born to a diabetic mother, and presenting with atypical pre/postaxial acrofacial dysostosis, nosologically related to the Genée-Wiedemann syndrome. Clinical and genetic aspects of this acrofacial dysostosis and its relationship to diabetic embryopathy are discussed.

Aarskog syndrome in a Brazilian boy born to consanguineous parents.

We report on a Brazilian boy (F = 1/16) born to consanguineous parents and presenting with typical Aarskog syndrome. Genetic aspects and phenotypic manifestations of this patient are compared with those of the (X-linked) Aarskog syndrome and with the autosomal recessive faciodigitogenital syndrome.