A novel heterozygous missense mutation G316D of SIX3 gene in a Brazilian patient with holoprosencephaly-like phenotype and Langerhans cell histiocytosis.

Here we report on a Brazilian female patient with the clinical manifestations of the holoprosencephaly-like phenotype who also presented with a retroocular granuloma diagnosed as Langerhans cell histiocytosis in early infancy. Mutation analysis showed a missense mutation (G316D) in the exon 2 of SIX3 gene, which was predicted as damaged by the PolyPhen program. We discuss the clinical and genetic aspects of this unusual case.

Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients.

Holoprosencephaly (HPE) is genetically heterogeneous. Variable phenotypic manifestations within families with normal and affected patients have been attributed to the number and type of HPE gene mutations. Environmental agents may also contribute to the severity as well as the requirement of multiple hits. Clinical expression is extremely variable ranging from minor facial signs to complex craniofacial anomalies such as cyclopia. Main genes involved include SHH, GLI2, PTCH1, TGIF, ZIC2, TDGF1, SIX3; however, several other candidates have been proposed. Recently it was established that the human growth arrest specific gene 1 (GAS1) is a potential locus for several human craniofacial malformations. Here, we report on four Brazilian patients with GAS1 DNA sequence change who presented variable phenotypical manifestations ranging from classic HPE to HPE-like signs. Two patients had single DNA sequence change in the GAS1 gene, while in other two, an additional mutation in the SHH gene was observed. Clinical manifestations presented by these patients suggest that GAS1 could be considered a candidate locus for one of the types of human HPE.

Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil.

Here we report on the clinical and genetic data for a large sample of Brazilian patients studied at the Hospital de Reabilitação de Anomalas Craniofaciais-Universidade de São Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype. The sample included patients without detected mutations in some HPE determinant genes such as SHH, GLI2, SIX3, TGIF, and PTCH, as well as the photographic documentation of the previously reported patients in our Center. The HPE-L phenotype has been also called of HPE "minor forms" or "microforms." The variable phenotype, the challenge of genetic counseling, and the similarities to patients with isolated cleft lip/palate are discussed.

Holoprosencephaly, ectrodactyly, and bilateral cleft of lip and palate: exclusion of SHH, TGIF, SIX3, GLI2, TP73L, and DHCR7 as candidate genes.

We describe a Brazilian boy with semilobar holoprosencephaly, ectrodactyly, bilateral cleft of lip and palate, and severe mental retardation. The karyotype was normal and the screening for mutations in the genes SHH, TGIF, SIX3, GLI2, TP73L, and DHCR7 did not show any change. This rare condition was described previously in seven male patients. Clinical and genetic aspects are discussed.

Variable phenotypic manifestations of a K44N mutation in the TGIF gene.

The etiologies and clinical spectra of HPE are extremely heterogeneous. Here, we report a Brazilian boy with lobar holoprosencephaly who was ascertained in a sample of 60 patients with HPE and HPE-like phenotypes and screened for molecular analysis of the major HPE causative genes: SHH, PTCH, SIX3, GLI2, and TGIF. This boy presented a p.K44N (c.132G>T) mutation in exon 2 of the TGIF gene which was inherited from his phenotypically normal mother. This mutation leads to lysine to arginine amino acid change and is predicted to be a damaging mutation. Clinical aspects involving variable phenotypical manifestations in different mutations of TGIF are discussed.

Desempenho em consciência fonológica, memória operacional, leitura e escrita na dislexia familial / Phonological awareness, working memory, reading and writing performances in familial dyslexia

TEMA: dislexia familial. OBJETIVO: caracterizar o desempenho em consciência fonológica, memória operacional, leitura e escrita do probando com dislexia e de seus familiares afetados. MÉTODO: participaram deste estudo 10 núcleos familiais de parentesco natural de indivíduos com queixa específica de problemas de leitura e compreensão. Foram selecionadas famílias de probandos naturais e residentes na região do oeste do estado de São Paulo. Os requisitos de inclusão dos probandos foram: ser falante nativo do Português Brasileiro, ter idade acima de oito anos, apresentar histórico familial positivo para os problemas de aprendizagem, ou seja, apresentar no mínimo um outro parente com dificuldade para aprender em três gerações. Os critérios de exclusão para o grupo de probandos foram: apresentar qualquer distúrbio neurológico-genético tais como distonia, doenças extras piramidais, deficiência mental, epilepsia, transtorno do déficit de atenção e hiperatividade (TDAH); sintomas ou condições psiquiátricas; ou outras condições pertinentes que poderiam gerar erros no diagnóstico. Para o diagnóstico de dislexia do desenvolvimento foram coletados dados de antecedente familial na histórica clínica com os pais das crianças e adolescentes para realização do heredograma. Foram realizadas avaliações neurológica, fonoaudiológica, psicológica e de desempenho escolar nos probandos e em seus parentes. RESULTADOS: os resultados deste estudo sugeriram que os probandos e seus familiares com dislexia apresentaram desempenho inferior ao grupo controle quanto à nomeação rápida, leitura, escrita e consciência fonológica. CONCLUSÃO: alterações em consciência fonológica, memória de trabalho, leitura e escrita tem susceptibilidade genética que possivelmente em interação com o meio ambiente determinam o quadro de dislexia.

BACKGROUND: familial dyslexia. AIM: to characterize and compare the phonological awareness, working memory, reading and writing abilities of individuals whose family members are also affected. METHOD: in this study 10 familial nuclei of natural family relationship of individuals with dyslexia were analyzed. Families of natural individuals living in the west region of the state of São Paulo were selected. Inclusion criteria were: to be a native speaker of the Brazilian Portuguese language, to have 8 years of age or more, to present positive familial history for learning disabilities, that is, to present at least one relative with difficulties in learning. Exclusion criteria were: to present any neurological disorder genetically caused or not, in any of the family members, such as dystonia, extra pyramidal diseases, mental disorder, epilepsy, attention deficit and hyperactivity disorder (ADHA); psychiatric symptoms or conditions; or any other pertinent conditions that could cause errors in the diagnosis. As for the diagnosis of developmental dyslexia, information about the familial history of the adolescents and children was gathered with the parents, so that a detailed pedigree could be delineated. Neurological, psychological, speech-language, and school performance evaluations were made with the individuals and their families. RESULTS: the results of this study suggest that the dyslexic individuals and their respective relatives, also with dyslexia, presented lower performances than the control group in terms of rapid automatic naming, reading, writing and phonological awareness. CONCLUSION: deficits in phonological awareness, working memory, reading and writing seem to have genetic susceptibility that possibly determine, when in interaction with the environment, the manifestation of dyslexia.

[Phonological awareness, working memory, reading and writing performances in familial dyslexia]. / Desempenho em consciência fonológica, memória operacional, leitura e escrita na dislexia familial.

BACKGROUND: familial dyslexia. AIM: to characterize and compare the phonological awareness, working memory, reading and writing abilities of individuals whose family members are also affected. METHOD: in this study 10 familial nuclei of natural family relationship of individuals with dyslexia were analyzed. Families of natural individuals living in the west region of the state of São Paulo were selected. Inclusion criteria were: to be a native speaker of the Brazilian Portuguese language, to have 8 years of age or more, to present positive familial history for learning disabilities, that is, to present at least one relative with difficulties in learning. Exclusion criteria were: to present any neurological disorder genetically caused or not, in any of the family members, such as dystonia, extra pyramidal diseases, mental disorder, epilepsy, attention deficit and hyperactivity disorder (ADHA); psychiatric symptoms or conditions; or any other pertinent conditions that could cause errors in the diagnosis. As for the diagnosis of developmental dyslexia, information about the familial history of the adolescents and children was gathered with the parents, so that a detailed pedigree could be delineated. Neurological, psychological, speech-language, and school performance evaluations were made with the individuals and their families. RESULTS: the results of this study suggest that the dyslexic individuals and their respective relatives, also with dyslexia, presented lower performances than the control group in terms of rapid automatic naming, reading, writing and phonological awareness. CONCLUSION: deficits in phonological awareness, working memory, reading and writing seem to have genetic susceptibility that possibly determine, when in interaction with the environment, the manifestation of dyslexia.

GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum?

We report four patients with GLI2 mutations together with their associated phenotypes: (1) holoprosencephaly-like phenotype, (2) anophthalmia, branchial arch anomalies, and CNS abnormalities, (3) heminasal aplasia and orbital anomalies, and (4) lobar holoprosencephaly. This diversity of phenotypes expands our understanding. Findings include not only (1) holoprosencephaly or a holoprosencephaly-like phenotype, but also (2) heminasal aplasia with orbital anomalies, and (3) branchial arch anomalies of the type seen in hemifacial microsomia with anophthalmia and in oculoauriculofrontonasal syndrome. Finally, this is the first report of a double mutation involving GLI2 and PTCH in the same patient.

SIX3 mutations with holoprosencephaly.

Here, we report six Brazilian patients with holoprosencephaly caused by SIX3 mutations. Missense mutations were more common than frameshift mutations. Comparison of patients with missense versus frameshift mutations was essentially unremarkable. Our cases suggest that SIX3 mutations result in a more severe phenotype than other gene mutations for holoprosencephaly. One patient had a double SIX3 mutation, which has not been reported previously. In our SIX3 mutations, three were transmitted by the paternal side, two were transmitted by the maternal side, and one was a de novo event. Mutations in normal parents with severe involvement of their offspring does not allow prediction of phenotypic severity, which makes genetic counseling difficult.

Holoprosencephaly-like phenotype: clinical and genetic perspectives.

We report 22 patients with normal neuropsychological development and a holoprosencephaly-like (HPE-like) phenotype screened for SHH, SIX3, TGIF, and GLI2. These patients were divided into two groups: (1) 6 patients with SHH and GLI2 mutations and (2) 16 patients with no detectable mutations. We discuss the phenotypic manifestations, evolution of the phenotype, and neuroimaging in the two groups. Conclusions about the HPE-like phenotype include (1) initial appearance as an unusually wide, and very severe unilateral cleft lip-palate in some cases; (2) variability with the expression of minor anomalies in some cases, such as single maxillary central incisor; (3) identifiable mutations in some cases and absence of mutations in others; (4) essentially normal MRI in the most cases (pituitary tumor in two cases and choroid fissure cyst in one case in Group 1; empty sella turcica in one case in Group 2); (5) intelligence within the normal range; and (6) familial aggregation in some instances. Implications include (1) thorough examination of family members for minor anomalies; (2) MRI and developmental assessment for the proband; and (3) molecular analysis.

PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.

We report five Brazilian probands with PATCHED (PTCH) mutations and highly variable phenotypes with holoprosencephaly in four cases and holoprosencephaly-like facial features with a normal MRI in a fifth case. Three of our mutations were novel: Ala443Gly, Val751Gly, and Val908Gly. Two patients had the same mutation (Val908Gly), but were phenotypically different: alobar holoprosencephaly, absent nasal septum, and midline cleft lip-palate in one case, and lobar holoprosencephaly, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other. One of our patients had a Thr1052Met mutation, holoprosencephaly-like facial features, and a normal MRI. Ming et al. [(2002); Hum Genet 110:297-301] reported an identical mutation, but with alobar holoprosencephaly.

Single maxillary central incisor, holoprosencephaly, and holoprosencephaly-like phenotype.

Three patients--one with alobar holoprosencephaly and two with a holoprosencephaly-like phenotype--are reported with no identifiable mutations. In each case, one parent had a single maxillary central incisor (SMCI). We briefly review the holoprosencephaly-like phenotype and present a table of 25 conditions with SMCI.

Macrostomia, preauricular tags, and external ophthalmoplegia: a new autosomal dominant syndrome within the oculoauriculovertebral spectrum?

OBJECTIVE: First and second branchial arch involvement during early embryonic development results in a wide spectrum of anomalies that encompass diverse, superimposed, and heterogeneous phenotypes within the so-called oculoauriculovertebral spectrum. Nine members of a Brazilian family presenting typical branchial arch involvement in association with external opthalmoplegia are reported. CONCLUSION: Macrostomia or abnormal mouth contour, preauricular tags, and uni- or bilateral ptosis were present in association in several patients. To our knowledge, this is the first report on this type of autosomal dominant condition. Clinical and genetic aspects are discussed.

Language skills and neuropsychological performance in patients with SHH mutations and a holoprosencephaly-like phenotype.

Here, we evaluate linguistic skills and neuropsychological performance in a sample of patients with SHH mutations and a holoprosencephaly (HPE)-like phenotype, a minor form of classic HPE. Our findings suggest that patients with SHH mutations and a HPE-like phenotype have normal cognitive ratios and significant language impairment. Imaging evaluation by magnetic resonance imaging (MRI) was normal in three patients and in one there was hypoplasia of the anterior commissure and the presence of a temporal cyst, apparently not related to the clinical findings.

Transmission analysis of candidate genes for nonsyndromic oral clefts in Brazilian parent-child triads with recurrence

Cleft lip and/or palate (CL/P) is a major congenital defect with complex etiology, including multiple genetic and environmental factors. Approximately two thirds of the cases are not accompanied by other anomalies and are called nonsyndromic (NS). In the present study, we performed transmission distortion analysis of the MSX1-CA, TGFB3-CA and MTHFR-C677T polymorphisms in 60 parent-child triads, in which the NS-CL/P affected child had at least one affected parent. No association with genes MSX1 or TGFB3 was found, but the results were suggestive of an association of the MTHFR-C677T polymorphism with NS-CL/P.

X monosomy and balanced Robertsonian translocation in a girl with Turner Syndrome

We describe a case of X monosomy associated with a maternally inherited t(13;14) Robertsonian translocation in a girl with Turner syndrome. The girl's X chromosome was demonstrated to be maternally inherited, ruling out the hypothesis that the translocation exerted an interchromosomal effect on the origin of the monosomy. Chromosomes 13 and 14 showed biparental inheritance.