Lucilene Arilho Ribeiro

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.

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.

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.

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.

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.

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.

Single median maxillary central incisor, hypophyseal tumor, and SHH mutation.

Here, we report a patient with single median maxillary central incisor (SMMCI), neurohypophyseal tumor, and small head circumference. Clinical examination of this 50-year-old male high school teacher showed small head circumference (51 cm, <3rd centile), hypotelorism (outer canthal distance, 8.4 cm, <25th centile; inner canthal distance 2.4 cm, <3rd centile), large ears, narrow nasal bridge (Fig. 1), and SMMCI. MRI (Fig. 2) showed a well-delimited mass corresponding to neurohypophysis region. A younger brother had died of leukemia at age 4 years. The propositus had an SHH mutation (420C!G, resulting in His140Gln), which was also present in his only daughter, who was normal.

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.

Holoprosencephaly: clinical evaluation on audiological and brainstem electrophysiological profiles.

This study evaluated audiological and electrophysiological profiles in 13 patients with holoprosencephaly. All patients had imaging evaluation by magnetic resonance imaging and molecular screening for the genes SHH, GLI2, and SIX3. Each patient underwent clinical (otological and vestibular antecedents, otoscopy) and instrumental (tympanometry, auditory brainstem response—ABR) evaluation to compare hearing and the electrophysiological profile possibly occurring in patients with these mutations. To our knowledge there are no systematic studies correlating molecular/imaging and evoked potentials in patients with HPE. Here, we discuss the audiological and electrophysiological profiles of patients and the possible role of the genes studied on the overall findings.