Intracranial cystic lesions and polydactyly associated with acrocallosal syndrome: Sonographic findings in two cases.

We describe two cases of intracranial cystic lesions associated with acrocallosal syndrome. These fetal anomalies were detected on antenatal sonography and confirmed postnatally. Imaging findings include corpus callosum agenesis with interhemispheric cysts and craniofacial anomalies associated with polydactyly. Identifying the above imaging features is of importance to plan management and provide supportive care that may be required.

Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice.

Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by agenesis or hypoplasia of corpus callosum (CC), polydactyly, craniofacial dysmorphism and severe intellectual deficiency. We previously identified KIF7, a key ciliary component of the Sonic hedgehog (SHH) pathway, as being a causative gene for this syndrome, thus including ACLS in the group of ciliopathies. In both humans and mice, KIF7 depletion leads to abnormal GLI3 processing and over-activation of SHH target genes. To understand the pathological mechanisms involved in CC defects in this syndrome, we took advantage of a previously described Kif7-/- mouse model to demonstrate that in addition to polydactyly and neural tube closure defects, these mice present CC agenesis with characteristic Probst bundles, thus recapitulating major ACLS features. We show that CC agenesis in these mice is associated with specific patterning defects of the cortical septum boundary leading to altered distribution of guidepost cells required to guide the callosal axons through the midline. Furthermore, by crossing Kif7-/- mice with Gli3Δ699 mice exclusively producing the repressive isoform of GLI3 (GLI3R), we demonstrate that decreased GLI3R signaling is fully responsible for the ACLS features in these mice, as all phenotypes are rescued by increasing GLI3R activity. Moreover, we show that increased FGF8 signaling is responsible in part for CC defects associated to KIF7 depletion, as modulating FGF8 signaling rescued CC formation anteriorly in Kif7-/- mice. Taken together our data demonstrate that ACLS features rely on defective GLI3R and FGF8 signaling.

A de novo GLI3 mutation in a patient with acrocallosal syndrome.

Acrocallosal syndrome is characterized by postaxial polydactyly, macrocephaly, agenesis of the corpus callosum, and severe developmental delay. In a few patients with this disorder, a mutation in the KIF7 gene has been reported, which was associated with impaired GLI3 processing and dysregulaton of GLI3 transcription factors. A single patient with acrocallosal syndrome and a de novo p.Ala934Pro mutation in GLI3 has been reported, whereas diverse and numerous GLI3 mutations have also been described in syndromes with overlapping clinical manifestations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, trigonocephaly with craniosynostosis and polydactyly, oral-facial-digital syndrome, and non-syndromic polydactyly. Here, we describe a second patient with acrocallosal syndrome, who has a de novo, novel c.2786T>C mutation in GLI3, which predicts p.Leu929Pro. This mutation is in the same domain as the mutation in the previously reported patient. These data confirm that mutations in GLI3 are a cause of the acrocallosal phenotype.

Acrocallosal syndrome in a young hypertensive male.

Acrocallosal syndrome is an extremely rare genetic disorder with autosomal recessive inheritance. It is characterised by moderate to severe mental retardation, hypotonia, agenesis of the corpus callosum and preaxial polydactyly involving both feet and the facial features like broad forehead and hypertelorism. The authors report a case of a young hypertensive male who presented with unprovoked seizures for the first time who had multiple craniofacial, digital dysmorphic features with moderate mental retardation. The diagnosis of acrocallosal syndrome was arrived at after neuroimaging showed agenesis of corpus callosum with interhemispheric cysts.

Absence of the anterior fontanelle due to a fontanellar bone.

Improved accessibility to supraregional centers in the United Kingdom has led to an increased referral of minor craniofacial anomalies. We have recognized a group of patients referred with absence of the anterior fontanelle and possible associated craniosynostosis. The aim of this study was to assess the group of patients in which the anterior fontanelle was entirely replaced by a single bone, examining associations, relationship to craniosynostosis, and prognostic implications.Eleven patients had fontanellar bones replacing the anterior fontanelle on computed tomographic imaging in the 3-year study period. Five were referred solely because of absence of the anterior fontanelle; and the remainder, because of concern of concomitant craniosynostosis. Five children had associated craniosynostosis (sagittal synostosis, 3; metopic synostosis, 1; and bicoronal synostosis, 1), 1 had acrocallosal syndrome, and 5 had no other craniofacial abnormalities. The patient group with craniosynostosis have been managed in line with the unit protocol and have good early postoperative results (mean postoperative follow-up, 9.4 mo). The 5 patients who had an anterior fontanellar bone as an isolated finding were observed and have developed normally with a mean follow-up of 2 years 1.4 months (range, 8 mo to 3 y 4 mo).Replacement of the anterior fontanelle with a fontanellar bone is an uncommon finding, often associated with craniosynostosis. Cases with craniosynostosis can be treated in line with unit protocols. Isolated anterior fontanellar bones can be managed conservatively without adverse impact on the child.

Consideration of median cleft lip with frenulum labii superior.

Median cleft lip is usually divided into true and false when being discussed. Owing to recent developments of diagnostic imaging methods that have improved the accuracy, the presence of an intermediate type of median cleft lip, which cannot simply be divided into true and false, has been suggested. However, the simple method of classification is still clinically valuable. We have previously reported in this Journal a case of median cleft lip with 2 upper labial frenums. In the present study, based on our experience with false median cleft lip, we set forth a hypothesis that 2 upper labial frenums can be found in true median cleft lip, whereas no upper labial frenum is found in false median cleft lip. A review of the results of previous Japanese cases (7 true and 4 false cases) supported our hypothesis. We also reviewed one of our cases of right cleft lip accompanied by holoprosencephaly and discuss the case from the developmental perspective. The shape of the upper labial frenum may be a factor that can be used for clinically classifying intermediate median cleft lip into either true or false in cases that are otherwise difficult to classify.

Acrocallosal syndrome: a case report and literature survey.

Acrocallosal syndrome (ACS) is a rare, genetically transmitted disorder characterized by facial deformities. These include a large forehead, large anterior fontanelle, broad nasal bridge with increased intercanthal distance, partial or complete agenesis of the corpus callosum, polysyndactyly, polydactyly, and mental retardation. Limited information concerning the dental development and treatment has been published. In addition to the classic facial deformities aforementioned, the other most commonly reported oral findings are: short philtrum/upper lip (30%); high-arched palate (30%); cleft lip/palate (20%); micro/retrognathia (13%); open mouth (15%); thin lips (11%); and 1 report of over-retained primary teeth. Seizure disorders are also a common finding due to the neuroanatomical deformities associated with this disorder. The purpose of this report was to describe the case of a 7-year-old male child with acrocallosal syndrome who presented with a cleft lip and palate, hydrocephalus, a seizure disorder, and delayed exfoliation of his primary dentition and was observed for 4 years. A review is conducted to present the pertinent medical literature concerning the oral findings associated with ACS. Dental management of this case and possible contributing factors of delayed exfoliation/permanent tooth eruption are also discussed.