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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. [ABSTRACT FROM AUTHOR]

We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation. [ABSTRACT FROM AUTHOR]

Acrocallosal syndrome is a rare autosomal recessive disorder. The prevalence of the disease is not known but fewer than 55 cases have been published since 1979. ACS is characterized by the total or partial absence of the corpus callosum, Minor craniofacial anomalies (prominent forehead, hypertelorism, short nose with anteverted nostrils and large anterior fontanel) moderate to severe psychomotor retardation (with hypotonia), polydactyly or polysyndactyly. We are reporting a case of 6 month old infant child who was admitted to the hospital with pneumonia, measles, episodes of fits, large anterior fontanelle, prominent forehead, high arched palate, fused tongue, micrognathism , hypotonia, motor developmental delay , polysyndactyly and absent corpus callosum. His clinical diagnosis was confirmed by CT-Brain. The patient was managed for superimposed pneumonia and measles. He was provided with other supportive treatment as well as parental counseling, physiotherapy sessions, and multiple disciplinary approaches was undertaken for further management.

We present two children who both had two missense mutations in the Kinesin Family Member 7 ( KIF7) gene. A seven year old female with severe developmental delays, failure to thrive and growth retardation, infantile spasms, a cardiac vascular ring and right-sided aortic arch, imperforate anus, hydronephrosis with a right renal cyst, syndactyly and abnormal white matter was a compound heterozygote for c.3365C > G, predicting p.(Ser1122Trp) that was maternally inherited and c.2482G > A, predicting p.(Val828Met) that was paternally inherited. An eight year old female with severe developmental delays, epilepsy, left postaxial polydactyly of the hand and abnormalities of brain development including hydrocephalus, pachygyria and absence of the body and splenium of the corpus callous was a compound heterozygote for c.461G > A, predicting p.(Arg154Gln) and c.2959 G > A, predicting p.(Glu987Lys) that was maternally inherited and her father was unavailable for testing. The presentations in these children include features of acrocallosal syndrome, such as hypoplasia of the corpus callosum, enlarged ventricles, facial dysmorphism with a prominent forehead and broad halluces in the first child, but included atypical findings for individuals previously reported to have truncating mutations in KIF7, including imperforate anus, infantile spasms and severe growth retardation. We conclude that these phenotypes may result from the KIF7 sequence variants and abnormal hedgehog signaling, but that the full spectrum of KIF7-associated features remains to be determined. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The presentation of the typical characteristics of the acrocallosal syndrome (ACLS) are hypoplasia/agenesis of corpus callosum, moderate to severe mental retardation, characteristic craniofacial abnormalities, distinctive digital malformation, and growth retardation in a neonate. An Indian neonate presented on day 1 of life (youngest in the literature to be reported) with combination of abnormalities consistent with the acrocallosal syndrome and some additional findings. The baby, born to non-consanguineous, healthy parents, presented with macrocephaly, prominent forehead, hypertelorism, polydactyly of the hands and feet, duplication of hallux, hypotonia, recurrent cyanotic episodes, rib anomalies, dextro-positioning of heart, and delayed fall of umbilical cord. As the mode of inheritance of ACLS is autosomal recessive, the risk of recurrence is 25%. Genetic counselling is of prime importance, Polydactyly, and central nervous system malformations can be detected by ultrasonography in the second trimester, but due to variability of presentation, prenatal diagnosis may not always be possible. [ABSTRACT FROM AUTHOR]

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. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Acrocallosal syndrome (ACLS) is a rare genetically heterogeneous disorder characterised by a variety of developmental anomalies including agenesis or hypoplasia of the corpus callosum. ACLS and the related disorder, hydrolethalus syndrome, have recently been reported to be caused by mutations in the KIF7 gene. In the present study we report a 15 year follow up of a consanguineous family with ACLS and the results of exome sequencing. Results: A novel in-frame deletion KIF7 mutation (p.218-221del) was detected. This is the first deletion mutation in KIF7 described in ACLS and is predicted to disrupt the KIF7 protein within the kinesin motor domain. Also present, in addition to the homozygous KIF7 mutation, were loss of function variants in known ciliopathy genes; AHI1 (p.R830W), BBS2 (p.N70S) and BBS4 (p.M472V). Conclusion: KIF7 has previously been demonstrated to regulate function of primary cilia and ACLS is now categorised as a ciliopathy – a group of disorders in which oligogenic disease is frequent. The finding of known loss of function variants in ciliopathy associated genes, AHI1, BBS2 and BBS4 in addition to KIF7 mutations provides evidence for oligogenic inheritance in ACLS and suggests that this might contribute to the phenotypic variability of KIF7-related disorders. [Copyright &y& Elsevier]

Background Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. Methods We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. Results Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. Conclusions These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS. [ABSTRACT FROM AUTHOR]

Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a ∼600-kb deletion 5′ of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a ∼900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35. [ABSTRACT FROM AUTHOR]

Background: Structural abnormalities of the corpus callosum (CC), such as reduced size and increased shape variability, have been documented in individuals with fetal alcohol spectrum disorders (FASD). However, the regional specificity of altered CC structure, which may point to the timing of neurodevelopmental disturbances and/or relate to specific functional impairments, remains unclear. Furthermore, associations between facial dysmorphology and callosal structure remain undetermined. Methods: One hundred and fifty-three participants (age range 8 to 16) including 82 subjects with FASD and 71 nonexposed controls were included in this study. The structural magnetic resonance imaging data of these subjects was collected at 3 sites (Los Angeles and San Diego, California, and Cape Town, South Africa) and analyzed using classical parcellation schemes, as well as more refined surface-based geometrical modeling methods, to identify callosal morphological alterations in FASD at high spatial resolution. Results: Reductions in callosal thickness and area, specifically in the anterior third and the splenium, were observed in FASD compared with nonexposed controls. In addition, reduced CC thickness and area significantly correlated with reduced palpebral fissure length. Conclusions: Consistent with previous reports, findings suggest an adverse effect of prenatal alcohol exposure on callosal growth and further indicate that fiber pathways connecting frontal and parieto-occipital regions in each hemisphere may be particularly affected. Significant associations between callosal and facial dysmorphology provide evidence for a concurrent insult to midline facial and brain structural development in FASD. [ABSTRACT FROM AUTHOR]

Uniform conduction slowing has been considered a characteristic of inherited demyelinating neuropathies. We present an 18-year-old girl, born from first cousins, that presented a late motor and psychological development, cerebellar ataxia, facial diplegia, abnormal eye movement, scoliosis, and corpus callosum agenesis, whose compound muscle action potentials were slowed and dispersed. A mutation was found on KCC3 gene, confirming Andermann syndrome, a disease that must be included in the differential diagnosis of inherited neuropathies with non-uniform conduction slowing. [ABSTRACT FROM AUTHOR]

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. [ABSTRACT FROM AUTHOR]

The article provides information on optic nerve apoplasia (OPN), the major cause of blindness in children in developed nations. A study is presented which concludes that OPN is a spectrum disorder encompassing a broad range of symptoms and outcomes and that commonalities with autism spectrum disorder (ASD) suggest a shared neurodevelopmental origin. Common attributes with ASD include echochlia, obsession and sensitivity to particular sounds, textures, tastes and smells. Also mentioned is an ongoing research study on the prenatal environmental risk factors of optic nerve hypoplasia (ONH).

Background and Aim: The purpose of the present study was to investigate the effect of vestibuloproprioceptive stimulations of sensory integration theory on the development of gross and fine motor, language and personal-social functions in a child with agenesis of the corpus callosum. Case: We report a 10.5 month old boy with agenesis of the corpus callosum. The intervention was administered based on sensory integration theory an hour a week for 20 weeks. The exercise intervention consisted of proprioceptive and linear, sustained and low frequency vestibular stimulations on suspension device and physio roll. A Denver Developmental Screening- II and milestones skill testing was completed pre-intervention and monthly. Post-intervention, age of gross motor, fine motor adaptive, language, and personal-social functions significantly improved. Based on milestones skills, maintenance of gross motor functions (e.g. sitting and quadruped position) improved. The child could roll from side to side and released objects voluntarily. The reaction time to auditory stimulations became less than 2 seconds. Conclusion: vestibulo-proprioceptive stimulations using the neuroplasticity ability of the central nervous system is effective for development of gross and fine motor, language, and personal-social functions. These exercises can be administered for a child with agenesis of the corpus callosum. [ABSTRACT FROM AUTHOR]

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%); microlretrognathia (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. [ABSTRACT FROM AUTHOR]

Acrocallosal syndrome (ACS) is an autosomal recessive disorder characterized by craniofacial dysmorphism, agenesis or hypoplasia of the corpus callosum, duplication of the phalanges of the hallux, more rarely the thumbs, post-axial polydactyly, syndactyly and severe mental retardation. Here we report the two first descriptions of acrocallosal syndrome in fetus with extensive neuropathological study and provide new data regarding additional brain abnormalities in ACS. The first case was a 25-gestational week male fetus displaying craniofacial and limb abnormalities, with bilateral syndactyly of the fourth and fifth fingers, preaxial polydactyly of the left foot and an inter-frontal extra-bone. The second fetus was a 33-gestational week male fetus. His left hand displayed a broad thumb and 4/5 syndactyly. In both cases, gross examination of the brain showed an absence of corpus callosum associated with interhemispheric cysts. The cerebral cortex in front of the cysts was nodular. Upon microscopic examination, the nodular masses corresponded to large dysplastic areas represented by clusters of undifferentiated neurons in the white matter. The cyst wall showed arachnoidal and ependymal covering and contained numerous choroid plexus, suggesting a developmental abnormality of the ventricles. The pons and the cerebellum were hypoplastic. The dentate nuclei were fragmented. Numerous neuronal heterotopias associated with ectopic ependymal cavities were observed in the vermis in one case. The olivary nuclei were severely dysplastic too. We hope that these new data will make both the ante- and post-natal diagnosis easier, facilitate comparisons with animal models and encourage the identification of the genes responsible for this syndrome. [ABSTRACT FROM AUTHOR]

The authors describe a boy presenting with acrocallosal syndrome and autism. Clinical features included craniofacial dysmorphisms, polydactyly, and mental retardation, besides behavioral symptoms compatible with autism. Neuroimaging revealed hypoplasia of the corpus callosum and cerebellar abnormalities. The role of this entity and other associated conditions in autism may be coincidental or reveal new clues to the understanding of autism as a behavioral syndrome. [ABSTRACT FROM AUTHOR]

Acrocallosal syndrome (ACLS), also known by its synonyms: Schinzel Acrocallosal syndrome and Hallux duplication, Postaxial polydactyly and absence of corpus callosum, is a rare genetic disorder that is apparent at birth. Although autosomal recessive inheritence has been suggested, ACLS often appears to occur sporadically. Typical characteristics of ACLS are hypoplasia/agenesis of corpus callosum, moderate to severe mental retardation, characteristic craniofacial abnormalities, distinctive digital malformations and growth retardation. It has not been reported from India so far. This article reports a 5-month-old boy with combination of abnormalities consistent with acrocallosal syndrome. [ABSTRACT FROM AUTHOR]

Acrocallosal syndrome (ACLS) is a rare genetic disorder having characteristic craniofacial abnormalities, distinctive limb malformations, and brain anomalies. Though the typical phenotypic features help the clinician to identify this syndrome at birth, few overlapping features with Joubert syndrome and hydrolethalus syndrome, could confuse the clinical picture. In this report, we describe a neonate with ACLS having additional features not described previously. The inheritance and overlapping clinical features with other disorders are also discussed. [ABSTRACT FROM AUTHOR]

The kinesin-4 member KIF7 plays critical roles in Hedgehog signaling in vertebrate cells. KIF7 is an atypical kinesin as it binds to microtubules but is immotile. We demonstrate that, like conventional kinesins, KIF7 is regulated by auto-inhibition, as the full-length protein is inactive for microtubule binding in cells. We identify a segment, the inhibitory coiled coil (inhCC), that is required for auto-inhibition of KIF7, whereas the adjacent regulatory coiled coil (rCC) that contributes to auto-inhibition of the motile kinesin-4s KIF21A and KIF21B is not sufficient for KIF7 auto-inhibition. Disease-associated mutations in the inhCC relieve auto-inhibition and result in strong microtubule binding. Surprisingly, uninhibited KIF7 proteins did not bind preferentially to or track the plus ends of growing microtubules in cells, as suggested by previous in vitro work, but rather bound along cytosolic and axonemal microtubules. Localization to the tip of the primary cilium also required the inhCC, and could be increased by disease-associated mutations regardless of the auto-inhibition state of the protein. These findings suggest that loss of KIF7 auto-inhibition and/or altered cilium tip localization can contribute to the pathogenesis of human disease. [ABSTRACT FROM AUTHOR]

A cranial MRI revealed agenesis of corpus callosum, 10 cm large interhemispheric cysts in midline and in frontal region, and cortical dysplasia of the bilateral frontal lobe [Figure 4]. He had no seizures, but electroencephalography (EEG) revealed focal epilepsy originating from the centrotemporal region of the left hemisphere.{Figure 1}{Figure 2}{Figure 3}{Figure 4} Any patient with polysyndactyly and absence of corpus callosum with craniofacial abnormalities should be examined carefully to rule out this syndrome. [Extracted from the article]

A letter to the editor is presented which is concerned with preserved interhemispheric functional connectivity in a case of corpus callosum agenesis.

A letter to the editor is presented which discusses the case of a young adult with agenesis of the corpus callosum.

The article discusses the case of a child with Greig syndrome in relation to balanced chromosome translocation involving the 7p13 region. Phenotypic findings in the differential diagnosis of other polysyndactyly and acrocallosal syndromes, genetic counseling and de novo translocation for the elder sibling and future pregnancies for this also discussed.

This article reports two families with children having acrocallosal syndrome, an autosomal recessive disorder characterized by agenesis of corpus callosum, facial dysmorphism and polydactyly along with psychomotor retardation. Both families sought genetic counseling in subsequent pregnancies. Although the gene for the disorder is not yet identified, prenatal diagnosis was attempted by ultrasound studies. In both families, an affected fetus was diagnosed in the presence of postaxial polydactyly of hands and absence of corpus callosum. It is emphasized that pediatricians should make precise diagnosis in cases of dysmorphism and mental retardation, as this enable prenatal diagnosis in future pregnancies. [ABSTRACT FROM AUTHOR]

A large highly inbred kindred with 3 definite and 1 possibly affected siblings with acrocallosal syndrome is reported from the Kaplan Hospital, Rehovot and the Emek Central Hospital, Afula, Israel.