Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3.
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SUBMITTER: Hurst JA
PROVIDER: S-EPMC3128494 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPreaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly type IV and other clinical features of Greig cephalopolysyndactyly syndrome (GCPS).Methods and resultsSequencing analysis of the GLI3 coding region identified a novel donor splice site variant NC_000007.14(NM_000168.6):c.473+3A>T in the proband and the same pathogenic variant was subsequently identified in other affected family members. Functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) sample revealed that the splice site variant c.473+3A>T disrupts the original donor splice site, thus leading to exon 4 skipping. Based on further in silico analysis, this pathogenic splice site variant consequently results in a truncated protein NP_000159.3:p.(His123Argfs*57), which lacks almost all functionally important domains. Therefore, functional cDNA analysis confirmed that the haploinsufficiency of the GLI3 is the cause of GCPS in the affected family members.ConclusionDespite the evidence provided, pathogenic variants in the GLI3 do not always definitely correlate with syndromic or nonsyndromic clinical phenotypes associated with this gene. For this reason, further transcriptomic and proteomic evaluation could be suggested.
| S-EPMC6732282 | biostudies-literature
Project description:The Greig cephalopolysyndactyly syndrome (GCPS) is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of incidence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000). The primary findings include hypertelorism, macrocephaly with frontal bossing, and polysyndactyly. The polydactyly is most commonly preaxial of the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment. GCPS is caused by loss of function mutations in the GLI3 transcription factor gene and is inherited in an autosomal dominant pattern. The disorder is allelic to the Pallister-Hall syndrome and one form of the acrocallosal syndrome. Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical have been delineated. For this reason, we have proposed a combined clinical-molecular definition for the syndrome. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Patients with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 mutation may be diagnosed definitively with GCPS. In addition, persons with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may be diagnosed definitively as well. Antenatal molecular diagnosis is technically straightforward to perform. Differential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. Treatment of the disorder is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations. The prognosis for typically affected patients is excellent. There may be a slight increase in the incidence of developmental delay or cognitive impairment. Patients with large deletions that include GLI3 may have a worse prognosis. The Article is a work of the United States Government. Title 17 U.S.C 5 105 provides that copyright protection is not available for any work of the United States Government in the United States. The United States hereby grants to anyone a paid-up, nonexclusive, irrevocable worldwide license to reproduce, prepare derivative works, distribute copies to the public and perform publicly and display publicly the work, and also retains the nonexclusive right to do all of the above for or on behalf of the United States.
| S-EPMC2397380 | biostudies-other
Project description:Background:Bilambdoid and sagittal synostosis (BLSS), also called "Mercedes Benz synostosis," is a multisutural craniosynostosis that has been described as a specific entity. However, this synostotic pattern can also be found in syndromic craniostenosis. To better define this entity we reviewed our experience with bilambdoid and sagittal synostosis. Methods:We searched our prospective database for cases of bilambdoid and sagittal synostosis among all types of craniosynostosis. Two groups were distinguished - patients with isolated BLSS and the group of syndromic craniostenosis for whom BLSS was observed at initial presentation. We reviewed the clinical findings, associated diseases, and their management specifically for isolated BLSS patients. Results:Thirty-nine patients were diagnosed with bilambdoid and sagittal synostosis among 4250 cases of craniosynostosis treated in our department over a period of 42 years. Among them, 8 were finally diagnosed as Crouzon syndrome. Of the 31 patients identified with isolated bilambdoid and sagittal synostosis, 25 (81%) were males and 6 (19%) were females. The average age at diagnosis was 17 months. At diagnosis, 16% of the population presented with papillary edema and 58% posterior digitate impressions. Two types of craniofacial dysmorphy were observed - a pattern with narrow occiput (71% of cases) and a pattern with dolichocephaly (29% of cases). Cerebellar tonsillar herniation was the most frequently associated malformation (61% of the isolated BLSS). Surgical management evolved during the years, and several surgical techniques were used to treat patients with BLSS, including isolated biparietal vault remodeling, posterior vault remodelling, and posterior vault expansion with internal or external distraction. In some cases, a craniocervical junction decompression was also performed. The mean follow-up was 82 months (7 years). The overall mental development was within normal limits in most children, but a mental delay was found in 25%. Conclusion:Bilambdoid and sagittal synostosis constitute an isolated entity in almost 80% of the cases, whereas in the remaining 20% it is part of a faciocraniosynostosis syndrome. Two phenotypes may be found. Early surgical management is indicated, and several techniques can be used in this heterogeneous population. A cerebellar tonsillar prolapse is present in a majority of cases.
| S-EPMC6194734 | biostudies-other
Project description:BackgroundA proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS).Case presentationHere, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site.ConclusionsAlthough agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.
| S-EPMC6389258 | biostudies-literature
Project description: Not available
| S-EPMC10564306 | biostudies-literature
Project description:Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.
| S-EPMC1199298 | biostudies-literature
Project description:BACKGROUND:Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. CASE PRESENTATION:We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. CONCLUSIONS:We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.
| S-EPMC6477736 | biostudies-literature
Project description:Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder (about 200 cases reported), characterized by macrocephaly, hypertelorism, and polysyndactyly. Most of the reported GCPS cases are the results of heterozygous loss of function mutations affecting the GLI3 gene (OMIM# 175700), while a small proportion of cases arise from large deletions on chromosome 7p14 encompassing the GLI3 gene. To our knowledge, only 6 patients have been reported to have a deletion with an exact size (given by genomic coordinates) and a gene content larger than 1 Mb involving the GLI3 gene. This report presents a patient with Greig cephalopolysyndactyly contiguous gene syndrome (GCP-CGS) diagnosed with a large, 18 Mb deletion on chromosome 7p14.2-p11.2. Similar cases are reviewed in the literature for a more accurate comparison between genotype and phenotype.
| S-EPMC8623992 | biostudies-literature
Project description:Spondylocarpotarsal synostosis syndrome (SCT) is characterized by vertebral fusions, a disproportionately short stature, and synostosis of carpal and tarsal bones. Pathogenic variants in FLNB, MYH3, and possibly in RFLNA, have been reported to be responsible for this condition. Here, we present two unrelated individuals presenting with features typical of SCT in which Sanger sequencing combined with whole genome sequencing identified novel, homozygous intragenic deletions in FLNB (c.1346-1372_1941+389del and c.3127-353_4223-1836del). Both deletions remove several consecutive exons and are predicted to result in a frameshift. To our knowledge, this is the first time that large structural variants in FLNB have been reported in SCT, and thus our findings add to the classes of variation that can lead to this disorder. These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT.
| S-EPMC8065484 | biostudies-literature
Project description:PurposeGreig cephalopolysyndactyly (GCPS) (OMIM 175700), a rare autosomal dominant disorder, is characterized by a distinct combination of craniofacial, hand and foot malformations. The hand and foot malformations often require orthopedic assessment and treatment. The disorder is caused by point mutations or deletions in the GLI3 gene, located on chromosome 7p14.3. Herewith, we review the hand and foot malformations in a cohort of 13 patients referred for genetic testing.MethodsWe reviewed the medical files of 13 patients with GCPS seen at the Center for Human Genetics in Leuven between 2003 and 2005. Clinical, molecular and radiological findings, when available, were recorded.ResultsWe identified six different point mutations in the GLI3 gene, two microdeletions and three larger chromosomal deletions. In the hands, preaxial polydactyly was never observed, but the malformations included postaxial polydactyly, broad thumbs, clinodactyly of the thumbs and various degrees of syndactyly. In the feet the spectrum of malformations included preaxial polydactyly, postaxial polydactyly, different degrees of syndactyly and broad halluces. Syndactyly of the toes and hallux abnormalities were present in all patients. Most frequently, syndactyly was present between toes 1-2-3. The broadening of the hallux was either due to a complete or partial duplication of the first toe or to broadening of the distal phalanx. Mental retardation was found in three cases and was associated with a large chromosomal deletion of the GLI3 region.ConclusionWe found the classic hand and foot malformations associated with GCPS in our cohort of patients. Patients with a large chromosomal deletion had mental retardation, but no structural brain anomalies were found.
| S-EPMC2656707 | biostudies-literature