Phenotype of five patients with Greig syndrome and microdeletion of 7p13

Kroisel, Peter M.; Petek, Erwin; Wagner, Klaus

doi:10.1002/ajmg.1443

Cited by 32 publications

(28 citation statements)

References 22 publications

(29 reference statements)

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“…Most point mutations result in intellectually normal patients and manifest with variable grades of polysyndactyly [Biesecker, 2008]. In contrast, GCPS-CGS always associates with moderate to severe intellectual disability and a consistent appearance of PPD of the great toe [Kroisel et al, 2001]. Also, recent advance of DNA microarray technology revealed haploinsufficiency of several genes around GLI3 responsible for the additional phenotypes of patients with the 7p13 deletion.…”

Section: Discussionmentioning

confidence: 99%

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Human Malformation Syndromes of Defective GLI: Opposite Phenotypes of 2q14.2 (GLI2) and 7p14.2 (GLI3) Microdeletions and a GLIA/R Balance Model

Niida

Inoue

Ozaki

et al. 2017

Cytogenet Genome Res

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GLI family zinc finger proteins are transcriptional effectors of the sonic hedgehog signaling pathway. GLI regulates gene expression and repression at various phases of embryonic morphogenesis. In humans, 4 GLI genes are known, and GLI2 (2q14.2) and GLI3 (7p14.1) mutations cause different syndromes. Here, we present 2 distinctive cases with a chromosomal microdeletion in one of these genes. Patient 1 is a 14-year-old girl with Culler-Jones syndrome. She manifested short stature, cleft palate, and mild intellectual/social disability caused by a 6.6-Mb deletion of 2q14.1q14.3. Patient 2 is a 2-year-old girl with Greig cephalopolysyndactyly contiguous gene deletion syndrome. She manifested macrocephaly, preaxial polysyndactyly, psychomotor developmental delay, cerebral cavernous malformations, and glucose intolerance due to a 6.2-Mb deletion of 7p14.1p12.3 which included GLI3, GCK, and CCM2. Each patient manifests a different phenotype which is associated with different functions of each GLI gene and different effects of the chromosomal contiguous gene deletion. We summarize the phenotypic extent of GLI2/3 syndromes in the literature and determine that these 2 syndromes manifest opposite features to a certain extent, such as midface hypoplasia or macrocephaly, and anterior or posterior side of polydactyly. We propose a GLIA/R balance model that may explain these findings.

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Section: Discussionmentioning

confidence: 99%

“…She has a macrocephaly (+2.3 SD) with frontal bossing and hypertelorism. These phenotypes indicated GCPS (OMIM 175700), and her apparent psychomotor delay suggested GCPS-CGS [Kroisel et al, 2001;Biesecker, 2008]. Brain MRI showed multiple cerebral cavernous malformations (CCM) ( Fig.…”

Section: Patientmentioning

confidence: 99%

Human Malformation Syndromes of Defective GLI: Opposite Phenotypes of 2q14.2 (GLI2) and 7p14.2 (GLI3) Microdeletions and a GLIA/R Balance Model

Niida

Inoue

Ozaki

et al. 2017

Cytogenet Genome Res

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“…17 Hypertrichosis has not been reported in GLI3-associated syndromes, except for some cases harboring 7p13 microdeletions involving GLI3. 18 This feature is therefore likely due to the contiguous gene deletion. Given the central role of SHH in the anteroposterior polarization of the limb and in the follicle morphogenesis, [10][11][12] we hypothesized that the PPD-hypertrichosis phenotype is consistent with a deregulation of SHH expression.…”

Section: Discussionmentioning

confidence: 99%

The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis

et al. 2015

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The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.

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“…GCPS patients with mental retardation were the ones who had large deletions of the region on chromosome 7p harboring the GLI3 gene. Mental retardation has been associated with GCPS [22,24,29,31,38], and as mentioned above, GCPS and ACLS have several overlapping features. None of our patients with large deletions had agenesis of the corpus callosum.…”

Section: Discussionmentioning

confidence: 99%

“…Very seldom, postaxial polydactyly is seen in the feet [12]. After the original description by Greig in 1926, several other authors have contributed to the delineation of the characteristic features of this syndrome [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31].…”

Section: Gli3mentioning

confidence: 99%

The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly

Debeer¹,

Devriendt²,

Smet³

et al. 2007

Journal of Children's Orthopaedics

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Purpose Greig 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. Methods We 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. Results We 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. Conclusion We 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.

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Phenotype of five patients with Greig syndrome and microdeletion of 7p13

Cited by 32 publications

References 22 publications

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis

The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly

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