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Orphanet Journal of Rare Diseases Aug 2011VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac... (Review)
Review
VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.
Topics: Abnormalities, Multiple; Anal Canal; Anus, Imperforate; Esophagus; Female; Heart Defects, Congenital; Humans; Infant, Newborn; Kidney; Limb Deformities, Congenital; Male; Radius; Spine; Trachea; Tracheoesophageal Fistula
PubMed: 21846383
DOI: 10.1186/1750-1172-6-56 -
American Journal of Medical Genetics.... Nov 2013MED12: is a member of the large Mediator complex, which has a critical and central role in RNA polymerase II transcription. As a multiprotien complex, Mediator regulates... (Review)
Review
MED12: is a member of the large Mediator complex, which has a critical and central role in RNA polymerase II transcription. As a multiprotien complex, Mediator regulates signals involved in cell growth, development, and differentiation, and it is involved in a protein network required for extraneuronal gene silencing and also functions as a direct suppressor of Gli3-dependent Sonic hedgehog signaling. This may explain its role in several different X-linked intellectual disability syndromes that share some overlapping clinical features. This review will compare and contrast four different clinical conditions that have been associated with different mutations in MED12, which is located at Xq13. To date, these conditions include Opitz-Kaveggia (FG) syndrome, Lujan syndrome, Ohdo syndrome (Maat-Kievit-Brunner type, or OSMKB), and one large family with profound X-linked intellectual disability due to a novel c.5898insC frameshift mutation that unlike the other three syndromes, resulted in affected female carriers and truncation of the MED12 protein. It is likely that more MED12 mutations will be detected in sporadic patients and X-linked families with intellectual disability and dysmorphic features as exome sequencing becomes more commonly utilized, and this overview of MED12-related disorders may help to correlate MED12 genotypes with clinical findings.
Topics: Agenesis of Corpus Callosum; Anus, Imperforate; Child; Child, Preschool; Constipation; Craniofacial Abnormalities; Facies; Female; Genes, X-Linked; Genetic Diseases, Inborn; Humans; Male; Marfan Syndrome; Mediator Complex; Mental Retardation, X-Linked; Muscle Hypotonia; Mutation; Phenotype
PubMed: 24123922
DOI: 10.1002/ajmg.a.36183 -
Genetics in Medicine : Official Journal... Jan 2023Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full...
Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
PURPOSE
Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
METHODS
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
RESULTS
Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
CONCLUSION
We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
Topics: Pregnancy; Female; Humans; Muscle Hypotonia; Epilepsy; Abnormalities, Multiple; Hernia, Diaphragmatic; Seizures; Phenotype; Genetic Association Studies; Congenital Disorders of Glycosylation; Syndrome
PubMed: 36322149
DOI: 10.1016/j.gim.2022.09.007 -
Genes Apr 2021MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and... (Review)
Review
MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Anus, Imperforate; Blepharophimosis; Blepharoptosis; Cholestasis; Cleft Palate; Constipation; Craniofacial Abnormalities; Heart Defects, Congenital; Humans; Intellectual Disability; Marfan Syndrome; Mediator Complex; Mental Retardation, X-Linked; Muscle Hypotonia; Phenotype; Retinitis Pigmentosa
PubMed: 33925166
DOI: 10.3390/genes12050663 -
Journal of Medical Genetics Feb 1988
Topics: Abnormalities, Multiple; Consanguinity; Diaphragm; Fingers; Humans; Infant; Nails, Malformed; Nose; Syndrome
PubMed: 3346889
DOI: 10.1136/jmg.25.2.135 -
Protein & Cell Sep 2013The Mediator Complex plays key roles in activating gene transcription in eukaryotes. Mediator of RNA polymerase II transcription subunit 12 homolog (MED12) is a subunit... (Review)
Review
The Mediator Complex plays key roles in activating gene transcription in eukaryotes. Mediator of RNA polymerase II transcription subunit 12 homolog (MED12) is a subunit of the Mediator Complex and regulates the activity of the complex. MED12 is involved in a variety of cellular activities, and mutations in MED12 gene impair MED12 activities and are associated with several diseases, including Opitz-Kaveggia syndrome, Lujan syndrome, uterine leiomyomas and prostate cancer. This review will discuss the biological function of MED12 and the relationship between MED12 mutations and diseases.
Topics: Agenesis of Corpus Callosum; Anus, Imperforate; Constipation; Craniofacial Abnormalities; Female; Genetic Predisposition to Disease; Humans; Leiomyoma; Male; Marfan Syndrome; Mediator Complex; Mental Retardation, X-Linked; Muscle Hypotonia; Mutation; Prostatic Neoplasms; Transcription, Genetic; Uterine Neoplasms
PubMed: 23836153
DOI: 10.1007/s13238-013-3048-3 -
Frontiers in Genetics 2021Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome, with diaphragmatic defects and secondary lung hypoplasia as cardinal features. Despite it... (Review)
Review
Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome, with diaphragmatic defects and secondary lung hypoplasia as cardinal features. Despite it was reported first in 1979, its exact etiology has not been established to date. With this review, we would like to draw attention to the prenatal presentation of multiple congenital anomalies syndromes, resulting from defects in the synthesis of glycosylphosphatidylinositol anchors, to be considered in a prenatal assessment of fetuses with DH and Fryns-like phenotype.
PubMed: 34163527
DOI: 10.3389/fgene.2021.674722 -
Journal of Postgraduate Medicine 2002
Topics: Abnormalities, Multiple; Adolescent; Apgar Score; Cornea; Craniofacial Abnormalities; Ear; Fatal Outcome; Female; Gestational Age; Hand Deformities; Hernia, Diaphragmatic; Humans; Infant, Newborn; Male; Neck; Nose; Pregnancy; Pregnancy Outcome; Syndrome; Ultrasonography, Prenatal
PubMed: 12215698
DOI: No ID Found -
Turk Psikiyatri Dergisi = Turkish... 2020Lujan-Fryns Syndrome (LFS) is defined as a set of symptoms including mild-moderate mental retardation, marfanoid appearance, hypotonia at birth, hypernasal speech,...
Lujan-Fryns Syndrome (LFS) is defined as a set of symptoms including mild-moderate mental retardation, marfanoid appearance, hypotonia at birth, hypernasal speech, characteristic craniofacial appearance and normal testis size. The frequency of the syndrome is not known thus the information obtained is solely based on case reports. Hereby, we present a patient with LFS diagnosis. The 29-year old male patient had mental retardation, aggression, and persecutory delusions, characteristic craniofacial and marfanoid features. During his speech pronominal reversal was observed ('the hurt him, he is so upset' when talking abour himself). After examination and genetic analysis, fragile X, Klinefelter, Marfan and Down syndromes and homocystinuria were eliminated as causes of mental retardation. A preliminary diagnoses of LFS done. No mutation was detected in exon 22 of the MED12 gene; but. Whole Exome Sequencing (WES) is ongoing. The patient was started on risperidone (4 mg/day) for psychotic symptoms and carbamazepine (200 mg/day) for impulse control and as an antiepileptic. After a follow up of 8 months, impulse control, psychotic symptoms and aggression improved significantly. Since the specific gene mutation of LFS was not determined in our case, we solely had to depend on clinical evaluation and genetic analysis. Although it is not easy to fully define or classify these syndromes, we believe every reported case will be a step in overcoming these difficulties.
Topics: Adult; Autistic Disorder; Craniofacial Abnormalities; Diagnosis, Differential; Humans; Male; Marfan Syndrome; Mental Retardation, X-Linked; Psychotic Disorders
PubMed: 32978958
DOI: 10.5080/u23940