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We report on the presence of craniosynostosis in four patients with the 22q11.2 deletion. In light of previous reports of the association, we propose that the occurrence is higher than the general population incidence. Therefore, we suggest that craniosynostosis should be considered a manifestation of the 22q11.2 deletion and conversely that the 22...
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Chromosome 22q11.2 microdeletion syndrome is due to microdeletion of 22q11.2 region of chromosome 22. It is a common microdeletion syndrome however mosaic cases are very rare and reported only few previous occasions. In this report we describe two unrelated male children with clinical features consistent with 22q11.2 microdeletion syndrome characte...
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... Finally, in thinking about CDC45 as a putative cause for craniosynostosis in these patients we contacted authors who had previously reported such patients. [9][10][11][12] The Children's Hospital of Eastern Ontario and University of Ottawa (Canada) had DNA available for their previously reported patient 9 (Table S1). ...
... Patient 1 (patient 3 from McDonald-McGinn et al. 12 and patient 8 from Unolt et al. 14 ), a female born via spontaneous vaginal delivery at 39 weeks gestation (WG) following an uneventful pregnancy, at birth experienced severe cardiorespiratory distress leading to the diagnosis of a complex congenital cardiac defect-truncus arteriosus (TA) and atrioventricular septal defect-and an anterior right-sided congenital diaphragmatic hernia (CDH). Additional clinical findings ( Fig. 1) included low birth weight (1980 g, <1%), bicoronal craniosynostosis, hypertelorism with short palpebral fissures, microtia, left preaxial polydactyly with bilateral digitalized thumbs, anteriorly displaced anus (ADA), and a sacral dimple. ...
... The CDC45 (p.Arg283Cys) variant was identified in the remaining allele using ES. Patient 2, currently a 20-year-old female, presented for genetics consultation as part of the craniofacial clinic at CHOP at 16 months of age with a history of repaired unicoronal synostosis ( Fig. 1) performed at an outside hospital (patient 2 from McDonald-McGinn et al. 12 ), failure to thrive, gastroesophageal reflux disease, nasal regurgitation, and severe dysphagia requiring gastric tube placement. She was the former 2400 g (<2%) product of a 35-week pregnancy born to a G2P1-2 mother with a history of hypothyroidism. ...
Purpose:
The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis.
Methods:
We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations.
Results:
We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings.
Conclusion:
This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.
... 82 Interestingly, in at least two cases, it has been shown with multiple chromosomal aberrations that both had deletions in chromosomes 7p21 (ranging in size from 3 to 12 Mb) 83,84 and 22q11.2. 37,85,86 All these genetic and cytogenetic factors make craniosynostosis a highly complex condition. ...
Craniosynostosis is one of the pathologic craniofacial disorders and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of non-ossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes are correlated to the craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be seen as nonsyndromic formed without any additional anomalies. More than 50 nuclear genes that are relating to the craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. Due to craniosynostosis being a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetical analysis, epigenetic or environmental factors or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic including environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.
... testing in all cases [Halder et al., 2008;McDonald-McGinn et al., 2011]; phenocopies due to mutations in TBX1 only [Zweier et al., 2007]; the presence of cooccurring conditions such as 22q11.2DS and trisomy 8 mosaicism [McDonald-McGinn et al., 2005b] and 22q11.2DS and CHARGE syndrome due to a CHD7 mutation ; and the 22q11.2 ...
Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000-4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70-84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
... Duplications of this locus share features with the more common deletion and include genitourinary abnormalities (Portnoi 2009). The incidence of urogenital abnormalities in the classic 22q deletion syndrome is well documented and can include renal agenesis, hydronephrosis, multicystic/dysplastic kidneys, duplicated kidney, horseshoe kidney, absent uterus, hypospadias, inguinal hernia, and cryptorchidism (McDonald-McGinn et al. 2005). We observed one 22q deletion (in patient 2330) and one 22q duplication (in patient 21790). ...
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, hearing loss and renal dysmorphology. Although haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients. In this study, we used high-resolution array-based comparative genomic hybridization on 32 BOR probands negative for coding-sequence and splice-site mutations in known BOR-causing genes to identify potential disease-causing genomic rearrangements. Of the >1,000 rare and novel copy number variants we identified, four were heterozygous deletions of EYA1 and several downstream genes that had nearly identical breakpoints associated with retroviral sequence blocks, suggesting that non-allelic homologous recombination seeded by this recombination hotspot is important in the pathogenesis of BOR. A different heterozygous deletion removing the last exon of EYA1 was identified in an additional proband. Thus, in total five probands (14 %) had deletions of all or part of EYA1. Using a novel disease-gene prioritization strategy that includes network analysis of genes associated with other deletions suggests that SHARPIN (Sipl1), FGF3 and the HOXA gene cluster may contribute to the pathogenesis of BOR.
... In addition, variation in head measurement technique may account for some discrepancy between reference charts, and affect conclusions [Wright et al., 2011]. As craniosynostosis is increased in 22q11 DS [McDonald-McGinn et al., 2005] a considered approach to skull and brain imaging is appropriate when developmental and neurological symptoms or signs are present. The OFC findings in 22q11 DS reflect reduction in brain volume and neural connections [Barnea-Goraly et al., 2005;Campbell et al., 2006]. ...
Growth faltering occurs frequently in infancy in the 22q11 Deletion syndrome (22q11 DS). The subsequent course of growth in childhood and outcome for final adult height lacks consensus. We analyzed 5,149 growth data points from 812 Caucasian subjects with 22q11 DS, from neonates to 37 years old. Charts were constructed for height, weight, body mass index, and head circumference (OFC) using the LMS Chart Maker program. These charts were compared with the WHO birth to 4 years growth standard and US CDC 2000 growth reference between 5 and 20 years. Starting from the 50th centile at birth, by 6-9 months of age boys mean height and weight had fallen to the 9th centile, as did girls height but their weight fell less markedly, to the 25th centile. Feeding difficulties were non-contributory. In children under 2 years old with congenital heart disease (CHD) mean weight was -0.5 SD lighter than no CHD. Catch up growth occurred, more rapid in weight than height in boys. Up to 10 years old both sexes tracked between the 9th and 25th centiles. In adolescence, the trend was to overweight rather than obesity. At 19 years mean height was -0.72 SD for boys, -0.89 SD girls. OFC was significantly smaller than the WHO standard in infancy, between the 9th and 25th centile, rising to the 25th centile by 5 years old. Thereafter the mean was close to the 9th centile of the OFC UK growth reference, more prolonged and marked than in previous studies. © 2012 Wiley Periodicals, Inc.
... However, other form of craniosynostosis with 22q11.2 microdeletion syndrome is not so rare and reported in some previous occasions2728293031. Ryan et al. (1997) [31] described five patients of microdeletion 22q11.2 ...
... syndrome with craniosynostosis without description of its type. McDonald-McGinn et al. (2005) [30] reported on the presence of craniosynostosis in another four patients with the 22q11.2 microdeletion syndrome. ...
Chromosome 22q11.2 microdeletion syndrome is due to microdeletion of 22q11.2 region of chromosome 22. It is a common microdeletion syndrome however mosaic cases are very rare and reported only few previous occasions. In this report we describe two unrelated male children with clinical features consistent with 22q11.2 microdeletion syndrome characterized by cardiac defect, facial dysmorphism and developmental deficiency. One of the cases also had trigonocephaly. Interphase & metaphase FISH with 22q11.2 probe demonstrated mosaicism for hemizygous deletion of 22q11.2 region. Mosaicism is also observed in buccal cells as well as urine cells. Parents were without any deletion. These two cases represent rare cases of mosaic 22q11.2 microdeletion syndrome.
... In terms of genetic counseling, it can be approached by dividing the topic into three groups [McDonald-McGinn et al., 2002, 2005c: affected individuals; unaffected parents of an affected child; and the general population. ...
... thermore, eliciting the risk for medically relevant findings such as congenital heart disease is generally complicated by ascertainment bias. To this end, McDonald-McGinn et al. [2005c] reported findings in 36 affected persons following the diagnosis in their relative. This cohort included 23 parents of affected children and 13 children born before or after the diagnosis in the parent. ...
... In providing genetic counseling to seemingly unaffected couples who have had one child with the 22q11.2 deletion, parental studies are recommended, as discussed previously, in an effort to ascertain mildly affected individuals and also to rule out low level mosaicism [McDonald-McGinn et al., 2002, 2005c. Following normal parental studies, since germ line mosaicism is a true, but ill-defined risk [Consevage et al., 1996;Hatchwell et al., 1998;Kasprzak et al., 1998;Sandrin-Garcia et al., 2002], the couple may choose to monitor a subsequent pregnancy utilizing either noninvasive techniques, including Level II ultrasonography and fetal echocardiography as outlined earlier, or couple these studies with a definitive diagnostic test such as amniocentesis using FISH specifically for the 22q11.2 ...
Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to identify previously undiagnosed patients as they reach reproductive age and to refer them for genetic counseling. To date, most deletions are de novo, secondary to homologous recombination between low-copy repeat sequences located within 22q11.2. Nonetheless, both somatic and germ line mosaicism has been observed giving unaffected parents a small risk of recurrence. Once present though there is a 50% chance for a person with this contiguous deletion to have an affected child. With this in mind, a variety of prenatal monitoring techniques, as well as, preimplantation genetic diagnosis are available depending on the specific level of risk.
... There is a high association of craniosynostosis with duplication 13q21-q34 and deletion 7p15-p21, 9p21-p24 and 11q23-q25 [50,51]. Furthermore, an increasing number of craniosynostotic patients with deletion 22q11 and deletion and or duplication 1p36 have been reported [12,33]. ...
Craniosynostosis is a very heterogeneous group of disorders, in the etiology of which genetics play an important role. Chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases. Mutations in 7 genes are unequivocally associated with mendelian forms of syndromic craniosynostosis: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23. Mutations in 4 other genes, FBN1, POR, TGFBR1 and TGFBR2, are also associated with craniosynostosis, but not causing the major clinical feature of the phenotype or with an apparently low penetrance. The identification of these genes represented a great advance in the dissection of the genetics of craniosynostosis in the last 15 years, and today they explain the etiology of about 30% of the syndromic cases. The paucity in the identification of genes associated with this defect has partly been due to the rarity of familial cases. In contrast, very little is known about the molecular and cellular factors leading to nonsyndromic forms of craniosynostosis. Revealing the molecular pathology of craniosynostosis is also of great value for diagnosis, prognosis and genetic counseling. This chapter will review (1) the chromosomal regions associated with syndromic forms of the malformation, (2) the genes in which a large number of mutations have been reported by independent studies (FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1) and (3) the molecular mechanisms and genotype-phenotype correlations of such mutations.
... include auricular abnormalities, nasal abnormalities, "hooded eyelids," ocular hypertelorism, cleft lip and palate, asymmetric crying facies, and craniosynostosis [McDonald-McGinn, Gripp et al 2005]. However, the presence of these features as well as other facial findings, such as a long face and malar flatness, is variable. ...
Estimates suggest that the 22q11.2 deletion occurs in approximately 1 in 4000 live births, making this disorder a significant health concern in the general population. The 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome, suggesting that they are phenotypic variants of the same disorder. The findings associated with the 22q11.2 deletion are extensive and highly variable from patient to patient. In this chapter, we discuss the features of this disorder, with an emphasis on the clinical findings and an approach to the evaluation of these patients. In addition, we present the current understanding at the molecular level, of the genomic mechanisms and genes that are likely to play a central role in causing this frequent genetic condition.
The 22q11.2 deletion has been identified in the majority of individuals with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome, and in some people with the autosomal dominant Opitz G/BBB syndrome and Cayler Cardiofacial syndrome/asymmetric crying facies syndrome. It is the most common microdeletion syndrome in humans. There is wide phenotypic variability most frequently involving congenital cardiac anomalies, palatal differences, immune deficiency, hypoparathyroidism, renal anomalies, dysphagia, and mild craniofacial differences. However, some individuals with the 22q11.2 deletion have none of these features. Behavioral abnormalities and learning disabilities are common, and psychiatric symptoms are present in a subset. The 22q11.2 deletion most often occurs as a de novo event, but affected individuals have a 50% recurrence risk.
