The earliest descriptions of Emanuel syndrome appear in the English-language literature in the 1960s and 70s. Although G-banding was not yet available, there are several case reports of siblings with multiple malformations and developmental disability with “an extra small acrocentric chromosome resembling that in the G group, exclusive of Down syndrome or XYY,” which was thought to be trisomy 22 [Uchida et al., 1968
; Penchaszadeh and Coco, 1975
; Alfi et al., 1975
; Emanuel et al., 1976
; Shokeir, 1978
]. Once chromosomal banding techniques became available, the atypical nature of the extra chromosome was noted, and eventually it was recognized to be a derivative chromosome of 22 and 11 material derived from a balanced translocation carrier parent [Kessel and Pfeiffer, 1977
; Feldman and Sparkes, 1978
; Nakai et al., 1979
]. The characterization of the breakpoints on chromosomes 11 and 22 demonstrated that t(11;22) is a recurrent translocation, and it is the most common recurring reciprocal translocation in humans [Zackai and Emanuel, 1980
; Schinzel et al., 1981
; Griffin et al., 1986
; Budarf et al., 1989
; Shaikh et al., 1999
; Edelmann et al., 1999
; Tapia-Perez et al., 2000
; Kurahashi et al., 2000c
]. The breakpoints of the t(11;22) translocation are within palindromic AT-rich repeats (PATRRs) on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks in meiosis leading to recombination between 11q23 and 22q11, resulting in this recurrent translocation [Kurahashi et al., 2000a
; Kurahashi et al., 2001
; Kurahashi et al., 2004
In 2004, founding members of the online parent support group, Chromosome 22 Central, successfully lobbied to have Emanuel syndrome added as an entry in the OMIM database. Prior to this, there was concern among parents about the disparate names given to their children's condition (for example, supernumerary derivative 22 and partial 11q trisomy), which impeded parents' ability to find online support. The eponym “Emanuel syndrome” was therefore suggested by the parent group in recognition of Dr. Emanuel's cytogenetic work and molecular characterization of the breakpoints, as well as her consistent involvement with the support group.
Over 100 individuals with Emanuel syndrome have been reported [Fraccaro et al., 1980
; Zackai and Emanuel 1980
; Biederman et al., 1980
; Pihko et al., 1981
; Schinzel et al., 1981
; Iselius et al., 1983
; Lin et al., 1986
]. However, the most recent large case series was published 25 years ago [Iselius et al., 1983
]. While the characteristic dysmorphic features and congenital anomalies most frequently associated with ES have been well described, information about natural history is more limited, making the task of providing prognostic information and anticipatory guidance rather difficult. This study reports data from the largest cohort of individuals with Emanuel syndrome ever described in the literature.
Pregnancy and perinatal issues have not been described previously for this syndrome. Overall, the frequency of pregnancy complications was low (19%) and prematurity was not common. Intrauterine growth restriction was the most commonly reported complication (24%) and birth weights averaged in the lower range of normal. These data imply that, not surprisingly, growth deficiency begins prenatally in these children. Ultrasound abnormalities during pregnancy were only reported in 16%, which is surprising given the high rate of congenital anomalies in this syndrome. Given that many of our study subjects are adolescents and adults, this likely reflects the more limited availability of ultrasound technology in the past. Nonetheless, this suggests that a normal prenatal ultrasound does not rule out Emanuel syndrome, and therefore carrier parents who wish to have prenatal diagnosis need to have more invasive testing such as chorionic villus sampling or amniocentesis.
Congenital anomalies associated with Emanuel syndrome have been well described. The most commonly reported congenital anomalies reported by parents in our study are listed in . Heart defects were reported in 57% of our study subjects, and the most common lesions were atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA). This is similar to the results of a literature review by Lin et al. 
, in which 62% of reported cases had a congenital heart malformation, with ASD, VSD and PDA being the three most common. The apparent high frequency of ASDs and VSDs included both isolated defects, and those that were associated with more significant congenital heart defects. Other heart malformations that were reported in our study included coarctation of the aorta, pulmonic stenosis, and total anomalous pulmonary venous return (TAPVR). We had no reports of tetralogy of Fallot, truncus arteriosus, transposition of great arteries, or tricuspid atresia, which have been reported previously [Giraud et al., 1975
; Fraccaro et al., 1980
; Pangalos et al., 1980
; Lin et al., 1986
]. The vast majority of individuals with congenital heart defects, both in our study and in the literature, have acyanotic lesions. Our results also confirm the reported incidence of cleft palate (54% in our study vs 53% [Fraccaro et al., 1980
]) and imperforate anus (14% vs 13% [Fraccaro et al., 1980
]). Renal malformations were reported to occur in 19% in the largest study [Fraccaro et al., 1980
] but were seen in 36% in our cohort; this increase is likely secondary to improved imaging techniques. Congenital anomalies reported by parents in our study that have not previously been reported include pyloric stenosis and choanal atresia (). Intestinal malrotation was reported in 8%; this malformation has been reported only once previously [Prieto et al., 2007
The incidence of structural brain anomalies in individuals with Emanuel syndrome is unknown, as it has not been studied systematically. Pallotta et al 
reviewed the reported central nervous system (CNS) anomalies in Emanuel syndrome, and determined that 30% of reported individuals have some CNS abnormality. They found the most frequent anomalies to be consistent with a developmental field defect affecting the midline, such as arrhinencephaly, Dandy-Walker malformation, hypoplasia of the corpus callosum, pons and cerebellar vermis, dilatation of the third and fourth ventricles, and trigonocephaly. Our study is inconclusive with regard to CNS anomalies in Emanuel syndrome, as we relied on reports from parents and not medical records. While 65% of respondents indicated that their child had had some form of brain imaging, they were generally not aware of the specific findings. The most common brain anomalies reported in our study were ventriculomegaly, atrophy, white matter abnormalities and hypoplastic corpus callosum (). Microcephaly was reported in only 23% of our subjects, while other literature states that 100% of individuals with Emanuel syndrome have microcephaly [Medne et al., 2007
]. This most likely represents underreporting of microcephaly by parents in our study.
The malformations seen in individuals with Emanuel syndrome overlap with those of cat eye syndrome (CES). These conditions have in common extra chromosome 22 material spanning the proximal p and q arms. CES is usually associated with a supernumerary bisatellited marker chromosome containing material of chromosome 22 (idic(22)(pter->q11.2::q11.2->pter)), which results in partial tetrasomy 22 [McDermid et al., 1986
]. Both conditions have in common a high frequency of preauricular pits and skin tags, anorectal anomalies, and congenital heart defects [Rosias et al., 2001
]. Iris colobomata, however, which are a cardinal feature of CES, are not reported in Emanuel syndrome. Unlike ES, the majority of individuals with CES have mild or no intellectual impairment [Rosias et al., 2001
]. The most obvious explanation for this discrepancy is the presence in individuals with ES of partial 11q trisomy. Indeed, the published cases of isolated 11q trisomy have almost universally reported severe intellectual and physical disability [Pihko et al., 1981
; Zhao et al., 2003
]. In addition, it is notable that some congenital anomalies seen in ES, such as congenital diaphragmatic hernia, hip dysplasia, cleft palate, heart and kidney malformations, and structural brain malformations have also been reported in individuals with 11q trisomy [Pihko et al., 1981
; Zhao et al., 2003
; Klassens et al., 2006
]. Further study of the genomic imbalances present in individuals with ES, CES and 11q trisomy will be useful in delineating the causative genes for the shared anomalies.
Facial dysmorphism in individuals with Emanuel syndrome is well described in infants and very young children, however information about how the facial phenotype evolves with age is limited. Medne et al. 
suggest that the facial features of individuals with ES coarsen over time. Our review of the available photographs from individuals participating in this study did not demonstrate coarsening of facial features. The faces of individuals with ES lengthen over time with micrognathia becoming less pronounced, as would be expected (). There was significant variability in the facial appearance of individuals with ES. The most common facial features observed include hooded eyelids, deep-set eyes, upslanting palpebral fissures, low-hanging columnella, facial asymmetry and ear anomalies. We cannot comment more specifically on the ear anomalies in our study participants, as we did not have the appropriate views in the photographs we obtained from parents. In childhood the combination of deep-set eyes, long philtrum and micrognathia is seen in many, but not all, children.
Fifty percent of our subjects were over the age of 13 years, which allowed us to gather useful natural history information on Emanuel syndrome. The medical issues most commonly reported in our subjects with Emanuel syndrome are summarized in . Most of these have been previously unrecognized or under-recognized, probably due to the small numbers of older children and adults reported in the literature. One of the most clinically relevant findings was the high incidence (72%) of hearing loss. The degree of hearing loss was mild to moderate in the majority. Our questionnaire did not differentiate between sensorineural and conductive hearing loss. However, there was a very high rate of recurrent ear infections and tympanostomy tube placement in these children, so it is likely that conductive hearing loss would be a significant contributing factor. Similarly, visual problems have been underreported in the literature. In our study, vision is impaired in at least one-third of subjects, with myopia and strabismus being the most commonly reported problems. The case report literature has not emphasized seizures as a frequent feature of ES. Our data suggest that seizures are common (48%) but unfortunately we were not able to determine the type of seizure(s) experienced in all cases, so this figure likely includes febrile seizures and all other types of seizures. Gastrointestinal problems, such as gastroesophageal reflux, impaired swallowing and chronic constipation, are common in children with severe developmental disability. Therefore it is not surprising that over half of respondents identified these as ongoing issues for their children. A significant percentage (at least 20%) of individuals in our study required a gastric feeding tube (G-tube) at some point in their lives. Failure to thrive is a common problem in the neonatal period and into childhood. In neonates, poor feeding due to hypotonia and the presence of cardiac and gastrointestinal malformations are the most likely cause. Aside from feeding issues, which are ongoing in childhood, recurrent infections may be partly responsible for failure to thrive as these children get older. Chronic and recurrent ear infections were especially prevalent (96%) in our study subjects. Low immunoglobulins have been reported in children with ES [Tovo et al., 1986
]. Nineteen percent of respondents in our study reported low immunoglobulins and 9% had been treated with intravenous immunoglobulin (IVIG) with reported benefit. However, no conclusions can be drawn about the use of IVIG in children with Emanuel syndrome, as the numbers are small.
As expected from the literature, 100% of children with Emanuel syndrome have global developmental delay and intellectual disability. We were able to more precisely define the extent of these disabilities and determine the average developmental trajectory, by asking parents about age of developmental milestone attainment () and current abilities. While most children do not independently ambulate, over 70% of our subjects eventually learned to walk with support. This ability is largely overlooked in the literature. Expressive language is significantly impaired, with rudimentary speech acquisition in only 20%. However, our study indicates that receptive language is less impaired (at least from the point of view of the parents), which has been noted previously [Medne et al., 2007
], although this is anecdotal.
There are two important limitations to this study. Questionnaire studies in general are subject to recall or reporting bias. The accuracy of the medical history information provided by parents about their children will vary depending on a number of factors including the age of the child, whether the child is still living, whether the parent kept records, the complexity of the medical needs of the child, and the education and socioeconomic status of the parents. We cannot verify that the information given by parents is accurate, as we did not collect medical records on our study subjects. Instead, we endeavored to design the questionnaire in simple language with primarily “yes or no” questions and kept the questions that would require additional medical knowledge to a minimum. The results of this study may also be influenced by ascertainment bias, as recruitment was limited to those whose parent or guardian belongs to an online support group. It is possible that parents of the more severely affected children are more likely to seek this type of support. This would bias our results in favor of a poorer prognosis. On the other hand, the majority of those participating in this study have a child with Emanuel syndrome still living, which excludes parents whose children died earlier in life. Thus, our findings apply primarily to long-term survivors, who in general may have had fewer life-threatening congenital anomalies.
Our study has identified several healthcare issues that can now be anticipated for individuals with Emanuel syndrome. Vision and hearing impairment and potential seizure activity can be identified and addressed early. Failure to thrive may be ameliorated with special attention to gastrointestinal issues and prompt treatment of infection. Children with recurrent infections may benefit from an assessment by an immunologist. Speech and physical therapy are of utmost importance for optimizing development and quality of life; this study has clearly demonstrated that, at least in some individuals, limited communication and ambulation is possible and should be strived for.
This study summarizes the clinical features and long-term outcome of a cohort of 63 individuals with Emanuel syndrome ranging in age from infancy to 33 years. The information gained from this survey will be very useful to carriers of the 11;22 translocation in making reproductive decisions, and to health care providers taking care of children and adults with such a rare condition. Most importantly, new parents of children with Emanuel syndrome can be provided with more accurate and up-to-date prognostic information, which may help ease the anxiety of parenting a child with a rare diagnosis.