DiagnosisClinical DiagnosisEmanuel syndrome is characterized by:A distinct phenotype consisting of the following [Fraccaro et al 1980, Zackai & Emanuel 1980, Lin et al 1986, Carter et al 2009]:Severe intellectual disabilityMicrocephaly Failure to thrive Preauricular tag or sinus Ear anomalies Cleft or high-arched palate Micrognathia Kidney abnormalities Congenital heart defects Genital abnormalities in males A chromosomal imbalance consisting of either of the following (see Figure 1): Most commonly, a derivative chromosome 22[der(22)] (Figure 1A) as a supernumerary chromosome with the following karyotype: 47,XX,+der(22)t(11;22)(q23;q11) in females or 47,XY,+der(22)t(11;22)(q23;q11) in males Rarely, a balanced (11;22) translocation as well as the supernumerary derivative chromosome. Figure 1B shows a karyotype of a balanced t(11;22) carrier. FigureFigure 1
A. Karyotype and schematic ideogram showing the supernumerary derivative chromosome 22, which results in trisomy of chromosome 11q23-qter and 22q cen-q11
B. Karyotype and schematic ideogram showing a balanced translocation carrier. (more...)Affected individuals are usually identified in the newborn period as the offspring of balanced (11;22) translocation carriers. The progeny affected with Emanuel syndrome are genotypically unbalanced because the der(22) is a supernumerary chromosome.TestingCytogenetic testing. When a chromosomal abnormality is suspected, routine cytogenetic analysis is recommended. The supernumerary der(22) chromosome is easily identified by routine G-band analysis at the 500-550 band level in individuals with the disorder. Parental karyotypes should be performed to determine whether one parent is a carrier of the balanced translocation, t(11;22). In the rare instance in which one of the parents is not a balanced translocation carrier, commercially available FISH probes for the 22q11.2 deletion and for the telomere of 11q can identify the supernumerary chromosome in the karyotype as being derived from chromosomes 11 and 22. The combined use of these testing modalities identifies 100% of the small acrocentric chromosomes resulting in Emanuel syndrome.Molecular Genetic TestingGenes. Duplication of genes on the supernumerary derivative chromosome 22 is the only genetic defect known to be associated with Emanuel syndrome. The clinical phenotype arises from duplication of 22q10-22q11 and duplication of 11q23-qter on the supernumerary der(22). Note: Duplication of the short (p) arm of chromosome 22 is clinically insignificant, as chromosome 22 is an acrocentric chromosome with the p arm containing heterochromatin.Clinical testing Chromosome analysis with G banding identifies the supernumerary der(22). FISH testing is accomplished using probes N25 or TUPLE1 mapping to 22q11.2 and using 11q subtelomeric probe. Whole chromosome paint (WCP) using chromosome 11 and 22 probes would show that the supernumerary chromosome is derived from chromosomes 11 and 22. This method is not routinely used and FISH testing readily confirms the origin of the supernumerary der(22) observed on chromosome analysis. Array genomic hybridization (aGH) detects the supernumerary der(22) as all commercial BAC-based arrays include pericentromeric, subtelomeric, and 22q11.2 region BAC clones. In addition, oligonucleotide-based aGH detects the duplications of 11q and 22q of the supernumerary der(22). Research testing Breakpoint-specific PCR-based testing. Using PCR with primer pairs that amplify across the breakpoints can confirm the typical recurrent translocation breakpoint [Kurahashi et al 2000a, Kurahashi et al 2000c]. MLPA (multiplex ligation-dependent probe amplification) assay has been developed to detect duplication of 22q. MLPA is a quantitative multiplex PCR approach for determining the relative copy number of a genomic target sequence. It has been successful in identifying supernumerary der(22) [Vorstman et al 2006]. Table 1. Summary of Molecular Genetic Testing Used in Emanuel SyndromeView in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityChromosome analysis Supernumerary der(22) 100% ClinicalFISH Duplication 22q11 and 11q23 100% when both probes are used ClinicalArray GH (aGH)Copy number variations of chromosome 11 and chromosome 22 100% ClinicalMLPA Duplication 22q11 100% Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated geneTesting StrategyTo confirm/establish the diagnosis in a proband. When supernumerary der(22) is suspected, perform routine cytogenetic analysis since the additional chromosome is easily identified as an additional small acrocentric chromosome. Use FISH probes for 22q to determine that the extra chromosome is partially derived from chromosome 22. Use FISH probes for the 11q telomere to confirm that the translocation is between 11q and 22q. Carrier testing for at-risk relatives requires prior identification of the translocation in a family member. (Balanced translocation carriers are typically asymptomatic.) Prenatal diagnosis for at-risk pregnancies requires prior identification of the translocation in a family member. Genetically Related (Allelic) DisordersNo other phenotypes are associated with supernumerary der(22).Female carriers of a balanced t(11;22) may have a somewhat increased risk for premenopausal breast cancer. This possible association was first proposed by Lindblom et al [1994], who noted one woman with breast cancer in five of the eight families studied. More recently, two unrelated families have been reported with multiple instances of breast cancer cosegregating with the balanced t(11;22) across several generations [Jobanputra et al 2005, Wieland et al 2006]. However, other studies looking at a larger number of families have not confirmed this association [Kurahashi et al 2000c]. In a recent study that examined 80 pedigrees, the conclusion was that the incidence of breast cancer is not increased in 11;22 translocation carriers over that which is expected in the general population [Carter et al 2010]. The results of this study suggest that enhanced breast cancer surveillance may only be warranted in female carriers of a balanced t(11;22), if there is a family history of breast cancer. Further, an increased risk for esophageal cancer and melanoma in carriers of the 11;22 translocation could not be excluded in this study, suggesting that larger studies are needed to clarify the issue. As a result of these findings, increased vigilance with respect to sun protection and investigation of skin lesions in t(11;22) carriers, and close attention to possible cancer symptoms as per the general population have been suggested.

Natural HistoryWell over 100 individuals with supernumerary der(22) have been reported [Fraccaro et al 1980, Zackai & Emanuel 1980, Lin et al 1986]. Significant mortality is associated with life-threatening congenital malformations such as congenital heart defects, diaphragmatic hernia, or renal insufficiency. The highest mortality rate is in the first months of life. With improved palliative care and time, survival chances improve and survival into adulthood has been well documented.Affected children are usually identified in the newborn period as the offspring of balanced (11;22) translocation carriers.Constitutional. Most individuals have pre- and postnatal growth retardation and associated dysmorphic features. Craniofacial. Observed dysmorphic features include micro-brachycephaly, prominent forehead, epicanthal folds, downslanting palpebral fissures, broad and flat nasal bridge, long and pronounced philtrum, microretrognathia, and abnormal auricles (ranging from microtia to large ears) often associated with preauricular ear pits and/or tags (see Figure 2). FigureFigure 2. Four individuals with Emanuel syndrome. Note the round face, deep-set, round eyes, and prominent forehead in children A (age ~6 months) and B (age 3 years). Note the coarsening of facial features over time in individual D; photos are taken at (more...)Cardiac. Congenital heart defects, seen in approximately 60% of individuals with supernumerary der(22), contribute to morbidity and mortality. Heart defects include atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, truncus arteriosus, tricuspid atresia, coarctation of the aorta, aberrant subclavian artery, persistent left superior vena cava, and patent ductus arteriosus. Genitourinary. Renal malformations, seen in approximately 30% of affected individuals, range from complete renal agenesis to various degrees of renal hypoplasia. Males often have cryptorchidism, small scrotum, and micropenis. Uterine malformations can occasionally be observed in females. Gastrointestinal. Diaphragmatic hernia and hypoplasia or eventration of the diaphragm have been observed. Anal atresia with or without fistula is seen in about 20% of affected individuals. Anal stenosis without complete atresia is observed as well.Inguinal hernias are uncommon but well documented.Biliary atresia, Hirschsprung disease, abnormal liver lobation, extrahepatic biliary ducts, absent gallbladder, and polysplenia have been observed occasionally.Poor weight gain is common. While specific feeding problems are often not described, gastroesophageal reflux and difficulties with suck and swallow are common.Musculoskeletal. All affected individuals have significant centrally based hypotonia. Curvature of the spine is most likely a secondary complication of severe hypotonia and resulting motor delays.Congenital hip dislocation or subluxation is common. Arachnodactyly and tapering fingers are characteristic.Club foot and joint contractures can be congenital or develop later in life. Other, less frequently observed skeletal malformations include 13 pairs of ribs, hypoplastic clavicles, cubitus valgus, radio-ulnar synostosis, and 4-5 syndactyly of the toes. Lumbar myelomeningocele has been reported once . Sacral dimple is common.Delayed bone age is mentioned in a few case reports.Palate. Cleft palate is seen in approximately 50% of affected individuals. Eyes. Most persons with Emanuel syndrome have normal vision. Although uncommon, eye abnormalities have included strabismus and myopia. Ptosis and degenerative retinal changes are rarer. Ears, nose and throat. The external ear auricle is typically malformed and preauricular ear pits and/or tags are characteristic. Severe microtia with atresia of the external auditory canal and deafness have been reported. Hearing loss is uncommon, but milder forms may be underestimated because of the difficulties associated with accurate hearing evaluation in individuals with severe developmental delay. Angular mouth pits or clefts, cleft maxilla, laryngomalacia, and branchial sinuses have been reported. Bifid uvula is also associated.CNS. Microcephaly is present in all affected individuals. The incidence of structural brain abnormalities is not known as brain imaging is not required to establish the diagnosis. Reported malformations have included Dandy-Walker malformation, agenesis of the corpus callosum, arrhinencephaly, and absent olfactory bulbs and tracts.Seizures are reported in a few affected individuals and abnormal EEGs without clinical seizures in another small subset.Development. All children with Emanuel syndrome have severe global developmental delays. Adults function in the spectrum of severe to profound intellectual disability. Most individuals can sit unsupported. Walking is often difficult because of poor motor coordination; only a small number learn to walk. Speech and language development is significantly delayed. Receptive language is better than expressive language and some individuals are able to use single words to communicate. Other. Congenital immunoglobulin deficiency; thymic-dependent immunodeficiency; dysplastic teeth.

Genotype-Phenotype CorrelationsAll individuals with Emanuel syndrome have the supernumerary der(22), which results from almost identical breakpoints on both 11q23 and 22q11. The breakpoints differ by only a few nucleotides [Shaikh et al 1999, Kurahashi et al 2000b, Kurahashi & Emanuel 2001]. Genotype-phenotype correlation, however, is difficult as the clinical findings result from duplicated genetic material. While systemic involvement can vary, developmental outcome is uniformly in the spectrum of severe to profound intellectual disability.

Differential DiagnosisClinical features that overlap with Emanuel syndrome can be seen in the syndromes listed below. Chromosome analysis always confirms the diagnosis of Emanuel syndrome and rules out other diagnoses.Fryns syndrome Smith-Lemli-Opitz syndrome Pallister-Killian syndrome Kabuki syndrome Wolf-Hirschhorn syndrome Other chromosomal abnormalities Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisNo current guidelines to evaluate the clinical manifestations that contribute to morbidity and mortality have been published. The following recommendations to establish the extent of disease in an individual diagnosed with Emanuel syndrome are based on the literature and the authors' experience:Cardiac evaluation with an echocardiogram to screen for cardiac defects. ASDs (atrial septal defects) are the most common defects and may not be detected by auscultation alone. Renal ultrasound examination to evaluate for structural kidney anomalies; if indicated, vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux Palatal evaluation for cleft palate Gastrointestinal evaluation with appropriate radiologic studies for structural anomalies of the gastrointestinal (GI) tract, in particular anal stenosis or diaphragmatic abnormalities, gastroesophageal reflux Feeding and swallowing assessment Orthopedic evaluation with appropriate radiologic studies for hip dysplasia as well as joint contractures, club foot, curvature of the spine, and radio-ulnar synostosis Otolaryngology (ENT) evaluation for stenosis or atresia of ear canals Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing (see Hereditary Hearing Loss and Deafness for more information about this testing)Ophthalmologic evaluation, including dilated fundoscopic examination, to assess visual acuity and to evaluate for strabismus Urologic evaluation in males with cryptorchidism and/or micropenisEvaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills Medical genetics evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.) Treatment of ManifestationsDepending on the age and extent of systemic involvement of the individual with Emanuel syndrome, evaluations involving healthcare providers from multiple specialties are necessary.In some cases, palliative care is appropriate when there are severe structural defects and/or renal failure.Standard management of gastroesophageal reflux; supplementary formulas and consideration of enteral feeds if there is failure to thrive Surgical correction for anal atresia (or stenosis if indicated) and inguinal hernias Standard interventions for: Cardiac defects Cleft palate Hip dysplasia and other skeletal complications; assistive devices such as walkers are often required for ambulation Hearing loss Cryptorchidism and/or micropenisRefractive errors, strabismus, or other ophthalmologic issues Seizures, if present Ongoing physical, occupational, and speech therapies to optimize developmental outcome Alternative communication methods to facilitate communication as verbal skills are often very limited Prevention of Secondary ComplicationsCare during sedation and/or operative procedures should be provided by a pediatric anesthesiologist as small airways, various palatal abnormalities, and laryngomalacia can be seen in children with Emanuel syndrome.SurveillanceThe following are appropriate:Follow-up as needed based on the extent of systemic involvement in the affected individual Regular assessment of developmental progress to guide therapeutic interventions and educational modalities Periodic reevaluation by a medical geneticist to apprise the family of new developments and/or recommendations Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherPatients and their families should be informed regarding natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table B. OMIM Entries for Emanuel Syndrome (View All in OMIM) View in own window 609029EMANUEL SYNDROMEMolecular Genetic PathogenesisMolecular genetic pathogenesis is not known as Emanuel syndrome results from duplicated genomic segments of chromosomes 11q and 22q, which include a significant number of genes.