Emanuel Syndrome

Clinical characteristics.

Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.

Diagnosis/testing.

The diagnosis of Emanuel syndrome is established in a proband by detection of a duplication of 22q10-22q11 and duplication of 11q23-qter on a supernumerary derivative chromosome 22 [der(22)].

Management.

Treatment of manifestations: Care by a multidisciplinary team is usually necessary; standard management of gastroesophageal reflux, nutrition, anal atresia (or stenosis), inguinal hernias, cardiac defects, cleft palate, hip dysplasia, other skeletal complications, hearing loss, cryptorchidism and/or micropenis, refractive errors, and strabismus or other ophthalmologic issues; ongoing physical, occupational, and speech therapies; alternative communication methods to facilitate communication.

Prevention of secondary complications: Attention to the airway during sedation and/or operative procedures in an institution with pediatric anesthesiologists.

Surveillance: Follow up as needed based on the extent of systemic involvement in each individual; regular developmental assessments; periodic reevaluation by a clinical geneticist.

Genetic counseling.

In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. In most cases, a carrier parent has inherited the t(11;22) from one of his or her parents. When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the parents include: normal chromosomes, supernumerary der(22) syndrome, balanced t(11;22) carrier, and spontaneous abortion as a result of supernumerary der(22) or another meiotic malsegregant. Risks vary depending on whether the mother or father of a proband is the balanced translocation carrier. Prenatal diagnosis for pregnancies at increased risk is possible if the chromosome abnormality has been confirmed in the family.

Suggestive Findings

Emanuel syndrome should be suspected in individuals with the following clinical features:

• Severe intellectual disability
• Microcephaly
• Failure to thrive
• Preauricular tag or pit
• Ear anomalies
• Cleft or high-arched palate
• Micrognathia
• Kidney abnormalities
• Congenital heart defects
• Genital abnormalities in males

Establishing the Diagnosis

The diagnosis of Emanuel syndrome is established in a proband by detection of a duplication of 22q10-22q11 and duplication of 11q23-qter on a supernumerary derivative chromosome 22 [der(22)] (see Table 1). Individuals with Emanuel syndrome have the following karyotypes:

• Most commonly:
  • 47,XX,+der(22)t(11;22)(q23;q11) in females
  • 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.

Figure 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

Genomic testing methods that determine the copy number of sequences can include karyotype, chromosomal microarray (CMA), or targeted duplication analysis by fluorescence in situ hybridization (FISH).

Clinical Description

Well over 400 individuals with supernumerary der(22) have been identified by support groups and by report. 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 documented.

Affected children are usually identified in the newborn period as the offspring of balanced (11;22) translocation carriers.

Growth. Most individuals have pre- and postnatal growth deficiency.

Craniofacial. Observed dysmorphic features include microbrachycephaly, prominent forehead, epicanthus, downslanted palpebral fissures, wide and depressed nasal bridge, long and deep philtrum, and microretrognathia (see Figure 2).

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Figure 2.

Four individuals with Emanuel syndrome. Note the round face, deeply 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 age one (more...)

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.

Cleft palate is seen in approximately 50% of affected individuals. Angular mouth pits or clefts, cleft maxilla, laryngomalacia, and branchial sinuses have been reported. Bifid uvula is also associated.

Cardiac. Congenital heart defects, seen in approximately 60% of individuals with Emanuel syndrome, contribute to morbidity and mortality. Heart defects include atrial septal defect, 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.

Sacral dimple is common.

Congenital hip dislocation or subluxation is common.

Arachnodactyly and tapering fingers are characteristic.

Clubfoot 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, radioulnar synostosis, and 4-5 syndactyly of the toes. Lumbar myelomeningocele has been reported once.

Delayed bone age is mentioned in a few reports.

Eyes. Most persons with Emanuel syndrome have normal vision. Although uncommon, eye abnormalities have included strabismus and myopia. Ptosis and degenerative retinal changes are less common.

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 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 findings include congenital immunoglobulin deficiency, thymic-dependent immunodeficiency, and dysplastic teeth.

Genotype-Phenotype Correlations

All 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 2000, 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.

Penetrance

Penetrance is complete in individuals with the supernumerary der(22).

Nomenclature

Older case reports published prior to G banding described this chromosome abnormality as "partial trisomy 22" or "partial trisomy 11."

Prevalence

Supernumerary der(22) is a rare chromosome disorder; its prevalence is unknown.

The prevalence of balanced t(11;22) carriers is unknown in the general population.

Evaluations Following Initial Diagnosis

No current guidelines to evaluate the clinical manifestations that contribute to morbidity and mortality have been published. The following measures ‒ based on the literature and the authors' experience ‒ are recommended (if they have not already been completed) to establish the extent of disease and needs in an individual diagnosed with Emanuel syndrome:

• Palatal evaluation for cleft palate
• Cardiac evaluation with an echocardiogram to screen for cardiac defects. 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
• 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, clubfoot, curvature of the spine, and radioulnar 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 Overview 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 micropenis
• Evaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills
• Consultation with a clinical geneticist and/or genetic counselor for evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.)

Treatment of Manifestations

Depending on the age and extent of systemic involvement of the individual with Emanuel syndrome, evaluations involving health care providers from multiple specialties are necessary.

In some individuals, 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 micropenis
  • Refractive 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 Complications

Care 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.

Surveillance

The 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 clinical geneticist to apprise the family of new developments and/or recommendations

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Other

Patients and their families should be informed regarding natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources.