Emanuel syndrome

What is Emanuel syndrome?

This rare disease is a chromosomal condition, believed to have been diagnosed in more than 100 people to date.

Some of its symptoms may be life threatening in infancy. Severe to profound intellectual disability is one of the most prominent symptoms of the syndrome.

Syndrome Synonyms:
Supernumerary Der(22)t(11;22) Syndrome

What gene changes cause Emanuel syndrome?

The syndrome is caused by extra genetic material of part of chromosomes 11 and 22, product of unbalanced translocation.

Parents are carriers of balanced translocations between chromosomes 11 and 22 without loss or gain of genetic material, but in meiosis (generation of gametes or reproductive cells) these translocations lead to unbalanced cells, which have gain of genetic material from chromosomes 11 and 22.

What are the main symptoms of Emanuel syndrome?

In infancy the main symptoms include weak muscle tone and failure to thrive due to feeding difficulties.

Congenital heart defects and or very small kidneys in an individual can be life threatening to an infant.

Severe developmental delay and profound intellectual disability are characteristic of the syndrome.

Physical features of the condition include a very small head and jaw, ear issues. Over 50% of affected individuals are born with a cleft or elevated palate.

Supernumerary Der(22)t(11;22) Syndrome
Patent ductus arteriosus, Preauricular skin tag, Truncus arteriosus, Renal agenesis, Recurrent otitis media, Thickened nuchal skin fold, Renal hypoplasia, Seizure, Single umbilical artery, Hypoplasia of the corpus callosum, Delayed speech and language development, Hearing impairment, High palate, Gastroesophageal reflux, Global developmental delay, Kyphosis, Constipation, Congenital hip dislocation, Congenital diaphragmatic hernia, Low hanging columella, Delayed eruption of primary teeth, Dental crowding, Deeply set eye, Cryptorchidism, Facial asymmetry, Feeding difficulties in infancy, Muscular hypotonia, Preauricular pit, Macrotia, Abnormality of metabolism/homeostasis, Myopia, Low-set ears, Long philtrum, Low-set nipples, Intrauterine growth retardation, Intellectual disability, Inguinal hernia, Micropenis, Micrognathia, Pulmonic stenosis, Ventricular septal defect, Microcephaly, Strabismus, Upslanted palpebral fissure, Broad jaw, Scoliosis, Recurrent respiratory infections, Aortic valve stenosis

How does someone get tested for Emanuel syndrome?

The initial testing for Emanuel syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Emanuel syndrome

DISEASE OVERVIEW:
Patients with Emanuel syndrome have severe global developmental delay and/or severe to profound intellectual disability (100%). The patient present further multiple additional features, like microcephaly (100%), cardiac defects - mostly aortic valve stenosis (60%), cleft palate (50%), renal malformations (30%), anal atresia or stenosis (20%), cerebral atrophy and hip dysplasia (30-80%, each). Additional findings are a typical dysmorphic face, craniofacial and skeletal abnormalities, gastroesophageal reflux, hypotonia, hearing loss, strabismus or other ophthalmologic issues, inguinal hernia, seizures, genital abnormalities (in males) and other less frequently observed manifestations. The syndrome is caused by a complex small supernumerary marker chromosome (sSMC) containing material from chromosomes 11 and 22. This is the result of 3:1 malsegregation of a parental balanced translocation between chromosomes 11 and 22; in human the translocation t(11;22)(q23;q11.2) is the most frequently observed one, excluding Robertsonian translocations.

CLINICAL DESCRIPTION (GENERAL):
Patients with Emanuel syndrome are severely mentally impaired and normally hardly able to communicate by single word sentences. They present with a typical facial appearance including  microcephaly, brachycephaly, prominent forehead, , downslanted palpebral fissures, epicanthal folds, depressed nasal bridge, long philtrum and microretrognathia. In children, round face with deeply set eyes are observed. Coarsening of facial features with time has been observed. Individuals with Emanuel syndrome are unable to walk at all or only with assistance. The physical capacities are primarily dependent on i) the severity of life-threatening conditions and the possibility to cure them by surgery and ii) the individual mental capacities of the patient, depending on its ‘genetic background’ apart from the syndrome.

CLINICAL DESCRIPTION (BODY SYSTEMS):
Brain/nervous system: cerebral atrophy, developmental delay, intellectual disability, speech impairment, seizures, hearing loss, seizures
Face: cleft palate; typical dysmorphies, craniofacial abnormalities
Eyes: strabismus or other ophthalmologic issues
Bones: microcephaly, hip dysplasia, other skeletal complications
Heart: cardiac defects like aortic valve stenosis
Urogenital system: renal malformations, genital abnormalities (in males)
Colon: anal atresia or stenosis, gastroesophageal reflux, inguinal hernia
Muscles: hypotonia

SYNDROME CHARACTERISTICS:
MODE(S) OF INHERITANCE: In carriers of a t(11;22)(q23;q11.2) the sSMC is a result of 3:1 malsegregation of the balanced translocation within a gamete. There is no clear Mendelian mode of inheritance;the risk for a couple with one of the putative parents being a carrier of the translocation to have an affected child is between 2 to 6%.
PENETRANCE: 100%
PREVELANCE: 0.003% in newborn; 0.02 in intellectually disabled individuals
LIFE EXPECTANCY: Several decades (oldest known patient died in mid-40s)
AGE OF ONSET: Prenatal/at birth
PRENATAL PRESENTATION: Intrauterine growth retardation, microcephaly, ear abnormalities, cleft palate, heart defect, enhanced nuchal translucency; risk of abortion is estimated to be 30%.

MOLECULAR GENETICS:
GENE LOCATION(S): Partial trisomy chr11:116,440,000-116,920,000 and chr22: 0-21,767,000 [GRCh37/hg19]
KNOWN MUTATION(S): Copy number variant – partial trisomy of chromosomes 11 and 22
TYPE OF MUTATION(S): complex sSMC

KEY PUBLICATIONS:
Emanuel syndrome in connection with the der(22)t(11;22) was first described in 1980, also referring to older, partially misdiagnosed older reports from the 1970s (Zackai and Emanuel, 1980). Hill et al. (2000) reported the for the Emanuel syndrome typical breakpoints in chromosomes 11 and 22, and Kurahashi and Emanuel (2001) demonstrated that palindrome mediated double-strand breaks during meiosis cause illegitimate recombination between subbands 11q23 and 22q11. Also it seems that the specific translocation t(11;22) is predominantly formed de novo during male spermatogenesis (Kurahashi and Emanuel 2001; Kato et al. 2006). Carriers of the balanced constitutional t(11;22) translocation are phenotypically normal. However, there is a 2-6% risk of their having live-born progeny with ES (Liehr 2012). Clinical features and their frequencies are best summarized under https://www.ncbi.nlm.nih.gov/books/NBK1263/. Recently, it became possible to identify Emanuel syndrome patients based on facial photographies (Liehr et al., 2018).

SURVEILLANCE:
Follow up is based on the expression of each individual’s symptoms; regular developmental assessments and reevaluation by a clinical geneticist are recommended.

MANAGEMENT AND TREATMENT:
As Emanuel syndrome cannot be cured, only symptomatic management is possible. Thus a multidisciplinary team is necessary; standard medication and surgical management of physical problems is indicated; also physical, occupational, and speech therapies should be prescribed; if applicable alternative communication methods maybe taught.

CLINICAL TRIALS:
N/A

PATIENT ORGANIZATIONS:
- http://www.c22c.org/
- https://rarediseases.info.nih.gov/diseases/9835/index
- http://www.rarechromo.org
- http://www.emanuelsyndrome.org/gandd.htm


AFFILIATIONS:
(1) Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Am Klinikum 1, D-07747 Jena, Germany


DATE OF UPDATE:
May 16, 2018

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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