Emanuel Syndrome

A number sign (#) is used with this entry because Emanuel syndrome is caused by malsegregation of the t(11;22)(q23;q11.2) translocation, one of only a few recurrent non-Robertsonian constitutional translocations in humans (Fraccaro et al., 1980; Zackai and Emanuel, 1980).

See also supernumerary der(22)t(8;22) syndrome (613700).

Description

Emanuel syndrome is characterized by multiple congenital anomalies, craniofacial dysmorphism, and significant developmental delay and mental retardation. Features include ear anomalies, preauricular tag or sinus, cleft or high-arched palate, micrognathia, microcephaly, kidney abnormalities, heart defects, and genital abnormalities in males (summary by Carter et al., 2009).

Carriers of the balanced constitutional t(11;22) translocation are phenotypically normal but have a 10% risk of having progeny with supernumerary der(22)t(11;22) syndrome as a result of malsegregation of the der(22). The affected progeny are genotypically unbalanced because they carry the der(22) as a supernumerary chromosome--either 47,XX,+der(22)t(11;22) or 47,XY,+der(22)t(11;22) (Zackai and Emanuel, 1980; Lin et al., 1986).

Clinical Features

Carter et al. (2009) reported questionnaire-based information on 63 individuals with Emanuel syndrome, ranging in age from newborn to adult. The most common anomalies were ear pits (76%), micrognathia (60%), heart malformations (57%), and cleft palate (54%). Renal defects were found in 36%, small penis in 64%, and cryptorchidism in 46%. Dysmorphic features included hooded eyelids, deep-set eyes, upslanting palpebral fissures, low-hanging columella, micrognathia, and facial asymmetry. Micrognathia became less apparent with age. Other features included myopia, strabismus, hearing impairment, seizures, failure to thrive, and recurrent infections, particularly otitis media. Most had feeding difficulties with gastroesophageal reflux and/or constipation, resulting in poor growth. Psychomotor development was uniformly delayed. The majority of individuals (over 70%) eventually learn to walk with support, but had limited language development and ability for self-care.

Cytogenetics

To elucidate the mechanism of the malsegregation of the der(22), Shaikh et al. (1999) analyzed 16 families with the t(11;22) translocation using short tandem repeat polymorphism markers on both chromosomes 11 and 22. In all informative cases the proband received 2 of 3 alleles, for markers above the breakpoint on chromosome 22 and below the breakpoint on chromosome 11, from the t(11;22) translocation carrier parent. These data strongly suggested that 3:1 meiosis I malsegregation in the t(11;22) balanced translocation carrier parent was the mechanism in all 16 families. Shaikh et al. (1999) concluded that most t(11;22) translocations occur within the same genomic intervals and that most supernumerary der(22) offspring result from a 3:1 meiosis I malsegregation in the balanced translocation carrier.

Diagnosis

Kurahashi et al. (2000) developed a PCR-based translocation detection system for the t(11;22) translocation using PCR primers flanking the palindromic AT-rich repeats (PATRRs) of both chromosomes. They compared the translocation breakpoints of 40 unrelated carriers of the t(11;22) balanced translocation and 2 additional, independent cases with supernumerary der(22) syndrome. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation.

Pathogenesis

Kurahashi et al. (2000) identified the breakpoints of the t(11;22) translocation within palindromic AT-rich repeats on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks leading to the translocation. Kurahashi et al. (2000) sequenced the der(11) junction fragment. Kurahashi and Emanuel (2001) presented data lending support to the hypothesis that palindrome-mediated double-strand breaks in meiosis cause illegitimate recombination between 11q23 and 22q11, resulting in this recurrent translocation.

Kurahashi and Emanuel (2001) described an unexpectedly high rate of de novo constitutional t(11;22) translocations in sperm from normal males. Somatic DNA from these and other normal individuals or from people with chromosomal breakage syndromes did not yield PCR junction fragments, indicating that this translocation originates during meiosis.

Kato et al. (2006) found that the PATRR on chromosome 11 is variable in size in normal healthy individuals. The most common allele is about 450 basepairs, termed by them L-PATRR11, and forms a nearly perfect palindrome. Several types of short variants (S-PATRR11s) were identified that appear to be derived from the longer version primarily by deletion near the symmetric center of the palindromic structure. Kato et al. (2006) classified the S-PATRR11s into 4 groups. The most frequent 350-bp variant, S1-PATRR11, has a 50-bp deletion at both of the palindromic arms but still remains completely symmetrical. S2-PATRR11 has an asymmetric deletion at its center, but the new center manifests a symmetric palindrome. S3-PATRR11 does not possess palindromic features by virtue of a deletion at the center of the palindrome. Kato et al. (2006) identified a rare 434-bp S-PATRR11, S4-PATRR11, which sustained an asymmetric central deletion followed by the insertion of an AT-rich sequence of unknown origin. Kato et al. (2006) also identified another rare allele, EL-PATRR11, with a duplication of the proximal arm, which constitutes a 603-bp asymmetric palindrome. They then analyzed sperm DNA from individuals with various genotypes for the PATRR11. Five men homozygous for the L-PATRR11 genotype produced de novo translocations at a frequency ranging between 1.52 x 10(-5) and 1.57 x 10(-4). A heterozygote for the L-PATRR11 and S1- or S2-PATRR11 alleles produced de novo translocations at a similar overall frequency, as did homozygotes for the L-PATRR11. Further sequence variation revealed that virtually all of the de novo translocations appeared to originate from the L-PATRR11, which has an overall allele frequency in the general population of 87.1%. Kato et al. (2006) concluded that their work demonstrates genetic variation over more than 3 orders of magnitude in the susceptibility for generating the recurrent translocation in humans, and pointed to the importance of genomic sequence variation on the frequency of chromosomal rearrangements.