Emanuel Syndrome

Emanuel syndrome (ES) is a rare genetic disorder caused by an unbalanced translocation between chromosomes 11 and 22, resulting in multiple congenital anomalies and developmental disabilities. It was first described by Emanuel et al. in 1979 as a variant of the 11q- syndrome. The prevalence of ES is estimated to be around 1 in 110,000 live births, with a higher incidence in offspring of carriers of the balanced translocation. The molecular mechanism of ES involves the formation of a derivative chromosome 22 (der(22)) that contains extra genetic material from chromosome 11, leading to gene dosage imbalance and disrupted gene expression. The diagnosis and treatment of ES are important and challenging, as the disorder affects various aspects of the patients’ physical and mental health.

Clinical Features

The clinical features of ES are diverse and variable, affecting multiple organ systems and developmental domains. The major clinical characteristics of ES include craniofacial anomalies, such as microcephaly, brachycephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthal folds, low-set ears, small nose, cleft lip and/or palate, micrognathia, and dental malocclusion. Other common features include congenital heart defects, such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot; renal anomalies, such as hydronephrosis, vesicoureteral reflux, renal hypoplasia or agenesis, and horseshoe kidney; genital anomalies, such as cryptorchidism, hypospadias, micropenis, and bicornuate uterus; limb anomalies, such as polydactyly, syndactyly, clinodactyly, and clubfoot; and neurological abnormalities, such as hypotonia, seizures, intellectual disability, speech delay, autism spectrum disorder, and behavioral problems.

Fig.1 9-month-old male with Emanuel syndrome presenting with hearing loss. (Xie CL, 2019)

The clinical presentation of ES is heterogeneous and variable, depending on the size and location of the extra chromosomal material. Some patients may have mild or subtle features that are not easily recognized, while others may have severe or lethal manifestations that require intensive care. Moreover, ES can be confused with other syndromes that share similar phenotypes, such as DiGeorge syndrome (22q11.2 deletion syndrome), Cat-eye syndrome (22q11.2 duplication syndrome), Pallister-Killian syndrome (tetrasomy 12p), and Jacobsen syndrome (11q deletion syndrome). Therefore, careful clinical evaluation and differential diagnosis are essential for the accurate identification of ES.

The correlation between the clinical features and the genotype of ES is complex and incompletely understood. Some studies have suggested that the size of the der(22) chromosome may influence the severity of the phenotype, with larger der(22) chromosomes being associated with more severe features. However, other studies have found no significant correlation between the size of the der(22) chromosome and the clinical outcome. Furthermore, some patients with ES may have additional chromosomal abnormalities or genetic mutations that may modify or contribute to their phenotype. Therefore, more research is needed to elucidate the molecular mechanisms and genetic modifiers that underlie the phenotypic variability and complexity of ES.

Clinical Diagnosis and Treatment

The clinical diagnosis of ES is based on the detection of the der(22) chromosome in the patient’s cells. The conventional diagnostic technique is chromosome analysis, also known as karyotyping, which involves staining and visualizing the chromosomes under a microscope. This technique can identify large chromosomal abnormalities, such as translocations, deletions, and duplications. However, it has some limitations, such as low resolution, high cost, and long turnaround time. Moreover, it may miss small or cryptic chromosomal changes that are not visible by karyotyping.

To overcome these limitations, more advanced diagnostic techniques have been developed, such as fluorescence in situ hybridization (FISH) and microarray comparative genomic hybridization (aCGH). FISH uses fluorescent probes that bind to specific DNA sequences on the chromosomes, allowing the detection of small or subtle chromosomal abnormalities that are missed by karyotyping. FISH can also be performed on interphase cells, which do not require cell culture or metaphase preparation. aCGH is a high-throughput technique that compares the copy number of thousands of DNA segments across the genome between the patient and a reference sample. aCGH can detect both large and small chromosomal imbalances, such as deletions, duplications, and copy number variations (CNVs), without prior knowledge of the target region. aCGH can also provide higher resolution and accuracy than karyotyping or FISH.

The choice of the diagnostic technique depends on the clinical indication, availability, cost, and preference of the clinician and the patient. The future direction of ES diagnosis may involve the use of next-generation sequencing (NGS) technologies, such as whole-genome sequencing (WGS) or whole-exome sequencing (WES), which can provide more comprehensive and detailed information about the genetic variation and mutations in ES patients.

The treatment of ES is symptomatic and supportive, aiming to improve the quality of life and reduce the complications of the disorder. The treatment plan should be individualized according to the patient’s needs and preferences, involving a multidisciplinary team of specialists, such as pediatricians, cardiologists, nephrologists, urologists, orthopedists, neurologists, psychologists, speech therapists, physical therapists, occupational therapists, and social workers. Treatment options may include surgery to correct congenital anomalies or malformations, medication to control seizures or infections, physical therapy to improve muscle tone or mobility, speech therapy to enhance communication skills, behavioral therapy to address emotional or behavioral problems, and genetic counseling to provide information and support to the patient and the family.

The treatment outcome and prognosis of ES vary depending on the severity and type of the clinical features. Some patients may have a normal life expectancy with appropriate medical care and intervention, while others may have a reduced life span due to severe complications or comorbidities. Factors that may influence the prognosis include the size and location of the der(22) chromosome, the presence or absence of additional chromosomal abnormalities or genetic mutations, the type and frequency of congenital anomalies or malformations, and the availability and accessibility of medical resources and services. Therefore, more research is needed to identify prognostic markers and predictors that can help optimize the management and care of ES patients.

References

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2. Emanuel BS, et al. The Emanuel (11;22) (q23;q11) translocation: a non-Robertsonian translocation generated by prezygotic and postzygotic events. Am J Hum Genet. 1991 Sep;49(3):657-68.
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