Chopra-Amiel-Gordon Syndrome (CAGS)

Chopra-Amiel-Gordon syndrome (CAGS), also known as ANKRD17-related neurodevelopmental syndrome, is an ultra-rare genetic disorder that primarily affects the development of the brain, face, and limbs. CAGS is caused by a heterozygous loss-of-function variant of the ankyrin-repeat domain-containing protein 17 (i.e., ANKRD17 gene). It is suggested that this protein may regulate multiple signal-transduction pathways as well as the formation and maintenance of blood vessels. Named for the researchers who first described it, CAGS is characterized by a set of physical features, including dysmorphic craniofacial anomalies and limb changes. Individuals may also experience intellectual disability, delays in motor and speech development, and ophthalmologic changes.

CAGS is caused by a loss-of-function alteration to the ANKRD17 gene, resulting in the reduction or loss of the ANKRD17 gene product. The mechanism by which ANKRD17 loss-of-function leads to each individual’s clinical phenotype is currently unknown; however, it is hypothesized that this protein regulates various cell-signaling pathways, gene transcription, cytoskeletal structure, as well as the formation and maintenance of blood vessels. The majority of cases arise from de novo, or spontaneous, gene alterations and, therefore, are not inherited from one’s parents. Nonetheless, several cases of familial inheritance have also been reported. Because CAGS is ultra-rare (i.e., less than 40 case reports in the medical literature), the epidemiology and risk factors are currently unknown. Based on current data, there is no evidence suggesting that individuals with CAGS have a shortened lifespan; however, it is likely that this condition is underreported and underrecognized.

The signs and symptoms of CAGS are nonspecific, variable, and overlap with other genetic conditions. They include dysmorphic facial features, such as a triangular face shape; high anterior hairline; low-set ears; thin vermilion of the upper lip; and almond-shaped eyes. Less common features include cleft lip and/or palate and scoliosis. Individuals may also experience developmental and speech delays, varying degrees of intellectual disability, neurobehavioral manifestations (i.e., epilepsy, autism spectrum disorder), and ophthalmologic changes (i.e., strabismus and refractive errors). Recurrent respiratory infections have been reported in approximately one-third of individuals with CAGS, subsequently leading to failure to thrive.

The diagnosis of CAGS begins with a thorough medical history and physical examination. Individuals with signs and symptoms suggestive of CAGS are typically advised to undergo molecular genetic testing. The diagnosis is confirmed if a pathologic variant of ANKRD17 is identified. Since the presentation of CAGS is nonspecific and overlaps with other intellectual disabilities, other conditions of interest (e.g., Down syndrome or Pierre-Robin sequence) may also be considered to rule out differential diagnoses. Routine laboratory tests  (e.g., complete blood count, urinalysis) can be used to aid diagnosis and to screen for comorbidities (e.g., infections, endocrine and renal anomalies) associated with CAGS. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) may be helpful in excluding structural abnormalities (e.g., intracranial neoplasm) as a cause for the symptoms associated with the syndrome. Notably, over 50% of individuals with CAGS will have non-specific MRI findings, such as decreased white matter volume, focal hyperintensities, and sclerosis.

There is currently no cure for CAGS and treatment consists of supportive measures aimed at improving quality of life and reducing complications. For example, facial changes may be corrected with surgery, respiratory infections can be treated with antibiotics, and seizures can be managed with pharmacotherapy. Individuals may also benefit from a multidisciplinary team consisting of a neurologist, speech and language pathologist, ophthalmologist, physical therapist, and geneticist. Genetic counseling and educational resources may be provided to all individuals and families with this condition. 

CAGS is an ultra-rare genetic condition that primarily affects the development of the brain, face, and limbs. CAGS is caused by a heterozygous loss-of-function alteration of the ankyrin-repeat domain-containing protein 17 (i.e., ANKRD17 gene), a gene that regulates multiple signal-transduction pathways as well as the formation and/or maintenance of blood vessels. The mechanism by which ANKRD17 loss-of-function leads to each individual’s clinical phenotype is currently unknown. The signs and symptoms of CAGS are nonspecific, variable, and overlap with other genetic conditions. Diagnosis involves a thorough medical history and physical examination along with genetic testing to confirm the diagnosis. Currently, there is no cure for CAGS and treatment consists of supportive measures aimed at improving individuals’ quality of life. The paucity of existing data highlights the need for further research into the mechanisms and treatment of this genetic condition.