Scientists from The City University of New York present a protocol for collecting and analyzing data for KBG syndrome that emphasizes the use of videoconference and artificial intelligence (AI). Based on this information, the authors make recommendations for diagnostic and treatment approaches for KBG syndrome.

The study reports 25 previously unpublished individuals from 22 families who have molecularly confirmed diagnoses. The most common characteristics in the cohort were short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, and synophrys. Global developmental delays and behavioral issues were prevalent. 

KBG syndrome is a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies caused by genetic variants in Ankyrin Repeat Domain 11 (ANKRD11) and deletions on 16q24.3. 

There was a high incidence of neurological abnormalities (44%), suggesting that seizure prophylaxis and early detection might be important intervention points. 24% of those diagnosed suffered from attention deficit hyperactivity disorder, while 28% suffered from autism spectrum disorder. A diagnostic and treatment approach for KBG syndrome is recommended based on the data obtained by analyzing 25 patients.   

Herrmann et al. first described the KBG syndrome, named after the surnames (K-B-G) of the first families affected by the syndrome. There were specific craniofacial dysmorphisms, short stature, skeletal abnormalities, cognitive disabilities, and cognitive impairments described in the original report. 

As a result of subsequent research, congenital heart defects, seizures, and gastrointestinal problems have been added to the list of anomalies. KBG syndrome is associated with variants of Ankyrin Repeat Domain 11 (ANKRD11) and deletions of 16q24.3.   

A case report published by GJL describing a 13-year-old boy with epilepsy, severe developmental delay, distinct facial features, and hand anomalies was the first description of KBG syndrome. As a result of his epilepsy, his development was adversely affected. 

Aiming to characterize KBG syndrome better and investigate how epilepsy and other conditions affect neurodevelopment in individuals with KBG syndrome, GJL interviewed and met with 25 individuals with KBG syndrome. 

After exome or genome sequencing, facial photographs could also be used to classify new pathogenic missenses and other variants in rare syndromes, along with medical records. Based on phenotypic features, facial images, and exome data, PEDIA integrates phenotypic features, facial recognition software algorithms, and variant prioritization.  

The Face2Gene program is illustrated in this image: Individual R’s DeepGestalt results indicate a high gestalt score and a medium feature score. Heatmaps visualize areas of the individual’s image that correspond to the KBG syndrome.   

Facial Phenotyping for KBG Syndrome
Image Description: Illustration of Face2Gene. DeepGestalt results of Individual R indicating high gestalt and medium feature scores.
Heatmap visualization shows goodness-of-fit between areas of the individual’s image and the suggested syndrome, KBG.
Image Source:

Common Signs and Symptoms of the Disease

Myoclonic, tonic-clonic, and absence seizures are the most commonly reported types of seizures. Three of eleven individuals with seizures had abnormal electroencephalograms (EEGs). Self-injurious behavior, including self-biting, was categorized as abnormal mood, depression, and/or anxiety.  

  1. Vision and ENT (ear, nose, throat): The tympanic membrane consisted of abnormalities, an enlarged vestibular aqueduct, and nasopharyngeal adenoids that were enlarged. Chronic otitis media also had a preauricular pit, abnormal or blocked Eustachian tubes, and abnormality in the tympanic membrane. Infections of the sinuses, chronic ear, and upper respiratory tract along with hearing loss.   
  2. Skeletal features: Physico-chemical evidence of low bone mineral density in the lumbar spine, hips, and femoral neck leads to osteopenia and then later to osteoporosis.
  3. Features of the cardiovascular system: There were cardiac abnormalities observed, and many cases could be resolved without surgical intervention, however, some Tetralogy of Fallot with spared pulmonary valves still require surgery. 
  4. Features of the gastrointestinal tract: Symptoms of abdominal migraines include stomach pain, nausea, and vomiting. There were cyclic vomiting syndromes associated with abdominal migraines.  
  5. The function of the immune system, endocrinology, and metabolism: There is a high prevalence of short stature among those with KBG syndrome, with up to 66% below the 10th centile in height.  
  6. Features of the urogenital system: In addition to urethral and bladder abnormalities, recurrent urinary tract infections also occurred. Pollakiuria, polyuria, and enuresis were also diagnosed.   
  7. Characteristics of dermatology: It is possible that this may have blood issues, psoriasis, eczema, fingernail dysplasia, and recurrent fungal infections, including hirsutism, low anterior hairline, and abnormal hair whorl, cellulitis, and keratosis pilaris, in addition to hirsutism, acne, and dry skin.  

Recommendations for treatment  

  • It is recommended that physical, occupational, and speech therapies be initiated early. The frequency of at least once a week is likely ideal, based on anecdotal reports from families. To rule out hearing defects that may hinder speech development, children with ANKRD11 variants should undergo baseline auditory screening.  
  • Short stature individuals (those who are under their target range) may benefit from growth hormone treatment. Guidelines and recommendations must be based on systematic studies.  
  • In the case of seizures, EEG screening may be useful after diagnosis, in conjunction with regular monitoring by a neurologist. In rare diseases with a high prevalence of seizures, such as Tuberous Sclerosis, EEG screening is recommended for baseline, although more research is necessary to support such recommendations.  
  • Cardiovascular screening (including echocardiography) may be helpful to patients after a diagnosis is made. 
  • Hearing loss is a common symptom of chronic otitis media. The effectiveness of aggressive antibiotic treatment in preventing hearing loss needs to be further investigated.  
  • Future research and clinical efforts should focus more on gastrointestinal symptoms (e.g., abdominal migraines). 
  • Due to KBG syndrome’s often mild cognitive deficits and subtle dysmorphic features, artificial intelligence-assisted facial applications can reduce missed diagnoses. As a result of combining data from AI with patient registries, diagnostics can be optimized, and guidelines and treatment recommendations can be developed.  

Article Source: Guo, L., Park, J., Yi, E., Marchi, E., Hsieh, T.-C., Kibalnyk, Y., Moreno-Sáez, Y., Biskup, S., Puk, O., Beger, C., Li, Q., Wang, K., Voronova, A., Krawitz, P. M., & Lyon, G. J. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients. European Journal of Human Genetics: EJHG.  (2022).

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