Clinical and genetic aspects of KBG syndrome

Original research article by K. Low et al. (2016).

Read the article here.

KBG syndrome is a rare disorder characterized by short stature, distinctive facial features, skeletal abnormalities, and developmental delay / intellectual disability. In the past, people with KBG syndrome were diagnosed based on a shared clinical presentation. However, genetic testing can now be used to as well. As of 2006, only 46 cases of KBG syndrome had been identified, but the number has grown since then as genetic testing has become more available. Most children with a clinical diagnosis of KBG syndrome have been found to have changes in the ANKRD11 gene. This is currently the only gene known to be associated with KBG syndrome..

Previous studies have determined that changes in the ANKRD11 gene cause KBG syndrome (Sirmaci et al., 2011, summarized below). This study examined the clinical and genetic profiles of 31 people recently diagnosed with KBG syndrome and one adult who had been diagnosed with the syndrome as a child and had not previously had genetic testing. In addition to looking at these 32 people, the authors compared their findings with the information collected in other KBG studies. The researchers highlighted nine categories in their analysis, provided here:

Facial Features. Participants often had triangle shaped faces, short necks, large eyebrows, large ears, and large noses.

Growth. 40% of study participants were short.

During Pregnancy. Moms did not have major issues while pregnant with their children who would later be diagnosed with KBG syndrome. A few babies did have problems with feeding after birth.

Developmental Progress / Learning Difficulties. The ages at which developmental milestones were reached was delayed. Speech was very delayed; most children were between ages 2 and 3 when they spoke their first word. Mobility was also delayed, but all children managed to walk; the oldest age to begin walking was 3 years and 2 months. When looking at all KBG syndrome research studies, 99% of individuals had learning difficulties.

Neurodevelopment/Behavior. 14 of the 32 participants had seizures, and the age at which the seizures started ranged from infancy to mid-teens. Eight participants had a formal diagnosis of autism spectrum disorder (ASD). Five participants had a diagnosis of attention deficit hyperactivity disorder (ADHD).

Ear, Nose, Throat, and Oral Cavity. Macrodontia (enlargement) of the upper incisors was seen in most of the people recruited for this study and in 82% of the people with KBG syndrome involved in previous clinical studies. Eight of the thirty-two participants had palatal abnormalities. Eight participants also had varying degrees of permanent hearing loss.

Skeleton. Brachydactyly (shortening of the fingers or toes) and clinodactyly (curving of the fingers or toes) was reported in several participants. Seven participants had delayed closure of the large anterior fontanelle (the bones of the front part of the skull that fuse during development).

Gastrointestinal System. Feeding difficulties were the most commonly seen GI issue, affecting eight participants, in some cases persisting into adolescence. Gastroesophageal reflux and severe constipation were also reported.

Other Aspects of Phenotype. Seventeen of thirty-two participants had eye abnormalities, with the most common being strabismus (any misalignment of the eyes) and refractive errors (nearsightedness, farsightedness, astigmatism, etc.). Four participants had congenital heart abnormalities. Many people displayed hypertrichosis (excessive hair growth; thick hair and full eyebrows), and skin abnormalities were reported. Five participants had surgery for cryptorchidism (undescended testicles) and one person had an inguinal (groin) hernia repair.

The authors provided a breakdown of the most common medical concerns of note in their clinical analysis and the frequency that these were reported in people with KBG syndrome, both in their study and in other KBG studies:

Medical Concern Number of Patients Affected/Number of Patients Included in Assessment Percentage (%)
Learning difficulties 80/82 98
Macrodontia (enlargement of teeth) 67/81 82
Behavioral issues 50/71 70
Delayed bone age 15/36 42
Hand abnormalities 50/71 70
Seizures 17/60 28
Hearing loss 19/71 27
Postnatal short stature 39/82 40
Palate abnormalities 15/71 21
Feeding issues 10/32 31
Autism 8/32 25
Persistent/large fontanelle (bones at front of skull) 7/32 22
Cardiac abnormalities 14/71 20
ADHD 4/32 13
Breech presentation during birth 3/32 9
Cryptorchidism (undescended testicles) 11/26 42
Decreased fetal movements 3/32 9
Polyhydramnios (excessive amniotic fluid in amniotic sac during pregnancy) 1/32 3
Hernia 2/51 4


The authors also included a table with recommendations for clinical management of people with KBG syndrome. This could be a helpful resource to bring to your child’s pediatrician for discussion.

Table II: Recommendations for Clinical Management of Patients with KBG Syndrome
  • Molecular testing for ANKRD11 genetic change
    • Array CGH for 16q24 microdeletion if KBG phenotype and ANKRD11 sequencing normal
Care coordinated by key clinician
  • Pediatrician for children and general practitioner for adults
Investigations to consider in all patients
  • Echocardiogram
  • Palatal assessment with specialist team
  • Hearing and vision assessment
  • Specialist dental review
Referrals and on-going surveillance that may be required
  • Neurology for seizures and movement disorders
  • Cardiology if heart lesion identified
  • Dietitian for feeding issues
  • Endocrinology for investigation of short stature if present
  • Surgery for cryptorchidism and hernia
  • Respiratory/sleep studies for apnea
  • Ear, nose, and throat/audiology for recurrent otitis media and/or hearing loss
Management of learning and behavior
  • Pediatric MDT assessment for developmental delay, ASD/ADHD, and complex behavior patterns
  • Educational support where needed
Investigations that may be indicated in individuals
  • Skeletal survey/assessment of bone age
  • Renal ultrasound
  • MRI brain scan