KBG Syndrome - Causes, Clinical Features, Diagnosis, and Management

Introduction

KBG syndrome is named after the initials of the last names of the original families reported in 1975 by Herrmann et al. It is an autosomal dominant disorder characterized by macrodontia, short stature, developmental disorders, behavioral problems, and delayed fontanels closure. More than 100 patients were reported in the literature. This syndrome is more commonly seen in males and less common in females.

What Is KBG Syndrome?

KBG syndrome is a rare genetic disorder characterized by macrodontia of the upper central incisors, craniofacial abnormalities such as a prominent nasal bridge, triangular face, thin upper lip and synophrys, skeletal abnormalities such as short stature, delayed bone age sometimes associated with seizures and EEG (electroencephalography) abnormalities.

What Are the Other Names for the Syndrome?

The other names or synonyms of this syndrome include the following.

• Macrodontia, characteristic facies, short stature, mental retardation, and skeletal anomalies.

• Short stature-macrodontia-characteristic facies-mental retardation-skeletal anomalies-macrodontia syndrome.

What Causes KBG Syndrome?

The following factors cause KBG syndrome.

• KBG syndrome is caused either by changes in the ANKRD11 gene or microdeletion (loss of genetic material) on chromosome 16q which involves the ANKRD11 gene. This gene contains instructions for creating proteins in the nerve cells (neurons). It is essential in developing the brain and bone, learning, and memory. A mutated ANKRD11 gene leads to a short ANKRD11 gene with impaired functions, which causes the signs and symptoms of this syndrome. However, the exact role of proteins is still being determined, and more research is needed.

• KBG syndrome occurs spontaneously or is inherited in an autosomal dominant pattern. One copy of the altered gene causes the disorder. The affected gene is inherited from either parent or due to new gene mutations in the affected individual.

What Are the Clinical Characteristics of KBG Syndrome?

The following are the major and minor clinical features of KBG syndrome on various organ systems.

Craniofacial Abnormalities:

• High or prominent nasal bridge.

• Thin upper lip.

• Anteverted nostrils.

• Long philtrum.

• Epicanthal folds.

• Ptosis (drooping of the upper eyelid).

• Facial asymmetry.

• Brachycephaly (short skull with flattened back) or turricephaly (tall skull).

• Coarse hairs with a low frontal or posterior hairline.

• Prominent or anteverted ears.

• Wide eyebrows.

• Telecanthus (increased distance between the eyelids) or hypertelorism.

• Mild synophrys (fusion of the eyebrows).

Dental Abnormalities:

• Wide upper central incisors.

• Macrodontia or taurodontia

• Oligodontia or hypodontia.

• Premature loss of the tooth.

• Odontogenic cyst of the mandible.

Skeletal Abnormalities:

• Abnormal ribs or vertebrae.

• Deficient or absent vertebral arches(schisis or spina bifida).

• Abnormal spine curvature(scoliosis or kyphosis).

• Sternum abnormalities.

• Shorthand tubular bones and short tibia.

• Brachy-clinodactylous fifth finger.

• Wormian bones in the skull.

• Short femoral neck or hip dysplasia.

• Lower limb asymmetry.

Developmental and Behavioral changes:

• Delayed psychomotor development.

• Retarded language skills.

• Mild to severe mental retardation.

• Reduced intelligence quotient(IQ).

• Poor communication skills.

• Poor inter-social relationships.

• Hyperactivity.

• Easily frustrated.

• Attention deficit.

• Feeding difficulties.

Neurological Disturbances:

• Transient childhood epilepsy.

• Grand mal seizures.

• Hypoplastic cerebellar vermis.

• Enlarged cisterna magna.

• Chiari malformation type 1.

• Meningomyelocele.

Growth Abnormalities:

• Birth weight is usually average, while the patients show short stature compared to their parents and siblings. In addition, the levels of growth hormone and insulin growth factors are normal.

Otolaryngologic and Hearing Abnormalities:

• Mild to moderate hearing loss.

• Recurrent otitis media.

• Deafness(conductive, sensorineural, or mixed).

• Soft cleft palate.

• Bifid uvula.

• Hard palate notching in the posterior border.

• Velopharyngeal insufficiency.

• Hypertrophic tonsils and adenoid tissues.

• Dysphonic voice(hypernasal or low-pitched voice).

Other Features:

• Strabismus.

• Congenital bilateral cataract.

• High-grade myopia.

• Megalocornea.

• Congenital heart defects.

• Left pulmonary artery stenosis.

• Ventricular septal defect.

• Bicuspid aortic valve.

• Partial atrioventricular canal defect.

How to Diagnose KBG Syndrome?

There are no specific diagnostic procedures to diagnose KBG syndrome. However, some of the diagnostic procedures in practice include the following.

• Clinical evaluation, detailed family and patient history, and the presence of one or more characteristic features of the syndrome.

• Cytogenic and molecular studies such as gene panel analysis, whole exome or genome sequencing, and a-CGH (array-comparative genome hybridization) are used to investigate the multiple genetic causes of intellectual disability.

• The presence of a heterozygous pathogenic DNA variant in the ANKRD11 gene or the deletion of the 16q24.3 chromosome is the confirmation criterion for KBG syndrome.

What Are the Differential Diagnosis of KBG Syndrome?

The following are the differential diagnosis of KBG syndrome that have similar findings.

• Cornelia de Lange syndrome is a rare congenital genetic disorder with symptoms similar to KBG syndromes, such as facial features, developmental disorders, growth restriction, and hearing loss.

• Silver-Russel syndrome has facial features, growth retardation, and cryptorchidism, similar to KBG syndrome's findings.

• Aarskog-Scott syndrome presents macrodontia, short stature, and facial features similar to the KBG syndrome.

• Individuals with Cohen syndrome have prominent central incisors and developmental disorders similar to KBG syndrome.

• A small head, broad nose, abnormal facial appearance, and cryptorchidism characterize Filippi syndrome.

• Kabuki syndrome is a rare disorder characterized by distinctive facial features, delayed growth, and intellectual disability similar to the KBG syndrome's findings.

What Is the Management of KBG Syndrome?

The treatment of KBG syndrome is directed to manage specific symptoms in individuals. The treatments include the following.

• Cardiologists, ophthalmologists, pediatricians, orthopedists, neurologists, physical therapists, and orthodontists provide standard therapies to individuals with this syndrome.

• Growth hormone therapy is considered for the management of short stature.

• Patients with palatal anomalies require surgical correction and speech therapy.

• Pressure-equalizing tubes, tonsillectomy, and adenoidectomy treat chronic otitis media.

• Amplification is used for patients with hearing loss.

• Infants with feeding issues require a nasogastric tube.

• Endocrinologists recommend medications to arrest puberty and reduce the risk of premature puberty.

• Pharmacological treatment for gastroesophageal reflux disease.

• Routine monitoring of vision, growth, hearing, and cognitive development is necessary.

• Pregnant women with this syndrome are managed carefully to control seizures and other disorders.

• Orthopedic surgery corrects spine and hip abnormalities.

• Genetic counseling and psychosocial support help the affected individuals and their families.

Conclusion

KBG syndrome is often underdiagnosed due to mild and nonspecific individual symptoms. Further studies are required to learn more about the ANKRD11 gene functions and proper diagnostic procedures to detect KBG syndrome.