Kbg Syndrome
Summary
Clinical characteristics.
KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.
Diagnosis/testing.
The diagnosis of KBG syndrome is confirmed in a proband by detection of either a heterozygous pathogenic variant in ANKRD11 or deletion of 16q24.3 that includes ANKRD11.
Management.
Treatment of manifestations. Surgical corrections and/or speech therapy for palatal anomalies; nasogastric tube feeding in infants; pharmacologic treatment for gastroesophageal reflux disease; pressure-equalizing tubes and/or tonsillectomy/adenoidectomy for chronic otitis media; consideration of amplification for hearing loss; consideration of growth hormone therapy for short stature and medication to arrest puberty for premature pubertal development; standard treatment of seizure disorder, undescended testis in males, congenital heart defects, strabismus / refractive errors, and developmental disabilities.
Surveillance. Routine monitoring of hearing, vision, growth, pubertal status (in prepubertal individuals), and cognitive development.
Agents/circumstances to avoid. Ototoxic drugs should be avoided because of the risk for hearing loss.
Pregnancy management. Pregnancy management should be tailored to the specific features in the affected woman. For example, involvement of a cardiologist and maternal fetal medicine physician for a pregnant woman with a history of a congenital heart defect; control of seizures during pregnancy for those with a seizure disorder.
Genetic counseling.
Recurrence risk for sibs of a proband with KBG syndrome depends on the genetic alteration:
- Deletion of 16q24.3 (~75% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner.)
- ANKRD11 sequence variants (~66% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner.)
Prenatal testing and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member.
Diagnosis
While no consensus clinical diagnostic criteria for KBG syndrome have been published, several authors have suggested diagnostic criteria [Brancati et al 2006, Skjei et al 2007, Low et al 2016].
Suggestive Findings
KBG syndrome should be suspected in an individual with developmental delay / cognitive impairment or significant behavioral issues who has [Brancati et al 2006, Skjei et al 2007, Goldenberg et al 2016, Low et al 2016]:
- At least two of the findings highlighted by an asterisk (*); OR
- One finding highlighted by an asterisk and at least two additional findings.
Craniofacial features
- * Macrodontia (mesiodistal width of permanent central incisors ≥10 mm in males, ≥9.7 mm in females) (see Figure1), especially of the upper central incisors
- * Characteristic facial appearance (see Figure 2)
- Conductive hearing loss and/or chronic/recurrent otitis media
- Palatal abnormalities
- Hair anomalies (e.g., low hairline, coarse hair)
Figure 1.
Macrodontia of permanent upper central incisors, dental pits, and prominent mamelons
Figure 2.
Triangular face, synophrys, prominent nasal bridge, anteverted nares, long philtrum, and thin vermilion of the upper lip in two affected males
Skeletal features
- Costovertebral anomalies
- * Postnatal short stature (length and/or height <10th centile)
- Delayed bone age (>2SD below mean)
- Brachydactyly
- Large anterior fontanelle with delayed closure
- Scoliosis
Neurologic features
- Learning difficulties of variable severity
- EEG abnormalities with or without seizures
Family history
- * A first-degree relative with KBG syndrome
- Note: Absence of a family history of KBG syndrome does not preclude the diagnosis.
Other
- Feeding difficulties
- Cryptorchidism in males
Establishing the Diagnosis
The diagnosis of KBG syndrome is established in a proband by detection of either a heterozygous pathogenic variant in ANKRD11 or deletion of 16q24.3 that includes ANKRD11 (see Table 1). However, some individuals with clinical findings highly suggestive of KBG syndrome do not have a detectable pathogenic ANKRD11 variant or 16q24.3 deletion [Sirmaci et al 2011].
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive features described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of KBG syndrome, genetic testing approaches can include EITHER:
- Single-gene testing or use of a multigene panel; OR
- Chromosomal microarray analysis.
Single-gene testing. Sequence analysis of ANKRD11 is performed first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered (see Table 1 for information on deletion/duplication analysis).
A multigene intellectual disability panel that includes ANKRD11 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this condition, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or single nucleotide polymorphism (SNP) arrays in current clinical use target the 16q24.3 region.
Option 2
When the diagnosis of KBG syndrome has not been considered, comprehensive genomic testing (when clinically available) including exome sequencing and genome sequencing is likely to be the diagnostic modality selected.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in KBG Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ANKRD11 | Sequence analysis 3 | 69% 4 |
| Gene-targeted deletion/duplication analysis 5, 6 | 14% 4 | |
| CMA 7 | 17% 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
The percentage represents the proportion of affected individuals who were detected to have a causative ANKRD11 variant using each method [Low et al 2016, Goldenberg et al 2016]. The proportion of individuals who have suggestive clinical findings of KBG syndrome but do not have a detectable ANKRD11 variant has not been clearly established.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Gene-targeted deletion/duplication testing will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Note that one intragenic duplication variant that included ANKRD11 exons 3-9 was reported [Crippa et al 2015].
- 7.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q24.3 region. Note: The 16q24.3 deletion may not have been detectable by older oligonucleotide or bacterial artificial chromosome (BAC) platforms.
Clinical Characteristics
Clinical Description
KBG syndrome was first described in 1975. The name KBG is derived from the initials of the first three families in which the condition was characterized [Herrmann et al 1975]. More than 100 affected individuals have been reported in the literature – the majority of whom are simplex (meaning the first individual in the family to be affected by the condition); although familial cases have been described. There is variable expressivity among and within families. More males than females with KBG syndrome have been reported. In some families a mildly affected mother is diagnosed only after a typically affected son is recognized [Brancati et al 2006].
Macrodontia of the permanent upper incisors is a main finding, making diagnosis prior to the eruption of these teeth more difficult. It is likely this syndrome is underdiagnosed, since many of the features are nonspecific [Sirmaci et al 2011].
Dental
Macrodontia of permanent upper central incisors is reported in 85%-95% of affected individuals [Skjei et al 2007, Ockeloen et al 2015, Low et al 2016]. In addition to macrodontia (see Suggestive Findings), cleft teeth, shovel-shaped incisors, enamel hypoplasia, hypo/oligodontia, dental pits, talon cusps, dental crowding, large dental pulps, and supernumerary mamelons can be seen [Kumar et al 2009, Ockeloen et al 2015].
Craniofacial
Craniofacial findings have been reported in 62%-80% of affected individuals. The characteristic facial appearance (see Figure 1) includes a triangular face, brachycephaly, synophrys with full eyebrows, and widely spaced eyes. A prominent nasal bridge, bulbous nose, anteverted nares, broad or bushy eyebrows, prominent ears, long philtrum, and thin vermilion of the upper lip are also common [Brancati et al 2006, Goldenberg et al 2016, Low et al 2016]. Less commonly, cleft of the soft palate or submucous cleft, bifid uvula, and velopharyngeal insufficiency have been reported [Brancati et al 2006, Goldenberg et al 2016, Low et al 2016]. The craniofacial findings may not always be apparent, so lack of these features does not preclude the diagnosis.
Feeding
Feeding problems, especially during infancy, are reported in 20% of affected individuals and include vomiting, constipation, and gastroesophageal reflux disease [Low et al 2016].
Growth
Short stature (below the 3rd centile) has been observed in 40%-77% of affected individuals [Reynaert et al 2015, Goldenberg et al 2016]. Birth weight, length, and head circumference are usually normal. Delayed bone age is an additional finding [Brancati et al 2006]. Endocrinologic evaluations for short stature typically are normal. Preliminary evidence suggests that growth hormone therapy may increase the height potential of affected individuals [Reynaert et al 2015].
Skeletal
Variable skeletal anomalies have been reported in 75% of affected individuals [Skjei et al 2007, Low et al 2016]. The most frequent findings are costovertebral anomalies, such as cervical ribs, abnormal vertebral shape, end plate abnormalities, posterior fusion defects, or spina bifida occulta [Skjei et al 2007]. A large anterior fontanelle with delayed closure can also be seen [Ockeloen et al 2015, Low et al 2016]. Other abnormalities include a short and webbed neck, abnormal ribs, brachydactyly, clinodactyly, syndactyly of toes 2-3, kyphosis, scoliosis, hip dysplasia or Perthes disease, sternum abnormalities, and wormian bones in the skull [Brancati et al 2006]. Clavicular pseudoarthrosis and osteopenia have also been reported [Murray et al 2017].
Neurologic
Intellectual abilities – childhood. Cognitive skills can be quite variable among affected individuals. More than 90% will have some degree of developmental delay, especially in speech [Lo-Castro et al 2013, Goldenberg et al 2016]. The voice character may be hoarse. No developmental regression has been reported. Average age for walking is 21 months [Brancati et al 2006, Low et al 2016]. Average age for first words is 36 months [Brancati et al 2006]. Some affected children attend mainstream classes with minimal additional aid while others require special education [Low et al 2016].
Intellectual abilities – adulthood. Intelligence ranges from moderate intellectual disability to normal intelligence, with most patients having mild intellectual disability [Lo-Castro et al 2013, van Dongen et al 2017]. It is not uncommon for verbal IQ to surpass performance IQ. Completing a regular high school without support appears to be rare; however, some reported adults have completed trade school. More than half of affected adults had jobs and were self-sufficient. Some were able to live completely independently, while others required some assistance with tasks at home, such as finances. Some affected women have had children and raised them with help from a spouse or other family members [Goldenberg et al 2016, Low et al 2016].
Seizures. EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [Skjei et al 2007]. Age of onset can range from infancy to the teenage years [Low et al 2016]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with antiepileptic medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [Lo-Castro et al 2013]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; Samanta & Willis 2015].
Brain malformations. Various brain abnormalities have been reported, including cerebellar vermis hypoplasia [Zollino et al 1994], enlarged cysterna magna, chiari I malformation, periventricular nodular heterotopia, pineal cyst, dysgenesis of the corpus callosum, colpocephaly, posterior fossa arachnoid cyst, and optic nerve hypoplasia [Oegema et al 2010, Willemsen et al 2010, Ockeloen et al 2015]. Meningomyelocele has also been reported [Maegawa et al 2004, Brancati et al 2006]. The frequency of brain malformations is not known because brain MRI has not been performed in large cohorts of affected individuals. In a cohort of 13 affected children, two had mild periventricular leukomalacia with normal ventricles and an isolated dilated left ventricle, and the other two showed moderate enlargement of the cisterna magna with normal ventricles [Low et al 2016]. In another cohort five out of six affected individuals who had neuroimaging had significant brain changes including widespread calcification, agenesis of corpus callosum, and small optic nerves [Murray et al 2017].
Behavior. Behavioral issues are reported in at least half of affected persons with KBG syndrome. Milder problems include poor concentration and restless movement. More severe problems include obsessions and deteriorating behavior when routines are changed. Anxiety and shyness are common, as are reports of difficulty in understanding social situations.
- Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [Goldenberg et al 2016, Low et al 2016].
- While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting:
- Previous studies reported an association between ASD and the 16q24.3 deletion [Willemsen et al 2010, Handrigan et al 2013].
- ASD has not been commonly seen in affected individuals with intragenic ANKRD11 pathogenic variants: Goldenberg et al [2016] reported one affected individual with ASD in a cohort of 35 affected people; in a study by Murray et al [2017] one of 18 affected individuals met DSM-V criteria for ASD; Ockeloen et al [2015] reported ASD in eight of 20 affected individuals (40%); Low et al [2016] reported eight children with ASD out of 32 (25%) who had intragenic ANKRD11 pathogenic variants. Ascertainment bias may have played a role in this discrepancy.
Hearing
Hearing problems are seen in 25%-31% of affected individuals. Recurrent otitis media has been shown to cause hearing loss in some individuals with KBG syndrome. All types of hearing loss (conductive, mixed, and sensorineural) have been reported in association with the condition, with conductive loss being the most common.
Less Common Findings
Undescended testicles have been reported in 25%-35% of males [Brancati et al 2004, Low et al 2016].
Cardiac defects, including ASD and VSD, have been reported [Goldenberg et al 2016] in 10%-26% of affected individuals.
Various ocular findings, including strabismus, congenital bilateral cataract, high myopia, and megalocornea [Brancati et al 2006], have also been reported.
Advanced puberty, sometimes requiring treatment, has been reported in some individuals.
Skin and hair abnormalities, such as hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, and dystrophic nails, have been reported [Low et al 2016].
Prenatal
There is one report of prenatal diagnosis of KBG syndrome [Hodgetts Morton et al 2017]. A 1.86-Mb microdeletion encompassing ANKRD11 and 25 other genes was identified in a male fetus showing multiple external congenital anomalies including a triangular-shaped face, mildly low-set ears, and a right retained testis. Internal congenital anomalies included incomplete lobation of the left lung, lobulated spleen, cervical ribs, irregularity of vertebral body C1-4, and calcification of the liver associated with the portal tracts.
Genotype-Phenotype Correlations
The vast majority of pathogenic variants are loss-of-function variants. No specific genotype/phenotype correlations have been reported, with the exception of those who have a larger 16q24.3 deletion.
16q24.3 deletions. Individuals with a 16q24.3 deletion have the findings of KBG syndrome listed previously in addition to intellectual disability and autism spectrum disorder (although the increased frequency of autism spectrum diagnoses in this cohort may be due to ascertainment bias) [Willemsen et al 2010, Sacharow et al 2012, Khalifa et al 2013, Miyatake et al 2013].
- Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [Sacharow et al 2012, Lim et al 2014].
- Individuals with a 16q24.3 deletion that includes ANKRD11 and surrounding genes have a more severe phenotype, with brain anomalies detected in 28%, congenital heart defects in 33%, severe astigmatism in 28%, and thrombocytopenia in 22% [Novara et al 2017].
Prevalence
KBG syndrome was initially thought to be quite rare; however, it is likely underdiagnosed due to mild and nonspecific features in some affected individuals especially before eruption of the permanent dentition [Sirmaci et al 2011]. To date, more than 100 individuals have been reported in the literature.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of KBG Syndrome
| DiffDx Disorder | Gene(s) | MOI | Clinical Features of the DiffDx Disorder | |
|---|---|---|---|---|
| Overlapping w/KBG syndrome | Distinguishing from KBG syndrome | |||
| Cornelia de Lange syndrome | NIPBL SMC1A HDAC8 SMC3 RAD21 | AD XL |
| Typically:
|
| Silver-Russell syndrome | See footnote 1. | See footnote 1. |
|
|
| Aarskog-Scott syndrome (OMIM 305400) | FGD1 | XL |
|
|
| Cohen syndrome | VPS13B | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked
- 1.
Silver-Russell syndrome has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal UPD7, and (infrequently) autosomal dominant or autosomal recessive inheritance.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with KBG syndrome, the evaluations summarized in Table 3 (if they have not already been completed) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis of KBG Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Oropharynx | Dental eval for anomalies incl macrodontia, oligodontia, enamel hypoplasia [Kumar et al 2009] | |
| Assessment for cleft palate, bifid uvula, velopharyngeal insufficiency | Refer to cleft/craniofacial team if palatal anomalies are present or suspected. | |
| Neurologic | EEG if seizures are suspected | Consider head MRI to evaluate for brain malformations if seizures are present. |
| Genitourinary | Assessment for undescended testes in males | Refer to urologist as needed. |
| Hearing | Audiologic eval | |
| Cardiovascular | Echocardiogram to assess for congenital heart disease | Refer to cardiologist as needed. |
| Eyes | Ophthalmologic eval | |
| Miscellaneous/ Other | Developmental assessment | Consider psychiatric eval for severe behavioral issues. |
| Consultation w/clinical geneticist &/or genetic counselor |
Table 4.
Evaluations To Consider Following Initial Diagnosis of KBG Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Gastrointestinal | Feeding & nutrition eval [Goldenberg et al 2016, Low et al 2016] | Consider nasogastric or gastrostomy tube placement if clinically indicated. |
| Musculoskeletal | Skeletal survey to assess for costovertebral anomalies, scoliosis, kyphosis | Consider referral to orthopedist if indicated. |
| Endocrine | Assess for short stature. | Consider bone age assessment. |
| Assess for advanced or premature puberty. | Refer to endocrinologist as needed. |
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with KBG Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Palatal anomalies | Surgical correction &/or speech therapy may be required. | |
| Feeding issues | Nasogastric tube during infancy or medication for GERD may be required. | Refer to nutritionist or dietician as needed [Goldenberg et al 2016, Low et al 2016]. |
| Seizures | Treatment per neurologist based on type of seizure present [Lo-Castro et al 2013] | |
| Undescended testes | Standard treatment per urologist | |
| Chronic otitis media | Referral to otolaryngologist for consideration of pressure-equalizing tubes &/or tonsillectomy / adenoidectomy | |
| Hearing loss | Consider amplification. | See Hereditary Hearing Loss and Deafness Overview. |
| Cardiovascular anomalies | Standard treatment per cardiologist | |
| Vision issues / strabismus | Standard treatment per ophthalmologist | |
| Short stature | Consider growth hormone therapy. | |
| Premature puberty | Consider medication to arrest puberty, as per endocrinologist. |
GERD = gastroesophageal reflux disease
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages