CWM Au, S Ho, HM Luk

What is the diagnosis?

In view of short stature, facial gestalt, developmental delay, hearing loss and maternal macrodontia, KBG syndrome was our initial clinical suspicion. Whole exome sequencing revealed that the proband has a heterozygous canonical splice site c.602-2 A>G p.(?) variant in ANKRD11 gene (NM_013275.6). The variant is absent from the control populations, while it is also absent from disease databases including Human Gene Mutation Database (HGMD) and ClinVar. ANKRD11 is a known haploinsufficient gene with a Haploinsufficiency Score of 3, and the variant was predicted to disrupt RNA splicing. By ACMG guidelines, it was classified as a likely pathogenic variant. Further parental testing using Sanger sequencing revealed that this variant was maternally inherited, confirming the diagnosis of familial KBG syndrome (MIM #148050).

Molecular basis of KBG syndrome

KBG Syndrome was first identified by Hermann et al in 1975, and it was named using the initials of the three affected families' last names.¹ It is usually caused by loss-of-function variants of the ankyrin repeat domain-containing protein 11 gene (ANKRD11, MIM #611192), or less commonly by deletion of chromosomal region 16q24.3 that is encompassing the gene. ANKRD11 is a widely expressed non-histone transcription factor that consists of 2663 amino acid residues, and plays a potential role in the epigenetic modification of genes involved in brain development.² KBG syndrome belongs under the umbrella of chromatinopathies, and is inherited in an autosomal dominant manner with variable expressivity and intra-familial variation. Children of an affected parent have a 50% chance of inheriting the condition.

To date, there are more than 200 individuals in the literature, yet the true prevalence of the condition is unclear. Studies estimate that about 32.3% of individuals with KBG syndrome have an affected parent, though no clear relationship between genotype and phenotype has been identified.

Clinical features

Patients affected by KBG syndrome are typically reported to have short stature (>50%), neurodevelopmental issues (>90%), a characteristic facial gestalt (60-80%; triangular face, brachycephaly, broad or bushy eyebrows, synophrys, hypertelorism, prominent ears, anteverted nostrils, thin upper lip), as well as dental (85%) and skeletal anomalies (75%).^1,2 Macrodontia, that is defined as a mesiodistal width of central incisors >=10 mm in males and >=9.7 mm in females, is the most common dental finding, but it is not usually present in early childhood until the eruption of permanent teeth. Other reported dental findings such as cleft teeth, shovel-shaped incisors, enamel hypoplasia, hypoplasia/oligodentia are less commonly seen.

Our patient concerned has bilateral moderate hearing impairment that was picked up by newborn hearing screening. Hearing loss is present in about 30% of patients with KBG syndrome, with conductive hearing loss being the most frequently reported form, likely linked to recurrent otitis media. Cases with sensorineural and mixed hearing loss have also been reported. However, preauricular polyps, as seen in this patient, are not commonly associated with the condition.

Seizures and psychiatric disturbances are present in up to half of affected individuals, while brain malformations are variably present in such patient group. Regarding the skeletal aspects, KBG syndrome patients were generally reported to have brachydactyly among our Chinese cohort.² Some reported skeletal features among other cohorts include costovertebral anomalies, large anterior fontanelle with delayed closure and a delayed bone age. However, not all affected individuals may undergo a comprehensive skeletal survey, and the true incidence of skeletal anomalies may be underestimated. Other less common clinical features include congenital heart disease, ocular anomalies, cryptorchidism, precocious puberty, skin and hair abnormalities.

It has been postulated that the disease entity has been under-diagnosed in different populations owing to its non-specific clinical phenotype, particularly in early childhood. Emerging evidence shows that it is potentially one of the most prevalent monogenic neuro-developmental disorders, alongside with ARID1B and DDX3X genes.³ To facilitate the diagnosis, various diagnostic criteria or aids for KBG Syndrome have been proposed by different authors in the literature (Table 1), although no consensus guidelines on diagnosis have been published. In this instance, the clinical characteristics of our patient satisfy the diagnostic criteria put forth by various authors.

What is the management?

Management of KBG syndrome is largely supportive in nature. Multi-disciplinary input is warranted following the initial diagnosis for baseline evaluation and subsequent surveillance, including paediatricians, otolaryngologists, ophthalmologists, dental surgeons and allied health professionals in physiotherapy, occupational therapy and speech therapy. A baseline echocardiogram should be performed at diagnosis. Patients should be referred for a detailed developmental assessment, with early intervention provided if necessary. Concerning growth and feeding issues, dietitians should be consulted if significant feeding issues are present, and there has also been evidence suggesting the use of growth hormone for treating short stature in such patient group. In case of cryptorchidism, referral to paediatric surgeons should be made for intervention.

Regular audiologic evaluation is indicated for individuals with KBG syndrome, and tympanostomy tube placement may be considered if there is recurrent otitis media. Ototoxic medications should also be avoided to prevent additional hearing loss. Surveillance for growth, neurodevelopment, pubertal status and visual aspects should also be provided for the patients.

Lastly, appropriate genetic counselling should be provided for families with KBG syndrome, in terms of mode of inheritance, recurrence risk to future offsprings, disease course, prognosis and availability of support groups. Following identification of the causative variant in affected individuals, prenatal diagnosis via invasive testing during pregnancy, or preimplantation genetic testing can be offered to at-risk couples if preferred.

Acknowledgement

We would like to thank our patient and his family for their contribution, as well as the referring clinical team for taking care of the patient. Informed consent was obtained for publication.

Declaration of Interest

The authors state that there are no conflicts of interest to disclose.

References

1. Morel Swols D, Foster J, Tekin M. KBG syndrome. Orphanet J Rare Dis 2017;12:183.

2. Ho S, Luk H, Lo IFM. KBG syndrome in a Chinese population: A case series. Am J Med Genet A 2022;188:1693-9.

3. Kaplanis J, Samocha KE, Wiel L, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 2020;586:757-62.

4. Skjei KL, Martin MM, Slavotinek AM. KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. Am J Med Genet A 2007;143A:292-300.

5. Ockeloen CW, Willemsen MH, De Munnik S, et al. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Eur J Hum Genet 2015;23:1176-85.

6. Low K, Ashraf T, Canham N, et al. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A 2016;170:2835-46.