Clinical characteristics.

KCNK9 imprinting syndrome is characterized by congenital central hypotonia (manifest as decreased movement, lethargy, and weak cry), severe feeding difficulties (resulting from facial weakness and poor suck), delayed development/intellectual disability, and dysmorphic manifestations. Poor feeding can cause failure to thrive during infancy unless managed appropriately. Significant dysphagia of solid foods typically persists until puberty. Intellectual disability can be severe. To date 19 individuals with a molecularly confirmed diagnosis have been reported.

Diagnosis/testing.

The diagnosis of the KCNK9 imprinting syndrome is established in a proband with suggestive clinical findings and detection of the heterozygous KCNK9 pathogenic variant p.Gly236Arg on the maternal allele.

Management.

Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended (depending on the individual’s needs). Standard treatment for lacrimal duct obstruction, obstructive sleep apnea, scoliosis, and seizures. Feeding problems typically require use of special nipples and/or bottles and/or nasogastric/gastrostomy tube feedings. Cleft palate and velopharyngeal insufficiency are managed as per standard practice as are developmental delay/intellectual disability. Transient neonatal hypoglycemia responds to diazoxide treatment.

Surveillance: Monitoring of serum glucose levels for hypoglycemia in the neonatal period. At least annual ophthalmology evaluation, monitoring for the development of scoliosis, and monitoring of nutritional status, growth, and feeding.

Genetic counseling.

KCNK9 imprinting syndrome is inherited in an autosomal dominant maternally imprinted manner (i.e., a heterozygous pathogenic variant on the maternally derived KCNK9 allele results in disease; a pathogenic variant on the paternally derived KCNK9 allele does not result in disease because normally the paternally derived KCNK9 allele is silenced). The KCNK9 pathogenic variant can either be inherited from the mother (80%) or arise de novo on the maternally derived KCNK9 allele (20%). The risk to the sibs of the proband depends on the genetic status of their mother: if she is heterozygous for the KCNK9 pathogenic variant, the risk to the sibs is 50%; if the KCNK9 pathogenic variant cannot be detected in her leukocyte DNA, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism. To date, no individual with KCNK9 imprinting syndrome has been known to reproduce. Once the KCNK9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for KCNK9 imprinting syndrome (i.e., one in which the mother is heterozygous for a KCNK9 pathogenic variant) and preimplantation genetic testing are possible.

Suggestive Findings

KCNK9 imprinting syndrome should be suspected in individuals with normal brain imaging and the following clinical findings:

• Congenital central hypotonia and persistent generalized weakness
• Severe feeding difficulties, often requiring placement of gastrostomy tube.
• Delayed development / intellectual disability

Establishing the Diagnosis

The diagnosis of the KCNK9 imprinting syndrome is established in a proband with suggestive clinical findings and the heterozygous KCNK9 p.Gly236Arg pathogenic variant on the maternal allele detected by molecular genetic testing (see Table 1). To date, it is unknown if other KCNK9 pathogenic variants can cause the same phenotype.

Because the phenotype of the KCNK9 imprinting syndrome is indistinguishable from many other inherited disorders with hypotonia, feeding difficulties, and developmental delay/intellectual disability, molecular genetic testing approaches can include genomic testing (comprehensive genome sequencing) OR gene-targeted testing (multigene panel). Note that gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not.

• Comprehensive genome sequencing (when available) including exome sequencing and genome sequencing can be considered. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes KCNK9 and other genes of interest (see Differential Diagnosis) can 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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

KCNK9 imprinting syndrome is characterized by congenital central hypotonia, severe feeding difficulties, delayed development/intellectual disability, and dysmorphic features. To date 19 individuals with a molecularly confirmed diagnosis have been reported: 15 from an Arab-Israeli family [Barel et al 2008] and four representing simplex cases (i.e., a single occurrence in a family) [Graham et al 2016]. Note that 15 individuals from the original family were reexamined for the report by Graham et al [2016].

The phenotype has been severe and consistent in all individuals examined to date.

Congenital central hypotonia, evident in neonates, is associated with decreased movement, lethargy, weak cry, weak facial muscles, poor suck, and feeding difficulties. Prenatally, hypotonia can manifest as decreased fetal movement and breech presentation necessitating cesarean section.

While the hypotonia may improve over time, it is present during childhood and into adulthood. Occasionally weakness of proximal muscles and the supra- and infrascapular and trapezius muscles is observed later in life. Generalized hypotonia at an early age followed by weakness of proximal muscles can lead to contractures and scoliosis.

Poor feeding can cause failure to thrive during infancy unless managed appropriately (see Management). Significant dysphagia of solid foods due to hypotonia and poorly coordinated swallowing typically persists until puberty [Barel et al 2008].

Cleft palate (including full cleft, submucous cleft or velopharyngeal insufficiency) is present in 42% of affected individuals.

Delayed motor and speech milestones / intellectual disability are observed in all individuals with the KCNK9 imprinting syndrome. Intellectual disability is usually moderately severe with limited speech. Wide-based gait can also be observed.

Other

Occasional neurologic findings include clonus and rarely seizures.

Subtle dysmorphic features that can evolve over time include dolichocephaly with a narrow forehead; mild atrophy of the temporalis and masseter muscles; myopathic elongated facies with a tented vermillion of the upper lip and short broad philtrum; reduced facial movement; mild micro/retrognathia with relatively prominent maxillary and premaxillary regions; medially flared, arched eyebrows; and ptosis [Graham et al 2016].

Body habitus is asthenic; a long neck and tapered chest are evident in later childhood. Fingers are tapered; fetal fingertip pads are prominent [Barel et al 2008].

A pilonidal dimple or sinus is evident in most individuals. Rarely, it is associated with a filar cyst (cystic structure in the proximal filum terminale) and lipoma in the sacral region.

Some affected individuals have transient neonatal hypoglycemia associated with hyperinsulinism that resolves with diazoxide treatment [Graham et al 2016].

Decreased lacrimation and increased risk for corneal dryness can be observed.

Sleep disturbance can be due to both central and obstructive sleep apnea, and usually responds to BiPAP.

Normal findings typically include: hearing, ophthalmologic evaluation (including vision), neuroimaging, and muscle biopsy (which may show nonspecific findings such as fiber-size disproportion). X-rays of long bones are normal [Barel et al 2008].

Penetrance

Penetrance for maternally inherited pathogenic variants in KCNK9 appears to be complete; however, the number of affected individuals with a molecularly confirmed diagnosis is so limited that no conclusions can be made at present.

Prevalence

KCNK9 imprinting syndrome has been identified in approximately 19 individuals, with most individuals from the original Arab-Israeli family reported by Barel et al [2008] having the same KCNK9 pathogenic variant. Since 2008 an additional four simplex cases (i.e., a single occurrence in a family) have been reported [Graham et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KCNK9 imprinting syndrome, the evaluations following diagnosis summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

No specific management guidelines have been developed. Management is mostly supportive.

A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended depending on the affected individual’s manifestations.

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

KCNK9, which is imprinted and expressed from the maternal allele with paternal silencing, encodes a member of the two pore-domain potassium channel (K2p9.1 or TASK3). The only KCNK9 pathogenic variant reported to date, p.Gly236Arg, reduces the outward current of the TASK3 channel by approximately 80% [Veale et al 2014].

Three members of the nonsteroidal anti-inflammatory fenamic acid class of drugs – flufenamic acid (FFA), niflumic acid (NFA) and mefanamic acid (MFA) – have been shown to stimulate two pore-domain potassium channels [Takahira et al 2005]. The reduced outward current through abnormal p.Arg236-containing TASK3 channels has been shown to be partially rescued by FFA, suggesting that fenamic acid compounds could be useful in treating this condition [Veale et al 2014].

Two affected individuals to date have been treated with oral MFA starting at age 14 months, with noted increased energy while on the medication and no adverse reactions. Clinical features are still present, and long-term studies are necessary to predict the outcome of individuals treated with MFA [Graham et al 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

KCNK9 imprinting syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the maternally derived KCNK9 allele results in disease; a pathogenic variant on the paternally derived KCNK9 allele does not result in disease because normally the paternally derived KCNK9 allele is silenced). In any given affected individual, a pathogenic variant (typically p.Gly236Arg) that causes KCNK9 imprinting syndrome can either be inherited from the mother or arise de novo on the maternally derived KCNK9 allele.

Risk to Family Members

Parents of a proband

• Approximately 80% of affected individuals reported to date inherited the p.Gly236Arg KCNK9 pathogenic variant from a clinically unaffected mother.
• Approximately 20% of individuals diagnosed with KCNK9 imprinting syndrome have the disorder as the result of a de novo pathogenic variant on the maternally derived KCNK9 allele [Graham et al 2016].
• Recommendations for the evaluation of the mother of a proband include KCNK9 molecular genetic testing. If the pathogenic variant found in the proband cannot be detected in maternal leukocyte DNA, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in the mother. Although no instances of germline mosaicism have been reported to date, it remains a possibility.
• The father of an affected individual will not be affected with KCNK9 imprinting syndrome nor will he be heterozygous for a KCNK9 pathogenic variant.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s mother.
• If the mother of the proband is heterozygous for the KCNK9 pathogenic variant, the risk to the sibs is 50%.
• If the KCNK9 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.

Offspring of a proband. To date, no individual affected with KCNK9 imprinting syndrome has been known to reproduce.

Other family members

• The risk to other family members depends on the genetic status of the proband's mother.
• If the proband’s mother is heterozygous for a KCNK9 pathogenic variant, other male and female family members may also be heterozygous for the pathogenic variant.
  • Offspring of heterozygous females would be at risk for KCNK9 imprinting syndrome.
  • Offspring of heterozygous males would not be at risk for KCNK9 imprinting syndrome because the paternally inherited KCNK9 allele is silenced. However, a heterozygous male can transmit the pathogenic variant to his daughter, who would then be at risk of having affected children.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females heterozygous for a paternally inherited KCNK9 pathogenic variant.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the KCNK9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for KCNK9 imprinting syndrome (i.e., one in which the mother is heterozygous for a KCNK9 pathogenic variant) and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Literature Cited

• Bando Y, Hirano T, Tagawa Y. Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex. Cereb Cortex. 2014;24:1017–29. [PubMed: 23236211]
• Barel O, Shalev SA, Ofir R, Chone A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N, Birk OS. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet. 2008;83:193–199. [PMC free article: PMC2495061] [PubMed: 18678320]
• Brickley SG, Aller MI, Sandu C, Veale EL, Alder FG, Sambi H, Mathie A, Wisden W. TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. J Neurosci. 2007;27:9329–40. [PMC free article: PMC6673138] [PubMed: 17728447]
• Graham JM Jr, Zadeh N, Kelley M, Tan ES, Liew W, Tan V, Deardorff MA, Wilson GN, Sagi-Dain L, Shalev SA. KCNK9 imprinting syndrome-further delineation of a possible treatable disorder. Am J Med Genet A. 2016;170:2632–7. [PubMed: 27151206]
• Redman JB, Fenwick RG Jr, Fu YH, Pizzuti A, Caskey CT. Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring. JAMA. 1993;269:1960–5. [PubMed: 8464127]
• Takahira M, Sakurai M, Sakurada N, Sugiyama K. Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels. Pflugers Arch. 2005;451:474–8. [PubMed: 16075240]
• Veale EL, Hassan M, Walsh Y, Al-Moubarak E, Mathie A. Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol. 2014;85:397–407. [PubMed: 24342771]

Author Notes

KCNK9 Imprinting Syndrome website

Facebook: KCNK9 Imprinting Syndrome - Birk-Barel

Acknowledgments

Melissa Kelley

Revision History

• 23 March 2017 (bp) Review posted live
• 14 July 2016 (jmg) Original submission