How is Birk-Barel syndrome inherited?

Birk-Barel syndrome follows an autosomal dominant inheritance pattern. This means inheriting just one copy of the altered gene from either parent can cause the condition.

How rare is Birk-Barel syndrome?

Birk-Barel syndrome is classified as very rare. The estimated prevalence is approximately <1 in 1,000,000. Because rare disease data can be limited, actual numbers may differ from published estimates.

How is Birk-Barel syndrome diagnosed?

Information about diagnosis is currently limited for this condition.

Are there treatments for Birk-Barel syndrome?

Information about treatment is currently limited for this condition.

What are the potential complications of Birk-Barel syndrome?

Birk-Barel syndrome can lead to various complications due to its effects on brain development and muscle tone. Individuals may face challenges with learning and physical activities because of intellectual disability and low muscle tone. Additionally, hyperactivity can affect their ability to focus and participate in everyday activities.

How does Birk-Barel syndrome affect daily life and management?

Living with Birk-Barel syndrome can require special support and management strategies. Children may need help with learning and physical activities, and they might benefit from therapies to improve muscle tone and focus. Families often work closely with teachers and therapists to create a supportive environment for their loved ones.

What is the life expectancy for someone with Birk-Barel syndrome?

Currently, there is limited information about the life expectancy of individuals with Birk-Barel syndrome. Since the condition affects brain development and muscle tone, it may lead to various health challenges. Ongoing care and support can help improve quality of life, but specific life expectancy data is not available.

Are there any specific specialists recommended for managing Birk-Barel syndrome?

For managing Birk-Barel syndrome, it is important to work with a team of specialists. This may include a pediatrician, neurologist, and physical therapist who can help address the unique challenges of the condition. These professionals can provide tailored support and therapies to help improve the individual's development and daily functioning.

Kisho

Kisho is an information platform, not a medical provider. Nothing on this site constitutes medical advice, diagnosis, or treatment recommendations. All content is aggregated from publicly available sources (including ClinicalTrials.gov, PubMed, FDA.gov, and Orphanet) and is provided for informational purposes only. Clinical trial eligibility, treatment decisions, and any health-related actions should always be discussed with a qualified healthcare professional. Kisho does not endorse any specific therapy, organization, or clinical trial. Terms of use · Privacy policy

Birk-Barel syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Features include always present findings: Narrow forehead, Global developmental delay, and Feeding difficulties in infancy; and common findings: Submucous cleft soft palate, Tented upper lip vermilion, Long face, and Microretrognathia and others. 18 total HPO annotations.

Organ System	Phenotype Count	Example Features
Head and neck	4	Submucous cleft soft palate, Tented upper lip vermilion, Long face
Brain and nerves	3	Difficulty swallowing (dysphagia), Global developmental delay, Intellectual disability
Digestive system	2	Difficulty swallowing (dysphagia), Feeding difficulties in infancy
Muscles	1	Low muscle tone (hypotonia)
Skin	1	Reduced subcutaneous adipose tissue

Age of onset: infancy.

GeneReviews

Clinical Guidance

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 and four representing simplex cases (i.e., a single occurrence in a family) . Note that 15 individuals from the original family were reexamined for the report by . 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.

Source: GeneReviews — "KCNK9 Imprinting Syndrome"

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Consensus clinical diagnostic criteria for the KCNK9 imprinting syndrome have not been established.

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 and the heterozygous KCNK9 p.Gly236Arg pathogenic variant on the maternal allele detected by molecular genetic testing . To date, it is unknown if other KCNK9 pathogenic variants can cause the same phenotype.

Source: GeneReviews — "KCNK9 Imprinting Syndrome"

GeneReviews

Differential Diagnosis

A number of disorders can mimic some aspects of the KCNK9 phenotype. See . Table 2. Disorders to Consider in the Differential Diagnosis of KCNK9 Imprinting Syndrome

Disorder	Genetic Mechanism	MOI	Clinical Features of Differential Diagnosis Disorder
Congenital myotonic dystrophy type 1	1000 CTG trinucleotide repeat expansion in DMPK1	AD	Hypotonia severe generalized weakness at birth; Intellectual disability
Usually no cleft palate Prader-Willi syndrome (PWS)

Genetic testing for KCNK9 is available. Testing is considered confirmatory for diagnosis.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for Birk-Barel syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

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 (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis of KCNK9 Imprinting Syndrome

System/Concern	Evaluation	Comment
Oropharynx	Assessment by cleft/craniofacial team if cleft palate, bifid uvula, or velopharyngeal insufficiency is present	—
Feeding	Feeding swallowing eval	Consider gastrosotomy tube placement if clinically indicated by significant microretrognathia /or recurrent aspiration.
Pulmonary	Polysomnogram if obstructive apnea is suspected	—
Musculoskeletal	Eval for skeletal manifestations (i.e., joint contractures, scoliosis)	Consider referral to orthopedist if indicated. Neurologic
Endocrine	Assess for hypoglycemia during neonatal period infancy.	If present, consider consultation w/endocrinologist to discuss possible treatment w/diazoxide. Miscellaneous/ Other
Treatment of Manifestations in Individuals with KCNK9 Imprinting Syndrome Manifestation/Concern	Treatment	Considerations/Other
Lacrimal duct obstruction	Tear duct massage; consider lacrimal duct stent placement.	—
Cleft palate, bifid uvula, or velopharyngeal insufficiency	Mgmt by cleft/craniofacial team; retrognathia underdevelopment of mandible may require mandibular distraction osteogenesis.	—
Obstructive sleep apnea	CPAP or BiPAP; ENT eval for tonsillectomy/adenoidectomy	Pulmonary consultation; consider treatment w/mefanamic or flufenamic acid (See .)
Feeding difficulties or signs of aspiration	Use of a special nipple or bottle w/cleft palate; short-term nasogastric feeding tube; consideration of gastrostomy tube	—
Gastroesophageal reflux disease	Standard positioning pharmacologic treatment	—
Musculoskeletal findings (i.e., contractures, scoliosis)	Ankle-foot orthoses or other assistive devices; standard treatment for scoliosis	PT /or OT eval; consultation w/orthopedist
Seizure disorder	Eval of blood sugar electrolytes; standard treatment for seizures	Consider EEG referral to neurologist.
Unexplained hypoglycemia or suspected hyperinsulinism	Consideration of diazoxide therapy	Consider referral to an endocrinologist.
Developmental delay	Early referral for developmental support/special education, which may incl: PT, OT, speech therapy, /or cognitive therapy	Consider referral to neurodevelopmental specialist /or neuropsychiatric testing. OT = occupational therapy; PT = physical therapy Surveillance Table 5.
Recommended Surveillance for Individuals with KCNK9 Imprinting Syndrome System/Concern	Evaluation	Frequency/Comment
Growth	Eval of nutritional status growth	Every 6 mos until age 2 yrs, then annually
Eyes	Ophthalmology assessment for lacrimation risk for corneal dryness	At least annually
ENT/Mouth	Eval of feeding difficulties	Every 6 mos until age 2 yrs, then annually
Respiratory	Sleep study (if history of sleep disturbance)	Pulmonary eval every 6 mos until age 2 yrs, then annually
Musculoskeletal	Eval for scoliosis	At least annually
Endocrine	Monitor serum glucose levels for hypoglycemia secondary to poor feeding risk for hyperinsulinemia.	Every 6 mos until age 2 yrs Evaluation of Relatives at Risk See for issues related to testing of at-risk relatives for genetic counseling purposes.

Source: GeneReviews — "KCNK9 Imprinting Syndrome"

GeneReviews

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% . 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 . 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 .

Source: GeneReviews — "KCNK9 Imprinting Syndrome"

Clinical Trials

View trials for Birk-Barel syndrome

Explore Trials

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with KCNK9 Imprinting Syndrome

System/Concern	Evaluation	Frequency/Comment
Growth	Eval of nutritional status growth	Every 6 mos until age 2 yrs, then annually
Eyes	Ophthalmology assessment for lacrimation risk for corneal dryness	At least annually
ENT/Mouth	Eval of feeding difficulties	Every 6 mos until age 2 yrs, then annually
Respiratory	Sleep study (if history of sleep disturbance)	Pulmonary eval every 6 mos until age 2 yrs, then annually
Musculoskeletal	Eval for scoliosis	At least annually
Endocrine	Monitor serum glucose levels for hypoglycemia secondary to poor feeding risk for hyperinsulinemia.	Every 6 mos until age 2 yrs

Source: GeneReviews — "KCNK9 Imprinting Syndrome"

Phenotype severity distribution: 3 always present features, 8 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:612292

Orphanet

European rare disease database

Orphanet:166108

GARD

Genetic and Rare Diseases Info Center

GARD:10358

Questions for Your Care Team

→Should I pursue genetic testing for KCNK9, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

FAQ

Frequently Asked Questions

Common questions about Birk-Barel syndrome

Birk-Barel syndrome is an inherited condition that mainly affects brain development and muscle tone. People with this condition may show intellectual disability, low muscle tone (hypotonia), and a tendency for hyperactivity. In addition, they often have unusual facial features which can help in recognizing the syndrome. The condition is caused by changes (mutations) in the KCNK9 gene on chromosome 8 and follows a unique pattern of inheritance known as dominant inheritance with paternal imprinting. This means that when the mutation is inherited from the mother, it leads to the disease, while a mutation inherited from the father does not affect the individual.

Common signs of Birk-Barel syndrome include intellectual disability, hypotonia (low muscle tone), and hyperactivity. People with this condition also tend to have distinctive facial features. These symptoms are central to the condition as described in the available sources.

Birk-Barel syndrome is caused by mutations in the KCNK9 gene on chromosome 8. The condition is inherited in a dominant manner, but due to paternal imprinting, only the mutation inherited from the mother leads to the syndrome. This unique genetic mechanism is key to understanding the cause of the condition. Associated genes include KCNK9.

Kisho

Birk-Barel syndrome

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Establishing the Diagnosis

Differential Diagnosis

Treatment

Management Guidelines

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

Latest News & Developments

Gene therapy for children with sickle cell disease approved by FDA

Etiological Diagnosis and Disease Course of Birk-Barel Syndrome in an Adult Woman with a KCNK9 Variant.

Birk-Barel syndrome

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Penetrance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Establishing the Diagnosis

Differential Diagnosis

Treatment

Management Guidelines

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

What is Birk-Barel syndrome?

What are the symptoms of Birk-Barel syndrome?

What causes Birk-Barel syndrome?

How is Birk-Barel syndrome inherited?

How rare is Birk-Barel syndrome?

How is Birk-Barel syndrome diagnosed?

Are there treatments for Birk-Barel syndrome?

What are the potential complications of Birk-Barel syndrome?

How does Birk-Barel syndrome affect daily life and management?

What is the life expectancy for someone with Birk-Barel syndrome?

Are there any specific specialists recommended for managing Birk-Barel syndrome?

Latest News & Developments

Gene therapy for children with sickle cell disease approved by FDA

Etiological Diagnosis and Disease Course of Birk-Barel Syndrome in an Adult Woman with a KCNK9 Variant.