Temple–Baraitser Syndrome

Overview

Temple–Baraitser syndrome (TBS) is an extremely rare genetic disorder characterized by distinctive facial features, severe developmental delays, intellectual disability, and abnormalities of the fingers and toes, particularly involving the thumbs and great toes. The condition was first described by Karen Temple and Michael Baraitser in the early 2000s. Temple–Baraitser syndrome is considered a neurodevelopmental disorder and is part of the expanding group of syndromes associated with mutations in potassium channel genes, which play critical roles in brain function and development. Fewer than 50 cases have been documented in the medical literature, making it a very rare and poorly understood condition.

Causes

Temple–Baraitser syndrome is caused by mutations in the KCNH1 gene, located on chromosome 1. This gene encodes a voltage-gated potassium channel involved in regulating electrical signaling in the brain. The mutation leads to dysfunction of neuronal potassium channels, disrupting normal brain development and contributing to seizures and cognitive impairment.

The condition is inherited in an autosomal dominant pattern, but most cases are due to de novo mutations, meaning they occur spontaneously and are not inherited from the parents. In rare instances, parental mosaicism has been suspected. Genetic testing is required to confirm the mutation.

Symptoms

The clinical features of Temple–Baraitser syndrome typically appear in infancy and vary in severity. Common signs and symptoms include:

Neurological and Developmental:

• Severe developmental delay – Most children experience delays in reaching milestones such as sitting, walking, and speaking.

• Intellectual disability – Ranging from moderate to profound.

• Seizures – Often refractory epilepsy that begins in early infancy and is difficult to control.

Craniofacial Features:

• Prominent forehead

• Wide mouth with thick lips

• Broad nasal bridge

• Low-set or malformed ears

Digital Anomalies:

• Hypoplastic or absent nails – Particularly of the thumbs and great toes.

• Broad thumbs and halluces (big toes) – Often with abnormal bone development visible on X-ray.

• Shortened fingers and toes – Also known as brachydactyly.

Other Features:

• Feeding difficulties in infancy

• Low muscle tone (hypotonia)

• Possible behavioral issues or autistic features

Diagnosis

Diagnosis of Temple–Baraitser syndrome is challenging due to its rarity and overlap with other developmental disorders. A thorough clinical evaluation is combined with genetic testing. Diagnostic steps include:

• Clinical evaluation – Identification of characteristic facial features, digital anomalies, and developmental delays.

• Developmental and neurological assessments – To evaluate cognitive and motor delays, seizure activity, and hypotonia.

• Radiographic imaging – X-rays of the hands and feet often show abnormal or absent bone structures in the thumbs and toes.

• Electroencephalogram (EEG) – To detect abnormal brain activity and monitor seizure patterns.

• Genetic testing – Targeted sequencing or whole exome sequencing to identify mutations in the KCNH1 gene.

In cases where KCNH1 mutations are identified alongside the clinical picture, a diagnosis of Temple–Baraitser syndrome can be confirmed.

Treatment

There is currently no cure for Temple–Baraitser syndrome. Treatment is supportive and aims to manage symptoms and improve the quality of life. A multidisciplinary approach is essential, involving pediatricians, neurologists, geneticists, therapists, and special educators. Key treatment strategies include:

Seizure Management:

• Antiepileptic drugs (AEDs) – Such as valproate, levetiracetam, or other agents depending on seizure type and response.

• Ketogenic diet – May be considered in refractory cases.

Developmental and Supportive Care:

• Speech and language therapy – To support communication skills.

• Occupational therapy – For fine motor development and adaptive skills.

• Physical therapy – To address muscle tone, posture, and gross motor delays.

• Special education services – Customized educational plans based on cognitive ability.

Monitoring and Additional Interventions:

• Regular neurological follow-up – To monitor seizures and cognitive development.

• Feeding support – Nutritional support or feeding tubes may be needed in infancy for severe feeding issues.

• Behavioral therapy – If behavioral challenges or autism-like symptoms are present.

Prognosis

The long-term prognosis of Temple–Baraitser syndrome varies depending on the severity of the symptoms, especially intellectual disability and epilepsy. Key aspects of prognosis include:

• Development – Most affected individuals remain significantly delayed in cognitive and motor skills. Some may achieve basic milestones such as walking or using simple words, but many remain nonverbal or dependent on caregivers throughout life.

• Seizure control – Epilepsy is often difficult to manage, though some patients achieve partial control with medications or dietary therapy.

• Life expectancy – While no specific data exist due to the rarity of the condition, most individuals can live into adulthood with supportive care. The primary risks include complications related to seizures and feeding difficulties.

• Quality of life – With early intervention and a comprehensive care team, many children with TBS can achieve a good quality of life and participate in specialized educational and social programs.

Ongoing research is necessary to better understand the syndrome and to explore potential targeted therapies based on the underlying potassium channel dysfunction.