Coffin–Lowry syndrome

Overview

Coffin–Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability, distinctive facial features, skeletal abnormalities, and developmental delays. It primarily affects males more severely than females due to its X-linked dominant inheritance pattern. Males with CLS typically have moderate to severe intellectual disability and more pronounced physical features, while females may have milder symptoms or be asymptomatic carriers. The syndrome is named after Drs. Grange Coffin and Robert Lowry, who first described the condition in the 1970s.

Causes

Coffin–Lowry syndrome is caused by mutations in the RPS6KA3 gene, located on the X chromosome (Xp22.2). This gene encodes a protein called RSK2, which plays an essential role in cell signaling related to brain development and bone growth. Mutations disrupt normal protein function, leading to abnormalities in neuronal development and skeletal structure. CLS is inherited in an X-linked dominant pattern, meaning the gene mutation is on the X chromosome. Males with the mutation are typically affected, while females may be less affected due to having a second, normal X chromosome.

Symptoms

The severity of Coffin–Lowry syndrome varies between individuals and between genders. Common symptoms include:

• Intellectual disability: Ranging from moderate to severe in males; milder or absent in females

• Distinctive facial features: Including a prominent forehead, wide-set and downward-slanting eyes, thick lips, large mouth, and soft hands

• Developmental delays: Delayed motor skills, speech, and learning milestones

• Skeletal abnormalities:

  • Short stature

  • Kyphoscoliosis (curved spine)

  • Broad, tapering fingers

  • Hyperextensible joints

• Hypotonia: Reduced muscle tone, especially in infancy

• Stimulus-induced drop attacks: Sudden loss of muscle tone triggered by auditory or tactile stimuli, seen in some affected males

• Hearing loss: May be present in some individuals

• Cardiac anomalies: Including mitral valve prolapse or other structural heart defects in some cases

Diagnosis

Diagnosis of Coffin–Lowry syndrome is based on clinical features and confirmed through genetic testing. Key diagnostic steps include:

• Clinical examination: Evaluation of characteristic facial features, skeletal signs, and developmental history

• Genetic testing: Molecular analysis to identify mutations in the RPS6KA3 gene

• Radiological imaging: X-rays or MRI to assess bone and spine abnormalities

• Neurological evaluation: To identify hypotonia, cognitive impairment, or drop attacks

• Cardiac and hearing assessments: Echocardiogram and audiologic testing as part of a comprehensive workup

• Family history analysis: May help identify carrier females or other affected individuals

Treatment

There is no cure for Coffin–Lowry syndrome, so treatment is supportive and tailored to individual needs. Management typically involves a multidisciplinary approach, including:

• Early intervention programs: Physical, occupational, and speech therapy to support developmental progress

• Educational support: Special education services and individualized learning plans

• Seizure and drop attack management: Medications and safety precautions to prevent injury

• Orthopedic interventions: Bracing or surgery for scoliosis or other skeletal deformities

• Cardiac monitoring: Regular follow-up if heart abnormalities are present

• Hearing aids or assistive devices: For individuals with hearing impairment

• Genetic counseling: For affected families to understand inheritance and recurrence risks

Prognosis

The prognosis for individuals with Coffin–Lowry syndrome depends on the severity of symptoms. Males with CLS often require lifelong care and supervision due to significant intellectual and physical challenges. Females may live relatively normal lives, especially if mildly affected. Life expectancy can be reduced in cases with severe neurological symptoms or cardiac complications. Early diagnosis, intervention, and consistent medical care can improve quality of life and help manage complications associated with the syndrome.