Coffin–Lowry syndrome

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Rare X-linked genetic disorder with intellectual disability and skeletal abnormalities


Coffin–Lowry syndrome
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Synonyms CLS, Progressive intellectual and skeletal syndrome
Pronounce N/A
Specialty N/A
Symptoms Intellectual disability, kyphoscoliosis, growth retardation, facial dysmorphism, hypotonia, seizures, cardiac abnormalities
Complications Hearing loss, visual impairment, cardiomyopathy, scoliosis
Onset Infancy or early childhood
Duration Lifelong
Types
Causes Mutations in the RPS6KA3 gene
Risks Family history of CLS
Diagnosis Clinical examination, genetic testing
Differential diagnosis Fragile X syndrome, Angelman syndrome, Lujan–Fryns syndrome
Prevention Genetic counseling
Treatment Supportive care, physical therapy, speech therapy, educational support
Medication As needed for seizures or cardiac issues
Prognosis Variable; males typically more severely affected than females
Frequency 1 in 50,000 to 1 in 100,000
Deaths Rare, often related to severe cardiac or neurological complications


Coffin–Lowry syndrome (CLS) is a rare X-linked dominant genetic disorder characterized by intellectual disability, skeletal abnormalities, delayed development, and distinctive facial features. The condition is more severe in males due to their single X chromosome and typically presents during infancy or early childhood.

Genetic Basis[edit | edit source]

Coffin–Lowry syndrome is caused by loss-of-function mutations in the RPS6KA3 gene, which encodes the enzyme ribosomal S6 kinase 2 (RSK2). RSK2 is a component of the mitogen-activated protein kinase (MAPK) signaling pathway and is involved in regulating cell growth and development, particularly in the brain and skeletal system.

More than 140 different mutations in RPS6KA3 have been identified, including missense mutations, nonsense mutations, and small insertions or deletions. These mutations impair the normal function of RSK2, leading to disrupted cellular signaling and abnormal development.

Most cases of CLS arise from de novo mutations, meaning the mutation occurs spontaneously in the affected individual with no prior family history. However, in 20–30% of cases, the condition is inherited from a carrier mother. Due to X-inactivation in females, the severity of symptoms can vary. Affected females typically have milder manifestations compared to males, although rare cases of homozygous females have been reported with severe phenotypes.

Clinical Features[edit | edit source]

The clinical presentation of CLS is variable but typically includes:

Diagnosis[edit | edit source]

Diagnosis of Coffin–Lowry syndrome is based on:

  • Detailed clinical evaluation and recognition of characteristic features
  • Family history and pedigree analysis
  • Genetic testing to identify mutations in the RPS6KA3 gene

Prenatal testing is available when there is a known mutation in the family.

Differential Diagnosis[edit | edit source]

Conditions that may resemble CLS and should be considered include:

Management[edit | edit source]

There is no cure for CLS. Management is supportive and involves a multidisciplinary approach:

Prognosis[edit | edit source]

The prognosis for individuals with CLS varies. While some affected individuals may achieve some level of independence, most require lifelong support. Life expectancy may be reduced in cases with severe cardiac or neurological complications. Females generally have milder symptoms and a better prognosis.

Epidemiology[edit | edit source]

Coffin–Lowry syndrome is considered rare, with an estimated prevalence between 1 in 50,000 and 1 in 100,000 live births. It affects both males and females, although males are usually more severely affected.

History[edit | edit source]

The syndrome was first described by Dr. Grange S. Coffin and Dr. Robert B. Lowry in the 1960s and 1970s. Advances in molecular genetics have since clarified the genetic basis of the disorder.

See also[edit | edit source]

External links[edit | edit source]

Classification
External resources

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Contributors: Prab R. Tumpati, MD