COFFIN-LOWRY SYNDROME

Coffin-Lowry syndrome (CLS)  is an X-linked dominant disorder that mainly affects males and leads to mental retardation and characteristic physical features. Symptoms vary greatly. Women are generally less affected, depending on X inactivation. The syndrome is caused by pathogenic variants in the RPS6KA3 gene on the X chromosome, with about 60% occurring de novo.

Symptoms

The main symptoms in males are mental retardation (IQ 15–60) and a characteristic appearance.

The external characteristics are:

• Prominent forehead
• Wide-set eyes
• Downward-sloping eyes
• Broad nose with everted nasal base
• Full lips and an everted lower lip
• Hyperextensible hand and finger joints
• Broad, tapered fingers

Muscle hypotonia is evident in infancy and early childhood. The final height is usually below the 3rd percentile. 80% of those affected develop progressive kyphoscoliosis, sometimes with cardiovascular complications, and just as many have a funnel (sunken) or pigeon chest.

In addition, about 15% show mitral regurgitation, and about 30% have sensorineural hearing loss. Seizures occur in about 5%, and drop attacks, a sudden loss of muscle tone without loss of awareness that occurs in response to acoustic or tactile stimuli, occur in about 20%.

Women are generally less severely affected, with the spectrum of symptoms ranging from an inconspicuous phenotype with normal intelligence to the full clinical picture seen in males, depending on X inactivation.

Inheritance

CLS is an X-linked dominant inherited syndrome.

Frequency

The prevalence is estimated to be between 1:50,000 and 1:100,000.

Causes

CLS is caused by variants in the RPS6KA3 gene on the short arm of the X chromosome (Xp22.1-22.2). The gene codes a serine-threonine kinase. Approximately 60% are new mutations.

Germ cell mosaics have been described.

References

Rogers and Abidi. 2002 Jul 16 [updated 2018 Feb 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021 / Pereira et al. 2010, Eur J Hum Genet 18:627 / Pereira et al. 2007, Hum Genet 122:541 / Horn et al. 2001, Prenat Diagn 21:881 / Field et al. 2006, Clin Genet 70:509 / Delaunoy et al. 2006, Clin Genet 70:161 / Hunter 2002, Am J Med Genet 111:345 / Hanauer et al. 2002, J Med Genet 39:705 / Trivier et al. 1996, Nature 384:567