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Coffin-Lowry syndrome (CLS) is a rare genetic neurological disorder characterized by psychomotor and growth retardation, facial dysmorphism, digit abnormalities, and progressive skeletal changes.
ORPHA:192Classification level: Disorder
The exact prevalence is not known but is estimated to be 1/50,000 to 1/100,000. Male patients are generally moderately to severely affected while female carriers have mild features (Coffin-Lowry syndrome in female carriers, see this term).
Obesity and psychiatric disorders and epilepsy have been described. Although the clinical presentation is usually severe in male patients, marked variability has been reported. In the very young, physical characteristics are generally mild and not specific. Affected newborn males often show hypotonia and hyperlaxity of joints with growth parameters in the normal range. Broad, tapering fingers may be present at birth and are a strong diagnostic feature. Facial abnormalities (hypertelorism, frontal bossing, thick lips) become apparent in early childhood. However, the typical facial appearance is usually apparent only by the 2nd year with progressive coarsening (increased prominence of glabella and protrusion of lips). Growth and psychomotor retardation become apparent in the first years of life. Other early signs may be sensorineural hearing deficit and microcephaly. The typical facial aspect in adult males includes a prominent forehead, orbital hypertelorism, downward-slanting palpebral fissures, epicanthic folds, large and prominent ears, thick everted lips, and a thick nasal septum with anteverted nares. Orodontal findings include a high narrow palate, a midline lingual furrow, hypodontia, and peg-shaped incisors. Patients show hyper-extensible, soft, and fleshy hands with lax skin and joints and tapering stubby fingers. Skeletal malformations appear gradually in most cases and may include delayed bone development, spinal kyphosis/scoliosis, and pectus carinatum or excavatum. Cognitive deficiencies and impaired speech development are prominent but variable in severity. Other uncommonly associated manifestations include epileptic seizures and sensorineural hearing loss, which can be profound. Stimulus-induced drop episodes are common. Cardiac involvement has been reported (15%).
CLS is caused by mutations in the RPS6KA3 gene (Xp22.2-p22.1), which encodes RSK2, a growth-factor-regulated protein kinase. RPS6KA3 mutations are highly heterogeneous and lead to loss of phosphotransferase activity in the RSK2 kinase.
Diagnosis is usually based on the clinical presentation and radiological findings (cranial hyperostosis, abnormal shape and end plates of the vertebral bodies, delayed bone age, metacarpal pseudoepiphyses, and tufting of the distal phalanges). Early on, RPS6KA3 mutation analysis may be used for rapid diagnosis.
Differential diagnosis includes alpha-thalassemia-intellectual deficit, Borjeson-Forssman-Lehmann syndrome, FG syndrome, Williams syndrome, and Pitt-Hopkins syndrome (see these terms).
Prenatal diagnosis and carrier testing for at-risk pregnancies are available in at-risk families. CLS is transmitted in an X-linked semi-dominant manner. Approximately 70-80 % of affected patients have no family history, while 20-30 % have more than one affected family member. Genetic counseling is recommended. Early diagnosis is essential for proper management. Surveillance includes periodic hearing and dental examinations, and annual cardiac examinations.
Management and treatment
There is no specific treatment.
Prognosis is poor and depends on the severity of the disease.