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At a glance

A syndrome of mental retardation, peculiar facies and osteocartilaginous abnormalities.

Synonyms

Coffin-Siris-Wegienka Syndrome (do not confuse with ☞Coffin Siris Syndrome, which is a different disease); Soft Hands Syndrome.

History

First described in 1966 by Grange S. Coffin, an American pediatrician, Evelyn Siris, an American radiologist, and Laurence C. Wegienka, an American physician. However, to avoid (further) confusions with ☞Coffin-Siris Syndrome, it had been decided to name the syndrome described here as Coffin-Lowry Syndrome (after Robert Bryan Lowry, a British medical geneticist, who described a fourth family with the same findings in 1971).

Incidence

Estimated to be in the range of 1:50,000-100,000 live births. No sexual predilection has been reported, but the disease is more severe in males.

Genetic inheritance

X-linked dominant inherited disorder caused by mutations in the gene coding for the RPS6KA3 (Ribosomal Protein S6 Kinase, 90-KD, 3; also known as RSK2), a growth factor-regulated serine-threonine protein kinase (involved in promotion of mitosis and activation of genes) that has been mapped to Xp22.12. However, research shows that only a minority of patients with this disorder actually have a mutation in the RPS6KA3 gene. Skewed X-chromosome inactivation in a heterozygous female can result in female patients with CLS.

Pathophysiology

Abnormal proteodermatan sulfate, glycolipid-like lysosomal granules, and vacuoles have been found in cultured skin fibroblasts. Accumulations of hyaluronate and hyperprolinemia have been reported in some patients.

Diagnosis

Based on the clinical association of growth and psychomotor retardation with hypotonia, progressive skeletal deformations, characteristic facial dysmorphism, and large soft hands. Molecular genetic testing is used to identify a hemizygous pathogenic variant of RPS6KA3.

Clinical aspects

There is a wide variability in the expression of the features of this syndrome. Involvement of the head and neck can present as thickened calvarium, prominent forehead, flat occiput, delayed suture closure with large anterior fontanelle, small paranasal sinuses, prominent supraorbital ridges with bushy eyebrows, downward slanting of the palpebral fissures, hypertelorism, blepharoptosis, large and prominent ears, large nose with wide base, blunt tip and thickened alae nasi and septum, elongated philtrum, maxillary/midfacial hypoplasia, mandibular prognathism, open mouth with macrostomia and big lips, and a longitudinally furrowed tongue with a dorsal groove. An enlarged trachea was reported in one patient. The facial features are generally not present at birth, but become apparent by the second year of life, after which they become more pronounced. Central nervous system features consist of generalized hypotonia, which may be the earliest presenting sign and related to paroxysmal stimulus-induced drop attacks (cataplexy or hyperexplexia), in which an unexpected tactile or auditory stimulus or excitement triggers an electromyographic silence in the lower limbs of 60-80-millisecond duration that results in collapse without loss of consciousness. ...

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