Coffin–Lowry syndrome

Coffin-Lowry syndrome (CLS) represents the more severe end of the RPS6KA3-related intellectual disability continuum. Affected males show developmental delay with moderate-to-severe intellectual disability, speech being more severely affected than motor skills. Neurologic manifestations include hypotonia, spastic paraparesis, seizures, and stimulus-induced drop attacks (SIDAs), in which an unexpected tactile or auditory stimulus triggers a brief electromyographic silence in the lower limbs with momentary collapse but no loss of consciousness. Characteristic craniofacial features comprise widely spaced eyes with downslanted palpebral fissures, a depressed nasal tip with thick alae nasi and broad columella, protruding ears, a wide mouth with thick vermilion, and a coarse face that may further coarsen with age. Hands are small, soft, and fleshy, with distally tapered fingers, small terminal phalanges and nails, and hyperextensibility. Other features may include cardiovascular anomalies, reduced height, dental issues, hearing loss, vision issues or sleep apnoea. Onset is in infancy to early childhood. Heterozygous females manifest markedly variable expression, ranging from mild facial coarsening, tapered fingers, and short stature to findings indistinguishable from those of hemizygous males.

The estimated prevalence is 1/40,000-1/50,000.

Coffin-Lowry syndrome is caused by germline pathogenic variants in RPS6KA3 at Xp22.12, which encodes ribosomal protein S6 kinase alpha-3 (S6K-alpha-3), a growth factor-regulated serine/threonine kinase within the Ras signalling cascade. S6K-alpha-3 regulates neurite formation, synaptic plasticity, neurotransmitter release, and genomic stability. The disease mechanism is loss of function: most pathogenic variants result in total loss of ribosomal S6 kinase enzyme activity, whereas milder phenotypes are associated with partial reductions in activity.

Coffin-Lowry syndrome is inherited in an X-linked manner. Hemizygous males are typically severely affected; heterozygous females show markedly variable manifestations. Each daughter of an affected male will inherit the pathogenic variant; sons of an affected male will not. Severely affected males usually do not reproduce. Each child of a heterozygous female has a 50% risk of inheriting the variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of Coffin-Lowry syndrome is established in a proband with suggestive clinical findings and the identification of a hemizygous (in males) or heterozygous (in females) pathogenic variant in RPS6KA3 by molecular genetic testing.

Main differential diagnoses include:

• FG syndrome type 1: shares broad forehead, downslanted palpebral fissures, thick lower-lip vermilion, kyphoscoliosis, and pectus excavatum; distinguished by disproportionate macrocephaly, broad thumbs and halluces, and small cupped ears with overfolded superior helix; MED12
• Borjeson-Forssman-Lehmann syndrome: severe intellectual disability with tapered hand findings and kyphoscoliosis; distinguished by large prominent ears, extreme hypogonadism in affected males, and marked gynaecomastia; PHF6
• Alpha-thalassaemia X-linked intellectual disability syndrome: X-linked intellectual disability with distinctive craniofacial features and hypotonia; distinguished by genital anomalies and mild alpha-thalassaemia in approximately 75% of affected persons; ATRX

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for targeted family counselling.
• Identifying the causative variant enables specific and individualised surveillance addressing neurologic features (stimulus-induced drop attacks, spasticity, seizures, signs of spinal canal narrowing), progressive musculoskeletal involvement, cardiovascular status, hearing, vision, dental issues, and sleep apnoea, which is a prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive and carrier testing of at-risk relatives is technically possible and informs reproductive counselling.

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• Maity S, Montion M, Boothe D, Attarpour M, Mageto I, Agarwal S, et al. Coffin-Lowry syndrome: a systematic review of RPS6KA3 confirmed cases and implications for diagnosis and counseling. Front Genet. 2025;16:1715229. doi:10.3389/fgene.2025.1715229. PMID:; PMCID: PMC12832115.
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• Song A, Im M, Kim MS, Noh ES, Kim C, Jang J, et al. First female Korean child with Coffin-Lowry syndrome: a novel variant in RPS6KA3 diagnosed by exome sequencing and a literature review. Ann Pediatr Endocrinol Metab. 2023;28(1):67-72. doi:10.6065/apem.2142134.067. PMID:; PMCID: PMC10073030.