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A rare X-linked syndromic intellectual disability characterized by global development delay, postnatal growth retardation leading to short stature, facial dysmorphism, short hands with tapering fingers and progressive skeletal abnormalities including kyphoscoliosis and pectus carinatum/excavatum. Intellectual disability ranges from mild to severe.
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 most female carriers have mild features.
Severe clinical presentation was reported in the first male patients described. Following the wide application of molecular genetic testing, the phenotype is now recognized as very variable. Affected newborn males often show hypotonia and hyperlaxity of joints with normal growth parameters. Growth retardation and global developmental delay become visible in the first years of life. The facial dysmorphism visible in late childhood and adulthood include prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthic folds, prominent ears, wide mouth, thick lips with everted lower vermilion, thick nasal alae, and septum. Oral findings include a high narrow palate, a midline lingual furrow, hypodontia, and peg-shaped incisors. Microcephaly is common. Hands are short, soft, and fleshy with skin/joint laxity and tapering fingers. Full and fleshy forearms can be present in childhood. Skeletal abnormalities appear gradually and may include spinal kyphoscoliosis (often progressive) and pectus carinatum/excavatum. Cognitive impairment is variable in severity. Other neurological findings may include epilepsy, progressive paraplegia and stimulus-induced drop attacks (SIDAs). Brain abnormalities have been reported but without a consistent pattern. A happy personality is common although behavioral abnormalities can be present. Other less frequent manifestations are sensorineural hearing loss and heart anomalies. Final stature is usually below the third percentile.
Coffin-Lowry syndrome (CLS) is caused by pathogenic variations in the RPS6KA3 gene (Xp22.2-p22.1), which encodes ribosomal protein S6 kinase alpha-3, a growth-factor-regulated protein kinase.
Diagnosis is suspected on clinical presentation and confirmed by the following genetic tests: sequencing of RPS6KA3 or Intellectual Disability-related Next Generation Sequencing panel that includes this gene. If sequencing results are negative, multiplex ligation-dependent probe amplification analysis should be performed in order to assess deletions or duplications.
Differential diagnosis includes Alpha-thalassemia-X-linked intellectual disability (ATRX) syndrome, Borjeson-Forssman-Lehmann syndrome, FG syndrome type 1, Williams syndrome and Pitt-Hopkins syndrome.
Prenatal genetic counseling should be offered to parents of patients who are hemizygotes for the pathogenic variant to discuss genetic risk and reproductive options.
Coffin-Lowry syndrome is an X-linked dominant disorder. About two-thirds of cases occur de novo. The risk of recurrence for the sibs of a proband depend on the mother's genotype. If the mother is a carrier of the pathogenic variation, the risk of transmitting the variant in subsequent pregnancies is 50%. Male offspring inheriting the mutation are affected, and female carriers can be unaffected or show milder phenotypes (Symptomatic form of Coffin-Lowry syndrome in female carriers). If the mother is not a carrier, the risk of recurrence is very low and linked to the possibility of germinal mosaicism.
Management and treatment
Management requires an early multidisciplinary approach. Kyphoscoliosis/spinal stenosis and SIDAs should be recognized and treated to avoid secondary complications.
Prognosis is poor and depends on the severity of the disease. Life span is reported to be reduced.