Paula and Bobby
Parents of Lillie
Coffin-Lowry syndrome (CLS)
What is Coffin-Lowry syndrome (CLS)?
This rare disease exhibits more severe symptoms in males than females due to the way in which it is inherited. Females with the syndrome may display none to very few or very mild symptoms.
Severe mental and intellectual disability are characteristic of the syndrome. Other defining features include issues related to growth, heart problems, and visual and hearing impairments.
The condition is believed to occur in approximately 1 in 40-50,000 people, making it fairly rare.
CLS RPS6KA3 RSK2
What gene changes cause Coffin-Lowry syndrome (CLS)?
Mutations in the RPS6KA3 gene are responsible for the syndrome.
The condition is inherited in an X-linked dominant pattern which explains why symptoms are more severe in males than females.
With syndromes inherited in an X-linked dominant pattern, a mutation in just one of the copies of the gene, causes the syndrome. This can be in one of the female X chromosomes, and in the one X chromosomes males have. Males tend to have more severe symptoms than females.
What are the main symptoms of Coffin-Lowry syndrome (CLS)?
For males intellectual disability related to the syndrome may be moderate to severe. In females it is usually non existant or very mild.
Unique facial features of the syndrome include a prominent forehead, widely spaced eyes, downward slanting eyes, a short nose, a wide nasal tip, a wide mouth and full lips.
Other physical features of the condition include soft, thin or tapered fingers, a short stature,a very small head (microcephaly) and progressve curvature of the spine.
Another unique symptom of the diseases is collapsing after being startled by a loud or sudden noise. This is known as SIDES.
Possible clinical traits/features:
X-linked dominant inheritance, Rectal prolapse, Frontal bossing, Telecanthus, Thick eyebrow, Microcephaly, Thick lower lip vermilion, Scoliosis, Thickened calvaria, Thick nasal septum, Reduced number of teeth, Short metacarpal, Ventriculomegaly, Brachydactyly, Coarse hair, Coarse facial features, Everted lower lip vermilion, Epicanthus, Drumstick terminal phalanges, Downslanted palpebral fissures, Feeding difficulties in infancy, Dental malocclusion, Delayed skeletal maturation, Delayed eruption of teeth, Delayed closure of the anterior fontanelle, Decreased body weight, Cutis marmorata, Cutis laxa, Craniofacial hyperostosis, Coxa valga, Pectus carinatum, Pes planus, Sensorineural hearing impairment, Optic atrophy, Open mouth, Protruding ear, Uterine prolapse, Wide mouth, Widely spaced teeth, Single transverse palmar crease, Seizure, Short stature, Gait disturbance, Depressed nasal bridge, Cognitive impairment, High palate, Hyperextensibility of the finger joints, Hyperconvex fingernails, Highly arched eyebrows
How does someone get tested for Coffin-Lowry syndrome (CLS)?
The initial diagnosis of Coffin-Lowry can begin with facial genetic analysis screening, as offered by FDNA Telehealth, which can identify the key markers of the syndrome and outline the need for further testing. If further testing is recommended what will follow is a consultation with a genetic counselor and then a geneticist. These consultations will usually involve a comprehensive review of the patient’s medical history, a generational family history documenting health issues and genetic conditions, and a detailed physical examination. Based on this clinical consultation, the options and recommendations for genetic testing will be shared with the individual’s parents/guardians and consent will be sought for further testing. This process may take place over the course of several clinic visits. Genetic testing will involve a blood sample. Results from the testing will then be sent back to the geneticist who will explain the resulting report in detail with the parents/guardians of the individual being tested.
Medical information on Coffin-Lowry syndrome (CLS)
Coffin-Lowry syndrome is associated with intellectual disability, broad and tapering fingers and characteristic facial features. Microcephaly, cardiac abnormalities, stimulus-induced drop attacks, growth failure, dental anomalies and hearing loss can also be present. The syndrome is caused by mutations in the RPS6KA3 (RSK2) gene.
This syndrome is clinically recognizable in males, who are usually severely intellectually disabled and have the following facial features: hypertelorism with down-slanting palpebral fissures; broad nose with a thick septum and large and bow-shaped mouth with prominent everted lips. The head circumference may be small, and there is often fullness of the upper lids, especially at their lateral margins. The ears appear to be large, and many case reports refer to a long philtrum.
Heterozygous females can be partially affected with coarse facies, characteristic hands and a reduced IQ. Simensen et al., (2002) estimated the average IQ in carrier females to be 65 and in affected males to be 43.
An almost pathognomonic sign is the pudgy, tapering digits. Pectus carinatum or excavatum have been commented on, and a severe kyphoscoliosis develops in the older patients. Radiologically there might be degenerative changes in the spine, tufting of the distal phalanges, and poor modeling of the middle phalanges, as well as pseudo-epiphyses of the metacarpals.
Fryssira et al., (2002) reported a female with fully manifesting CLS, confirmed by molecular analysis, who experienced daily drop episodes, diagnosed as ""cataplexy"". The episodes were precipitated by emotional or auditory stimuli and were significantly reduced by selective serotonin re-uptake inhibitors. Nakamura et al., (2005) call these 'drop attacks'. Their patient had a RSK2 mutation.
Stephenson et al., (2005) suggest that these episodes (they occur in 20% of cases) are sometimes a complex combination of different paroxysmal events (cataplexy, hyperekplexia and startle epilepsy). O'Riordan et al., (2006) reported that the drop attacks responded reasonably well to clonazepam, and Havaligi et al., (2007) reported good response to sodium oxybate. Nonconvulsive status has also been reported (Gschwind et al., 2015).
A cardiomyopathy (in the case of Facher et al., (2004), a restrictive cardiomyopathy) has been reported a few times.
Ishida et al., (1992) reported a case with calcium pyrophosphate crystal deposition in the ligamenta flava. Crow et al., (1998) reported three cases with cataplexy (sudden and reversible loss of muscle tone without loss of consciousness). Fryns et al., (1998) and Nelson and Hahn (2003) reported further cases with similar features.
Kondoh et al., (1998) reported a case of Coffin-Lowry syndrome where an MRI scan showed small perivascular focal areas of hypointensity in the white matter on T1 weighted imaging, similar to those found in mucopolysaccharidosis. However, MRI on another case did not show these features.
Sivagamasundari et al., (1994) reported a family where two affected females had a psychotic illness with predominantly depressive features. The three affected males in the family had profound sensorineural deafness. Unfortunately, no clinical photographs were published.
Higashi and Matsuki (1994) reported a further case with sensorineural deafness. He was found to have hypoplasia of the left lateral semicircular canal. Hartsfield et al., (1993) also reported sensorineural deafness as a feature of this syndrome.
Hunter (2002) reports the features of the condition in adult cases. Features appearing later in life include late eruption and premature loss of teeth, sensorineural or conductive hearing loss, cataracts and retinal abnormalities, cardiomyopathy and valvular abnormalities, respiratory problems probably secondary to kyphoscoliosis, drop attacks and increased spasticity, and an increased risk of psychiatric disease, especially in female carriers. Igari et al., (2006) also comment on the premature exfoliation of the primary teeth.
The locus maps to Xp22 (see Biancalana et al., 1992; Bird et al., 1995). Trivier et al., (1996) demonstrated mutations in the gene for RSK2, a member of the growth factor regulated protein kinases. Intragenic deletions, nonsense mutations, splice site mutations, and missense mutations were demonstrated. Further mutations were reported by Jacquot et al., (1998). Further mutations were reported by Abidi et al., (1999). Merienne et al., (1998) reported a western blot protocol applied to lymphocyte protein extracts for the rapid diagnosis of the condition.
Some families with non-syndromic X-linked ID have RSK2 mutations (Field et al., 2006), and some families (Schneider et al., 2013) who are negative for RSK2 mutations on exon sequencing might have deep intronic mutations in RPS6KA3, which is associated with the retention of intronic sequences in the mRNA. The original Lowry family has now been found to have a RPS6KA3 mutation (Nishimoto et al., 2014).
Zeniou et al., (2002) say that in a series of 250 patients, mutations were only detected in 1/3rd. These authors studied 26 patients by western blot analysis and in vitro kinase assay. Seven RSK2 mutations were detected. The authors suggest that the disorder might be genetically heterogeneous. Delaunoy et al., (2006) reported 44 novel mutations in the RSK2 gene, and stressed the possibility of mosaicism in counselling.
Jacquot et al., (1998) reported a family where a mother was an apparent mosaic for the mutation. A further case of maternal mosaicism was reported by Horn et al., (2001).
Hanauer and Young (2002) provide an excellent review of the molecular and clinical features of the condition. They reported no skewing in X-inactivation in affected females, but Wang et al., (2006) found that affected females preferentially inactivated the normal RSK2 allele.
Merienne et al., (1999) reported a large X-linked family where affected males have mild intellectual disability, but with no dysmorphic features. A mutation was found in the RSK-2 gene. This resulted in a 5-6 fold decrease in activity but not complete inactivation of the gene. A further mild mutation in two sibs was reported by Manouvrier-Hanu et al., (1999).
A large duplication of RSK2 was reported by Pereira et al., (2007).
* This information is courtesy of the L M D.
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