• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Coffin-Lowry Syndrome

, MD and , PhD.

Author Information
, MD
Senior Clinical Geneticist
Greenwood Genetic Center
Greenville, South Carolina
, PhD
Molecular Diagnostic Laboratory
Greenwood Genetic Center
Greenwood, South Carolina

Initial Posting: ; Last Update: March 27, 2014.

Summary

Disease characteristics. Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Intellect ranges from normal to profoundly impaired in heterozygous females. The facial appearance is characteristic in the affected, older male child or adult. The hands are short, soft, and fleshy, often with remarkably hyperextensible fingers that taper from wide (proximally) to narrow with small terminal phalanges and nails. Males are consistently below the third centile in height. Microcephaly is common. Cardiac abnormalities may be present and can contribute to premature death. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Life span may be reduced.

Diagnosis/testing. The diagnosis of CLS is established in males with severe developmental delay, characteristic craniofacial and hand findings, and radiographic findings. Carrier females may be mildly affected. Molecular genetic testing of RPS6KA3, the only gene yet published in which pathogenic variants are known to cause CLS, can be used to confirm but not to rule out the diagnosis of typical CLS. Sequence analysis identifies pathogenic variants in approximately 25%-40% of clinically diagnosed probands.

Management. Treatment of manifestations: SIDAs are treated with medications such as valporate, clonazepam, or selective serotonin uptake inhibitors; individuals who experience frequent SIDAs may require use of a wheelchair and should be protected, if possible, from being startled. Risperidone may be of benefit to individuals who display destructive or self-injurious behavior. Feeding difficulties, abnormal growth velocity, behavioral problems, kyphoscoliosis, and obesity, if present, are treated in a standard manner.

Prevention of secondary complications: Intervention to prevent progression of kyphoscoliosis to the point of cardio-respiratory compromise.

Surveillance: Periodic hearing, dental, and vision examinations; annual clinical cardiac examination, adding an echocardiogram by age ten years and repeating every five to ten years; regular monitoring of the spine for progressive kyphoscoliosis.

Agents/circumstances to avoid: Individuals who experience SIDAs should be protected as much as possible from being startled and/or from falls.

Genetic counseling. CLS is inherited in an X-linked dominant manner. Approximately 70%-80% of probands have no family history of CLS, and 20%-30% have more than one additional affected family member. Children of a woman known to be a carrier are at 50% risk of inheriting the pathogenic variant. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and at high risk for at least some developmental delay and mild physical signs of CLS. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible in families in which the pathogenic variant has been identified in an affected family member or in which linkage studies can exclude the X chromosome that carries (or potentially carries) the pathogenic variant.

Diagnosis

Clinical Diagnosis

Affected Males

Clinical findings. The most important clinical signs of Coffin-Lowry syndrome (CLS) in affected males are the following [Hanauer & Young 2002] (see Figure 1, Figure 2, Figure 3, Figure 4, and Figure 5):

Figure 1

Figure

Figure 1. AP view of a two-year-old boy with CLS showing relatively fine facial features but with widely spaced eyes, mildly downslanted palpebral fissures, short nose with broad columella and thick, slightly everted vermilion of the lips. (Affected individual (more...)

Figure 2 A & B

Figure

Figure 2 A & B. AP and lateral view of the same boy at age five years showing a more triangular-shaped face, increasing coarseness, and expression of the typical facial signs of CLS. (Affected individual has a known RPS6KA3 mutation.)

Figure 3

Figure

Figure 3. AP view of an adolescent showing relatively mild facial signs but with widely spaced eyes, mildly downslanted palpebral fissures, thick vermilion of the upper and lower lips, and small teeth. The columnella is broad but nares are a good size, (more...)

Figure 4 A & B

Figure

Figure 4 A & B. Hand of the child illustrated in Figure 1 and Figure 2 at ages two years (A) and five years (B). (Affected individual has a known RPS6KA3 mutation.)

Figure 5 A & B

Figure

Figure 5 A & B.
A. Hand of an older child showing classic tapering and soft appearance.
B. More subtle differences seen in the hand of the individual illustrated in Figure 3. (Affected individuals have a known RPS6KA3 mutation.) (more...)

  • Development. Affected males typically have moderate to severe intellectual disability; since the advent of molecular genetic testing, more mildly affected males are being identified [Field et al 2006].
  • Craniofacial. In the affected older male child or adult, the facial appearance is characteristic (see Figure 1, Figure 2, and Figure 3):
    • Usually prominent forehead and supraorbital ridges with thick eyebrows
    • Usually marked widely spaced eyes with downslanted palpebral fissures; occasionally, relatively normal periorbital region with mild telecanthus
    • Consistent, often striking, nasal findings including depressed bridge, blunt tip, and thick alae nasi and septum, resulting in small nares
    • Wide mouth, usually held open; thick vermilion of the upper and lower lips with everted vermilion of the lower lip
    • Coarse facial appearance in childhood with progression to a more ‘pugilistic’ look with age
    • Prominent ears
  • Extremities
    • Short, soft, fleshy hands, often with remarkably hyperextensible fingers, and a short horizontal palmar crease across the hypothenar area
    • Fingers that taper markedly from relatively wide proximally to narrow distally, with small terminal phalanges and nails (see Figure 4). The differences in the hands may sometimes be subtle (see Figure 5).
    • Soft, malleable hands with an almost 'plush-cushion' feel to the palm, as may be seen in an obese individual
    • Full, fleshy forearms: a potentially useful sign in diagnosing a younger child
  • Musculoskeletal
    • Frequent pectus carinatum and/or excavatum
    • Childhood onset of kyphoscoliosis that is often progressive

Note: Several authors have stated that the diagnosis may be difficult in the young child. Indeed, more than in most syndromes, the facial characteristics of CLS become increasingly discernible with age. However, even in neonates, the diagnosis of CLS is most often apparent if considered.

Radiographic findings in CLS are nonspecific individually or as a pattern but may be helpful in confirming the diagnosis [Hanauer & Young 2002]:

  • Thickened skull with large frontal sinuses
  • Anterior beaking of the vertebrae with narrow disc spaces and related degenerative vertebral changes
  • Kyphoscoliosis
  • Narrow pelvis
  • Metacarpal pseudoepiphyses, poor modeling of the middle phalanges, and tufting of the distal phalanges (Metacarpophalangeal profiles do not appear to aid diagnosis.)

Affected Females

The degree of developmental delay and craniofacial and limb changes range from severe (as seen in males) to completely absent. Careful examination of an intellectually normal female relative of an affected individual may reveal mild facial and/or hand manifestations.

Testing

Ribosomal S6 kinase enzyme assay. Ribosomal S6 kinase enzyme assay, performed on cultured fibroblasts or transformed lymphoblasts, may show reduced activity in males with an RPS6KA3 pathogenic variant [Merienne et al 1998, Delaunoy et al 2001, Zeniou et al 2002a]. This is a research test available on a limited basis.

Note: The assay is not useful in females because of the broad range of enzyme activity resulting from X-chromosome inactivation [Delaunoy et al 2001].

Molecular Genetic Testing

Gene. RPS6KA3 (also known as RSK2) is the only gene in which pathogenic variants are known to cause CLS.

Evidence for locus heterogeneity. It has been suggested that not all individuals with a clinical picture thought to be consistent with CLS have pathogenic variants in RPS6KA3 [Delaunoy et al 2001, Zeniou et al 2002b]. However, whether this finding points to true genetic heterogeneity in CLS or to inability to distinguish disorders with overlapping features on clinical grounds alone remains to be determined. There are no published linkage data from a well-described Coffin-Lowry syndrome family that would suggest a second Coffin-Lowry syndrome locus.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Coffin-Lowry Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
Affected MalesCarrier Females 2
RPS6KA3Sequence analysis 3 / mutation scanning~25%-40% 4, 5, 6, 7~90%-95% 5, 8
Deletion/duplication analysis 9Unknown 100% 11

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. To date there are no data to support the assumption that skewed X inactivation, as measured from lymphocytes, accounts for the observed clinical variability in carrier females or that it is a useful means of carrier detection. Carrier female detection rate is based on selection of subjects. In females who have a family history of an affected male relative with a pathogenic variant in RPS6KA3, the carrier detection rate is approximately 90%-95%; in families with a suspected diagnosis of Coffin-Lowry syndrome the detection rate will be similar to that for affected males.

3. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

5. Detection rate in clinically typical cases; detection rate in atypical cases is significantly lower [Authors, unpublished observation].

6. Sequence analysis can detect putative exonic, multiexonic, and whole-gene deletions on the X chromosome in affected males based on failure of amplification by PCR; confirmation may require deletion analysis. Sequence analysis cannot detect exonic, multiexonic, and whole-gene duplications in affected males.

7. Jacquot et al [1998a], Delaunoy et al [2001], Zeniou et al [2002b], Abidi & Schwartz [unpublished] (see Molecular Genetics)

8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. Several cases of RPS6KA3 exonic and multiexonic deletions have been described (see Table A and Molecular Genetics).

11. Sequence analysis of genomic DNA cannot detect deletions or duplications of an exon, multi-exons, or whole genes on the X chromosome in carrier females.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • In an affected male, bidirectional sequencing of the 22 exons of RPS6KA3 should detect any single nucleotide variant and small deletion or duplication present in the coding region or at the intron/exon boundaries.
  • Deletion/duplication analysis can be considered in affected females who have NEITHER of the following:
    • A pathogenic variant identified by sequence analysis
    • An affected male relative in whom the pathogenic variant may be more readily detected
  • An assay of ribosomal S6 kinase enzyme activity can be performed on a research basis in males whose phenotype is consistent with CLS but in whom no RPS6KA3 pathogenic variant is found by sequence analysis; this test is not useful in females and is available on a limited research basis.

Clinical Description

Natural History

Development. Coffin-Lowry syndrome (CLS) is characterized by severe-to- profound intellectual disability in males; intellect ranges from normal to profoundly impaired in heterozygous females. Early developmental assessments may overestimate the ultimate developmental prognosis [Hunter 2002]. Touraine et al [2002] did not provide detail but stated “our data have shown that intellectual disability is only moderate in most patients as soon as proper care is provided”; and the families reported by Field et al [2006] showed variable and mild physical signs and included members with only mild impairment. The authors are aware of a patient with a proven RPS6KA3 pathogenic variant who works in a fast food restaurant [C Skinner, personal communication].

Neuropsychiatric. Individuals with CLS are often described as generally happy and easygoing, although self-injury and other behavioral problems have been reported.

Detailed neurologic assessment may be hampered by the severe intellectual disability. Findings reported include loss of strength and muscle mass, both decreased and increased deep tendon reflexes, sleep apnea, stroke, progressive spasticity, and progressive paraplegia with loss of the ability to walk. The latter has been ascribed to both calcification of the ligamenta flava and congenital stenosis of the spinal canal [Hunter 2002].

Of particular note are stimulus-induced drop attacks (SIDAs), with onset between ages four and 17 years and a mean age at onset of 8.6 years [Nakamura et al 2005]. During a SIDA, unexpected tactile or auditory stimuli or excitement trigger a 60- to 80-millisecond electromyographic silence in the lower limbs that results in a brief collapse though no loss of consciousness [Crow et al 1998, Nakamura et al 1998, Hahn & Hanauer 2012]. Nelson & Hahn [2003] provide a video illustration of SIDAs. Stephenson et al [2005] recorded a prevalence of 20% (34/170) from the CLS Foundation database. Recently, a female with clinical features of CLS including stimulus-induced drop episodes (SIDEs) was found to have a pathogenic variant that occurred within the C-terminal kinase domain of the protein [Rojnueangnit et al 2014].

Females may also be affected [Fryssira et al 2002]. In the second of two individuals reported by Nelson & Hahn [2003], typical SIDAs at age six years were later replaced by brief myoclonic jerks and tonic spasms, which were accompanied by increased tonic EMG activity.

Stephenson et al [2005] have also emphasized that the nature of the movement disorder may change with age and that a single individual may have more than one type of neurologic sign. The range of manifestations include cataplexy that varies with the stimulus; hyperekplexia, a prolonged tonic reaction; and true epileptic seizures.

Epileptic seizures affect approximately 5% of individuals [Stephenson et al 2005].

Female carriers may have a higher rate of psychiatric illness than that found in the general population. Six (8.8%) of 68 women (22 females with CLS, 38 heterozygotes, and 8 'affected' sisters) have had psychiatric diagnoses, including schizophrenia, bipolar disease, and 'psychosis' [reviewed in Hunter 2002]. One of two women studied by Micheli et al [2007] was described as having a ‘psychosis’ and one of two affected sisters reported by Wang et al [2006] as having schizophrenia.

Cardiovascular. Approximately 14% of affected males and 5% of affected females have cardiovascular disease [Hunter 2002]. These percentages may be underestimates as many individuals with CLS have not had thorough initial or ongoing cardiac assessment. Reports have included: abnormalities of the mitral, tricuspid, and aortic valves; short chordae; cardiomyopathy (in one individual, with endocardial fibroelastosis); unexplained congestive heart failure; and dilatation of the aorta and of the pulmonary artery [reviewed in Hunter 2002]. An individual reported by Facher et al [2004] had a restrictive cardiomyopathy. Martinez et al [2011] reported an individual with CLS who had left ventricular non-compaction cardiomyopathy with a restrictive pattern. Cardiac anomalies may contribute to premature death.

Musculoskeletal. Progressive kyphoscoliosis is one of the most difficult aspects of the long-term care of individuals with CLS. The precise prevalence is not known, but at least 47% of affected males and 32% of females have been reported to have progressive kyphoscoliosis [Hunter 2002]. The rates were higher in a series reported from an orthopedic referral clinic [Herrera-Soto et al 2007]. Although no accepted definition of severity has been adopted in published reports, it is clear that the severity often progresses over time and that respiratory compromise caused by kyphoscoliosis may contribute to premature death. At least two deaths have occurred during surgery for kyphoscoliosis.

Other minor skeletal changes that may be seen on radiographs are of no clinical consequence.

Growth. Prenatal growth is normal; growth failure usually occurs early in the postnatal period. Males and severely affected females generally fall below the third centile in height but are expected to track a curve. The reduced height may reflect disproportionately short limbs [Hunter 2002, Touraine et al 2002]. While microcephaly is common, many individuals with CLS have a normal head circumference.

Dental. Dental anomalies are common and include small teeth, malpositioning, open bite, hypodontia, advanced or delayed eruption, and premature loss that appears to have more than one cause. The palate is high. With age, the retrognathia in the younger child tends to be replaced by prognathism.

Hearing loss. It is likely that only a minority of individuals with CLS have had formal assessments of vision and hearing. However, 14/89 affected males and 1/22 affected females have been reported to have hearing loss [Hunter 2002].

An audiogram may reveal sensorineural hearing loss.

Malformation of the labyrinth has been reported, as has late onset of hearing loss [Rosanowski et al 1998]. Clustering of hearing loss within families may occur.

Vision problems. Significant visual problems seem to be uncommon, although cataract, retinal pigment atrophy, and optic atrophy have been reported; and the incidence of chronic eyelid irritation (blepharitis) may be increased [reviewed in Hunter 2002].

Neuroimaging studies may show increased intraventricular, subarachnoid, and Virchow-Robin spaces [Patlas et al 2003]. Virchow-Robin spaces appear to be a sign of brain aging and are associated with age and cognitive function. Abnormalities of the corpus callosum including thinning and agenesis have been reported by several authors [Kondoh et al 1998, Wang et al 2006]. An individual was reported with multiple focal frontal hypodensities visible on MRI [Kondoh et al 1998]. Hypodensities attributed to focal areas of CSF were reported in three affected sibs by Wang et al [2006]; they also showed thinning of the corpus callosum, vermian hypoplasia, and mild ventricular asymmetry. The authors concluded that the degree of intellectual disability correlated with the severity of the MRI findings.

Kesler et al [2007] performed quantitative MRI and demonstrated in affected males and females lower gray and white matter volume without evidence of ventriculomegaly ex vacuo, suggesting an early neurodevelopmental abnormality such as reduced cellular proliferation. Areas of maximal change were the cerebellum, temporal lobes, and hippocampus. The latter was increased in one family and decreased in the other; larger volumes correlated with increasing age (rho=.986, P<0.000). The corpus callosum and cerebellar vermis were also relatively enlarged compared to total brain volume.

In a single MRS study, the basal ganglia and periventricular white matter were reported as normal [Patlas et al 2003].

Neuropathology. Abnormal gyration and lamination have been noted at autopsy [Coffin 2003].

Other. Findings reported in single individuals include rectal prolapse, uterine prolapse, jejunal diverticuli, colonic diverticuli with reduced ganglion cells, popliteal ganglion, pyloric stenosis, unilateral renal agenesis, anteriorly placed anus, increased facial pigment, and enlarged trachea [reviewed in Hunter 2002].

Mortality. Life span is reduced in some individuals with CLS. Of individuals reported in the literature, death occurred in 13.5% of males and 4.5% of females at a mean age of 20.5 (range: 13-34) years [Hunter 2002]. Complicating factors have included cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis, and seizure-associated aspiration. Coffin [2003] reported that one of his original patients died at age 18.8 years of pneumonia superimposed on chronic lung and heart disease, and a second individual died at age 18 years of acute food aspiration. The authors are aware of an individual with CLS who had life-threatening central and obstructive sleep apnea, and of another male who had a history of chronic obstructive and central sleep apnea who died from respiratory complications after surgery for jaw advancement.

One affected male and one obligate carrier female died of Hodgkin disease. Another carrier mother had a Wilms tumor (see Wilms Tumor Overview), and a monozygotic twin of an affected individual died of a posterior fossa tumor [Manouvrier-Hanu et al 1999].

Genotype-Phenotype Correlations

Although no strong correlation exists between phenotype and location or type of RPS6KA3 pathogenic variant, individuals with certain missense pathogenic variants may tend to have milder disease expression [Delaunoy et al 2001]. The family classified as having a form of nonsyndromic intellectual disability (MRX19; see Genetically Related Disorders) had a missense variant in RPS6KA3, which caused an 80% reduction in ribosomal S6 kinase enzyme activity, in contrast to most pathogenic variants in individuals with CLS, which cause a total loss of ribosomal S6 kinase enzyme activity [Merienne et al 1999]. This finding indicates that some RPS6KA3 variants probably give rise to non-CLS phenotypes or nonsyndromic X-linked intellectual disability.

In a sample of seven individuals, Harum et al [2001] showed a correlation between IQ and the degree of attenuation of the RPS6KA3-mediated CREBtide phosphorylation response in lymphoblasts.

Yang et al [2004] proposed that lack of phosphorylation of ATF4 by RPS6KA3 may interrupt the normal regulatory role of ATF4 in osteoblast differentiation, accounting for some of the bony anomalies seen in CLS, as well as possibly explaining the progressive nature of the kyphoscoliosis.

Nakamura et al [2005] suggested that truncating mutations, either in or upstream from the N-terminal kinase domain, may cause a particular susceptibility to SIDAs. However, the finding of an affected female with SIDAs who has a heterozygous c.1570dupA pathogenic variant that occurs in the region encoding the C-terminal kinase domain of the protein would argue against this correlation [Rojnueangnit et al 2014].

Clinical data on a series of affected males with and without a mutation in RPS6KA3 suggest that the presence of certain clinical signs – such as the fleshy, tapering fingers, widely spaced eyes, and downslanted palpebral fissures – may help distinguish those in which mutation of RPS6KA3 is present [F Abidi & CE Schwartz, personal communication].

Nomenclature

Early authors referred to Coffin syndrome until it was recognized that the individuals reported by Lowry et al [1971] had the same syndrome.

Some early texts and papers confused Coffin-Siris syndrome and CLS.

Prevalence

No estimate of the prevalence of CLS has been published. Based on the authors' experience, a rate of 1:40,000 to 1:50,000 may be reasonable; this may, however, underestimate the actual prevalence.

Differential Diagnosis

The diagnosis of Coffin-Lowry syndrome (CLS) in the older male child or adult usually does not present a problem. The findings in a young child or more mildly affected female may overlap with other syndromes. Similarly, older female children and adults, even when they are the proband, can be diagnosed readily when they fully express the syndrome.

Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive disorder characterized by severe intellectual disability, hand findings similar to those of CLS, short nose with anteverted nares that may have a thick septum and small nares, and kyphoscoliosis. Additional findings are large, prominent ears and visual problems. Individuals with BFLS also have extreme hypogonadism and tend to have marked gynecomastia. Females may show partial expression of the syndrome. Absent findings are marked widely spaced eyes, wide mouth, and thick vermilion of the lips. Mutation of PHF6 is causative [Lower et al 2002].

While CLS shares some facial findings with Williams syndrome, the genetically heterogeneous FG syndrome, and X-linked alpha-thalassemia intellectual disability (ATRX) syndrome, none of these disorders shows the hand changes seen in CLS, and each has additional distinguishing features:

  • Williams syndrome also includes cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to failure to thrive in infancy. More than 99% of affected individuals have a contiguous gene deletion at 7q11.2, detectable by fluorescent in situ hybridization (FISH) or targeted mutation analysis.
  • FG syndrome type 1 (see MED12-Related Disorders) shares with CLS: X-linked inheritance, intellectual disability, a broad forehead, widely spaced eyes with downslanted palpebral fissures, a thick vermilion of the lower lip, kyphoscoliosis, pectus excavatum, and characteristic behaviors. It is distinguished by its disproportionate macrocephaly; constipation that may be associated with anal anomalies; broad thumbs and halluces; prominent fingertip pads; and small, rounded, cupped ears that often have an overfolded superior helix [Graham et al 1998]. Hypotonia often evolves into joint restriction.

    Partial absence of the corpus callosum and fused mamillary bodies are relatively common.
  • Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies and severe developmental delays with hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female genitalia in individuals with a 46,XY karyotype. ATRX syndrome is caused by pathogenic variants in ATRX.

McCandless et al [2000] reported a family with del(10)(q25.1q25.3) in which affected members had findings suggestive of CLS. Thus, it is reasonable to obtain chromosome studies in individuals with an atypical or doubtful diagnosis of CLS.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Coffin-Lowry syndrome (CLS), the following evaluations are recommended:

  • Measurement of height, weight, and head circumference
  • History and neurologic examination to assess for changes in gait or in bowel or bladder function and for epilepsy or movement disorder
  • Developmental assessment and formulation of an intervention plan
  • Complete musculoskeletal examination with particular attention to the chest and spine; radiographic assessment if clinically indicated
  • Developmental, age-appropriate hearing assessment
  • Dental evaluation
  • Physical examination of the heart and ECG, with baseline echocardiogram by age ten years
  • Ophthalmologic evaluation, including refraction and fundoscopy
  • Evaluation of appropriate family members for signs of the condition
  • Assessment of the family’s capacity to care for the child, especially if mother is affected intellectually
  • Medical genetics consultation

Treatment of Manifestations

Individuals with CLS should be provided with every opportunity to develop communication skills and to participate in activities and self-care in order to develop a degree of independence.

Awareness of SIDAs should allow early intervention to minimize the occurrence of triggering stimuli and to provide protection from falls:

  • Trials with different medications and efforts to optimize the dosage may improve outcome [O'Riordan et al 2006].
    • A trial of antiepileptic drugs (AEDs) (e.g., valproate, clonazepam, or selective serotonin uptake inhibitors) may be indicated [Fryssira et al 2002], although generally they are not effective.
    • Benzodiazapines, sometimes in increasing doses, have proved effective in some cases [Touraine et al 2002, Nakamura et al 2005].
    • In an individual who was not helped by a variety of medications, Havaligi et al [2007] reported a good response with sodium oxybate.
  • If attacks occur with great frequency, use of a wheelchair may be required to prevent falling and injury.

Risperidone may be of benefit to individuals who display destructive or self-injurious behavior [Valdovinos et al 2002].

Feeding difficulties, abnormal growth velocity, and obesity, if present, should be assessed and treated in a standard manner.

Treatment of behavioral problems is standard and requires periodic reassessment.

Treatment of kyphoscoliosis is standard but requires reassessment well into adulthood.

Prevention of Secondary Complications

Early recognition of spinal problems such as kyphoscoliosis and stenosis may allow prevention of progression and/or intervention to prevent long-term cardiovascular or neurologic complications. Intervention should be directed at preventing progression of kyphoscoliosis to the point of cardio-respiratory compromise, which may be life threatening.

Similarly, early recognition of some cardiac anomalies may allow prevention of secondary complications or prolongation of adequate function. Some individuals with CLS may require SBE (subacute bacterial endocarditis) prophylaxis.

Attention to vision and hearing may prevent some secondary behavioral changes. Identification and treatment of blepharitis may prevent eye rubbing and potential retinal damage.

Attention to dental hygiene and gum disease may reduce the risk of premature tooth loss.

Surveillance

The following are appropriate:

  • Periodic tests of hearing and vision
  • Annual physical cardiac examination, with echocardiogram by age ten years. Even if normal, the latter should be repeated every five to ten years in light of uncertainty as to the incidence and range in age of onset of cardiomyopathy [Massin et al 1999, Facher et al 2004].
  • Monitoring of the spine for the development of progressive kyphoscoliosis. There should be a high index of suspicion for narrowing of the spinal canal with attention to change in gait and bowel/bladder habits, expression of pain, and focal neurologic changes such as clonus or abnormal tendon reflexes.
  • Routine dental evaluation as in the general population but with particular attention to the risk of tooth loss

Note: A table containing suggested guidelines for follow-up of individuals with CLS is provided in Hunter [2010].

Agents/Circumstances to Avoid

Individuals with CLS who experience SIDAs should be protected as much as possible from being startled and/or from falls.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Significant social resources may be required to support families of women with CLS and developmental delay.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Coffin-Lowry syndrome (CLS) is inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 70%-80% of probands have no family history of CLS, and 20%-30% have more than one affected family member [Delaunoy et al 2001]. The high incidence of simplex cases (i.e., CLS in a single individual in a family) can be attributed to genetic selection that occurs against heterozygous females who are intellectually disabled [Jacquot et al 1998a].
  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • Mothers of a proband should be examined for signs of CLS such as coarse facial features, full lips, and/or tapering fingers.
  • If a pathogenic variant has been identified in the proband, it is reasonable to offer molecular genetic testing to the mother.

Sibs of a proband

  • The risk to the sibs of a proband depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%:
  • In the absence of any physical signs or intellectual impairment, the mother of a proband with no known family history of CLS is probably at low risk of being a carrier.
  • Germline mosaicism has been demonstrated in this condition. Thus, even if the pathogenic variant found in the proband has not been identified in the mother's DNA, sibs of the proband are still at increased risk of inheriting the pathogenic variant [Jacquot et al 1998b, Horn et al 2001].

Offspring of a proband

  • Males and severely affected females with CLS typically do not reproduce.
  • Women with CLS have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters will be carriers and at high risk for at least some degree of developmental delay and mild physical signs of CLS.

Other family members of a proband. If the mother of the proband is found to have a pathogenic variant, her female family members may be at risk of being carriers (asymptomatic or symptomatic); and her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing of at-risk female relatives requires prior identification of the pathogenic variant in the family.

Related Genetic Counseling Issues

Specific counseling issues

  • Significant social resources may be required to support developmentally delayed women with CLS and their families with respect to reproductive choices and child care.
  • Caution should be used in interpreting the results of molecular genetic testing of a mother of a male with no known family history of CLS (i.e., a simplex case) in whom a pathogenic variant has been identified. Germline mosaicism has been observed; thus, it is appropriate to offer prenatal testing to such women even when the pathogenic variant identified in an affected offspring is not detected in their DNA.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Coffin-Lowry Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
RPS6KA3Xp22​.12Ribosomal protein S6 kinase alpha-3RPS6KA3 @ LOVDRPS6KA3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Coffin-Lowry Syndrome (View All in OMIM)

300075RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3
303600COFFIN-LOWRY SYNDROME; CLS

Molecular Genetic Pathogenesis

RPS6KA3 (RSK2), the gene associated with CLS, encodes a growth factor-regulated serine/threonine kinase. Humans have four closely related RPS6KA (RSK) genes; each gene has two non-identical kinase catalytic domains, both of which are required for maximal activity [Yntema et al 1999, Yang et al 2004].

RPS6KA3 expression shows both temporal and spatial restriction in human embryogenesis, with homogeneous brain expression from the telencephalon to the rhombencephalon at nine weeks' gestation, with higher levels in the ventricular zone than in the cortical plate [Guimiot et al 2004].

Ribosomal protein S6 kinase alpha-3 (RPS6KA3), the protein encoded by RPS6KA3, is involved in kinase activation in a number of pathways including ras-MAPK, protein kinase C, and adenyl cyclase [Harum et al 2001 Pereira et al 2010]. Through the MAPK/RSK pathway and the epidermal growth factor (EGF)-stimulated phosphorylation of histone H3, it appears to play a role in stimulation of the cell cycle between G0 and G1. RPS6KA3 has also been shown to activate CREB (cAMP response element binding protein), which is involved in neuronal survival and conversion from short- to long-term memory [Harum et al 2001]. Cells from individuals with CLS have shown defective EGF-stimulated phosphorylation of S6, H3 [Sassone-Corsi et al 1999], and CREB [Harum et al 2001]; and one or more of these pathways may play a role in causing some of the manifestations of CLS.

Gene structure. The RPS6KA3 transcript NM_004586.2 comprises 22 exons; it is named for ribosomal S6 kinase (alternate name: RSK2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Some variants in RPS6KA3 that are not associated with a disease phenotype have been described [Delaunoy et al 2001; Abidi & Schwartz, unpublished].

Pathogenic allelic variants. Pathogenic variants in RPS6KA3 are distributed throughout the gene with no evidence of clustering associated with a specific phenotype.

In the largest study to date (250 individuals), 71 pathogenic variants were found in 86 unrelated families. Almost 60% caused or predicted protein truncation; 38% were missense, 20% nonsense, 18% errors of splicing, and 21% intragenic deletions or insertions [Delaunoy et al 2001].

A smaller study of 106 unrelated individuals with suspected CLS found 28 pathogenic variants (26%). Of the 28 pathogenic variants, 60% caused or predicted protein truncation; 36% were missense, 21% nonsense, 11% errors of splicing, and 32% intragenic deletions or insertions [Abidi & Schwartz, unpublished].

Pathogenic variants of intronic alterations resulting in aberrant splicing and an intronic insertion of a LINE-1 element that disrupts the normal function of the protein have been reported [Zeniou et al 2002a, Martinez-Garay et al 2003, Zeniou et al 2004]. (For more information, see Table A.)

Recently, Schneider et al [2013] have identified a deep intronic pathogenic variant which results in an aberrant protein. This finding warrants mutation analysis at the RNA level in all patients with a highly suggestive clinical diagnosis of CLS and in whom exon screening has failed to detect a pathogenic variant.

Presence of full- and partial-gene duplications has been reported. Matsumoto et al [2013] report a microduplication including the entire RPS6KA3 in a family with mild ID, ADHD, localization-related epilepsy, and pervasive developmental disorder (PDD). Marques Pereira et al [2007] report in-frame tandem multiexonic duplication within RPS6KA3 in an individual with Coffin-Lowry syndrome, and noting the high frequency of Alu sequences within the gene, they suggest that these may be relatively common events. However, such studies have yet to be performed.

Normal gene product. Ribosomal protein S6 kinase alpha-3 (RPS6KA3) is a serine/threonine kinase and a member of the Ras signaling cascade. The protein is phosphorylated by MAPK kinases in response to growth factors, insulin, and oncogenic transformations. Members of the RSK family participate in cellular events such as proliferation and differentiation. The fact that a pathogenic variant in RPS6KA3 can result in nonsyndromic XLMR (MRX19; see Genetically Related Disorders) as well as CLS indicates that the gene is critical for some cognitive functions of the brain. RSK2 regulates neurite formation by phosphorylating phospholipase D1 (PLD1) [Ammar et al 2013]. Also, RSK2 mediated activation of PLD1 produces the lipids required for exocytosis [Zeniou-Meyer et al 2008, Zeniou-Meyer et al 2009] and regulates the release of neurotransmitters [Zeniou-Meyer et al 2010].

RSK2 also plays an important role in maintaining genomic stability by mediating cell cycle progression and DNA repair [Lim et al 2013].

Abnormal gene product. Pathogenic variants in RPS6KA3 give rise to both CLS and nonsyndromic XLMR. The pathogenic variants in individuals with CLS result in the loss of kinase activity of the gene product. However, the pathogenic variant associated with MRX19 occurs outside the two kinase domains of the gene and results in a reduction to 80% RPS6KA3 activity, suggesting that the brain is more sensitive to levels of RPS6KA3 activity than are the other organ systems affected in CLS.

References

Literature Cited

  1. Ammar MR, Humeau Y, Hanauer A, Nieswandt B, Bader MF, Vitale N. The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid. J Neurosci. 2013;33:19470–9. [PubMed: 24336713]
  2. Coffin GS. Postmortem findings in the Coffin-Lowry Syndrome. Genet Med. 2003;5:187–93. [PubMed: 12792428]
  3. Crow YJ, Zuberi SM, McWilliam R, Tolmie JL, Hollman A, Pohl K, Stephenson JB. "Cataplexy" and muscle ultrasound abnormalities in Coffin-Lowry syndrome. J Med Genet. 1998;35:94–8. [PMC free article: PMC1051210] [PubMed: 9507386]
  4. Delaunoy J, Abidi F, Zeniou M, Jacquot S, Merienne K, Pannetier S, Schmitt M, Schwartz C, Hanauer A. Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin- Lowry syndrome. Hum Mutat. 2001;17:103–16. [PubMed: 11180593]
  5. Facher JJ, Regier EJ, Jacobs GH, Siwik E, Delaunoy JP, Robin NH. Cardiomyopathy in Coffin-Lowry syndrome. Am J Med Genet A. 2004;128A:176–8. [PubMed: 15214012]
  6. Field M, Tarpey P, Boyle J, Edkins S, Goodship J, Luo Y, Moon J, Teague J, Stratton MR, Futreal PA, Wooster R, Raymond FL, Turner G. Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. Clin Genet. 2006;70:509–15. [PMC free article: PMC2714973] [PubMed: 17100996]
  7. Fryssira H, Kountoupi S, Delaunoy JP, Thomaidis L. A female with Coffin-Lowry syndrome and "cataplexy". Genet Couns. 2002;13:405–9. [PubMed: 12558110]
  8. Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rogers C, Corning K, Schwartz CE. FG syndrome: report of three new families with linkage to Xq12-q22.1. Am J Med Genet. 1998;80:145–56. [PubMed: 9805132]
  9. Guimiot F, Delezoide AL, Hanauer A, Simonneau M. Expression of the RSK2 gene during early human development. Gene Expr Patterns. 2004;4:111–4. [PubMed: 14678837]
  10. Hanauer A, Young ID. Coffin-Lowry syndrome: clinical and molecular features. J Med Genet. 2002;39:705–13. [PMC free article: PMC1734994] [PubMed: 12362025]
  11. Hahn JS, Hanauer A. Stimulus-induced drop episodes in Coffin-Lowry syndrome. Eur J Med Genet. 2012;55:335–7. [PubMed: 22490425]
  12. Harum KH, Alemi L, Johnston MV. Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation. Neurology. 2001;56:207–14. [PubMed: 11160957]
  13. Havaligi N, Matadeen-Ali C, Khurana DS, Marks H, Kothare SV. Treatment of drop attacks in Coffin-Lowry syndrome with the use of sodium oxybate. Pediatr Neurol. 2007;37:373–4. [PubMed: 17950427]
  14. Herrera-Soto JA, Santiago-Cornier A, Segal LS, Ramirez N, Tamai J. The musculoskeletal manifestations of the Coffin-Lowry syndrome. J Pediatr Orthop. 2007;27:85–9. [PubMed: 17195803]
  15. Horn D, Delaunoy JP, Kunze J. Prenatal diagnosis in Coffin-Lowry syndrome demonstrates germinal mosaicism confirmed by mutation analysis. Prenat Diagn. 2001;21:881–4. [PubMed: 11746134]
  16. Hunter AG. Coffin-Lowry syndrome. In: Cassidy S, Allanson J, eds. Management of Genetic Syndromes. 3 ed. Hoboken, NJ: Wiley-Liss; 2010:127-38.
  17. Hunter AG. Coffin-Lowry syndrome: a 20-year follow-up and review of long-term outcomes. Am J Med Genet. 2002;111:345–55. [PubMed: 12210291]
  18. Jacquot S, Merienne K, De Cesare D, Pannetier S, Mandel JL, Sassone-Corsi P, Hanauer A. Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Hum Genet. 1998a;63:1631–40. [PMC free article: PMC1377634] [PubMed: 9837815]
  19. Jacquot S, Merienne K, Pannetier S, Blumenfeld S, Schinzel A, Hanauer A. Germline mosaicism in Coffin-Lowry syndrome. Eur J Hum Genet. 1998b;6:578–82. [PubMed: 9887375]
  20. Kesler SR, Simensen RJ, Voeller K, Abidi F, Stevenson RE, Schwartz CE, Reiss AL. Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin-Lowry syndrome. Neurogenetics. 2007;8:143–7. [PMC free article: PMC3055244] [PubMed: 17318637]
  21. Kondoh T, Matsumoto T, Ochi M, Sukegawa K, Tsuji Y. New radiological finding by magnetic resonance imaging examination of the brain in Coffin-Lowry syndrome. J Hum Genet. 1998;43:59–61. [PubMed: 9610000]
  22. Lim HC, Xie L, Zhang W, Li R, Chen ZC, Wu GZ, Cui SS, Tan EK, Zeng L. Ribosomal S6 Kinase 2 (RSK2) maintains genomic stability by activating the Atm/p53-dependent DNA damage pathway. PLoS One. 2013;8:e74334. [PMC free article: PMC3781089] [PubMed: 24086335]
  23. Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, Lampe AK, Clayton-Smith J, Stewart H, van Ravenswaay CM, de Vries BB, Cox B, Grompe M, Ross S, Thomas P, Mulley JC, Gecz J. Mutations in PHF6 are associated with Borjeson-Forssman-Lehmann syndrome. Nat Genet. 2002;32:661–5. [PubMed: 12415272]
  24. Lowry B, Miller JR, Fraser FC. A new dominant gene mental retardation syndrome. Association with small stature, tapering fingers, characteristic facies, and possible hydrocephalus. Am J Dis Child. 1971;121:496–500. [PubMed: 5581017]
  25. Manouvrier-Hanu S, Amiel J, Jacquot S, Merienne K, Moerman A, Coeslier A, Labarriere F, Vallee L, Croquette MF, Hanauer A. Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome. J Med Genet. 1999;36:775–8. [PMC free article: PMC1734232] [PubMed: 10528858]
  26. Marques Pereira P, Heron D, Hanauer A. The first large duplication of the RSK2 gene identified in a Coffin-Lowry syndrome patient. Hum Genet. 2007;122:541–3. [PubMed: 17717706]
  27. Martinez-Garay I, Ballesta MJ, Oltra S, Orellana C, Palomeque A, Molto MD, Prieto F, Martinez F. Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin-Lowry syndrome. Clin Genet. 2003;64:491–6. [PubMed: 14986828]
  28. Martinez HR, Niu MC, Sutton VR, Pignatelli R, Vatta M, Jefferies JL. Coffin-Lowry syndrome and left ventricular noncompaction cardiomyopathy with a restrictive pattern. Am J Med Genet A. 2011;155A:3030–4. [PubMed: 22009732]
  29. Massin MM, Radermecker MA, Verloes A, Jacquot S, Grenade T. Cardiac involvement in Coffin-Lowry syndrome. Acta Paediatr. 1999;88:468–70. [PubMed: 10342551]
  30. Matsumoto A, Kuwajima M, Miyake K, Kojima K, Nakashima N, Jimbo EF, Kubota T, Momoi MY, Yamagata T. An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities. J Hum Genet. 2013;58:755–7. [PubMed: 23985797]
  31. McCandless SE, Schwartz S, Morrison S, Garlapati K, Robin NH. Adult with an interstitial deletion of chromosome 10 [del(10)(q25. 1q25.3)]: overlap with Coffin-Lowry syndrome. Am J Med Genet. 2000;95:93–8. [PubMed: 11078556]
  32. Merienne K, Jacquot S, Pannetier S, Zeniou M, Bankier A, Gecz J, Mandel JL, Mulley J, Sassone-Corsi P, Hanauer A. A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation. Nat Genet. 1999;22:13–4. [PubMed: 10319851]
  33. Merienne K, Jacquot S, Trivier E, Pannetier S, Rossi A, Scott C, Schinzel A, Castellan C, Kress W, Hanauer A. Rapid immunoblot and kinase assay tests for a syndromal form of X-linked mental retardation: Coffin-Lowry syndrome. J Med Genet. 1998;35:890–4. [PMC free article: PMC1051479] [PubMed: 9832033]
  34. Micheli V, Sestini S, Parri V, Fichera M, Romano C, Ariani F, Longo I, Mari F, Bruttini M, Renieri A, Meloni I. RSK2 enzymatic assay as a second level diagnostic tool in Coffin-Lowry syndrome. Clin Chim Acta. 2007;384:35–40. [PubMed: 17586481]
  35. Nakamura M, Yamagata T, Momoi MY, Yamazaki T. Drop episodes in Coffin-Lowry syndrome: exaggerated startle responses treated with clonazepam. Pediatr Neurol. 1998;19:148–50. [PubMed: 9744638]
  36. Nakamura M, Yamagata T, Mori M, Momoi MY. RSK2 gene mutations in Coffin-Lowry syndrome with drop episodes. Brain Dev. 2005;27:114–7. [PubMed: 15668050]
  37. Nelson GB, Hahn JS. Stimulus-induced drop episodes in Coffin-Lowry syndrome. Pediatrics. 2003;111:e197–202. [PubMed: 12612271]
  38. O'Riordan S, Patton M, Schon F. Treatment of drop episodes in Coffin-Lowry syndrome. J Neurol. 2006;253:109–10. [PubMed: 16021355]
  39. Patlas M, Joseph A, Cohen JE, Gomori JM. MRI and MRS of Coffin-Lowry syndrome: a case report. Neurol Res. 2003;25:285–6. [PubMed: 12739239]
  40. Pereira PM, Schneider A, Pannetier S, Heron D, Hanauer A. Coffin-Lowry syndrome. Eur J Hum Genet. 2010;18:627–33. [PMC free article: PMC2987346] [PubMed: 19888300]
  41. Rojnueangnit K, Jones JR, Basehore MJ, Robin NH. Classic phenotype of Coffin-Lowry syndrome in a female with stimulus-induced drop episodes and a genotype with preserved N-terminal kinase domain. Am J Med Genet A. 2014;164A:516–21. [PubMed: 24311527]
  42. Rosanowski F, Hoppe U, Proschel U, Eysholdt U. Late-onset sensorineural hearing loss in Coffin-Lowry syndrome. ORL J Otorhinolaryngol Relat Spec. 1998;60:224–6. [PubMed: 9646311]
  43. Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science. 1999;285:886–91. [PubMed: 10436156]
  44. Schneider A, Maas SM, Hennekam RC, Hanauer A. Identification of the first deep intronic mutation in the RPS6KA3 gene in a patient with a severe form of Coffin-Lowry syndrome. Eur J Med Genet. 2013;56:150–2. [PubMed: 23261961]
  45. Simensen RJ, Abidi F, Collins JS, Schwartz CE, Stevenson RE. Cognitive function in Coffin-Lowry syndrome. Clin Genet. 2002;61:299–304. [PubMed: 12030896]
  46. Stephenson JB, Hoffman MC, Russell AJ, Falconer J, Beach RC, Tolmie JL, McWilliam RC, Zuberi SM. The movement disorders of Coffin-Lowry syndrome. Brain Dev. 2005;27:108–13. [PubMed: 15668049]
  47. Touraine R-L, Zeniou M, Hanauer A. A syndromic form of X-linked mental retardation: the Coffin-Lowry syndrome. Eur J Pediatr. 2002;161:179–87. [PubMed: 12014383]
  48. Valdovinos MG, Napolitano DA, Zarcone JR, Hellings JA, Williams DC, Schroeder SR. Multimodal evaluation of risperidone for destructive behavior: functional analysis, direct observations, rating scales, and psychiatric impressions. Exp Clin Psychopharmacol. 2002;10:268–75. [PubMed: 12233987]
  49. Wang Y, Martinez JE, Wilson GL, He XY, Tuck-Muller CM, Maertens P, Wertelecki W, Chen TJ. A novel RSK2 (RPS6KA3) gene mutation associated with abnormal brain MRI findings in a family with Coffin-Lowry syndrome. Am J Med Genet A. 2006;140:1274–9. [PubMed: 16691578]
  50. Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004;117:387–98. [PubMed: 15109498]
  51. Yntema HG, van den Helm B, Kissing J, van Duijnhoven G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel BC, Heilbronner H, Pander HJ, Brunner HG, Ropers HH, Cremers FP, van Bokhoven H. A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics. 1999;62:332–43. [PubMed: 10644430]
  52. Zeniou M, Ding T, Trivier E, Hanauer A. Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet. 2002a;11:2929–40. [PubMed: 12393804]
  53. Zeniou M, Gattoni R, Hanauer A, Stevenin J. Delineation of the mechanisms of aberrant splicing caused by two unusual intronic mutations in the RSK2 gene involved in Coffin-Lowry syndrome. Nucleic Acids Res. 2004;32:1214–23. [PMC free article: PMC373406] [PubMed: 14973203]
  54. Zeniou M, Pannetier S, Fryns JP, Hanauer A. Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome. Am J Hum Genet. 2002b;70:1421–33. [PMC free article: PMC379129] [PubMed: 11992250]
  55. Zeniou-Meyer M, Liu Y, Béglé A, Olanich ME, Hanauer A, Becherer U, Rettig J, Bader MF, Vitale N. The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1. Proc Natl Acad Sci U S A. 2008;105:8434–9. [PMC free article: PMC2448854] [PubMed: 18550821]
  56. Zeniou-Meyer M, Béglé A, Bader MF, Vitale N. The Coffin-Lowry syndrome-associated protein RSK2 controls neuroendocrine secretion through the regulation of phospholipase D1 at the exocytotic sites. Ann N Y Acad Sci. 2009;1152:201–8. [PubMed: 19161391]
  57. Zeniou-Meyer M, Gambino F, Ammar MR, Humeau Y, Vitale N. The Coffin-Lowry syndrome-associated protein RSK2 and neurosecretion. Cell Mol Neurobiol. 2010;30:1401–6. [PubMed: 21061166]

Chapter Notes

Author History

Fatima E Abidi, PhD (2002-present)
R Curtis Rogers, MD (2014-present)
Alisdair GW Hunter, MD; University of Ottawa (2002-2014)
Charles E Schwartz, PhD; Greenwood Genetics Center (2002-2009)

Revision History

  • 27 March 2014 (me) Comprehensive update posted live
  • 15 January 2009 (me) Comprehensive update posted live
  • 6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
  • 31 August 2006 (me) Comprehensive update posted to live Web site
  • 27 December 2004 (cd) Revision: change in molecular genetic testing availability
  • 28 June 2004 (me) Comprehensive update posted to live Web site
  • 16 July 2002 (me) Review posted to live Web site
  • 24 January 2002 (ah) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1346PMID: 20301520
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...