Coffin-Lowry Syndrome

Clinical Diagnosis

Affected Males

Figure 1. AP view of two-year-old boy with CLS showing (more...)

Figure 1. AP view of two-year-old boy with CLS showing relatively fine facial features but with ocular hypertelorism, mildly downslanting palpebrae, short nose with wide columella and full, slightly everted lips. (Patient has a known RPS6KA3 mutation.)

Figure 2 A&B. AP and lateral view of the same (more...)

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. (Patient has a known RPS6KA3 mutation.)

Figure 3. AP view of an adolescent showing relatively (more...)

Figure 3. AP view of an adolescent showing relatively mild facial signs but with ocular hypertelorism, mildly downslanting palpebrae, full lips, and small teeth. The columnella is thick but nares are a good size, perhaps reflecting an interracial difference in disease expression. (Patient has a known RPS6KA3 mutation.)

Figure 4 A&B. Hand of the child illustrated (more...)

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

Figure 5 A & B
A. Hand of an older (more...)

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.
(Patients have a known RPS6KA3 mutation.)

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

• Development. Affected males typically are moderately to severely retarded; with the advent of molecular genetic testing more mildly affected males are now being identified [Field et al 2006].

• Craniofacial. In the affected older male child or adult, the facial appearance is characteristic (see Figures 1, 2, and 3):

  • Usually prominent forehead and eyebrows; full supraorbital ridges

  • Usually marked ocular hypertelorism with downslanting palpebrae; occasionally, relatively normal periorbital region with mild telecanthus

  • Consistent, often striking, nasal findings including low bridge, blunt tip, and thick alae nasi and septum, resulting in small nares

  • Large mouth, usually held open; patulous lips with everted lower lip

  • Thickened appearance in childhood, often coarsening 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.)

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 mutation. Such testing is available on a research basis only [Merienne et al 1998, Delaunoy et al 2001, Zeniou et al 2002a].
  
  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].

• Micheli et al [2007] have refined the approach using CREB-peptide as substrate and have successfully tested a male and two clinically affected females. Such testing is available on a research basis only.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. RPS6KA3 (also known as RSK2) is the only gene known to be associated with CLS.

Other loci. It has been suggested that not all individuals with a clinical picture thought to be consistent with CLS have mutations in the RPS6KA3 gene [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 suggest a second Coffin-Lowry syndrome locus.

Genes thought to interact in the RPS6KA3 pathway have been analyzed in affected individuals who did not have mutations identified in RPS6KA3, and some coding changes have been found [CE Schwartz, personal communication]; however, the significance of these mutations is not yet demonstrated as clinical data and photographs are not yet available for those who were studied. Thus, it is not known how well these individuals fit with the phenotype of Coffin-Lowry syndrome.

Clinical testing

• Sequence analysis. Although sequence analysis is available on a clinical basis, no studies have reported the mutation detection rate using this method. The data available on mutation detection rate are from studies using mutation scanning (currently available on a research basis only); it is expected that complete bidirectional sequencing of all exons and the intron-exon boundaries of RPS6KA3 would be at least as sensitive as the methods used in the following two mutation scanning studies:

  • In a study including more than 250 individuals with the clinical features of CLS, single-strand conformation polymorphism analysis (SSCP), combined in one study with cell function assays, identified mutations in approximately 37% of individuals [Jacquot et al 1998a, Delaunoy et al 2001, Zeniou et al 2002b].

  • In 106 unrelated individuals with CLS, mutations were identified in 26% [Abidi & Schwartz, unpublished]. In this study, one splice site mutation was found by bidirectional sequencing that was initially missed by mutation scanning using SSCP. Of note, almost all of the mutations found in this group were found in the first half of the study, lending support to the view that the low overall detection rate may reflect a lowered clinical threshold for testing.

• Deletion/duplication analysis. In affected males, sequencing of the exons of RPS6KA3 can detect intragenic deletions but will fail to identify any duplications, whereas neither deletions nor duplications are detected readily by exonic sequencing in carrier females. Marques Pereira et al [2007] have reported the first instance of an in-frame tandem multiexonic duplication within the RPS6KA3 gene 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. Several cases of RPS6KA3 exonic and multiexonic deletions have been described (see Table A: locus-specific databases and HGMD).

Table 1 summarizes molecular genetic testing for this disorder.

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

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method		Test Availability
			Affected Males	Carrier Females 1
RPS6KA3	Sequence analysis	Sequence variants	~90%-95% 2	~90%-95% 2	Clinical
		Partial- and whole-gene deletions		0% 3
	Deletion/duplication testing 4	Partial- and whole-gene deletions and duplications	Unknown 3	Unknown 5

1. 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.

2. The authors’ unpublished experience is that the detection rate is significantly higher (~90%-95%) in cases that are clinically typical.

3. Sequence analysis can detect putative exonic, multiexonic, and whole gene deletions on the X chromosome in affected males due to lack of amplification by PCR; confirmation may require deletion analysis. Sequence analysis cannot detect exonic, multiexonic, and whole gene duplications in affected males.

4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array CGH (see ) may be used.

5. 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.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband

• In an affected male, bidirectional sequencing of the 22 exons of RPS6KA3 should detect any mutation present in the coding region or at the intron/exon boundaries.

• Deletion/duplication analysis can be considered in affected females in whom a mutation is not identified by sequence analysis.

• 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 mutation is found by sequence analysis; this test is not useful in females.

Identification of female carriers requires either (1) prior identification of the disease-causing mutation in the family or (2) if an affected male is not available for testing, molecular genetic testing (a) first by sequence analysis and, if no mutation is identified, (b) by methods to detect exonic, multiexonic, or whole gene deletions.

Note: Carriers are heterozygotes for this X-linked disorder and may have clinical findings related to the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Nonsyndromic mental retardation. Two sibs with mild expression of CLS were reported to have missense mutations in RPS6KA3 [Manouvrier-Hanu et al 1999]; similar families have now been reported by Fields et al [2006].

One form of nonsyndromic mental retardation (MRX19) has been shown to be caused by an RPS6KA3 missense mutation [Merienne et al 1999]; another individual with a missense mutation and only mild mental retardation was reported by Delaunoy et al [2001]. The advent of molecular genetic diagnosis may aid in confirming the diagnosis of additional mild cases.

Natural History

Development. Coffin-Lowry syndrome (CLS) is characterized by severe-to- profound mental retardation in males; intellect ranges from normal to profoundly retarded 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 mental retardation 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 retardation. The authors are aware of a patient with a proven RPS6KA3 mutation 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 mental retardation. 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]. 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.

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 eight '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. 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 some mild ventricular asymmetry. The authors concluded that the degree of mental retardation 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 mutation, individuals with certain missense mutations may tend to have milder disease expression [Delaunoy et al 2001]. The family classified as having a form of nonsyndromic mental retardation (MRX19; see Genetically Related Disorders) had a missense mutation in RPS6KA3, which caused an 80% reduction in ribosomal S6 kinase enzyme activity, in contrast to most mutations in individuals with CLS that cause a total loss of ribosomal S6 kinase enzyme activity [Merienne et al 1999]. This finding indicates that some RPS6KA3 mutations probably give rise to non-CLS phenotypes or nonsyndromic X-linked mental retardation.

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.

Clinical data on a series of RPS6KA3 mutation-positive and mutation-negative individuals suggest that the presence of certain clinical signs, such as the fleshy, tapering fingers, ocular hypertelorism, and downslanting palpebrae, may help distinguish the RPS6KA3-positive group [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.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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 [Nakamura et al 2005, Touraine et al 2002].

  • 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 [2005].

Agents/Circumstances to Avoid

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

Testing 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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 mentally retarded [Jacquot et al 1998a].

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• 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 disease-causing gene mutation 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 disease-causing mutation, the chance of transmitting it in each pregnancy is 50%:

  • Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and at high risk for at least some developmental delay and mild physical signs of CLS.

  • As expected with random X-chromosome inactivation (lyonization), a mildly affected woman may have a severely affected daughter.

  • Female carriers show mild-to-moderate skewing of X-chromosome inactivation that does not correlate with IQ [Simensen et al 2002].

• In the absence of any physical signs or mental 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 disease-causing mutation 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 disease-causing mutation [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 disease-causing mutation to each child; sons who inherit the mutation 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 disease-causing mutation, 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 is possible if the mutation has been identified 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 disease-causing mutation has been identified. Germline mosaicism has been observed; thus, it is appropriate to offer prenatal testing to such women even when the mutation 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 adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

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]. 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.

Normal allelic variants. The gene, comprising 22 exons, is named RPS6KA3 for ribosomal S6 kinase (alternate name: RSK2). Some normal allelic variants in RPS6KA3 that are not associated with a disease phenotype have been found [Delaunoy et al 2001; Abidi & Schwartz, unpublished].

Pathologic allelic variants. Mutations 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 mutations 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 CLS found 28 mutations (26%). Of the 28 mutations, 60% caused or predicted protein truncation; 36% were missense, 21% nonsense, 11% errors of splicing, and 32% intragenic deletions or insertions [Abidi & Schwartz, unpublished].

Disease-causing mutations of intronic missense alterations resulting in aberrant splicing and an intronic insertion of a truncated LINE-1 element have been reported [Zeniou et al 2002a, Martinez-Garay et al 2003, Zeniou et al 2004]. (For more information, see Table A: locus-specific databases and HGMD.)

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 MARK 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 mutation 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.

Abnormal gene product. Mutations in the RPS6KA3 gene give rise to both CLS and nonsyndromic XLMR. The mutations in individuals with CLS result in the loss of kinase activity of the gene product. However, the mutation 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.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Author History

Fatima E Abidi, PhD (2002-present)
Alisdair GW Hunter, MD (2002-present)
Charles E Schwartz, PhD; Greenwood Genetics Center (2002-2009)

Revision History

• 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