Coffin-Lowry syndrome is a rare form of X-linked mental retardation characterized by skeletal malformations, growth retardation, hearing deficit, paroxysmal movement disorders, and cognitive impairment in affected males and some carrier females (Kesler et al., 2007).
Hendrich ... Coffin-Lowry syndrome is a rare form of X-linked mental retardation characterized by skeletal malformations, growth retardation, hearing deficit, paroxysmal movement disorders, and cognitive impairment in affected males and some carrier females (Kesler et al., 2007). Hendrich and Bickmore (2001) reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome. Marques Pereira et al. (2010) provided a review of Coffin-Lowry syndrome. Mutation in the RPS6KA3 gene can also cause nonsyndromic X-linked mental retardation-19 (MRX19; 300844), a milder disorder without skeletal anomalies.
Merienne et al. (1998) evaluated both immunoblot and RSK2 kinase assays as diagnostic tests for Coffin-Lowry syndrome using cultured lymphoblastoid or fibroblast cell lines. Western blot analysis failed to detect RSK2 protein in 6 patients, suggesting the presence ... Merienne et al. (1998) evaluated both immunoblot and RSK2 kinase assays as diagnostic tests for Coffin-Lowry syndrome using cultured lymphoblastoid or fibroblast cell lines. Western blot analysis failed to detect RSK2 protein in 6 patients, suggesting the presence of truncated proteins. This conclusion was confirmed in 4 patients, in whom the causative mutations, all leading to premature termination of translation, were identified. Of 4 patients showing normal amounts of RSK2 protein on Western blot and tested for RSK2 phosphotransferase activity, 1 had impaired activity. Analysis of RSK2 cDNA sequence in this patient showed a mutation of a putative phosphorylation site that would be critical for RSK2 activity. Merienne et al. (1998) concluded that both assays were reliable and rapid methods for diagnosis of Coffin-Lowry syndrome, and that, at least, the Western blot analysis could be used directly on lymphocyte protein extracted directly from blood samples.
As described by Coffin et al. (1966) in 2 unrelated adolescent boys, the features of CLS are mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by x-ray, and pectus carinatum. The occurrence of ... As described by Coffin et al. (1966) in 2 unrelated adolescent boys, the features of CLS are mental retardation with peculiar pugilistic nose, large ears, tapered fingers, drumstick terminal phalanges by x-ray, and pectus carinatum. The occurrence of minor manifestations in female relatives suggested a genetic basis. Procopis and Turner (1972) reported a family in which 4 brothers had the full syndrome and several female relatives had abnormal fingers and mild mental retardation. X-linked dominant inheritance was likely. Lowry et al. (1971) described a new mental retardation syndrome with small stature, retardation of bone age, hypotonia, tapering fingers, and facies characterized by hypertelorism, anteverted nares, and prominent frontal region. Arrested hydrocephalus may also be a feature. The disorder was transmitted through 3 generations, with no instance of male-to-male transmission. Temtamy et al. (1975) deserve credit for demonstrating that the syndromes described by Coffin and Lowry as separate entities are in fact the same, a rare experience in medical genetics where separation of entities with similar phenotype is much more frequent. The appearance of the hands with bulbous tapering fingers was striking in their family. Affected males showed patulous lips and large mouths. Kenyon (reported by Temtamy et al., 1975) found electron microscopic changes in fibroblasts, viz., single-membrane-limited inclusions. At least superficial similarity of the facies to that of Williams syndrome (194050) is evident in the photographs published by Hunter et al. (1982). Hunter et al. (1982) found no evidence of a primary disorder of lysosomes in their patients. Hersh et al. (1984) were impressed with marked fullness of the forearms as an early sign of Coffin-Lowry syndrome. The bones were normal, the fullness being due to increased subcutaneous fat. They also illustrated broad proximal part of the fingers with distal tapering in both affected males and heterozygotes. The hands in the infants have a puffy appearance. Young (1988) pictured the facial features of 2 pairs of brothers and a pair of sisters with this disorder. One of the brothers had severe kyphoscoliosis. Vine et al. (1986) cited evidence that there is proteodermatan sulfate storage in CLS. They further suggested that weakness in this disorder is neurogenic rather than myopathic in origin, consistent with a lysosomal storage disease. Gilgenkrantz et al. (1988) described in detail 7 families from 5 European centers. Machin et al. (1987) reported the pathologic findings in a sister and brother who died at ages 28 and 22, respectively. Visceral neuropathy was found as the basis of extensive intestinal diverticular disease. Mitral regurgitation, resulting from fused and shortened chordae tendineae, and panacinar emphysema were also found. Massin et al. (1999) described recurrent episodes of congestive heart failure from at least the age of 8 years in a boy with Coffin-Lowry syndrome. Surgical repair was performed on the mitral valves. Miyazaki et al. (1990) described calcification of the ligamenta flava which led to marked narrowing of the cervical spinal canal with resulting cervical radiculomyelopathy. Biochemical analyses suggested that an alteration in glycosaminoglycan metabolism was a pathogenetic factor in calcification of ligamenta flava. In 3 males in their twenties who had Coffin-Lowry syndrome, Ishida et al. (1992) observed myelopathy caused by calcification of the ligamentum flavum as a result of calcium pyrophosphate dihydrate crystal deposition disease (118600). This was interpreted as further evidence that a metabolic abnormality in collagen and in proteoglycans is present in CLS. They emphasized and illustrated the peculiar stooped posture and striking cervical lordosis in these cases as well as the changes in the fingers and the thick lips. Hartsfield et al. (1993) reported on 7 patients with CLS who had sensorineural hearing deficit. One of the patients also had premature exfoliation of primary teeth. Sivagamasundari et al. (1994) presented 3-generation pedigrees that segregated Coffin-Lowry syndrome with 2 mildly affected females and 3 severely affected males. Both mildly affected females had depressive psychosis and all 3 severely affected males had sensorineural deafness. The authors wondered if the depressive psychosis was coincidental or related. They referred to 2 previous reports of depressive psychosis in 2 other females in Coffin-Lowry pedigrees reported by Partington et al. (1988) and Haspeslagh et al. (1984). Nakamura et al. (1998) described a 16-year-old girl with fully manifested CLS and drop episodes. The patient experienced instantaneous loss of muscle tone in her legs as a result of sudden unexpected tactile or auditory stimuli. This may represent an unusual type of startle response associated with CLS. Hunter (2002) provided a 20-year follow-up of the 6 affected patients with Coffin-Lowry syndrome and 1 carrier mother reported by Hunter et al. (1982). Hunter (2002) also summarized the clinically important complications that have been reported in patients with Coffin-Lowry syndrome: premature death, often from cardiovascular complications; progressive kyphoscoliosis which may compromise mobility and cardiorespiratory status; spinal stenosis, which may cause neurologic symptoms; and drop attacks, which may be mistaken for seizures. Abnormalities in dentition, hearing loss, and ocular abnormalities were noted, as was a suggested excess of psychiatric illness in carrier females. Simensen et al. (2002) studied cognitive function in affected members of 2 African American families in which CLS was caused by a 340C-T transition in the RSK2 gene (300075.0006). The subjects included 6 affected males, 7 carrier females, 3 normal males, and 3 noncarrier (normal) females. Unaffected family members served as contrast/comparison cohorts to control for socioeconomic, sociocultural, and genetic variables that might impinge on intellectual abilities. The mean composite IQs of the cohorts were 90.8, 65.0, and 43.2 for normal, carrier, and affected individuals, respectively. Fryssira et al. (2002) described a female patient with full-blown CLS, manifested by facial dysmorphism, tapering fingers, and skeletal deformities (pectus excavatum and kyphoscoliosis), who was found to have a splice site mutation of the RSK2 gene (300075.0015). Her overall IQ was 53. At the age of 9 years, there was onset of a cataplexy-like phenomenon characterized by a sudden and reversible loss of muscle tone without loss of consciousness. Cataplexy was described in CLS by Fryns and Smeets (1998). Facher et al. (2004) described a 14-year-old boy with physical and developmental findings consistent with Coffin-Lowry syndrome in whom they identified a 3-bp deletion at nucleotide 1428 of the RSK2 gene (300075.0018). The patient was unusual in that he presented with a relatively sudden onset of signs of congestive heart failure due to a restrictive cardiomyopathy; endomyocardial biopsy demonstrated nonspecific hypertrophic myocyte alterations consistent with cardiomyopathy. The authors stated that this was the first documented case of restrictive cardiomyopathy in Coffin-Lowry syndrome. Wang et al. (2006) reported a woman with CLS who had 2 affected daughters and 1 affected son. All had moderate to severe mental retardation with the typical CLS phenotype. Brain MRI studies on the 3 children showed abnormalities in the deep subcortical white matter, thinning of the corpus callosum, hypoplastic cerebellar vermis, and asymmetry of the lateral ventricles. The degree of severity of the MRI findings correlated with the severity of mental retardation. Kesler et al. (2007) examined brain morphology in 2 families with CLS. One family included a 32-year-old carrier mother and her 2 affected sons aged 9 and 11 years; the second family included 7-year-old carrier female twins and a 4-year-old affected male. All individuals with CLS demonstrated significantly decreased total brain volumes compared to age-matched controls. The most affected areas were the temporal lobe, cerebellum, and hippocampus, with individuals having either disproportionately enlarged or reduced volumes of these regions. Kesler et al. (2007) interpreted the findings as evidence of altered early neurodevelopment and disruptions in neuronal organization and plasticity in patients with CLS. - Clinical Variability Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of CLS who had a missense mutation in exon 7 of the RSK gene (300075.0011). The phenotype was unusual in that the degree of mental retardation and other features was milder than had been reported. Both boys had hypotonia, macrocephaly, telecanthus, and broad great toes; in addition, one boy had pigmentary abnormalities, and the other had an anteriorly placed anus. In light of these findings, the diagnosis of FG syndrome (305450) was considered. As the boys grew, macrocephaly decreased, forearm fullness and tapering fingers were more obvious, and the facies coarsened with anteverted nares and everted lower lip, leading to the consideration of the diagnosis of CLS. This diagnosis was confirmed by mutation analysis.
The level of residual RPS6KA3 activity seems to be related to the severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20% residual enzymatic activity in patients with nonsyndromic X-linked mental retardation (MRX19; 300844), which was ... The level of residual RPS6KA3 activity seems to be related to the severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20% residual enzymatic activity in patients with nonsyndromic X-linked mental retardation (MRX19; 300844), which was postulated to result in the relatively mild phenotype without skeletal anomalies (300075.0010). The patients reported by Field et al. (2006) with nonsyndromic X-linked mental retardation also had a milder phenotype, which they thought likely resulted from residual protein activity. Field et al. (2006) noted that the mutations (see, e.g., 300075.0020-300075.0021) in their report and the mutation (300075.0011) reported by Manouvrier-Hanu et al. (1999) in a family with mild Coffin-Lowry syndrome were small in-frame deletions or missense mutations affecting the serine/threonine kinase domain. Field et al. (2006) hypothesized that the presence of a small amount of residual enzymatic activity may be sufficient to maintain normal osteoblast differentiation and ameliorate the skeletal phenotype associated with CLS.
Trivier et al. (1996) demonstrated deletion, nonsense, and missense mutations of the RSK2 gene in patients with CLS. The gene is located within an interval of approximately 3 cM, between DXS365 and DXS7161, on Xp22.3 where the CLS ... Trivier et al. (1996) demonstrated deletion, nonsense, and missense mutations of the RSK2 gene in patients with CLS. The gene is located within an interval of approximately 3 cM, between DXS365 and DXS7161, on Xp22.3 where the CLS gene had been located. McCandless et al. (2000) reported a man with features of Coffin-Lowry syndrome, including severe mental retardation, short stature, coarse facies, patulous lips, and characteristic radiographic hand findings, with a cytogenetic deletion of chromosome 10, 46,XY,del(10)(q25.1q25.3). Since the RSK2 gene is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein kinase cascade (see MAPK11; 602898), the authors suggested that a gene involved in MAPK signaling may be present in the deleted region. Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with CLS and identified 45 mutations, of which 44 were novel, confirming the high rate of new mutations at the RSK2 locus. The authors noted that no mutation was found in over 60% of the patients referred to them for screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations reported to date, 33% are missense mutations, 15% nonsense mutations, 20% splicing errors, and 29% short deletion or insertion events; and 4 large deletions have been reported. The mutations are distributed throughout the RPS6KA3 gene, and most mutations are private. In a 1.5-year-old boy with a clinical phenotype highly suggestive of CLS in whom no mutation had been identified by sequencing PCR-amplified exons of RPS6KA3 from genomic DNA, Marques Pereira et al. (2007) analyzed the gene by directly sequencing RSK2 cDNA and identified a tandem duplication of exons 17 to 20 (300075.0019). The authors stated that this was the first reported large duplication in the RPS6KA3 gene, and noted that immunoblot analysis or a molecular assay capable of detecting large genomic events is essential for the definitive diagnosis of CLS when exon screening fails to detect a mutation.
The estimated incidence of Coffin-Lowry syndrome is 1 in 50,000 to 1 in 100,000, and about 70 to 80% of patients are sporadic cases (Marques-Pereira et al., 2010).
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):...
DiagnosisClinical DiagnosisAffected MalesClinical 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):FigureFigure 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.) (more...)FigureFigure 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.) FigureFigure 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 (more...)FigureFigure 4 A&B. Hand of the child illustrated in Figure 1 and 2 at ages two years (A) and five years (B). (Patient has a known RPS6KA3 mutation.) FigureFigure 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.) 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 ridgesUsually marked ocular hypertelorism with downslanting palpebrae; occasionally, relatively normal periorbital region with mild telecanthusConsistent, often striking, nasal findings including low bridge, blunt tip, and thick alae nasi and septum, resulting in small naresLarge mouth, usually held open; patulous lips with everted lower lipThickened appearance in childhood, often coarsening to a more ‘pugilistic’ look with ageProminent earsExtremitiesShort, soft, fleshy hands, often with remarkably hyperextensible fingers, and a short horizontal palmar crease across the hypothenar areaFingers 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 individualFull, fleshy forearms: a potentially useful sign in diagnosing a younger childMusculoskeletalFrequent pectus carinatum and/or excavatumChildhood onset of kyphoscoliosis that is often progressiveNote: 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 sinusesAnterior beaking of the vertebrae with narrow disc spaces and related degenerative vertebral changesKyphoscoliosisNarrow pelvisMetacarpal pseudoepiphyses, poor modeling of the middle phalanges, and tufting of the distal phalanges (Metacarpophalangeal profiles do not appear to aid diagnosis.)Affected FemalesThe 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.TestingRibosomal S6 kinase enzyme assayRibosomal S6 kinase enzyme assay, performed on cultured fibroblasts or transformed lymphoblasts, may show reduced activity in males with an RPS6KA3 mutation [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. Molecular Genetic TestingGene. 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 testingSequence analysis. No studies have reported the mutation detection rate using this method. The data available on mutation detection rate are from studies using mutation scanning; 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).Table 1. Summary of Molecular Genetic Testing Used in Coffin-Lowry SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier Females 2RPS6KA3Sequence analysisSequence variants 3~90%-95% 4~90%-95% 4Clinical Partial- and whole-gene deletions 0% 5Deletion / duplication testing 6Partial- and whole-gene deletions and duplications Unknown 7Unknown 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Detection rate in clinically typical cases; detection rate in atypical cases is significantly lower [Authors, unpublished observation].5. 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.6. 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 GH may be used.7. 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 StrategyConfirming 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) DisordersNonsyndromic intellectual disability. 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 intellectual disability (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 intellectual disability was reported by Delaunoy et al [2001]. The advent of molecular genetic diagnosis may aid in confirming the diagnosis of additional mild cases.
Development. Coffin-Lowry syndrome (CLS) is characterized by severe-to- profound intellectual disability 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 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 retardation. The authors are aware of a patient with a proven RPS6KA3 mutation who works in a fast food restaurant [C Skinner, personal communication]....
Natural HistoryDevelopment. Coffin-Lowry syndrome (CLS) is characterized by severe-to- profound intellectual disability 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 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 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 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]. 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 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].
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 intellectual disability (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 intellectual disability....
Genotype-Phenotype CorrelationsAlthough 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 intellectual disability (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 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.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].
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....
Differential DiagnosisThe 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 anteverted nose 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 hypertelorism, large mouth, and full lips. Mutations in PHF6 are causative [Lower et al 2002].While CLS shares some facial findings with Williams syndrome, the genetically heterogeneous FG syndrome, and X-linked alpha-thalassemia mental retardation (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, ocular hypertelorism with downslanting palpebral fissures, a prominent lower lip, kyphoscoliosis, pectus excavatum, and some 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 mental retardation (ATRX) syndrome is characterized by genital anomalies and severe developmental delays with hypotonia and intellectual disability. Genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female genitalia in individuals with an 46,XY karyotype. ATRX syndrome is caused by mutations 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.
To establish the extent of disease in an individual diagnosed with Coffin-Lowry syndrome (CLS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 circumferenceHistory and neurologic examination to assess for changes in gait or in bowel or bladder function and for epilepsy or movement disorderDevelopmental assessment and formulation of an intervention planComplete musculoskeletal examination with particular attention to the chest and spine; radiographic assessment if clinically indicatedDevelopmental, age-appropriate hearing assessmentDental evaluationPhysical examination of the heart and ECG, with baseline echocardiogram by age ten yearsOphthalmologic evaluation, including refraction and fundoscopyEvaluation of appropriate family members for signs of the conditionAssessment of the family’s capacity to care for the child, especially if mother is affected intellectuallyTreatment of ManifestationsIndividuals 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 ComplicationsEarly 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.SurveillanceThe following are appropriate:Periodic tests of hearing and visionAnnual 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 lossNote: A table containing suggested guidelines for follow-up of individuals with CLS is provided in Hunter [2005]. Agents/Circumstances to AvoidIndividuals with CLS who experience SIDAs should be protected as much as possible from being startled and/or from falls.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherSignificant social resources may be required to support families of women with CLS and developmental delay.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRPS6KA3Xp22.12Ribosomal protein S6 kinase alpha-3Catalogue of Somatic Mutations in Cancer (COSMIC) RPS6KA3 @ LOVDRPS6KA3Data 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) View in own window 300075RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3 303600COFFIN-LOWRY SYNDROME; CLSMolecular Genetic PathogenesisRPS6KA3 (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.)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.