Coffin-Lowry Syndrome

A number sign (#) is used with this entry because of evidence that Coffin-Lowry syndrome (CLS) is caused by mutation in the RSK2 gene (RPS6KA3; 300075) on chromosome Xp22.

Description

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.

Clinical Features

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.

Diagnosis

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.

Mapping

Hanauer et al. (1987, 1988) found linkage of CLS to DNA markers on Xp, suggesting that the CLS locus may be situated in the Xp22.3-p22.1 region. The multipoint lod score was 2.2 at theta = 0.0 for linkage with 2 markers in this region. Partington et al. (1988) restudied the family first reported by Procopis and Turner (1972). They found that there were now 12 affected members in 3 generations. They examined 9 of them personally and concluded that the CLS locus is distal to DMD. Biancalana et al. (1992) extended their studies to 16 families, using 7 RFLP markers spanning the Xp22.2-p22.1 region. A multipoint linkage analysis placed the CLS locus, with a maximum multipoint lod score of 7.30, within a 7-cM interval defined by a cluster of tightly linked markers, DXS207-DXS43-DXS197, on the distal side and by DXS274 on the proximal side. No evidence of linkage heterogeneity was detected. Biancalana et al. (1994) defined the genetic localization of the CLS gene by construction of a high-resolution linkage map. The study permitted them to refine the localization of 5 other genes in that region. Crossover analysis in a British family suggested to Bird et al. (1995) that the CLS locus is in a region of approximately 3.4 cM in Xp22 with DXS365 as the closest proximal flanking marker identified to date. Features of the face and distally tapering fingers were demonstrated with photographs.

Molecular Genetics

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.

In cells derived from an affected member of the original family with Coffin-Lowry syndrome reported by Lowry et al. (1971), Nishimoto et al. (2014) identified an in-frame deletion in the RPS6KA3 gene (300075.0022).

Genotype/Phenotype Correlations

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.

Pathogenesis

Harum et al. (2001) noted that, based on evidence from experimental models, the transcription factor cAMP response element-binding protein (CREB; 123810) is thought to be involved in memory formation. RSK2 activates CREB through phosphorylation at serine-133. In 7 patients with Coffin-Lowry syndrome (5 boys and 2 girls), Harum et al. (2001) found a diminished activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all cells lines. The authors noted a linear correlation between RSK2 activation of CREB and cognitive levels of the patients, consistent with the hypothesis that CREB is involved in human learning and memory. Other characteristics of the syndrome, including facial and bony abnormalities, may be due to impaired expression of various CREB-responsive genes.

Population Genetics

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).

History

Mattei et al. (1981) reported 2 sisters with Coffin-Lowry syndrome; however, as noted by Gorlin (1981), these sisters actually had Coffin-Siris syndrome (135900).