CLS的特点通常是在男性中严重到极重的智力残疾；也有不太严重的病例报道。杂合携带的女性的智力可表现为正常到严重受损。容貌在受累的特性，受累的年长男孩或成人有特征性的容貌特点。手短，软，肉质，常有手指明显过度伸展，其指骨和指甲从近侧由宽变窄 。男性身高在第三百分位数以。常见小头畸形。可能存在心脏异常，并可能导致过早死亡。刺激诱导性跌倒发作（SIDAs），即在意想不到的触觉或听觉刺激或兴奋而引发的短暂的崩溃，但无意识丧失，会出现在约20%患者中。通常SIDAs会始于童年期到青少年期。渐进性脊柱侧后凸畸形是一个长期护理中最困难的方面。寿命可能会缩短。
Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Intellect ranges from normal to profoundly impaired in 杂合的 females. The facial appearance is characteristic in the 受累的, older male child or adult. The hands are short, soft, and fleshy, often with remarkably hyperextensible fingers that taper from wide (proximally) to narrow with small terminal phalanges and nails. Males are consistently below the third centile in height. Microcephaly is common. Cardiac abnormalities may be present and can contribute to premature death. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Life span may be reduced.

诊断／检测 Diagnosis/testing.

男性CLS患者的诊断是严重的发育迟缓，特征性的颅面和手部，以及影像学表现。女性携带者可能是轻度受累。RPS6KA3基因是目前为止发现的唯一的致病性变异会引起CLS的基因，其基因检测可以用来确诊但不能排除对典型的CLS的诊断。测序分析可以在约25% - 40%临床诊断的先证者中发现致病性变异。The diagnosis of CLS is established in males with severe developmental delay, characteristic craniofacial and hand findings, and radiographic findings. Carrier females may be mildly 受累的. Molecular genetic testing of RPS6KA3, the only 基因 yet published in which pathogenic variants are known to cause CLS, can be used to confirm but not to rule out the diagnosis of typical CLS. Sequence analysis identifies pathogenic variants in approximately 25%-40% of clinically diagnosed probands.

管理 Management.

对症治疗针对SIDAs的治疗药物如丙戊酸、氯硝西泮，或选择性5-羟色胺摄取抑制剂；对频繁出现SIDAs的患者可能需要使用轮椅，如果可能的话应避免惊吓。对表现出破坏性或自残行为的患者可给予利培酮。如果出现喂养困难，异常生长速度、行为问题、脊柱侧后凸畸形，肥胖，予以标准的处理。并发症的预防：预防进展的脊柱侧后凸畸形导致心肺损害。监测：定期的听力，牙科和视力检查；每年心脏检查，十岁开始加测超声心动图，每五至十年一次；针对渐进性脊柱后侧弯，定期脊柱监测；需避免的试剂／环境：有过SIDAs的患者需尽量避免受惊吓和/或跌倒。
Treatment of manifestations: SIDAs are treated with medications such as valporate, clonazepam, or selective serotonin uptake inhibitors; individuals who experience frequent SIDAs may require use of a wheelchair and should be protected, if possible, from being startled. Risperidone may be of benefit to individuals who display destructive or self-injurious behavior. Feeding difficulties, abnormal growth velocity, behavioral problems, kyphoscoliosis, and obesity, if present, are treated in a standard manner.

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

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

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

遗传咨询Genetic counseling.

CLS是X连锁遗传病。约70% - 80%的先证者没有CLS的家族史，20%-30%有一个以上的受累的家庭成员。女性携带者的孩子有50%的风险遗传致病性变异。遗传致病变异的男性会患病；遗传致病性变异的女性为携带者，且有出现一些发育迟缓和CLS的轻微生理体征的高风险。对于已确诊的家庭，或者连锁分析排除了X染色体携带（或有携带可能）致病性变异的家庭，可行携带者检测高风险的亲属和孕期产前检查。CLS is inherited in an X-linked manner. Approximately 70%-80% of probands have no family history of CLS, and 20%-30% have more than one additional 受累的 family member. Children of a woman known to be a 携带者 are at 50% risk of inheriting the 致病性变异. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and at high risk for at least some developmental delay and mild physical signs of CLS. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible in families in which the pathogenic variant has been identified in an affected family member or in which linkage studies can exclude the X 染色体 that carries (or potentially carries) the pathogenic variant.

临床诊断Clinical Diagnosis

男性患者临床表现Affected Males

Clinical findings. 最重要的受累男性的表现如下The most important clinical signs of Coffin-Lowry syndrome (CLS) in 受累的 males are the following [Hanauer & Young 2002] (see Figure 1, Figure 2, Figure 3, Figure 4, and Figure 5):

Figure 1.

图一前后位，2岁患病男孩的面部特征有双目距离远，轻度眼睑下斜，鼻短小而宽厚， 嘴唇轻度外翻唇红。 AP view of a boy age two years with CLS showing relatively fine facial features but with widely spaced eyes, mildly downslanted palpebral fissures, short nose with broad columella and thick, slightly everted vermilion of the lips. (Affected individual (more...)

Figure 2 A & B.

图2A，B前后位及侧位，同一个男孩在五岁时表现出更明显的三角形脸，粗糙度增加，以及CLS的典型面部表情（患者有已知RPS6KA3致病性变异。）AP and lateral view of the same boy at age five years showing a more triangular-shaped face, increasing coarseness, and expression of the typical facial signs of CLS. (Affected individual has a known RPS6KA3 pathogenic variant.)

Figure 3.

前后位显示一青少年表现轻度面部特征，但双眼距宽，轻度睑裂下斜，厚红双唇和小牙齿，鼻小柱宽而鼻孔正常。AP view of an adolescent showing relatively mild facial signs but with widely spaced eyes, mildly downslanted palpebral fissures, thick vermilion of the upper and lower lips, and small teeth. The columnella is broad but nares are a good size, perhaps (more...)

Figure 4 A & B. 图1和2中孩子的手，2岁时（A），5岁时（B）

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

Figure 5

年长儿童的手，表现典型的手指变尖而软。B.患者手部更多细节差异见图3A & B. A. Hand of an older child showing classic tapering and soft appearance. B. More subtle differences seen in the hand of the individual illustrated in Figure 3. (Affected individuals have a known RPS6KA3 pathogenic variant.)

• 发育Development. 受累男性有中度到重度智力障碍，自从分子遗传学检测的出现，更多中度受累的男性被检测。Development. Affected males typically have moderate to severe intellectual disability; since the advent of 分子遗传学检测, more mildly 受累的 males are being identified [Field et al 2006].
• 颅面Craniofacial.在受累的年长男孩或成人中，面部特征为Craniofacial. In the 受累的 older male child or adult, the facial appearance is characteristic (see Figure 1, Figure 2, and Figure 3):
  通常前额突出和眶上脊浓眉
  通常双眼距宽，眼睑裂下斜；偶见正常眶周区与轻度内眦
  特征的鼻部，包括鼻梁塌陷，钝尖，厚鼻翼及鼻中隔，导致的鼻孔小
  大嘴，通常开着；厚红唇，下唇外翻
  儿童期面容粗糙，并随年龄进展为更“拳击”样面容
  突出的耳朵
  • Usually prominent forehead and supraorbital ridges with thick eyebrows
  • Usually marked widely spaced eyes with downslanted palpebral fissures; occasionally, relatively normal periorbital region with mild telecanthus
  • Consistent, often striking, nasal findings including depressed bridge, blunt tip, and thick alae nasi and septum, resulting in small nares
  • Wide mouth, usually held open; thick vermilion of the upper and lower lips with everted vermilion of the lower lip
  • Coarse facial appearance in childhood with progression to a more ‘pugilistic’ look with age
  • Prominent ears
• Extremities
• 四肢
  • 短，软，肉质的手，常有手指明显过度伸展，和小鱼际区短横掌
    手指明显从近端宽到远端变窄，小指骨和指甲（见图4）。手上的差异有时可能很细小（见图5）。
    柔软、易弯曲的手，手掌有“毛绒垫”的感觉，在肥胖的人身上可以看到。
    丰满的前臂：有助于诊断年幼儿童
• • 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
• 肌肉骨骼系统
  • 鸡胸或漏斗胸
    儿童期发病的脊柱侧后凸畸形往往是渐进的
• • Frequent pectus carinatum and/or excavatum
  • Childhood onset of kyphoscoliosis that is often progressive

注：几位作者曾说过，在年幼的孩子的诊断可能是困难的。事实上，同大多数综合征相比，随着年龄的增长，CLS的面部特征变得越来越明显。然而，即使在新生儿，如果考虑CLS，其诊断是很明显的。在CLS的影像学检查是非特异性，但可能有助于确诊。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]:

• 颅骨增厚伴额窦
  椎间盘狭窄，相关椎体退行性变
  脊柱侧后凸畸形
  狭窄骨盆
  掌指pseudoepiphyses？，指骨建模差，远端指骨成簇状（掌指外形难以辅助诊断。）Thickened skull with large frontal sinuses
• Anterior beaking of the vertebrae with narrow disc spaces and related degenerative vertebral changes
• Kyphoscoliosis
• Narrow pelvis
• Metacarpal pseudoepiphyses, poor modeling of the middle phalanges, and tufting of the distal phalanges (Metacarpophalangeal profiles do not appear to aid diagnosis.)

Affected Females女性患者

发育迟缓和颅面部肢体从严重（如男性患者）到没有表型。对受累患者家属进行仔细检查可以发泄轻度面部和／或手部特征。The degree of developmental delay and craniofacial and limb changes range from severe (as seen in males) to completely absent. Careful examination of an intellectually normal female relative of an 受累的 individual may reveal mild facial and/or hand manifestations.

检测Testing

核糖体S6激酶酶测定。核糖体S6激酶酶测定，对体外培养的成纤维细胞或转化的淋巴母细胞中进行的，可在RPS6KA3致病性变异的男性患者表现酶活降低。这是一个有限的基础上的研究性检测。注：不适用于女性，因为X染色体失活导致酶活变化大。

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致病性变异 [Merienne et al 1998, Delaunoy et al 2001, Zeniou et al 2002a]. This is a research test available on a limited basis.

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

检测策略Testing Strategy

先证者的诊断

To confirm/establish the diagnosis in a 先证者

• 男性患者，对RPS6KA3的22个外显子行双向测序，可检测单核苷酸变异和在编码区或在内含子/外显子边界存在小缺失或重复。
  对受累的女性，没有以下情况的，可考虑缺失/重复分析：
  序列分析发现致病性变异
  一个受累的男性亲属更容易地检测致病性变异
  在男性患者，表型符合CLS，序列分析没有RPS6KA3致病性变异，可以在研究基础上进行的核糖体S6激酶酶活性的测定；这个测定对女性的检测没有帮助，且只在有限的研究基础上进行。
  In an 受累的 male, bidirectional sequencing of the 22 exons of RPS6KA3 should detect any single nucleotide variant and small 缺失 or 重复 present in the 编码区 or at the 内含子/外显子 boundaries.
• Deletion/重复 analysis can be considered in 受累的 females who have NEITHER of the following:
  • A 致病性变异 identified by 序列分析
  • An 受累的 male relative in whom the 致病性变异 may be more readily detected
• An assay of ribosomal S6 kinase enzyme activity can be performed on a research basis in males whose 表型 is consistent with CLS but in whom no RPS6KA3致病性变异 is found by 序列分析; this test is not useful in females and is available on a limited research basis.

Clinical Description

Development. Coffin-Lowry syndrome (CLS) is characterized by severe-to- profound intellectual disability in males; intellect ranges from normal to profoundly impaired in 杂合的 females. Early developmental assessments may overestimate the ultimate developmental prognosis [Hunter 2002]. Touraine et al [2002] did not provide detail but stated “our data have shown that intellectual disability is only moderate in most patients as soon as proper care is provided”; and the families reported by Field et al [2006] showed variable and mild physical signs and included members with only mild impairment. The authors are aware of a patient with a proven RPS6KA3致病性变异 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 先天的 stenosis of the spinal canal [Hunter 2002].

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

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

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

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

Female carriers may have a higher rate of psychiatric illness than that found in the general population. Six (8.8%) of 68 women (22 females with CLS, 38 heterozygotes, and 8 '受累的' 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 受累的 males and 5% of affected females have cardiovascular disease [Hunter 2002]. These percentages may be underestimates as many individuals with CLS have not had thorough initial or ongoing cardiac assessment. Reports have included: abnormalities of the mitral, tricuspid, and aortic valves; short chordae; cardiomyopathy (in one individual, with endocardial fibroelastosis); unexplained congestive heart failure; and dilatation of the aorta and of the pulmonary artery [reviewed in Hunter 2002]. An individual reported by Facher et al [2004] had a restrictive cardiomyopathy. Martinez et al [2011] reported an individual with CLS who had left ventricular non-compaction cardiomyopathy with a restrictive pattern. Cardiac anomalies may contribute to premature death.

Musculoskeletal. Progressive kyphoscoliosis is one of the most difficult aspects of the long-term care of individuals with CLS. The precise prevalence is not known, but at least 47% of 受累的 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 受累的 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 受累的 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 受累的 sibs by Wang et al [2006]; they also showed thinning of the corpus callosum, vermian hypoplasia, and mild ventricular asymmetry. The authors concluded that the degree of intellectual disability correlated with the severity of the MRI findings.

Kesler et al [2007] performed quantitative MRI and demonstrated in 受累的 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 受累的 male and one 肯定携带者 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 表型 and location or type of RPS6KA3致病性变异, individuals with certain 错义 pathogenic variants may tend to have milder disease expression [Delaunoy et al 2001]. The family classified as having a form of nonsyndromic intellectual disability (MRX19; see Genetically Related Disorders) had a missense variant in RPS6KA3, which caused an 80% reduction in ribosomal S6 kinase enzyme activity, in contrast to most pathogenic variants in individuals with CLS, which cause a total loss of ribosomal S6 kinase enzyme activity [Merienne et al 1999]. This finding indicates that some RPS6KA3 variants probably give rise to non-CLS phenotypes or nonsyndromic X-linked intellectual disability.

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

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

Nakamura et al [2005] suggested that truncating variants, either in or upstream from the N-terminal kinase 结构域, may cause a particular susceptibility to SIDAs. However, the finding of an 受累的 female with SIDAs who has a 杂合的 c.1570dupA 致病性变异 in the region encoding the C-terminal kinase domain of the protein would argue against this correlation [Rojnueangnit et al 2014].

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

Nomenclature

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

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

Prevalence

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

Evaluations Following Initial Diagnosis

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

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

Treatment of Manifestations

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

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

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

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

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

Treatment of behavioral problems is standard and requires periodic reassessment.

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

Prevention of Secondary Complications

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

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

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

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

Surveillance

The following are appropriate:

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

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

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 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.

Mode of Inheritance

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

Risk to Family Members

Parents of a 先证者

• Approximately 70%-80% of probands have no family history of CLS, and 20%-30% have more than one 受累的 family member [Delaunoy et al 2001]. The high incidence of 单发的 cases (i.e., CLS in a single individual in a family) can be attributed to genetic selection that occurs against 杂合的 females who are intellectually disabled [Jacquot et al 1998a].
• The father of an 受累的 male will not have the disease nor will he be a 携带者 of the 致病性变异.
• In a family with more than one 受累的 individual, the mother of an affected male is an 肯定携带者.
• Mothers of a 先证者 should be examined for signs of CLS such as coarse facial features, full lips, and/or tapering fingers.
• If a 致病性变异 has been identified in the 先证者, it is reasonable to offer 分子遗传学检测 to the mother.

Sibs of a 先证者

• The risk to the sibs of a 先证者 depends on the 携带者 status of the mother.
• If the mother of the 先证者 has a 致病性变异, the chance of transmitting it in each pregnancy is 50%:
  • Male sibs who inherit the 致病性变异 will be 受累的; female sibs who inherit the pathogenic variant 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, a mildly 受累的 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 intellectual impairment, the mother of a 先证者 with no known family history of CLS is probably at low risk of being a 携带者.
• Germline 嵌合 has been demonstrated in this condition. Thus, even if the 致病性变异 found in the 先证者 has not been identified in the mother's DNA, sibs of the proband are still at increased risk of inheriting the pathogenic variant [Jacquot et al 1998b, Horn et al 2001].

Offspring of a 先证者

• Males and severely 受累的 females with CLS typically do not reproduce.
• Women with CLS have a 50% chance of transmitting the 致病性变异 to each child; sons who inherit the pathogenic variant will be 受累的; 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 先证者. If the mother of the proband is found to have a 致病性变异, 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 受累的 depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing of at-risk female relatives requires prior identification of the 致病性变异 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 分子遗传学检测 of a mother of a male with no known family history of CLS (i.e., a 单发的 case) in whom a 致病性变异 has been identified. Germline 嵌合 has been observed; thus, it is appropriate to offer prenatal testing to such women even when the pathogenic variant identified in an 受累的 offspring is not detected in their DNA.

Family planning

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

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the RPS6KA3致病性变异 has been identified in an 受累的 family member, prenatal testing or 植入前遗传诊断 for a pregnancy at increased risk for CLS may be an option that a couple may wish to consider.

Molecular Genetic Pathogenesis

RPS6KA3(RSK2), the 基因 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 2001Pereira et al 2010]. Through the MAPK/RSK pathway and the epidermal growth factor (EGF)-stimulated phosphorylation of histone H3, it appears to play a role in stimulation of the cell cycle between G0 and G1. RPS6KA3 has also been shown to activate CREB (cAMP response element binding protein), which is involved in neuronal survival and conversion from short- to long-term memory [Harum et al 2001]. Cells from individuals with CLS have shown defective EGF-stimulated phosphorylation of S6, H3 [Sassone-Corsi et al 1999], and CREB [Harum et al 2001]; and one or more of these pathways may play a role in causing some of the manifestations of CLS.

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

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

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

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

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

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

Recently, Schneider et al [2013] have identified a deep 内含子的致病性变异 which results in an aberrant protein. This finding warrants analysis for pathogenic variants at the RNA level in all patients with a highly suggestive clinical diagnosis of CLS and in whom 外显子 screening has failed to detect a pathogenic variant.

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

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

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

Abnormal 基因产物. Pathogenic variants in RPS6KA3 give rise to both CLS and nonsyndromic XLMR. The pathogenic variants in individuals with CLS result in the loss of kinase activity of the gene product. However, the 致病性变异 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 受累的 in CLS.

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Author History

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

Revision History

• 27 March 2014 (me) Comprehensive update posted live
• 15 January 2009 (me) Comprehensive update posted live
• 6 August 2007 (cd) Revision: deletion/duplication analysis available clinically
• 31 August 2006 (me) Comprehensive update posted to live Web site
• 27 December 2004 (cd) Revision: change in 分子遗传学检测 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