Coffin-Lowry Syndrome (RPS6KA3)

X-linked syndromic intellectual disability caused by loss of function of the RSK2 kinase, with craniofacial and hand dysmorphism, progressive kyphoscoliosis, stimulus-induced drop episodes and variable expression in heterozygous females.

Literature and regulatory information updated: 18 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Founding descriptions

In 1966, Coffin and colleagues described in the American Journal of Diseases of Children two unrelated adolescent boys with intellectual disability, a "pugilistic"-looking nose, large ears, tapering fingers, drumstick terminal phalanges on radiographs and pectus carinatum; minor manifestations in female relatives suggested a genetic basis [3, 20]. In 1972, Procopis and Turner reported a family with four brothers with the full picture and several women with abnormal fingers and mild intellectual disability, and considered X-linked dominant inheritance likely [3]. In 1971, Lowry, Miller and Fraser published in the same journal a "new dominant gene mental retardation syndrome" with short stature, delayed bone age, hypotonia, tapering fingers, hypertelorism, anteverted nares and a prominent forehead, sometimes with arrested hydrocephalus, transmitted over three generations without male-to-male transmission [3, 21].

In 1975, Temtamy, Miller and Hussels-Maumenee studied eight patients from three families and concluded that the entities described by Coffin and by Lowry were a single syndrome; they described skeletal, orodental, dermatoglyphic and histopathological findings suggestive of a heritable connective tissue disorder, and noted that severe expression in males and transmission through mildly affected females pointed to X-linked or sex-influenced autosomal dominant inheritance [22]. In the same year, the group published a second description in the Birth Defects Original Article Series, which introduced the eponym "Coffin-Lowry syndrome" [10, 14, 23]. OMIM notes that this demonstration that two separately described entities were one and the same is unusual in medical genetics, where splitting of similar phenotypes is more common [3]. In 1982, Hunter, Partington and Evans pooled 12 cases from eight families at four centres: the physical and pedigree data favoured X-linked semidominant inheritance with a substantial proportion of new mutations, skin biopsies from four patients showed no lysosomal or degenerative disease, and the authors advised caution before assuming intellectual deterioration [12].

1.2. From linkage to gene

The locus was linked to Xp markers by Hanauer and colleagues in 1987–1988; in 1992, analysis of 16 families placed it in a 7-cM interval in Xp22.2–p22.1 with a maximum multipoint LOD (logarithm of the odds) score of 7.30 and no linkage heterogeneity, and a 1995 British study narrowed it to about 3.4 cM [3]. In 1996, Trivier and colleagues identified the RSK2 kinase gene (RPS6KA3) within the 2–3-Mb interval; screening of 76 unrelated patients revealed an intragenic deletion, a nonsense variant, two splicing variants and two missense variants at critical sites, and the mutant proteins were inactive in an S6 kinase assay. This work provided direct evidence that abnormalities of the mitogen-activated protein kinase (MAPK) and RSK pathway cause the disease [24]. In 1999, Merienne and colleagues showed that an RPS6KA3 missense variant with partially reduced kinase activity caused non-syndromic X-linked ID in the family in which the MRX19 locus had been mapped [6, 25]. In 2014, study of banked fibroblasts from a patient in Lowry's original family identified an in-frame deletion of exons 15 and 16, in the C-terminal kinase domain [7, 26].

1.3. Nomenclature and reclassification

Early authors spoke of "Coffin syndrome" until it was recognised that Lowry's patients had the same disorder, and some older texts confused Coffin-Siris and Coffin-Lowry syndromes [1]. OMIM records one example: two sisters published in 1981 as having CLS in fact had Coffin-Siris syndrome [3]. Non-syndromic X-linked ID due to RPS6KA3 was designated MRX19 and became XLID19 in OMIM [6]. With multigene panels and phenotype-agnostic genomic testing, the spectrum has become a continuum between classic CLS and less specific neurodevelopmental phenotypes of moderate severity; GeneReviews therefore adopted the title RPS6KA3-related intellectual disability, following the dyadic gene–phenotype approach of Biesecker and colleagues (2021), and stresses that identification of a pathogenic variant in RPS6KA3 "is not equivalent to a diagnosis of Coffin-Lowry syndrome" [1, 2]. OMIM has kept separate entries for CLS (#303600) and XLID19 (#300844) and describes patients with an intermediate phenotype, with ID and mild anomalies reminiscent of CLS [6].

1.4. Definition of the entities covered in this article

Classic CLS (OMIM #303600; ORPHA:192) is an X-linked ID with skeletal malformations, growth retardation, hearing impairment, paroxysmal movement disorders and cognitive impairment in affected males and some female carriers [3]; Orphanet defines it as a rare X-linked syndromic ID with global delay, postnatal growth retardation with short stature, facial dysmorphism, short hands with tapering fingers and progressive skeletal anomalies, including kyphoscoliosis and chest deformity, with ID ranging from mild to severe [4]. The symptomatic form in female carriers (ORPHA:276630) is the expression of the same disease in heterozygotes, with a highly variable phenotype (prominent forehead, hypertelorism, downslanting palpebral fissures, epicanthic folds, thick lips, short hands with tapering fingers, short stature and progressive kyphoscoliosis), intelligence ranging from normal to mild or moderate ID, and a high rate of psychiatric disorders [5]. XLID19 (OMIM #300844) is a mild to moderate ID without the typical facial, digital and skeletal changes, caused by variants that preserve residual protein activity; female carriers may be mildly affected [6]. The general approach to ID and developmental delay, including the choice of genomic tests and educational support, is not repeated here; this article deals with what is specific to RPS6KA3.

2. Molecular Genetics and Pathophysiology

2.1. The RPS6KA3 gene and the RSK2 protein

RPS6KA3 maps to Xp22.12 (GRCh38 chrX:20,149,911–20,267,519, minus strand; ENSG00000177189), and its coding sequence spans 22 exons [7, 9]. The MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_004586.3 / ENST00000379565.9, which encodes NP_004577.1, of 740 amino acids [9]. The 2025 systematic review normalised variants to NM_004586.2 with a different Ensembl transcript (ENST00000355265.9), and the 2022 Korean report also uses the .2 version, so reading published nomenclature requires confirming the transcript before comparing positions [10, 27]. Aliases include RSK2, MAPKAPK1B, ISPK1, HU-3, MRX19 and CLS [7, 8].

RSK2 belongs to the 90-kDa ribosomal S6 kinase (p90RSK) family, growth factor-regulated serine/threonine kinases. Each protein has two functional catalytic domains: the N-terminal domain belongs to the AGC family and the C-terminal domain to the calcium/calmodulin-dependent kinase (CamK) family, joined by a linker of about 100 amino acids that contains a PDK1 docking site. RSKs are directly phosphorylated and activated by MAPKs such as ERK1 in response to growth factors, polypeptide hormones and neurotransmitters, and in turn phosphorylate many substrates [7]. These include CREB1, ETV1, NR4A1, histone H3, RPS6 and EIF4B, linking MAPK signalling to transcription and translation [8]. RSK1, RSK2 and RSK3 are expressed in all human tissues studied; in the adult mouse brain, Rsk2 expression is highest in regions of high synaptic activity (neocortex, hippocampus and Purkinje cells), and in CLS, RSK1 and RSK3 remain at normal levels without compensating for the RSK2 deficiency [7].

2.2. Molecular, cellular and tissue mechanism

The mechanism is loss of function. Most CLS variants abolish enzyme activity, and about 57% of the variants in a 2001 series introduced a premature termination codon [7, 8]. RSK2 is involved in neurite formation through phosphorylation of phospholipase D1 and phosphatidic acid synthesis, in synaptic plasticity and neuronal excitability, in the lipid production required for exocytosis, in neurotransmitter release and in genome stability through the cell cycle and the ATM/p53-dependent DNA damage pathway [1, 28–33]. RSK2 is required for epidermal growth factor-stimulated phosphorylation of histone H3: fibroblasts from a patient lacked it, and reintroduction of the normal gene restored it; RSK2 also participates in regulating AMPA receptor-mediated excitatory synaptic transmission and localises to kinetochores during the mitotic spindle checkpoint [7].

RSK2 activates the transcription factor CREB by phosphorylating serine 133. In cell lines from seven patients (five boys and two girls), the ability of RSK2 to phosphorylate a CREB-like peptide was reduced in all, with a linear correlation between this activity and cognitive level [3]. In the Rsk2-null mouse, RSK2 is required for osteoblast differentiation and function through phosphorylation of the transcription factor ATF4, which regulates post-transcriptional synthesis of type I collagen; the animal develops progressive osteopenia due to osteoblast dysfunction, with normal osteoclasts [7]. The same model shows mild deficits in working memory and long-term spatial memory, exploratory disinhibition without anatomical brain abnormalities, increased cortical dopamine levels with overexpression of the DRD2 receptor and the dopamine transporter, and altered editing and splicing of Gria2 mRNA with reduced basal AMPA receptor-mediated transmission in hippocampal neurons [7]. These animal-model data underpin hypotheses about the human phenotype but have not been translated into therapy.

Connective tissue changes are documented histopathologically: electron microscopy of fibroblasts with single membrane-bound inclusions, evidence suggesting accumulation of proteodermatan sulphate, calcification of the ligamenta flava with altered glycosaminoglycan metabolism and, in three men in their twenties, myelopathy due to calcification of the ligamentum flavum from calcium pyrophosphate dihydrate crystal deposition [3]. The absence of a primary lysosomal disease was confirmed on skin biopsies [12].

2.3. Inheritance pattern and X inactivation

CLS and XLID19 are classified as X-linked dominant in OMIM [3, 6]. The Oxford Desk Reference uses CLS as an example of X-linked semidominant inheritance: it is expressed severely in hemizygous males and mildly or subclinically in a proportion of heterozygous females [11, 34]. The ORPHA:276630 web entry, accessed 18 October 2026 (Orphanet version 1.6.9 of 1 July 2026), records inheritance as "Autosomal dominant, Not applicable", whereas the definition on the same page describes an "X-linked" syndromic ID; this is an internal inconsistency of the source, and the inheritance of the carrier form is that of the X-linked disease [5, 12].

In heterozygous females, the X-inactivation pattern in blood does not reliably predict the phenotype. In a study of two African American families with the same variant, mean full-scale intelligence quotient (IQ) scores were 90.8 in relatives without the variant, 65.0 in female carriers and 43.2 in affected males [3]. Heterozygous females more often have favourably skewed inactivation in blood, but there is no significant correlation between IQ and inactivation pattern [35, 36]. In the report by Tise and colleagues, the mother had completely skewed inactivation (100:0) and a minimal phenotype, whereas her daughter had random inactivation (57:43) and overt clinical disease [35]. Conversely, in affected women with an X;autosome translocation disrupting RPS6KA3, preferential inactivation of the normal X explains full expression [1, 37], and in a family with an insertion creating a stop codon at codon 100, the affected women had inactivation skewed against the normal allele [38].

2.4. Variant spectrum

Variants are highly heterogeneous, private to most families and distributed throughout the gene without clear clustering [7, 8]. The large historical series give the following distribution: among 250 clinically suspected patients studied in 2001, 71 distinct variants in 86 families (38% missense, 20% nonsense, 18% splicing and 21% small deletions or insertions) [7, 39]; in 2006, among the 128 variants then known, 33% missense, 15% nonsense, 20% splicing, 29% small deletions or insertions and four large deletions [3]. In the 1998 series of 37 patients, 25 variants were identified (eight splicing, seven nonsense, five frameshift and five missense), with a 68% de novo rate [7]. The 2025 systematic review (72 cases, 2010–2025) found variants in all 22 coding exons with no single hotspot, recurrence at arginine residues (Arg259, Arg300, Arg310 and Arg729), allele frequencies below 0.0001 in population databases and a pLI score of 1.0 [10]. ClinGen assigns a haploinsufficiency score of 3 and a triplosensitivity score of 0 [8].

In ClinVar, accessed 18 October 2026, there were 997 records for RPS6KA3: 353 classified as pathogenic or likely pathogenic (P/LP), 206 as variants of uncertain significance (VUS) and 64 P/LP deletions, duplications or copy-number variants (CNVs). Among the 253 P/LP records with an available summary, the types were 95 single-nucleotide variants, 45 deletions, 42 copy-number losses and 39 copy-number gains, 14 duplications and isolated cases of other types [40]. ClinVar counts measure submissions, not frequencies in patients.

Historical nomenclature numbered variants from the cDNA sequences of the time ("C913T (R305X)", "298 ins TG"), so correspondence with the MANE transcript must be confirmed in VariantValidator or ClinVar before any comparison [38, 46]. For "C913T (R305X)" (historical numbering), the position matches NM_004586.3:c.913C>T p.(Arg305Ter) in VariantValidator; "298 ins TG" is kept as the published designation. Some published notations also do not follow Human Genome Variation Society (HGVS) nomenclature (for example, "c.1740delC p.Tyr580Ter" in the Romanian series, where a frameshift would be expected), and they are cited as published [41].

2.5. Non-canonical mechanisms

Mechanisms that escape exon sequencing include: a deep intronic variant that produces an aberrant protein and justifies RNA analysis when the phenotype is suggestive and conventional tests are negative [1, 47]; a variant at the 3' end of an exon that causes both a missense substitution and partial exon skipping, with the carrier mother expressing only normal transcripts and moderately skewed inactivation [48]; LINE-1 element insertions [7, 41]; in-frame intragenic tandem duplications [45]; an intragenic microduplication of exons 5–9 with reduced transcript levels and classic CLS in three siblings, which is functionally a loss of function [10, 49]; and a de novo X;autosome translocation disrupting the gene, identified by genome sequencing [37]. Whole-gene duplications behave differently: an Xp22.12 microduplication including RPS6KA3 was described in a family with mild ID, attention-deficit/hyperactivity disorder (ADHD), focal epilepsy and pervasive developmental disorder, and the 2025 review groups whole or partial duplications with dosage-dependent neuropsychiatric presentations and minimal dysmorphism [10, 50].

2.6. Genotype–phenotype correlations

Residual RSK2 activity is the main known determinant of severity. In the MRX19 family, the R383W variant reduced kinase activity to 10–20% of normal; the patients, re-examined at ages 38 and 29 years, had none of the facial, digital or skeletal features or the typical posture or gait, and their ID was very mild and compatible with social independence, which led the authors to conclude that 15–20% of RSK2 activity suffices for the MAPK–RSK2 signalling involved in skeletal development [7, 25]. In 2006, Field and colleagues identified three variants in families with non-syndromic X-linked ID; all affected the serine/threonine kinase domain and were small in-frame deletions or missense variants, as was the I189K variant in a family with mild CLS, and they were interpreted as preserving enough residual activity to sustain osteoblast differentiation [6]. Residual activity is also associated with cognitive performance [6]. GeneReviews concludes that there is no strong correlation with variant location or type, although certain missense variants are associated with milder expression; in one family, a missense variant was associated only with mild ID [1, 51]. Two related men from a three-generation family with a missense variant at residue 189 had different degrees of ID, and functional study of this variant and of another at the same residue showed significantly reduced kinase activity [52].

The hypothesis that truncating variants in or upstream of the N-terminal kinase domain confer particular susceptibility to drop episodes (Nakamura 2005) was contradicted by an adolescent girl with a classic phenotype, drop episodes and the c.1570dupA duplication in the C-terminal domain, and by the in-frame deletion of exons 15–16 from Lowry's family in a patient with drop episodes [1, 26, 46, 53]. In the 2025 systematic review (n = 72), the results and Table 3 show no significant association between variant type and severity of ID (χ² = 3.58; df = 12; p = 0.99), drop episodes (χ² = 1.10; df = 5; p = 0.95), seizures (p = 0.67), spasticity (p = 0.76) or cardiomyopathy (p = 0.81); descriptively, 35% of carriers of frameshift variants had drop episodes and 24% had seizures. The abstract and conclusion of the same article assert a significant association between these variants and drop episodes (p = 0.009) and seizures (p = 0.048), which contradicts the results; this article adopts the figures from the results [10].

The 2026 Romanian series (n = 10) describes a trend towards greater severity with truncating variants and a broader, sometimes milder, spectrum with missense variants, without statistical analysis [41]. Comparison across series is limited by publication bias towards severe or unusual cases and by incomplete phenotyping [10].

2.7. Allelic disorders, modifiers and dual diagnoses

The only recognised allelic disorder is XLID19; GeneReviews identifies no other germline RPS6KA3 phenotypes [1, 6]. No genetic modifiers have been established apart from the X-inactivation pattern in females. Co-occurrence of a second genetic disorder is documented and should be considered when findings are unexplained: 10-formyltetrahydrofolate dehydrogenase deficiency (ALDH1L2) in a patient with ichthyosis and a previously known RPS6KA3 variant [54]; galactosaemia in a 2-year-old girl with nephrolithiasis and recurrent pericardial effusions [55]; a distal 22q11.2 microdeletion in two of three Chinese women with mild mitral and tricuspid regurgitation [43]; and thyroid dysgenesis with variants of uncertain significance in IYD in a newborn with an intragenic RPS6KA3 deletion [56]. A man with a 10q25 deletion and a phenotype suggestive of CLS illustrates a cytogenetic phenocopy [3].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and data sources

More than 200 individuals with a pathogenic RPS6KA3 variant had been identified by the 2023 GeneReviews update, but the exact number is unknown because many reports predating the discovery of the gene relied on clinical diagnosis; the GeneReviews phenotypic description pools patients with and without molecular confirmation [1]. The Coffin-Lowry Syndrome Foundation database included at least 170 individuals of known age in 2005 [57]. In males, classic CLS combines developmental delay and ID with neurological manifestations (hypotonia, stimulus-induced drop episodes, spastic paraparesis, seizures), musculoskeletal manifestations (kyphoscoliosis, chest deformity) and characteristic craniofacial and hand features, together with dental problems, sensorineural hearing loss and obstructive sleep apnoea; at the mild end of the continuum are neurodevelopmental disorders with less marked multisystem involvement. Quality of life and prognosis depend mainly on neurological and musculoskeletal severity [1].

Published frequencies vary with the method of ascertainment. The table compares the GeneReviews synthesis (literature up to 2022, including clinically diagnosed patients), the reference textbooks, the 2025 systematic review (72 molecularly confirmed cases, 50 males and 22 females, median age 12 years, range 1–45), a single-centre Romanian series (10 patients diagnosed between 2020 and 2025, eight males) and the review of 28 published Chinese patients [1, 10, 14, 41, 58, 59].

The frequencies in the 2025 review are proportions of published cases, with incomplete phenotyping (especially longitudinal psychiatric, endocrine and cardiopulmonary data) and heterogeneous ages; the authors consider valvular disease (13.9%) and cardiomyopathy (2.8%) to be underestimated [10]. The per-feature denominators of the Chinese review are not given in the abstract [59]. None of these percentages is a population prevalence.

3.2. Craniofacial, hand and radiological phenotype

In males, the facial features become more pronounced in older children and adults: widely spaced eyes with downslanting palpebral fissures, maxillary hypoplasia, a prominent forehead, a depressed nasal tip with thick alae nasi and septum, a broad columella and anteverted nares, prominent ears, a wide open mouth with a thick vermilion of both lips and an everted lower lip, and progressive coarsening of the eyebrows and lips with age [1, 14, 58]. The hands are small or broad, soft and fleshy, with short fingers that are wide at the base and taper distally, small terminal phalanges and nails, hyperextensible fingers and an accessory transverse hypothenar crease; the forearms are full because of increased subcutaneous fat, with normal bones, a sign Hersh and colleagues considered an early one, and in infants the hands look "puffy" [3, 14]. Flat feet and ligamentous laxity complete the picture [14].

Radiological changes include metacarpal pseudoepiphyses, poor modelling of the middle phalanges and drumstick tufting of the distal phalanges, which are non-specific in isolation; metacarpophalangeal pattern profiles have no diagnostic value [1, 12]. Smith's adds dilated lateral ventricles, hypoplastic paranasal sinuses and mastoids, delayed bone age, calcification of the lower cervical ligamentum flavum, bifid sternum, anterosuperior marginal vertebral defects, narrowing of the foramen magnum and, in the thoracolumbar vertebrae, narrowed intervertebral spaces, irregular end plates and anterior wedging; Figure 1 of Smith's (p. 403) illustrates the facies, malocclusion, tapering fingers and drumstick phalanges [14]. A superficial resemblance of the facies to that of Williams syndrome has been noted since the 1982 photographs [3, 14].

The French PNDS adds that the facial and hand signs may be more subtle in the neonatal period and in non-Caucasian patients, that the appearance of the hands may be the only sign in a female carrier, and that radiographs show, alongside metacarpal pseudoepiphyses, poorly modelled middle phalanges and tufted distal phalanges; the hands are short, fleshy and frequently hyperlax, with a short middle palmar crease and sometimes an abnormal crease in the hypothenar region [15].

3.3. Neurodevelopment and behaviour

Early milestones are variably delayed, and language is more affected than motor skills; in males with classic CLS, ID is typically severe to profound, to the point that most do not speak, although there are mild cases that would now be classified as RPS6KA3-ID [1, 14]. Early assessments may overestimate the eventual cognitive outcome [1, 60]. Two brothers with a missense variant had an unusually mild presentation, initially with macrocephaly, telecanthus and broad halluces suggesting FG syndrome; with growth, the macrocephaly decreased, the full forearms and tapering fingers became evident and the facies coarsened [3, 44]. Males are usually cheerful, calm and friendly, but attention-deficit/hyperactivity disorder (ADHD), aggression, self-injury and features of autism spectrum disorder (ASD) may occur [1, 14]. In the Romanian series, 40% had aggression or anxiety, 40% had a sleep disorder and 20% had autistic features [41].

According to the PNDS, walking is acquired at around 3 years, with motor difficulties that may persist; language is more affected than motor skills, with variability within the same family and no genotype–phenotype correlation, but communication ability is usually preserved even without oral language. The cognitive regression suggested by the initial descriptions was not confirmed by later studies. A few males have mild ID, sometimes with a non-syndromic appearance. The literature reviewed by the PNDS describes no eating disorders, parasomnias or circadian rhythm dysregulation, and challenging behaviours are infrequent and non-specific [15].

3.4. Stimulus-induced drop episodes

Stimulus-induced drop episodes (SIDE) are the most characteristic neurological sign. An unexpected tactile or auditory stimulus, or excitement, triggers a brief electromyographic silence in the lower limbs with a collapse lasting a few seconds, without apparent loss of consciousness; the transient loss of tone usually involves the paraspinal muscles or the quadriceps, and some patients have myoclonus or increased tone in hyperekplexia-like episodes, with a startle response [1, 61]. Surface electromyography (EMG) with simultaneous video-electroencephalography (video-EEG) in two boys showed no epileptiform discharges: in the first, a brief loss of paravertebral tonic activity after the stimulus, resembling cataplexy; in the second, non-epileptic falls at age 6 years and, at age 11, brief myoclonus and a tonic spasm with increased EMG activity, resembling hyperekplexia [62]. SIDE are thus a heterogeneous group of non-epileptic events with features of cataplexy and of hyperekplexia in the same patient [61, 62]. In one adult, true cataplexy triggered by a joke, "cataplexy" induced by an acoustic startle, a hypertonic hyperekplexia reaction and spontaneous epileptic seizures coexisted [57].

Onset is between ages 4 and 17 years, with a mean of 8.6 years [1, 46]. In the foundation database, 34 of 170 individuals (20%) of known age had drop episodes, and nine of these also had epileptic seizures; onset was usually after age 5 years, peak frequency (27%) occurred between ages 15 and 20 years, and many became wheelchair-dependent [57]. Anxiety increases the likelihood of episodes, and fear of falling perpetuates them [63]. SIDE can become disabling because of fall-related injuries [1, 62]. They also occur in females [53, 64–66]. A female patient with the full phenotype and a full-scale IQ of 53 developed a cataplexy-like phenomenon at age 9 years [3, 64]. Reflex myoclonic seizures triggered by tactile stimuli in a girl, published in 2025, show that not all stimulus-triggered events are SIDE [67].

The PNDS gives a frequency of 10–20% in males (about 20% in the summary intended for the attending physician), with onset between ages 4 and 20 years and a peak between 10 and 20, figures that do not match the 13–20% and 4–17 years of GeneReviews (section 7.15). Triggers are sudden sensory stimuli, whether tactile, auditory or emotional, or a state of excitement; the EEG is normal and surface EMG shows a transient fall in lower-limb activity or a myoclonic increase in tone. Without treatment, frequency and severity tend to increase with age, and cataplexy-type episodes appear to predominate in childhood, whereas hyperekplexia-type episodes arise mainly in the second and third decades [1, 15].

3.5. Epilepsy, spasticity and neuroimaging

True epilepsy occurs in at least 5% and, in some series, up to 30%; according to Hahn and Hanauer, seizures last longer than SIDE, have a focal onset and may be associated with clonic movements and tonic posturing [1, 57]. Recurrent non-convulsive status epilepticus has been described [68]. In the Romanian series, epilepsy was well controlled with antiseizure medications [41]; one girl in that series had infantile spasms at age 6 months, which evolved into focal impaired-awareness seizures with partial control [41].

Progressive spasticity or paraplegia, with loss of ambulation, results from calcification of the ligamenta flava and spinal canal stenosis, with loss of muscle strength and bulk and decreased or increased deep tendon reflexes [1, 60, 69]. Early feeding difficulties result from hypotonia [1].

Neuroimaging shows no consistent pattern: thinning or agenesis of the corpus callosum; multiple focal frontal hypodensities, a thin corpus callosum, vermian hypoplasia and mild ventricular asymmetry in three siblings, with severity proportional to that of the ID; periventricular cystic lesions; and constriction of the foramen magnum [1, 38, 42, 70, 71]. Quantitative magnetic resonance imaging (MRI) in two families showed reduced total brain volume in affected males and females, with the temporal lobes, cerebellum and hippocampus most affected, interpreted as an early neurodevelopmental alteration [3, 72].

The PNDS places epilepsy at about 5% of males, a lower proportion than would be expected in severe ID and than the upper limit of 30% in GeneReviews; seizures may be generalised or focal, sometimes myoclonic, with onset in the first year or later in childhood; diagnosis is difficult in the absence of clonic movements, and response to the usual antiseizure medications is the rule. Spasticity and loss of muscle strength and bulk have a multifactorial origin (hypotonia, vertebral deformity, calcification of the ligamentum flavum with canal stenosis) and may lead to loss of ambulation, paraplegia or tetraparesis. On neuroimaging, in the absence of systematic studies, it adds vermian hypoplasia, enlarged perivascular spaces and agenesis or dysgenesis of the corpus callosum, also described in carriers without cognitive impairment; head circumference is usually normal, sometimes increased by thickening of the frontal bone. It also records central sleep apnoea syndrome in two published patients and a stroke in a young patient [15].

3.6. Spine, chest and musculoskeletal system

Progressive kyphoscoliosis is one of the most difficult aspects of follow-up. It affects at least 40% of males (Hunter 2002) and more in a referral orthopaedic clinic series; including thoracic lordosis and degenerative disc disease, vertebral anomalies approach 80% [1]. It generally does not manifest before age 6 years and is described as relentlessly progressive and surgical, and paraplegia or tetraplegia may develop despite aggressive treatment; a stooped posture is common [14]. OMIM mentions a stooped posture with marked cervical lordosis [3]. In the Herrera-Soto series (10 patients), eight had thoracolumbar kyphosis or kyphoscoliosis (mean coronal Cobb angle 45°, thoracolumbar kyphosis 31°), progressive and difficult to treat, requiring early surgery; 60% had bilateral flexible, painless pes planovalgus, and iliac hypoplasia and hand deformities caused no functional problems [73].

Welborn and colleagues studied the spinal natural history in males recruited through the foundation: six males aged 13 to 22 years with complete records, followed for a mean of 7.25 years (3–13), all had delayed skeletal maturation; the deformity progressed in 100%, and rapidly in half; calcification or hypertrophy of the lower cervical ligamentum flavum was accompanied in all calcified cases by neurological changes (lower-limb weakness and paraesthesiae and, in one, acute tetraparesis), and the calcifications were visible on computed tomography (CT) many years before the deficits [69]. The article is internally inconsistent regarding the number of patients with calcification (three in the results, four in the discussion) and of ambulatory patients (two in the abstract, four in the results, two of them with minimal ambulation); GeneReviews summarises the series as eight males, four with calcifications and two with hypertrophy [1, 69]. Of the two patients excluded for incomplete records, both of whom had surgery, one developed central cord syndrome after minor trauma due to cervical stenosis [69]. The first description of calcification of the ligamenta flava with cervical canal narrowing and radiculomyelopathy dates from 1990 [3].

Chest deformity (pectus carinatum and/or excavatum) is common [1]. In females, at least 32% have progressive kyphoscoliosis; one girl had scoliosis and spondylolisthesis at age 10 years, with L4–S1 arthrodesis at age 11 [1, 53]. Scoliosis in the Romanian series progressed radiographically in a subgroup, and four patients required bracing or surgical referral [41].

The PNDS estimates that about 80% of patients develop an abnormality of spinal alignment during follow-up, usually between ages 10 and 20 years, due to abnormal vertebral shape or degenerative disc disease, and considers it a cause of morbidity and mortality through motor and respiratory compromise when not treated in time. It adds delayed bone maturation with late closure of the anterior fontanelle, relative osteopenia and osteoporosis, possibly related to an alteration of calcium-phosphate metabolism with hypercalcaemia in childhood, and, as rare findings without functional consequence, limited elbow extension, polydactyly, a narrow pelvis and femoral anteversion [15, 69].

3.7. Heart and great vessels

About 14% of males have cardiovascular disease, a proportion probably underestimated because of the lack of systematic assessment [1]. Reported findings include mitral, tricuspid and aortic valve anomalies, short chordae tendineae, cardiomyopathy (one with endocardial fibroelastosis), unexplained congestive heart failure and dilatation of the aorta and pulmonary artery [1]. Smith's reports mitral valve prolapse in 15% and mitral regurgitation [14]. An autopsy of two brothers who died at ages 28 and 22 years showed mitral regurgitation due to fused and shortened chordae and panacinar emphysema, as well as visceral neuropathy with extensive intestinal diverticular disease [3]. One boy had recurrent episodes of heart failure from at least age 8 years, with surgical mitral valve repair [3, 74]. A 14-year-old boy with a three-nucleotide deletion developed heart failure of relatively sudden onset due to restrictive cardiomyopathy, with non-specific hypertrophic myocyte changes on endomyocardial biopsy [7, 75]. One man had left ventricular (LV) non-compaction cardiomyopathy with a restrictive pattern, and CLS is among the syndromes associated with LV non-compaction or hypertrabeculation [76, 77]. Two males aged 14 and 18 years underwent surgery for mitral and tricuspid regurgitation [78, 79]. In females, about 5% have cardiovascular disease [1]. No systematic review has quantified the incidence or age at onset of heart disease [1].

The PNDS describes the cardiomyopathies as progressive, mainly restrictive, in late childhood or adolescence, acknowledges that the frequency of malformations may have been underestimated in the early publications and points out that cardiac anomalies can cause premature death even in childhood [15].

3.8. Growth, metabolism and endocrine system

Prenatal growth is usually normal and slows in the early postnatal period; males are generally below the 3rd centile but follow their own curve, with an adult height of 115–158 cm (mean 143 cm), worsened by kyphoscoliosis [1, 80]. Bone age is usually delayed [14]. Microcephaly is common, but many have a normal head circumference; short stature, hypotonia and low activity increase the risk of obesity [1]. The 2025 review compiles endocrine and metabolic findings without quantification: severe recurrent hypercalcaemia with nephrocalcinosis, central precocious puberty, severe hypertriglyceridaemia in childhood, type 2 diabetes in adulthood, hypothyroidism in late adolescence, irregular menstrual cycles of 45–180 days, and cryptorchidism, hypospadias or hypoplastic genitalia [10]. A Lebanese family with a missense variant had type 2 diabetes in several members [81]. In a girl with infantile hypercalcaemia (calcium 14.7 mg/dL, 3.67 mmol/L, at age 12 months), parathyroid hormone (PTH) was suppressed (3.3 pg/mL) and PTH-related peptide (PTHrP) was elevated (9.7 pmol/L) with no cause identified, with grade 3–4 bilateral medullary nephrocalcinosis and resolution with age [35]. Central precocious puberty was described in a Korean girl with advanced bone age, contrary to the usual delay [27]. A causal relationship between CLS and congenital hypothyroidism in one newborn was not established [56].

According to the PNDS, prenatal growth is normal, and growth deceleration begins in the first months and persists into adulthood, with boys' height below the 3rd centile, partly because of short lower limbs; about half of women have short stature. Obesity has been described mainly in heterozygous women, with only two obese men published, and type 2 diabetes in one family, in men and women. There is no literature on puberty apart from one girl with central precocious puberty and irregular cycles; carriers do not, in principle, have impaired fertility; and transient neonatal hypertriglyceridaemia has been described [15].

3.9. Teeth, hearing and vision

Dental abnormalities include small, malpositioned teeth, open bite, hypodontia of the permanent dentition, large central incisors, widely spaced teeth, early or delayed eruption and premature loss of primary teeth, with hypoplastic root cementum in one case; the palate is high, and infantile retrognathia gives way to prognathism with age [1, 14, 82, 83]. Hypodontia has been described in females [1].

Hearing loss affects up to 30% (Pereira 2010) and, in Hunter's series, 14 of 89 males; it is sensorineural or mixed, may be associated with labyrinthine malformation, may have late onset and may cluster in families; in females, 1 of 22 [1]. Hartsfield and colleagues described seven patients with sensorineural hearing impairment, which, together with early tooth loss, they proposed as early manifestations [3, 84]. In the Romanian series, 5 of 10 patients had mild to moderate sensorineural hearing loss, three with hearing aids [41]. Significant visual problems are rare: cataracts, retinal pigmentary atrophy and optic atrophy; chronic blepharitis may be more common [1].

The PNDS reports hearing loss of variable severity in about one-third of patients, congenital or progressive, sensorineural or due to cochlear malformation. It adds that the high-arched palate and malocclusion (retrognathia, then prognathism), sometimes with bruxism, promote enamel wear and caries, and, in the eyes, exophthalmos and high myopia, severe visual problems being rare [15].

3.10. Respiratory system, sleep and other systems

Obstructive sleep apnoea (OSA) is recognised; in one patient, tracheostomy improved both the OSA and the drop episodes [1, 85]. Kyphoscoliosis causes restrictive lung disease, which can be severe and go unnoticed, as in the 33-year-old man described by Venter and colleagues with undiagnosed chronic hypercapnic respiratory failure (see section 10) [86]. Pulmonary complications include recurrent pneumonia, acute respiratory distress syndrome (ARDS) and aspiration pneumonia with abscess and fatal empyema [10]. Difficulties with intubation and ventilation call for a planned airway strategy [1, 87].

Isolated individuals have been reported with rectal prolapse, jejunal diverticula, colonic diverticula with reduced ganglion cells, popliteal cyst, pyloric stenosis, unilateral renal agenesis, anteriorly placed anus, increased facial pigmentation and an enlarged trachea; one man died of Hodgkin disease [1]. Smith's adds inguinal hernia, uterine prolapse and a single palmar crease [14]. The 2025 review records renal dysplasia, small kidneys, staghorn calculus and, at autopsy, intravascular coagulation, panacinar emphysema, right ventricular hypertrophy, mitral valve disease and a hypoplastic thymus [10]. Five autopsies (two new and three previously published) documented lesions of the heart, brain, lungs, liver, skeleton, kidneys and intestine [88].

Among less typical anomalies, the PNDS adds bicornuate uterus, renal duplication, jejunal or sigmoid diverticula and neonatal umbilical and inguinal hernias, and attributes gastro-oesophageal reflux and constipation to hypotonia [15].

3.11. Heterozygous females (ORPHA:276630)

Expression in heterozygotes ranges from typical development and cognition to the full facial, hand and skeletal phenotype, with mild facial coarsening, tapering fingers, short stature, obesity and variable ID, mild to moderate when present [1, 14, 64, 65]. The known figures are: progressive kyphoscoliosis in at least 32%; cardiovascular disease in about 5%; hearing loss in 1 of 22 (Hunter 2002); and, in a review of 68 women (22 with RPS6KA3-ID, 38 unaffected heterozygotes and 8 "affected" sisters), psychiatric diagnoses (schizophrenia, bipolar disorder, "psychosis") in 6 (8.8%) [1]. Smith's reports psychotic behaviour beginning around age 20 years in some affected women [14]. In a three-generation family, the two mildly affected women had depressive psychosis and the three severely affected men had sensorineural deafness, and the authors cited two earlier reports of depressive psychosis in women from families with CLS [3]. Also described are pervasive developmental disorder, compulsive eyebrow pulling and, in a 15-year-old girl, new-onset psychosis with white matter changes that improved with outpatient psychological and behavioural intervention [50, 89, 90].

Also described in females are idiopathic hypercalcaemia treated with a bisphosphonate in the second year of life, genitourinary anomalies (uterine prolapse, bicornuate uterus, duplicated renal collecting system), central precocious puberty and SIDE [1, 27, 35, 53]. In the 2025 review, duplications occurred mainly in female heterozygotes [10]. ERN ITHACA opened a call for collaboration on the female phenotype because the diagnosis in women is often considered only in adulthood, after a male relative has been diagnosed, and lack of knowledge of this phenotype hampers neurological and orthopaedic care and counselling [18]. Longevity in women is poorly documented; one affected woman died at age 48 years [1].

The PNDS stresses that women are rarely index cases, because intelligence is often preserved and the signs are subtle; SIDE with dysmorphism, or severe orthopaedic involvement, may be the entry point to diagnosis. It describes learning, social interaction and concentration difficulties in carriers, mild to moderate ID in some, and psychiatric disorders (depression, schizophrenia and other psychotic conditions) [15].

3.12. XLID19 (OMIM 300844)

The family in which the MRX19 locus was defined had, over four generations, boys with moderate ID without distinctive features, physical anomalies or specific neurological abnormalities, and three women with mild ID; linkage placed the locus in a 42-cM interval in Xp22 [6]. In 1999, two men from this family re-examined at ages 38 and 29 years had none of the facial, digital or skeletal features of CLS, and their ID was very mild [6, 25]. In 2006, two families clinically diagnosed with non-syndromic ID had mild additional features (in one, coarse facies, kyphoscoliosis and redundant palmar skin with horizontal creases, without tapering fingers or short stature; in the other, short stature, hypertelorism and a slightly full lower lip), considered insufficient for a diagnosis of CLS; in a third family, the suspicion of CLS rested on a single man [6]. The distinction between XLID19 and mild CLS is therefore one of degree, and it justifies evaluating any carrier for actionable manifestations of the spectrum, regardless of the reason for testing [1].

3.13. Natural history and treated disease

Data on the prevalence of complications come from patients who received heterogeneous care over decades, with no studies comparing groups with and without specific interventions. Spinal progression in the Welborn series occurred despite bracing in three patients, and the loss of ambulation and mortality in older series reflect natural history under the care of the time [60, 69]. In the Romanian series, with follow-up of 6 to 36 months (median about 12), the course was stable across systemic domains, except for scoliosis in a subgroup [41].

The PNDS repeats the figure of 20.5 years as "life expectancy" and attributes to the report by Venter and colleagues (2019) the oldest patient in the literature, aged 48 years; Venter's patient was 33 years old at admission and 34 at follow-up, and the man alive at age 48 is that of Di Stazio and colleagues (2021), according to GeneReviews; the meaning of the 20.5-year figure is discussed in section 11.1 [1, 15, 52, 86].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

In newborns and infants, the features are mild and non-specific, which makes clinical diagnosis difficult in very young children [51]. Hypotonia, feeding difficulties, "puffy" hands with tapering fingers, full forearms and hypertelorism in a boy with global delay should prompt inclusion of RPS6KA3 in the work-up [1, 3]. In the Romanian series, hypotonia appeared in the neonatal period or infancy, and the facial signs were recognisable from the first year [41]. In preschool and school-aged children, language delay disproportionate to motor delay, progressive facial coarsening, short stature of postnatal onset, hypodontia or premature loss of primary teeth, sensorineural hearing loss and pectus complete the picture [1, 14, 84]. From age 4 years, and especially in adolescence, sudden falls triggered by an unexpected noise or touch, without loss of consciousness, are highly suggestive; before diagnosis they have often been treated as refractory atonic seizures [57, 66]. Kyphoscoliosis appears after age 6 years [14]. In the Oxford Desk Reference, CLS belongs to the subgroup of coarse facies with severe delay without regression, and examination of the hands is the most informative step [91].

In females, suspicion arises mainly after diagnosis in a male relative, or in the setting of learning difficulties with mild facial and digital dysmorphism [7, 18]. In a family with X-linked ID, the findings that point to RPS6KA3 are hypertelorism, scoliosis and tapering fingers [58, 92]. Diagnostic delay is common: in the Romanian series, the median interval from first symptoms to diagnosis was 7 years (2–16), and 7 of 10 patients were diagnosed more than 4 years after onset, because of overlap with common neurodevelopmental disorders, unequal access to genetic testing and lack of reimbursement [41].

The PNDS summarises the circumstances of diagnosis in boys: marked hypotonia in the newborn or infant, delayed milestones or ID in the child and moderate to severe ID in the adolescent or adult, always with dysmorphism and skeletal anomalies that become more pronounced with age. The family history should look for ID, epilepsy and falls in boys on the maternal side, and examination of the mother's face and hands may be informative, with or without a neurodevelopmental disorder or unexplained learning difficulties [15].

4.2. Red flags and emergency signs

In France, the PNDS provides for organised emergency reception with a "notable patient" record or a rare disease emergency card issued by the reference or competence centres; the card, personal and pocket-sized, sometimes bilingual, records the contact details of the family and of the reference physicians and the actions to avoid and to recommend. The CLS PNDS does not include a dedicated emergency card. The attending physician should treat any bronchopulmonary infection promptly [15].

4.3. Newborn screening

The sources consulted describe no newborn screening for CLS; diagnosis rests on clinical suspicion and genetic testing.

5. Diagnosis: Criteria, Testing and Algorithms

5.1. Criteria

There are no validated formal clinical criteria. GeneReviews defines the diagnosis in a male by the presence of suggestive findings and a hemizygous pathogenic or likely pathogenic variant in RPS6KA3; in a female, by the usual presence of suggestive findings with a heterozygous variant. P and LP variants are equivalent for clinical decision-making under the ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) standards, and a VUS neither establishes nor excludes the diagnosis [1, 94]. A family history consistent with X-linked inheritance, without male-to-male transmission, supports the suspicion, but its absence does not exclude it, given the high number of sporadic cases [1, 3].

Suggestive findings in males are: developmental delay and moderate to severe ID, with language more affected; hypotonia, SIDE, progressive spasticity or paraplegia, and seizures; kyphoscoliosis beginning in childhood and pectus; the facies described in section 3.2, especially in older children and adults; and small, soft, fleshy hands with tapering fingers, small terminal phalanges and nails, and hyperextensible fingers [1]. Radiographs of the hands, chest and spine can support the clinical diagnosis [58, 91].

The French PNDS defines the diagnosis as the combination of a suggestive phenotype with a pathogenic variant or a deletion of RPS6KA3, studied in a targeted manner (sequencing and search for rearrangements), on a panel or by genome-wide testing. It recognises that, with high-throughput sequencing, the diagnosis is sometimes molecular, in a patient with delay or ID without prior clinical suspicion, and that in attenuated forms and in women testing is indispensable. Any diagnosis should be followed by a genetic counselling appointment [15].

5.2. Testing algorithm

The 2025 systematic review describes the methods used in the 72 cases: Sanger sequencing of the gene in 18 (25%), next-generation sequencing (NGS) panel or exome in 28 (38.9%), genome in 3 (4.2%) in atypical or mosaic cases, chromosomal microarray (CMA) or MLPA in 15 (20.8%), mainly for CNVs, and combined strategies in 8 (11.1%) [10]. Prioritisation tools (CADD, REVEL, AlphaMissense) serve only as triage before ACMG/AMP curation [10].

5.3. Test yield and limitations

GeneReviews attributes 85–90% of known pathogenic variants to sequencing and 10–15% to gene-targeted deletion/duplication analysis, based on HGMD [1, 96]. These figures are proportions of the detectable variant spectrum and are not equivalent to clinical sensitivity. Diagnostic yield in clinically suspected patients has always been much lower: in the pre-NGS era, a variant was detected in about 50% of patients with suggestive clinical features [51]; in the series of 250 patients studied by SSCP (single-strand conformation polymorphism), 165 (66%) remained without a variant, and Western blot and kinase assay study of 26 of these identified seven additional variants (two coding, one intragenic deletion and four intronic outside the canonical splice sites), none in the promoter [7]; and in 2006, no variant was found in more than 60% of patients referred for screening [3]. This shortfall results from two components that the published data do not separate: variants not detected by the methods of the time and patients with other disorders of similar phenotype [7].

Current limitations are: exon sequencing does not detect exon-level deletions and duplications, structural rearrangements or retrotransposon insertions; the Romanian series, tested by sequencing alone without MLPA or microarray, did not look for CNVs [10, 41]; deep intronic variants require RNA or genome analysis [47]; leucocyte DNA may miss low-level somatic mosaicism and does not detect germline-only mosaicism, so a negative parental result does not exclude recurrence [1, 10]; and a trio exome that is negative in the parents can give false reassurance [10]. A negative test does not exclude CLS when the phenotype is suggestive.

5.4. Report content and interpretation

The report should state the gene, the transcript with its version (NM_004586.3), the variant in HGVS nomenclature at the DNA and protein levels, the zygosity (hemizygous in males, heterozygous in females), the ACMG/AMP classification with the criteria applied and, in females, where relevant, the X-inactivation study [1, 41, 94]. The Romanian series illustrates the reclassification of four VUS as likely pathogenic on the criterion of confirmed de novo occurrence [41]. For VUS review, GeneReviews suggests contacting one of the authors with experience in the gene [1]. Methylation studies allow assessment of X inactivation in females, but their value in predicting the phenotype is limited (section 2.3) [35, 41]. A molecular diagnosis of CLS does not exclude a second disorder when there are findings it does not explain [54, 55].

5.5. Non-molecular ancillary investigations

No non-molecular test is confirmatory. Useful investigations include: radiographs of the hands and spine (kyphoscoliosis, thoracic lordosis, calcification or hypertrophy of the ligamentum flavum, end plates and disc spaces), echocardiography, audiometry, polysomnography, pulmonary function tests if kyphoscoliosis is severe, and EEG to distinguish seizures from SIDE [8]. In SIDE, surface EMG with simultaneous video-EEG documents muscle silence or increased muscle activity without epileptiform discharges [27, 62]; in one adolescent girl, the interictal EEG and the video-EEG during falls were normal, showing only muscle artefact [66].

5.6. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing (PGT-M) are possible [1]. Prenatal diagnosis revealed maternal gonadal mosaicism in a third pregnancy [97], and PGT-M with haplotype construction by long-read sequencing was applied in an affected woman with a de novo variant (section 8.4) [98]. The sources consulted describe no specific prenatal ultrasound signs; prenatal growth is usually normal [1].

6. Differential Diagnosis

6.1. Comparison table

6.2. Differential diagnosis of drop episodes

SIDE are confused with atonic seizures, narcoleptic cataplexy, hyperekplexia and startle epilepsy, and several of these disorders and epilepsy may coexist in the same person [57, 62]. Epileptic seizures last longer, have a focal onset and may be associated with clonic movements and tonic posturing [1]. The absence of epileptiform discharges on video-EEG during the episode, with surface EMG showing muscle silence or a tonic increase, is the discriminating finding [62, 66]. An adolescent girl with SIDE received six antiseizure medications without benefit before the condition was recognised [66]. In Coimbra, a functional gait disorder superimposed on CLS was described, a reminder that a patient with CLS can also have functional neurological symptoms [100]. Reflex myoclonic seizures triggered by tactile stimuli are epileptic and are distinguished from SIDE by EEG [67].

6.3. Other differential contexts

In the differential diagnosis of syndromic LV non-compaction, CLS is on the list of associated syndromes [77]. In the differential diagnosis of Angelman syndrome, the Oxford Desk Reference notes that the ATR-X facies is confused with that of CLS, but that ATRX carriers have no manifestations, unlike RPS6KA3 carriers [99]. In ID without suggestive signs, the differential is that of the OMIM phenotypic series of autosomal dominant, autosomal recessive and X-linked ID [1]. A CLS-like phenotype without an RPS6KA3 variant may correspond to another disorder: in the 2002 series, the authors concluded that some patients have a phenotypically very similar condition not caused by RPS6KA3 [7], and a man with a 10q25 deletion had a suggestive phenotype [3].

The PNDS lists as differential diagnoses ATR-X syndrome, Börjeson-Forssman-Lehmann syndrome, Williams syndrome, fragile X syndrome, with more subtle dysmorphism, and, occasionally, FG syndrome type 1, all included in table 6.1, and leaves the distinction to assessment by a clinical geneticist [15].

7. Treatment and Risk Management Strategies

7.1. Principles, French guideline and organisation of care

There is no cure or targeted treatment for CLS. The only published national guideline is the French HAS PNDS (January 2025), an expert consensus based on a literature review, whose scientific rationale document is hosted by the DéfiScience network; it does not set dosing and states that drugs are used within the indications and conditions of the marketing authorisation [15]. GeneReviews proposes multidisciplinary supportive care based on expert opinion [1]. The table of follow-up recommendations in Hunter's chapter in Management of Genetic Syndromes (2010), cited by GeneReviews, and the subsequent edition of that book (2021) were not consulted for this article [1]. No OrphanAnesthesia recommendation addresses CLS; the existing one refers to Coffin–Siris syndrome, a different entity [17]. The following interventions derive from the GeneReviews synthesis, small series and case reports. General management of ID and developmental delay includes early intervention, physiotherapy, occupational and speech and language therapy, augmentative and alternative communication, applied behaviour analysis, and educational and transition plans [1].

Organisation of care according to the PNDS. The PNDS requires medical and educational care to be coordinated by a rare disease reference or competence centre focused on ID or developmental anomalies, in liaison with the paediatrician or general practitioner, and to continue into adulthood. The aims are to monitor the neurodevelopmental trajectory, to start rehabilitation (speech and language therapy, physiotherapy, psychomotor therapy, occupational therapy) as soon as the first signs appear and before aetiological confirmation, to screen for and treat neurological, osteoarticular, cardiac and sensory complications, to monitor nutrition and growth and to provide genetic counselling and, when requested, prenatal or preimplantation diagnosis. Speech and language therapy starts early, for oral language and for oral and tongue motor skills, and augmentative and alternative communication (PECS, Makaton) can accompany the learning of oral language. Schooling is adapted to the level of ID: inclusion in mainstream settings is possible at least at preschool, always with a support assistant for pupils with disabilities; from age 6 years, most boys attend a medico-educational institute, because they rarely acquire reading and writing, whereas many girls lead lives without limitations; at around age 5 years a neuropsychological assessment should be offered to guide the choice between mainstream school, an inclusive school unit or the medico-educational institute. In dental care, brushing starts with the eruption of the first tooth, monitoring looks for crowding, malposition and caries, and some patients need teams experienced with disability and conscious sedation with an equimolar mixture of oxygen and nitrous oxide. Therapeutic education begins when the diagnosis is disclosed and prepares the family to manage SIDE, seizures and episodes of discomfort [15].

Doses of drugs cited by the PNDS without dosing. The PNDS mentions drugs without doses; as none has an indication in CLS, the doses below come from the official label for the closest indication or from a general paediatric consensus and constitute extrapolation to CLS. The doses of clonazepam, valproate, fluoxetine, clomipramine and sodium oxybate are given in sections 7.2 and 7.12.

Constipation: paediatric guideline and label. The 2014 joint ESPGHAN/NASPGHAN guideline, based on a systematic review using GRADE methodology and consensus by nominal voting, applies to functional constipation and not to constipation associated with an underlying disease; transposing its doses to CLS, in which the PNDS attributes constipation to hypotonia, is an extrapolation [15, 109]. The guideline recommends normal fibre and fluid intake and normal physical activity, demystification, explanation and guidance on toilet training from a developmental age of at least 4 years, and does not routinely recommend prebiotics, probiotics, intensive behavioural programmes, biofeedback, multidisciplinary treatment or alternative treatments [109]. In faecal impaction, oral macrogol and enemas had similar efficacy; the group preferred macrogol because it is oral, even though the high dose is accompanied by more faecal incontinence during disimpaction, and reserved a daily enema for 3–6 days for when macrogol is not available [109]. For maintenance, macrogol was more effective than lactulose, milk of magnesia, mineral oil and placebo; adding enemas to chronic macrogol is not recommended, lactulose is first line when macrogol is not available, and milk of magnesia, mineral oil and stimulant laxatives may be considered as additional or second-line treatment, on expert opinion [109]. Maintenance lasts at least 2 months, symptoms should have resolved for at least 1 month before stopping, reduction is gradual and, during toilet training, medication is stopped only once training is complete [109]. The UK SmPC of Movicol® Paediatric Plain states that treatment of chronic constipation in children should be prolonged (at least 6–12 months), but that safety and efficacy have been demonstrated only up to 3 months, and describes isolated cases of reduced efficacy of concomitantly taken medicines, for example antiseizure medications, which is relevant in patients with SIDE or epilepsy [110]. Mineral oil, accepted by the guideline as second line, is advised against by the PNDS in CLS because of the risk of aspiration [15, 109].

7.2. Stimulus-induced drop episodes

Non-pharmacological measures. Recognition of SIDE allows early intervention to minimise triggering stimuli and protect the patient from falls; the specific stimuli that trigger episodes in each person should be avoided [1]. The patient foundation reports that anxiety increases the likelihood of episodes and that many patients walk at home and use a wheelchair outside it [63]. A protective helmet and a wheelchair reduce injuries when episodes are frequent [1]. In one patient with OSA, tracheostomy also improved SIDE [1, 85].

Drugs. All drugs used for SIDE are off-label, and no trial has compared treatments. Agents used include benzodiazepines (clonazepam, clobazam, lorazepam), other antiseizure medications (tiagabine, felbamate, valproic acid, carbamazepine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, escitalopram), a tricyclic (clomipramine) and sodium oxybate [1, 66]. Benzodiazepines are usually the first choice, and conventional antiseizure medications are often ineffective; most drugs have not provided significant long-term control, with improvement in selected cases with clonazepam, unspecified benzodiazepines, sodium oxybate, fluoxetine and clomipramine, and valproic acid improved one patient [1, 46, 51, 66]. The table compiles the cases with sufficient description.

The Coffin-Lowry Syndrome Foundation states that clonazepam or clorazepate is partially effective, with tolerance, suggests schedules of three weeks on the drug and one week off, or a morning dose only, and asserts that lamotrigine "appears to be the most consistently effective drug"; these statements cite no primary source, and the two reports with detailed descriptions recorded lamotrigine as ineffective [63, 66, 106]. The discrepancy shows that information for families does not replace individual clinical decision-making.

Reference dosing. There are no established doses for SIDE. The doses below are those on the FDA labels for the approved indications and serve as safety limits, not as recommendations for CLS; in Portugal and Brazil, decisions follow the national summary of product characteristics, which was not consulted [114–118].

The European summary of product characteristics (SmPC) for Xyrem® defines dosing in the approved indication, which does not include CLS or SIDE; any use for these episodes is off-label [119]. In adults, the starting dose is 4.5 g/day in two equal doses of 2.25 g, the first at bedtime, at least 2–3 hours after a meal, and the second 2.5–4 hours later, both prepared before bedtime and diluted in 60 mL of water; titration is in increments of 1.5 g/day (0.75 g per dose), at intervals of at least one to two weeks, up to a maximum of 9 g/day (4.5 g + 4.5 g), which must not be exceeded because doses ≥18 g/day can cause serious symptoms [119]. A single 4.5-g dose is given only to patients titrated up to that dose, and an interruption of more than 14 consecutive days requires restarting at the lowest dose [119]. In children from age 7 years and 15 kg, the starting total daily dose is ≤1 g (15–<20 kg), ≤2 g (20–<30 kg), ≤3 g (30–<45 kg) or ≤4.5 g (≥45 kg), with weekly increases of ≤0.5 g, ≤1 g, ≤1 g and ≤1.5 g, respectively; the maximum is 0.2 g/kg/day below 45 kg and 9 g/day from 45 kg, with regular weighing during titration [119]. The product is not recommended under age 7 years and must not be given to children weighing less than 15 kg [119]. The starting dose is half the usual dose in hepatic impairment, and co-administration with valproate requires a 20% reduction (starting dose of 3.6 g/day in adults), because co-administration increased oxybate exposure by about 25% and worsened somnolence and cognitive impairment [119]. This European paediatric dosing differs from the US dosing, which makes no recommendation below 20 kg and sets starting doses per administration [115, 119].

The SmPC contraindicates sodium oxybate in hypersensitivity to the drug or its excipients, major depression, succinic semialdehyde dehydrogenase deficiency and patients treated with opioids or barbiturates [119]. The warnings most relevant to CLS are respiratory and central nervous system (CNS) depression, with prior assessment for sleep apnoea, caution in underlying respiratory disease and close monitoring with a body mass index ≥40 kg/m²; the recommendation to avoid combination with benzodiazepines because of the risk of respiratory depression and not to combine it with alcohol, sedative hypnotics or other CNS depressants; the recommendation against use in epilepsy, because seizures have been observed and safety and efficacy have not been established in these patients; cases of coma and increased GHB concentrations with topiramate; abuse potential; porphyria; neuropsychiatric events (confusion, depression, suicidal ideation, psychosis, sleepwalking); and the sodium content, 182.24 mg per gram of oxybate, which at the maximum dose equals 82% of the maximum daily intake recommended by the WHO and matters in heart failure, hypertension and renal impairment [119]. In children, parents or caregivers should observe breathing during the first two hours after each dose during titration, should not give the second dose if there is an abnormality after the first and should not repeat a dose when in doubt; if such monitoring is not possible, the product is not recommended without medical supervision [119]. In CLS, these warnings have practical consequences: OSA, pulmonary restriction and hypotonia increase respiratory risk, coexisting epilepsy argues against its use, and the usual SIDE treatments with benzodiazepines, valproate or topiramate interact with oxybate [1, 119]. In Havaligi's case, antiseizure medications (including phenobarbital and topiramate) had been ineffective before oxybate was introduced, and in Arslan's case oxybate was added to clonazepam, a combination the SmPC says to avoid [66, 106, 119].

The decision to start a drug should weigh the expected benefit, which in the reports is partial and inconsistent, against adverse effects that are relevant in a population with hypotonia, OSA and aspiration risk: sedation and respiratory depression with benzodiazepines and sodium oxybate, tolerance to benzodiazepines and hepatotoxicity of valproate, with increased risk in severe ID with seizures [114–116]. Benzodiazepines should be tapered gradually to limit withdrawal [114].

The PNDS assigns the diagnosis of SIDE and their distinction from epilepsy, cataplexy and hyperekplexia to the paediatric neurologist or neurologist, and cites as drugs that "appear to be effective" lamotrigine, benzodiazepines (clobazam, clonazepam), fluoxetine, valproic acid, tiagabine and sodium oxybate; the inclusion of lamotrigine contrasts with the lack of efficacy described in the two detailed reports (section 7.15). It also mentions the improvement of a refractory patient after treatment of sleep apnoea by tracheostomy, a reduction in episodes after treatment of scoliosis described by some authors, with no causal relationship established, because SIDE also occur without vertebral deformity, and the use of a helmet and wheelchair to limit injuries [15].

7.3. Epilepsy

Seizures are treated with standard antiseizure medications chosen by an experienced neurologist, because none has shown a specific benefit in CLS [1]. The 2025 review records that valproate was the most frequently reported antiseizure medication and cites, through indirect attribution, levetiracetam escalated to 1,250 mg (time unit not stated), topiramate to prevent febrile seizures and lamotrigine 75 mg twice daily, effective in a patient refractory to topiramate and levetiracetam [10]. In Havaligi's 22-year-old man, generalised tonic-clonic seizures, atypical absences and myoclonus since age 3 years were controlled with valproate and clonazepam, whereas the SIDE did not respond [106]. Distinguishing seizures from SIDE by video-EEG avoids escalation of ineffective antiseizure medications [66].

The PNDS requires confirmation first that the events are epilepsy and not SIDE, and treatment according to seizure type and the initial work-up, with no pharmacological specificity. When a previously stable epilepsy worsens, triggers should be sought: pain (constipation, orthopaedic or dental pain), urinary tract infection, otitis, sleep disturbance, altered bowel habit or poor adherence, especially in patients with limited communication. Motor or cognitive regression, or the onset of behavioural changes, should prompt consideration of epilepsy even without previous seizures [15].

7.4. Behaviour and mental health

GeneReviews cites a multimodal evaluation of risperidone for destructive behaviour (functional analysis, direct observation, rating scales and psychiatric impression) as the basis for considering this drug [1, 101]. The 2025 review lists, without verifiable doses, aripiprazole for compulsive behaviours; thioridazine, clotiapine and levomepromazine for psychosis and anxiety; and haloperidol, nitrazepam, lorazepam and chlorpromazine in older series [10]. ADHD is treated in the usual way, and severe aggression requires psychiatric care [1]. The adolescent girl with new-onset psychosis improved with outpatient psychological and behavioural intervention [90]. Psychiatric disorders in heterozygous females (section 3.11) justify active screening and early referral [1].

The PNDS recommends regular assessment of behaviour, looking first for pain and its cause in the face of any change, adapting care after psychological and/or psychiatric assessment and resorting, when necessary, to behavioural therapy, psychotropic drugs and multisensory relaxation techniques (Snoezelen) for anxiety [15].

7.5. Spine and orthopaedics

Bracing and spinal surgery may be indicated to prevent restriction of lung volume and neurological compromise [1]. In the Welborn series, bracing was used in three patients without improvement or slowing of progression; four instrumented posterior spinal fusions and one placement of magnetically controlled growing rods (MAGEC) were performed [69]. The authors recommend a lower threshold for correction and for early decompression, especially when there is calcification of the ligamentum flavum; growth-friendly constructs may be considered, and skeletal maturity may not be reached until the middle or end of the third decade, which requires planning with endocrinology [69]. Herrera-Soto and colleagues also consider spinal deformities difficult to treat and in need of early surgery, and recommend observation only for the hand, foot and pelvic changes [73]. For calcification of the cervical ligamentum flavum due to calcium pyrophosphate deposition, one patient was followed for eight years after laminectomy [120]; Welborn cites neurological improvement two weeks after early decompression and long-term preservation of ambulation [69]. Severe pectus excavatum may require surgery [1].

The PNDS considers spinal alignment a central axis of follow-up, to be examined at every visit; treatment is often orthopaedic (brace) and sometimes surgical, and surgery should be considered earlier than in other populations to limit the risk of spinal cord compression, with a multidisciplinary decision on timing according to bone maturation. Flat feet can be treated with insoles. Spasticity and joint stiffness require physiotherapy and orthoses, a search for the cause (calcification of the ligamentum flavum, stenosis of the canal or of the foramen magnum, vertebral deformity) and, as symptomatic treatment, muscle relaxants and/or local botulinum toxin injections, with physical medicine and rehabilitation and/or orthopaedics. The risk of fracture, greater with reduced mobility, justifies monitoring dietary calcium intake and supplementing it if insufficient, supplementing vitamin D as in all children and encouraging physical activity; the summary for the attending physician mentions preventive treatments for bone fragility, especially before orthopaedic surgery (doses in section 7.1) [15].

7.6. Heart

Valvular disease and cardiomyopathy are managed in the usual way under cardiology, with possible restriction of physical activity [1]. Published cases include mitral valve repair in a boy with recurrent heart failure, mitral and tricuspid surgery at age 14 years, and mitral repair with tricuspid annuloplasty at age 18 years [74, 78, 79]. The 2025 review records, without doses, angiotensin-converting enzyme inhibitors for worsening mitral regurgitation, digoxin, diuretics and angiotensin receptor blockers before surgery [10].

The PNDS manages congenital malformations according to general population protocols and acknowledges that there is no consensus recommendation for the risk of cardiomyopathy; in the absence of a malformation at the diagnostic work-up, it proposes an annual clinical examination and an echocardiogram at diagnosis and then at least every 2–5 years in childhood and every 5–10 years later, or as advised by the cardiologist (section 11.3) [15].

7.7. Respiratory system and sleep

OSA is treated with CPAP or surgery, under sleep medicine, with otorhinolaryngology and anaesthesia [1]. Tracheostomy was required in one patient and improved both the OSA and the SIDE [85]. Restrictive lung disease from severe kyphoscoliosis can cause undiagnosed chronic hypercapnic respiratory failure; in Venter's case, the acute exacerbation was treated with nebulised bronchodilators (ipratropium and salbutamol), intubation, and extubation the next day to bilevel positive airway pressure (BiPAP) non-invasive ventilation, and the patient was discharged on oxygen at 2 L/min by nasal cannula and BiPAP as needed [86]. In a 27-year-old Brazilian man with severe pneumonia, septic shock and moderate ARDS, lung-protective ventilation (tidal volume of 3–6 mL/kg of predicted body weight, driving pressure ≤15 cmH2O, plateau pressure <30 cmH2O, positive end-expiratory pressure of 12 cmH2O) and noradrenaline up to 0.1 µg/kg/min for 48 hours allowed weaning, despite mucus plugging and atelectasis on day seven of ventilation [121]. Aspiration is a cause of death in the historical series, and swallowing assessment should be part of follow-up [1, 88]. A chewing and swallowing training programme was registered on ClinicalTrials.gov (NCT04199546) and published as a case report, without confirmation that they are the same study [16, 122].

For sleep disorders, the PNDS requires a search for apnoeas and consideration of referral to a sleep centre; in the presence of central and/or obstructive apnoeas or alveolar hypoventilation, oxygen therapy or non-invasive ventilation is decided case by case, at a multidisciplinary meeting and according to the degree of disability. For delayed sleep onset or night-time awakenings without apnoea, bedtime routines or melatonin may be useful (dose in section 7.1) [15].

7.8. Growth and endocrine system

The safety and efficacy of growth hormone have not been studied, and it has been suggested that it might worsen the deformities and the calcification of the ligamentum flavum; the Romanian series concludes that current evidence does not support its use [1, 41, 123]. Nutritional surveillance aims to prevent obesity [41]. For central precocious puberty in the Korean girl (Tanner stage II at age 7 years 9 months, bone age 9 years 6 months, peak luteinising hormone 5.7 mIU/mL on gonadotrophin-releasing hormone stimulation testing), leuprorelin 3.75 mg every four weeks led to regression of pubertal development [27]. In the severe recurrent hypercalcaemia reported by Tise and colleagues, the first admission resolved with intravenous fluids; in the second, at age 12.5 months (calcium 14.3 mg/dL), calcitonin (four doses of 4 U/kg every 12 hours) was ineffective and a single dose of pamidronate 0.5 mg/kg gave a good response; in the third, at age 15 months (12.5 mg/dL), a single dose of zoledronate 0.0125 mg/kg was used in the expectation of a longer duration of effect [35]. These regimens come from isolated cases and do not constitute recommendations.

The PNDS states that growth hormone is not usually offered and might even be advised against, because of its potential effects on spinal alignment, bone growth and ligament calcification. Height, weight and head circumference are recorded regularly, and a fall-off in the curve prompts aetiological investigation. In women, the body mass index curve should detect overweight (IOTF-25 threshold up to age 18 years, ≥25 kg/m² thereafter) and obesity (IOTF-30, ≥30 kg/m²), and a change of centile channel prompts endocrinology or nutrition assessment. For nutrition and the digestive system, neonatal sucking-swallowing dysfunction requires weight monitoring and specialised speech and language therapy, with a temporary nasogastric tube if the risk of aspiration is significant and possible enteral nutrition; overt reflux is treated with thickening, positioning during and after meals and, if necessary, H2 antagonists or proton pump inhibitors; suspected occult reflux requires 24-h pH monitoring, and Nissen fundoplication is discussed in complicated, uncontrolled reflux; constipation is treated first with hydration, fibre, mobilisation, standing and abdominal massage and, if insufficient, with osmotic laxatives such as macrogol at a dose adjusted to bowel habit, avoiding liquid paraffin because of the risk of aspiration and limiting suppositories (doses in section 7.1) [15].

7.9. Perioperative care and anaesthesia

GeneReviews recommends addressing intubation and ventilation problems before any surgery or procedure under anaesthesia or sedation [1]. The historical series record several deaths after complications of general anaesthesia and the death of a patient with chronic apnoea from respiratory complications after mandibular advancement surgery [1, 88]. Three recent reports illustrate the risks:

A review of perioperative management in a patient with severe obesity is hosted by ERN ITHACA [18, 87]. Taken together, the reports point to preoperative assessment of the airway, the heart (echocardiography) and respiratory function, preparation for a difficult airway, and attention to prone positioning in patients with chest deformity [1, 93, 124].

The PNDS recommends that major surgery be weighed with the parents, setting out the expected benefits and the risks, as in any patient with severe ID or multiple disabilities. Given the difficult airway (severe ID and retrognathia), it considers fibreoptic intubation with preserved spontaneous ventilation preferable to awake intubation, based on Ghose's report, and requires the postoperative period to be planned in advance, with attention to the risk of osteoporosis [15, 124].

7.10. Agents and circumstances to avoid

The specific stimuli that trigger SIDE in each patient should be avoided, and physical activity may need to be restricted in valvular disease, as advised by the cardiologist [1]. Growth hormone has no supporting evidence (section 7.8) [41]. Long-acting sedative drugs call for caution in the presence of a difficult airway, OSA and pulmonary restriction [114, 115, 124]. Sodium oxybate carries a warning for CNS and respiratory depression, is contraindicated with opioids or barbiturates and should not be combined with benzodiazepines, alcohol or other CNS depressants [115, 119].

The PNDS advises against liquid paraffin for constipation, because of the risk of aspiration, and accepts that growth hormone may be advised against; the over-the-counter macrogol label prohibits mixing with starch-based thickeners used in dysphagia [15, 112].

7.11. Pregnancy, lactation and transition

The sources consulted describe no pregnancies in women with CLS outside the PGT-M setting (section 8.4) [98]. The GeneReviews recommendation to plan the airway before any procedure under anaesthesia or sedation also applies to labour analgesia and obstetric anaesthesia in affected women [1]. For the drugs used for SIDE, the labels state: valproate, a teratogenicity warning with reduced IQ and neurodevelopmental impairment [116]; clonazepam, neonatal sedation and withdrawal syndrome when used late in pregnancy, no clear association with major malformations in observational studies, and a pregnancy exposure registry for antiseizure medications [114]; sodium oxybate, no adequate data in pregnant women, excretion of GHB in milk and increased offspring mortality in rats exposed during pregnancy and lactation [115]; and fluoxetine, a risk of persistent pulmonary hypertension of the newborn and poor neonatal adaptation with late use [117]. Transition to adult care should be planned in adolescence, including the support available up to age 21 years in the US system described by GeneReviews [1]. ERN ITHACA identifies lack of knowledge of the female phenotype as an obstacle to neurological and orthopaedic care for adult women [18].

The PNDS provides no data on pregnancy in affected women and states that carriers do not, in principle, have impaired fertility. The child–adolescent–adult transition should be anticipated with the reference centre, which often has its own protocol, and covers medical follow-up, rehabilitation and medico-social support; updating of investigations and a complete clinical file for the new team should be prepared well in advance. In France, placement in a medico-educational institute can be extended beyond age 20 years under the "Creton" provision while awaiting a place in an adult facility; the transition to adulthood at the MDPH (at age 20 years) is prepared 9–12 months beforehand, and from age 18 years a legal protection measure (curatorship, guardianship or family authorisation) is discussed with the family [15].

7.12. Comparative regulatory status

No medicinal product has an approved indication for CLS or SIDE; all the uses described are off-label. The table compares the labels consulted.

Sources: [114–119, 126]. The public EPAR summary (updated in 2021) still describes the indication in adults only, whereas section 4.1 of the current SmPC includes children and adolescents from age 7 years; the SmPC prevails [119, 126].

7.13. Clinical trials and limits of the evidence

A ClinicalTrials.gov search on 18 October 2026 ("Coffin-Lowry", "RPS6KA3" and "stimulus-induced drop") identified no pharmacological therapeutic trials for CLS [16]. GeneReviews already acknowledged that there may be no trials for this disorder [1].

The therapeutic evidence is at the case-report level, with publication bias favouring positive responses, no control group, non-comparable doses (and, in one report, an implausible dose) and patients heterogeneous with respect to molecular diagnosis. Drugs cannot be compared across reports, nor can the response of one adult be extrapolated to children. The negative reports (lamotrigine, escitalopram, phenobarbital, levetiracetam, phenytoin and topiramate without benefit for SIDE) carry the same informational weight as the positive ones [66, 106]. A search of the European trials register returned no readable results, and the absence of trials on ClinicalTrials.gov does not prove that none exist in other registries.

7.14. Developments in the past 12 months and research

From October 2025 to October 2026, no authorisation, regulatory opinion or therapeutic trial for CLS was identified in the sources consulted. The publications from this period are observational: a systematic review of 72 molecularly confirmed cases (2025 volume; level of evidence: published case series) [10]; the Romanian series of 10 patients with the first intron 10 LINE-1 insertion diagnosed by RNA-seq (2026, single-centre series) [41]; the review of 28 Chinese patients (2025) [59]; cardiovascular collapse in the prone position during spinal fusion (2025, case report) [93]; and cases of co-occurrence with galactosaemia, of neonatal hypothyroidism and of a Mexican boy diagnosed with a 491-gene panel (2026, case reports) [55, 56, 127]. At the preclinical level, computational modelling has suggested drug combinations for synaptic plasticity disorders with shared signalling pathways, and RSK2-deficient mouse and Drosophila models are being used to study spatial learning, fear conditioning and glutamatergic signalling; none of these approaches has reached human studies [7, 10, 128].

7.15. Recommendations and divergences among sources

The available recommendations are those of the 2025 French PNDS, the only national guideline, those of GeneReviews (expert opinion), the proposals of the 2025 and 2026 series and the patient organisation's information [1, 15]. They converge on the need for spinal and neurological, cardiac, hearing, respiratory and sleep surveillance [1, 10, 41]. They diverge on three points: the 2025 review proposes endocrine-metabolic (glucose, lipids, puberty) and bone health screening, which is absent from GeneReviews [10]; GeneReviews specifies an echocardiogram every 5 to 10 years even if normal, whereas the Romanian series recommends an electrocardiogram and echocardiogram at diagnosis and periodically, without specifying an interval [1, 41]; and the patient organisation attributes to lamotrigine an efficacy for SIDE that the published reports do not confirm [63, 66, 106].

The divergences between the PNDS and the other sources are as follows; as the PNDS does not set doses, the reference doses remain those of the labels, the paediatric constipation guideline and the reports cited in sections 7.1 and 7.2.

8. Reproductive Options and Family Counselling

8.1. Mechanism of inheritance and proportion of de novo cases

RPS6KA3-ID is transmitted in an X-linked manner [1]. The proportion of cases without familial transmission is high, but the sources give different figures: OMIM, citing the review by Pereira and colleagues (2010), states that about 70–80% of patients are sporadic cases [3]; GeneReviews, citing the same review, writes that about two-thirds of CLS-associated variants arise de novo and that there are no equivalent data for the mild end of the spectrum [1]; in the 1998 series of 37 patients, 68% of variants were de novo [7]; and in the 2026 Romanian series all 10 variants were de novo [41]. The difference between "sporadic" (no other affected relatives) and "de novo" (variant absent in the parents) explains part of the divergence, because a sporadic case may have a mildly symptomatic heterozygous mother.

8.2. Recurrence risks by scenario

8.3. Germline mosaicism and cascade testing

Maternal germline mosaicism has been documented since 1998: in a family with a variant at the intron 4 splice acceptor site, which caused in-frame skipping of exon 5 and absence of RSK2 on Western blot, the variant was present in an affected son and a manifesting daughter, absent in two asymptomatic daughters who had inherited the at-risk haplotype, and absent in the lymphocyte DNA of the clinically normal mother, in whom SSCP analysis showed very faint bands corresponding to less than 1% of mutant DNA; linked markers would have led to incorrect counselling [7, 129]. In 2001, prenatal diagnosis in the third pregnancy of a mother without the variant in lymphocytes detected it in the fetus, a second example of gonadal mosaicism [97]. A negative maternal result in blood therefore does not exclude transmission, and the 2025 review recommends high-sensitivity methods (deep sequencing, digital PCR) when mosaicism is suspected [1, 10].

Heterozygote testing requires an identified familial variant; heterozygotes have a high risk of manifestations and should be evaluated for the actionable complications of the spectrum [1]. X-inactivation studies to identify carriers are hazardous, except where there is near-complete (>95%) skewing consistently present in all obligate carriers of a large family [58]. The maternal diagnosis made after the daughter's, in Tise's report, in a mother with completely skewed inactivation and a minimal phenotype, shows that cascade screening identifies heterozygotes that clinical examination misses [35]. Testing of at-risk minor girls has direct clinical utility, because heterozygotes may have ID, kyphoscoliosis, heart disease and psychiatric disorders that benefit from surveillance [1]; the decision is part of counselling for the family.

The PNDS adds rules for cascade testing: the father of an affected boy does not need testing; in de novo cases, the recurrence risk is limited to germline mosaicism, so the sisters of sporadic cases should be informed and tested from the age of majority; when the mother is a carrier, testing of the maternal grandmother should be offered and, if this is not possible or not wanted, women on the maternal side should be informed and offered testing after a genetics clinic appointment; and, even if the variant arose de novo in the mother, her sisters remain at risk because of possible mosaicism in one of the grandparents [15].

8.4. Prenatal diagnosis and preimplantation genetic testing

The ideal time to determine risk and discuss prenatal diagnosis and PGT-M is before pregnancy; both are possible once the familial pathogenic variant has been identified, and views on their use differ among professionals and among families [1]. Amniocentesis with targeted sequencing and exome sequencing of amniotic fluid DNA have been described [10]. In a woman with CLS due to the de novo variant c.1496delG p.(Gly499Valfs*25), with no other relatives available to establish phase, the haplotype of the variant and neighbouring polymorphisms was constructed by Oxford Nanopore long-read sequencing; embryos were analysed by the MARSALA method (haplotype and CNV), an unaffected embryo was transferred, and amniocentesis at 17 weeks (Sanger sequencing and karyotype) confirmed the result [98]. PGT-M, with or without aneuploidy testing, is also an option for families with maternal mosaicism [10].

In the French framework described by the PNDS, with an inherited or de novo variant, invasive prenatal diagnosis may be offered for a male fetus, preceded by determination of fetal sex in maternal blood; chorionic villus sampling is performed from 11 weeks of gestation and amniocentesis from 16. In a female fetus, the wide variability of expression, from asymptomatic to severe, makes the decision complex and requires case-by-case discussion. Preimplantation diagnosis is offered when the variant is inherited, and both require a favourable opinion from a multidisciplinary prenatal diagnosis centre [15].

8.5. Content of counselling

Counselling should explain the nature of the disease, the variability in women, the absence of a genotype–phenotype correlation useful for predicting severity, the residual risk due to germline mosaicism and the difference between an RPS6KA3 variant and a clinical diagnosis of CLS [1]. The Coffin-Lowry Syndrome Foundation informs families that 70–80% of cases occur without a family history and with a mother who does not have CLS, and that a woman with CLS has a 50% chance of transmitting the variant [130]. In the Romanian series, counselling was available only at reference centres [41]. GeneReviews includes renewed counselling on family planning among the topics to review at each visit [1].

The PNDS organises disclosure in a dedicated appointment, in a suitable setting and with both parents or the legal representatives, with information on the results, the disease and its complications, the multidisciplinary follow-up coordinated by the reference centre, the mode of transmission and the possibility of prenatal or preimplantation diagnosis; it systematically offers a psychology appointment, at a time chosen by the parents, and a medical appointment shortly after disclosure. The genetic counselling appointment, conducted by a geneticist or a genetic counsellor, is mandatory, separate from but close to disclosure, and serves to complete the information, explain transmission, offer testing to the mother, assess the recurrence risk, identify at-risk relatives and inform of the legal obligation to warn them (French Decree No. 2013-527 of 20 June 2013 on information to relatives), including the possibility of asking the physician to do so [15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what each figure measures

Sources: [1, 3–5, 14, 15, 66, 121]. GeneGuidance uses the Orphanet figure and stresses that all figures are expert impressions, not population ascertainment, and that the mild end of the spectrum is under-ascertained [8]. Underdiagnosis in women and in atypical presentations means that the true prevalence is unknown [10]. In the context of X-linked ID, the 20–40% excess of males among people with ID and the estimate that X-linked forms account for about 10% of ID have not been confirmed in clinical surveys [58].

9.2. Geography and ancestry

No geographical or ethnic clustering and no founder variants have been described; the disease has been reported worldwide and most variants are private [7, 41]. The distribution of the 72 cases in the 2025 review reflects where reports are published, not prevalence: USA 17 (23.6%), China 15 (20.8%), Japan 8 (11.1%), Italy 7 (9.7%), Turkey, Lebanon and Spain 6 each (8.3%), Poland 4 (5.6%) and isolated reports from Portugal, Iran and Korea; the abstract of the same article gives China 14, USA 14 and Japan 9, contradicting the results [10]. Other regional data: African American families with the Arg114Trp variant (published designation, consistent with NM_004586.3:c.340C>T p.(Arg114Trp)) in the USA, in whom assessment of the lips was considered difficult because of ethnic background [3, 7]; seven families from five European centres described in 1988 [3]; four novel variants in women described in 2010 [65]; a Lebanese family with type 2 diabetes [81]; an infant from the Cook Islands with a single-nucleotide deletion, whose brother died at 7 months [7]; 28 Chinese patients published up to 2025, with nonsense variants in 37.5%, frameshift in 20.8%, splicing in 16.7%, missense in 12.5% and exon deletions in 8.3% of 24 sequenced, with no hotspots [59]; and 10 patients at a Romanian centre over six years [41].

Portugal is represented by a case published by the Neurology Department of the Centro Hospitalar e Universitário de Coimbra in 2019, on a bizarre gait due to a functional disorder superimposed on CLS; only the article's metadata were consulted [100]. Brazil is represented by the case of a 27-year-old man treated at a tertiary public hospital in Brasília in 2015 for severe pneumonia with ARDS (section 7.7) [121]. The sources consulted contain no national epidemiological data for Portugal or Brazil, which does not demonstrate that none exist.

9.3. Special populations

Heterozygous women are the most underdiagnosed population: many are identified only in adulthood, after a male relative [18]. Adults are probably underdiagnosed, and the men described at older ages (34, 45 and 48 years) show that survival can far exceed the historical mean values [1, 10, 86]. In people with profound ID and no language, GeneReviews advises attention to changes in the expression of pain, in gait and in bowel and bladder habits [1].

9.4. Reference networks and patient organisations

In Europe, the relevant network is ERN ITHACA (congenital malformations and rare ID), which maintains a page on CLS and launched a call for collaboration, now closed, on the neurodevelopmental and malformative phenotype of women, coordinated at the Hôpital La Pitié-Salpêtrière in Paris [18]. The Coffin-Lowry Syndrome Foundation (USA), founded in 1991, provides information for families, a guide for the first 100 days after diagnosis (November 2024), a fact sheet revised in April 2026, a page on SIDE, family matching and a database that has served studies such as those of Stephenson and Welborn [19, 57, 69, 130]. NORD maintains a profile of the foundation [131]. GeneReviews also lists MedlinePlus and NINDS as information resources [1]. The sources consulted identify no CLS-specific organisations in Portugal or Brazil.

In France, the PNDS was coordinated by the reference centre "Déficiences intellectuelles de causes rares" (coordinated at the Hôpital Pitié-Salpêtrière, AP-HP, Paris), part of the DéfiScience network (rare neurodevelopmental disorders), which has 12 reference centres and 11 competence centres listed in the PNDS annex, including one in Pointe-à-Pitre; the centres of the AnDDI-Rares network (developmental anomalies) can also coordinate care. The Xtraordinaire association brings together families affected by X-linked ID, and there is a group of CLS families in France that took part in the review of the PNDS; the PNDS also lists UNAPEI, the Alliance Maladies Rares and the Maladies Rares Info Services helpline. Administratively, CLS gives access to exemption from the ticket modérateur (100% coverage) as an off-list long-term condition, and the MDPH grants the AEEH (up to age 20 years), the AAH (adults), the PCH, mobility inclusion cards and educational and medico-social placements (early medico-social action centres up to age 6 years, home-based special education services, medico-educational institutes, adult facilities and sheltered work services), and the CAF grants the AJPP; applications are renewed 6 months before rights expire. The coordination of the ERN ITHACA call on the female phenotype is based at the same Paris hospital [15, 18].

10. Illustrative Clinical Case

10.1. Girl with SIDE, precocious puberty and a de novo variant (Song and colleagues, 2022)

Song and colleagues described the first Korean girl with molecularly confirmed CLS [27]. Born at term weighing 3,210 g, the only child of non-consanguineous parents (father 182 cm, mother 168 cm), she had hypotonia and joint hyperlaxity from the first month, walked at 18 months and produced two-word sentences only at 5 years. At 5 years 5 months she measured 106 cm (standard deviation −1.386), weighed 20.0 kg and had a head circumference of 50.0 cm; she had a prominent forehead, hypertelorism, downslanting palpebral fissures, thick lips, micrognathia, pectus excavatum and short tapering fingers with "puffy" hands. Developmental assessment showed global delay; there was hypodontia (absent first molars), malocclusion and astigmatism, with normal hearing, echocardiogram and EEG. MRI showed multiple bilateral frontal white matter lesions and a left paraventricular cyst; bone age was advanced by 2 months, and there was lumbar scoliosis.

The initial suspicion was a RASopathy (Noonan or Costello syndrome), and exome sequencing, performed at 5 years 5 months, found no variants in ATRX, HRAS, MAP2K1, PHF6 or PTPN11, but identified the heterozygous variant c.326_338delinsCTCGAGAC p.(Val109Alafs*10) in RPS6KA3 (NM_004586.2), absent in the parents and in control databases, classified as likely pathogenic [27]. From age 7 years she had SIDE, dozens per day, documented by simultaneous surface EMG and video-EEG. At 7 years 9 months central precocious puberty appeared (Tanner II, bone age 9 years 6 months, peak luteinising hormone 5.7 mIU/mL), treated with leuprorelin 3.75 mg every four weeks, with pubertal regression. Clobazam was replaced by clonazepam because of somnolence, and the article states that the frequency of SIDE was "reduced to 30%" with clonazepam, without giving doses. At 8 years 7 months, the scoliosis measured 23° Cobb; the child communicated, wrote her name, counted to eight and walked unaided, but fell about 10 times a day because of hypotonia [27].

The figures of the article were consulted only through their legends, without visual reading of the images: Figure 1 shows "puffy" hands with short tapering fingers at 5 years 5 months (https://pmc.ncbi.nlm.nih.gov/articles/PMC10073030/figure/f1-apem-2142134-067/), and Figure 3 the anteroposterior and lateral spinal radiographs with 23° scoliosis (https://pmc.ncbi.nlm.nih.gov/articles/PMC10073030/figure/f3-apem-2142134-067/) [27].

The case brings together several points of this article: the full phenotype in a heterozygote with a de novo variant, the initial suspicion of another RAS-MAPK pathway disorder, SIDE confirmed by neurophysiology, bone age advanced by precocious puberty (contrary to the usual delay) and only a partial response to clonazepam. Leuprorelin was used in its indication of central precocious puberty, and the treatment of SIDE corresponds to the off-label use discussed in section 7.2, not to a routine regimen. The published notation uses the .2 version of the transcript; in VariantValidator, the variant has the same designation in NM_004586.3 (NM_004586.3:c.326_338delinsCTCGAGAC p.(Val109AlafsTer10); NC_000023.11:g.20195133_20195145delinsGTCTCGAG).

10.2. Adult man with restrictive lung disease (Venter and colleagues, 2019)

A 33-year-old man with previously diagnosed CLS, with no published variant, was admitted with a two-day cough, hypoxaemia and dyspnoea (heart rate 103/min, SpO2 88% on room air, pH 7.38, PCO2 58 mmHg, HCO3 34 mmol/L) [86]. He had a broad nose, large ears, hypertelorism, downslanting fissures, oligodontia, pectus excavatum and severe kyphoscoliosis with paraplegia due to spinal cord compression, which prevented standing and measurement of the Cobb angle. Investigation revealed undiagnosed chronic respiratory failure due to restrictive lung disease secondary to the kyphoscoliosis; with deterioration (pH 7.23, PCO2 84 mmHg) he was intubated, extubated the next day to BiPAP and discharged on oxygen at 2 L/min and BiPAP as needed, and was well at 6 months [86]. The authors present him as the third-oldest documented man. The legends consulted describe Figure 1 as a scout radiograph showing severe kyphoscoliosis (https://pmc.ncbi.nlm.nih.gov/articles/PMC6350156/figure/fig1-2324709618820660/) and Figures 3 and 4 as axial CT showing the severity of the skeletal anomalies and the associated restrictive lung disease (https://pmc.ncbi.nlm.nih.gov/articles/PMC6350156/figure/fig3-2324709618820660/) [86]. The case illustrates the need for periodic respiratory assessment in adults with severe kyphoscoliosis, which GeneReviews recommends when there is severe deformity or symptoms [1].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis and mortality

Prognosis is determined mainly by neurological and musculoskeletal severity [1]. In Hunter's review (2002), 13.5% of the males described in the literature had died, at a mean age of 20.5 years (13–34) [1, 60]. This figure is a proportion of published cases, not a lifetime risk or a population life expectancy, although it is cited as a "mean life expectancy of 20.5 years" [69, 121]. The reported causes are cardiac anomalies, panacinar emphysema, respiratory complications, progressive kyphoscoliosis and seizure-associated aspiration [1]; according to Welborn, all cases with documented cardiovascular death had panacinar emphysema [69]. The five autopsies compiled by Coffin recorded deaths between ages 18 and 28 years from progressive pneumonia, food aspiration or postoperative complications; one of the original patients died at 18.8 years of pneumonia superimposed on chronic lung and heart disease, and another at 18 years of acute food aspiration [1, 88]. One man died of Hodgkin disease [1]. The 20-year follow-up of the 1982 series (six patients and a carrier mother) documented premature death, loss of ambulation and tetraplegia, with few data beyond age 30 years [60].

These figures contrast with patients alive at older ages: a man aged 48 years [1, 52], one aged 45 years in the 2025 review [10] and Venter's 34-year-old man [86]. Adults are probably underdiagnosed, and the historical series are biased towards severe forms [1]. Longevity in women is poorly documented [1]. Functional morbidity depends on the spine and SIDE: the peak frequency of SIDE occurs between ages 15 and 20 years, many patients become wheelchair-dependent, and in the Welborn series only two to four of the six men remained ambulatory at last follow-up, depending on the section of the article [57, 69]. In the Romanian series, with short follow-up, the course was stable outside the spine, and follow-up needs were 100% for developmental paediatrics, 90% for physiotherapy, 80% for neurology, 70% for orthopaedics and 60% for audiology [41].

11.2. Initial evaluation after diagnosis

11.3. Surveillance

GeneReviews sets only one numerical interval, that of the echocardiogram; the French PNDS adds the schedule of coordinating visits, a more frequent echocardiogram in childhood, an annual ophthalmological examination and the ages for neuropsychological assessments [1, 15].

The 2025 review also proposes endocrine-metabolic (glucose, lipids, puberty) and bone health screening, pulmonary and echocardiographic assessment especially with progressive vertebral deformity, and longitudinal MRI in selected cases, without intervals [10]. The Romanian series recommends regular cardiology, audiology, neurology and genetics assessments and physical medicine, also without intervals [41]. The PNDS intervals result from expert consensus and not from surveillance studies; where figures are lacking, this reflects the absence of such studies and not the irrelevance of the examinations.

11.4. Transition to adulthood

The transition plan should begin in adolescence and provide for continuity of spinal, cardiac, respiratory and psychiatric follow-up in adulthood, airway assessment before procedures and caregiver support [1]. In adults, spinal surveillance continues until skeletal maturity is reached, and chronic respiratory failure should be actively sought in patients with severe kyphoscoliosis [69, 86].

The PNDS requires the transition to be anticipated with the reference centre, investigations to be updated and a complete clinical file for the adult team to be prepared in advance, and follow-up at a reference or competence centre to continue in adulthood, every 2–3 years (section 7.11) [15].

12. Summary and Concluding Remarks

Coffin-Lowry syndrome results from loss of function of the RSK2 kinase, encoded by RPS6KA3 at Xp22.12, and occupies the severe end of a continuum whose mild end is XLID19, distinguished mainly by residual enzyme activity. In males, moderate to profound ID, facies that coarsen with age, soft hands with tapering fingers, short stature and progressive kyphoscoliosis form a picture that is recognisable from school age; in heterozygous females, expression ranges from normal to the full phenotype, with an increased risk of kyphoscoliosis, heart disease and psychiatric illness, and the X-inactivation pattern in blood does not predict severity. Inheritance is X-linked dominant, with about two-thirds to 70–80% of cases lacking a family history and documented germline mosaicism, which makes maternal testing mandatory and leaves a residual risk even with a negative maternal result; the inconsistency of the Orphanet entry for the carrier form, which records autosomal dominant inheritance, does not change this mechanism.

Diagnosis is molecular, but tests have concrete limitations: exon sequencing misses deletions, duplications, LINE-1 insertions, deep intronic variants and rearrangements, and historically more than 60% of clinically suspected patients remained without a variant, for technical reasons or because of another disorder. With a suggestive phenotype and a negative test, CNV analysis, RNA analysis, genome sequencing or protein and kinase activity assays are the next steps, and a diagnosis of CLS does not exclude a second disorder.

There is no targeted treatment; the only national guideline is the 2025 French PNDS, based on expert consensus and without dosing, which adds to GeneReviews a schedule of visits and a more frequent echocardiogram in childhood. The priorities of follow-up are the cervical and thoracolumbar spine, because calcification of the ligamentum flavum precedes neurological deficits by years and spinal progression does not respond to bracing; SIDE, which are non-epileptic, are confused with atonic seizures and respond partially and inconsistently to benzodiazepines, with a single case of complete response to sodium oxybate in an adult; the heart, with an echocardiogram at diagnosis and every 5 to 10 years; hearing, sleep and respiratory function; and anaesthetic planning, given the difficult airway and the risk of cardiovascular collapse in the prone position. The mortality data from older series describe published cases under the care of the time, and the adults alive at ages 45 and 48 years show that the current prognosis is unknown. Knowledge of the female phenotype, standardisation of surveillance and controlled evaluation of SIDE treatments are the gaps with the greatest clinical impact.

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