Snyder-Robinson Syndrome
Summary
Clinical characteristics.
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.
Diagnosis/testing.
The diagnosis of SRS is established by identification of a hemizygous loss-of-function SMS pathogenic variant on molecular genetic testing.
Management.
Treatment of manifestations: Speech, physical, and/or occupational therapy may be helpful. Standard surgical treatment by craniofacial team for those with cleft palate. Calcium supplementation has slightly improved bone mineral density in a few individuals. Standard management of kyphoscoliosis by orthopedics. Seizures have shown varying responses to anti-seizure medications; Carbamazepine, phenobarbital, clobazam, levetiracetam, and valproic acid have been used successfully in some individuals.
Surveillance: Monitor developmental progress and educational needs. Clinical examination and DEXA scans to evaluate for progression of osteoporosis and investigate for factures if medically indicated. While receiving calcium supplementation, individuals should be evaluated regularly for ectopic calcification by endocrinology. Clinical examinations for kyphoscoliosis at each visit. Monitor those with seizures as clinically indicated.
Genetic counseling.
SRS is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%: Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers (to date, features of SRS have not been observed in heterozygous females). Affected males are not known to reproduce. Once an SMS pathogenic variant is identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria have not been established for Snyder-Robinson syndrome (SRS).
Suggestive Findings
Snyder-Robinson syndrome should be suspected in males with the following findings [Arena et al 1996, Cason et al 2003, de Alencastro et al 2008, Becerra-Solano et al 2009, Schwartz et al 2011, Peron et al 2013, Zhang et al 2013, Albert et al 2015, Abela et al 2016]:
- Intellectual disability (100% [20/20]); classified as moderate to severe generalized psychomotor delay that begins in infancy. IQ ranges from unmeasurable to 60.
- Hypotonia (100% [20/20]); secondary to poor muscular development
- Asthenic body build and diminished body bulk (95% [19/20]). Many individuals also have measurably long fingers and toes.
- Bone abnormalities including osteoporosis (100% [14/14]), fractures and kyphoscoliosis (84%; 16/19 individuals had both fractures and kyphoscoliosis), and joint contractures (15% [3/14])
- Facial dysmorphism including asymmetric face (64% [13/20]) and prominent lower lip (79% [16/20])
- Ambulation abnormalities ranging from unsteady gait to inability to walk (71% [14/19])
- Speech abnormalities including nasal, dysarthric, coarse, or absent speech (100% [19/19])
- Abnormal palate morphology including high, narrow, or cleft palate (83% [15/17])
- Mild short stature (73% [14/19]). Growth rates are normal but the length or height is at least 1 SD below the mean. Height in four of seven (on whom data are available) was less than 2 SD below the mean.
- Seizures (67%). Usually present by early childhood. Severity and frequency vary and success of treatment varies.
- Genital abnormalities (15% [3/20]) including low testicular volume, hypospadias, and undescended testes
- Renal complications (15% [3/20]). Nephrocalcinosis (unrelated to calcium administration) and renal cysts have been reported in three individuals with SRS.
Establishing the Diagnosis
Male proband. The diagnosis of Snyder-Robinson syndrome is established in a male proband with EITHER of the following:
- Spermine synthase (SMS) enzyme analysis. Decreased or absent SMS enzyme activity in fresh white cells or cultured lymphoblastsNote: Increased spermidine to spermine ratio in fresh white cells or cultured lymphoblasts is pathognomonic of SRS. (Absolute levels of spermidine or spermine do not differ significantly between affected individuals and controls.)
- Molecular genetic testing. Identification of a hemizygous loss-of-function pathogenic variant in SMS (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array or high-density microarray) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Snyder-Robinson syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic findings suggest the diagnosis of Snyder-Robinson syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of SMS detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, performing gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications should be done if possible. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- An intellectual disability multigene panel that includes SMS and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing, however, is slowly becoming the preferred approach.
If exome sequencing is not diagnostic, exome array (when clinically available) or high-density microarray may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Snyder-Robinson Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SMS | Sequence analysis 3, 4 | 37/37 5 |
| Gene-targeted deletion/duplication analysis 6 | No pathogenic deletion/duplication has been reported in an affected male 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Peron et al [2013]; Zhang et al [2013]; Albert et al [2015]; Abela et al [2016]; Larcher et al [2020]; Schwartz et al, unpublished data.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Among more than 11,300 individuals studied, 14 deletions and duplications have been reported to span SMS (see Genetically Related Disorders). Two other variants of unknown significance are reported in the database of genomic variants: an intronic deletion observed in 36 unaffected male and female controls [Mills et al 2006] and an exon 7 deletion observed in an unaffected Korean male [Kim et al 2009].
Clinical Characteristics
Clinical Description
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, and speech abnormalities.
To date, 20 individuals have been identified with a pathogenic variant in SMS [Peron et al 2013, Zhang et al 2013, Albert et al 2015, Abela et al 2016, Larcher et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Features of Snyder-Robinson Syndrome
| Feature | Proportion of Persons w/Feature | Comment |
|---|---|---|
| Intellectual disability | 22/22 | Moderate to severe |
| Hypotonia | 22/22 | Usually presents at birth & is persistent |
| Speech abnormalities | 19/21 | Nasal, dysarthric, coarse, or absent |
| Ambulation abnormalities | 15/19 | Ranges from unsteady gait to inability to walk |
| Asthenic body build | 19/20 | Low muscle mass persistent |
| Short stature | 14/19 | 1-2 SD below mean |
| Craniofacial features | 18/20 | Incl asymmetric face, prominent lower lip, & high, narrow, or cleft palate |
| Early-onset osteoporosis | 16/16 | Fractures |
| Seizures | 15/22 | |
| Long hands | 14/15 | |
| Long great toes | 10/14 |
Onset. Developmental delay and facial dysmorphism manifest within the first year of life.
Developmental delay. Hypotonia is usually present in the neonatal period which can persist into early childhood. Developmental delay usually presents as failure to meet milestones and then evolves to moderate to profound intellectual disability. The majority of males with SRS (22 published, 13 unpublished) do not appear to have progressive cognitive decline; rather, they remain cognitively stable throughout their lifetime. Those who develop speech (10/14) develop it late, some as late as age five years. Most individuals with SRS are able to follow simple commands. For two individuals who had no speech, it is unclear if a contributing factor was the absence of social contact [de Alencastro et al 2008]. Delay in motor development, observed in the majority of individuals with SRS, usually presents with delays in normal movements that occur in early childhood and do not resolve.
Progression. All reported males with SRS have maintained previously acquired skills; however, two recently identified unreported males have had progressive neurologic decline and loss of previously obtained skills. The measured IQ and cognitive functioning were highest in the original family, possibly due to the presence of residual SMS enzyme activity [Snyder & Robinson 1969, Cason et al 2003].
Asthenic habitus and low muscle mass usually develop during the first year. Although decreased strength is not described in males with SRS, most have progressive loss of muscle mass. Loss of muscle mass occurs even in males who are ambulatory, suggesting that the loss is probably the result of an underlying defect, not lack of use.
Mild short stature (73%). Growth rates are normal but the length or height is at least 1 SD below the mean. However, height on the 13 males for which data was available was variable, ranging from the 95th percentile to 3 SD below the mean.
Craniofacial features include asymmetric face (64% [13/20]), prominent lower lip (79% [16/20]), and high, narrow, or cleft palate (83% [15/17]). Head circumference is often in the upper centiles.
Osteoporosis. During the first decade of life, males with SRS develop osteoporosis. Most experience fractures in the absence of trauma or after minor trauma within the first decade, at which point the osteoporosis is discovered; the long bones are most severely affected. Among males reported, the osteoporosis and fracture activity do not progressively worsen with age but remain at the severity found at the time of diagnosis. Bone density measurements were documented in two individuals [Albert et al 2015]. The mechanism of decreased bone mineral density is not well understood
Other musculoskeletal features. Kyphoscoliosis (13/16) can appear within the first decade of life. This observation is rather rare in other X-linked conditions. Limb contractures are rare, having only been noted in four males. Abnormal pectus was noted in nine males.
Seizures (67%). Usually present by early childhood. Severity and frequency vary. In some affected individuals, seizures may be drug-resistant [Authors’ personal observation].
Brain MRI findings. In individuals for which brain imaging was done, ventricular dilation was noted in two of 11 individuals, a thin corpus callosum was noted in three of ten individuals. Abnormal calcification (which has been noted in a few individuals) occurs in the absence of calcium supplementation.
Genital abnormalities reported in 15% of males included low testicular volume, hypospadias, and undescended testes.
Renal complications have occurred in 15% of males including nephrocalcinosis (unrelated to calcium administration) and renal cysts reported in three individuals with SRS.
Skewed X-chromosome inactivation has been observed in heterozygous females in at least three families with SRS [Cason et al 2003; de Alencastro et al 2008; Author, personal communication]. It is unclear if skewed X-chromosome inactivation is a protective mechanism. In at least one of the families, presence of the SMS pathogenic variant in a heterozygous female is not associated with skewing of X-chromosome inactivation [Cason et al 2003].
Genotype-Phenotype Correlations
No clear genotype-phenotype correlations have been established for Snyder-Robinson syndrome. Even within a family, the phenotype varies; for example, in one family IQ values ranged from 46 to 77.
Based on the limited data available, the c.166G>A (p.Gly56Ser), c.388C>T (p.Arg130Cys), and c.443A>G (p.Gln148Arg) pathogenic variants have been associated with more severe manifestations [de Alencastro et al 2008, Albert et al 2015, Abela et al 2016].
A male infant with an SMS truncating variant, the first one observed, died a short time after birth [Larcher et al 2020]. The clinical presentation was quite severe, with multiple organ systems involved.
Penetrance
All individuals with SRS have deficient spermine synthase enzyme activity. However, as its prevalence in the general population has not been determined, penetrance of deficient spermine synthase activity as SRS cannot be stated.
Sequence variants of SMS have been reported for one seemingly unaffected male [Kim et al 2009]. Spermine synthase activity was not measured, and thus the functional consequences of this variant are unclear.
Additionally, five other nonsynonymous SMS variants were identified in large sequencing cohorts; phenotype, sex, and enzyme function are unavailable for these individuals.
Nomenclature
When Snyder and Robinson first described this syndrome, they labeled it "recessive sex-linked mental retardation in the absence of other recognizable abnormalities" [Snyder & Robinson 1969]. It is now considered an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, seizures, and speech abnormalities (see Clinical Description).
Prevalence
The prevalence of SRS is unknown. Of the twenty individuals evaluated and reported in the current literature, 13 were identified in the Americas: Mexico, Brazil, and the United States, and seven were identified in Western European countries, indicating that the disorder probably exists in most populations.
Differential Diagnosis
X-linked intellectual disability syndromes with osteoporosis. The observation that 30% more males than females have intellectual disability (ID) suggests that pathogenic variants of genes on the X chromosome are among the most frequent causes of ID among males [Stevenson et al 2012]. X-linked intellectual disability (XID) should be considered in males who are simplex cases (i.e., a single occurrence of ID in a family) as well as in males with a family history of intellectual disability consistent with X-linked inheritance. Consideration of XID as a cause of ID in simplex cases is relevant since approximately 33% of pathogenic variants causing the more severe forms of XID arise de novo.
Distinguishing between various forms of syndromic ID by clinical findings alone is often difficult because of overlapping clinical features, and diagnosis frequently requires identification of the molecular cause. Nonetheless, Snyder-Robinson syndrome (SRS) can be distinguished from many forms of syndromic XID by the combination of hypotonia, facial dysmorphism, asthenic body build, and both osteoporosis and kyphoscoliosis. While kyphoscoliosis is visible, osteoporosis is not, although the presence of fractures is suggestive of it. Because osteoporosis is rare in XID, it can be utilized as a distinguishing feature and should certainly be considered in a male with fractures.
XID intellectual disability syndromes with overlapping findings of SRS and osteoporosis are summarized in Table 3.
Table 3.
X-linked Intellectual Disability Syndromes with Overlapping Findings of Snyder-Robinson Syndrome and Osteoporosis
| Gene(s) | Differential Diagnosis Disorder | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|
| Overlapping w/SRS | Distinguishing from SRS | ||
| GK | Glycerol kinase deficiency (OMIM 307030) |
| Adrenal insufficiency |
| GRIA3 | GRIA3-related ID (OMIM 300699) |
| Aggressive behavior |
| MAOA MAOB NDP | Xp11.3 duplication 1 |
|
|
| SLC16A2 | MCT8-specific thyroid hormone cell-membrane transporter deficiency (Allan-Herndon-Dudley syndrome) |
| Different facial features |
DD = developmental delay, ID = intellectual disability, SRS = Snyder-Robinson syndrome
- 1.
Klitten et al [2011]
Other syndromes with osteoporosis to be considered in the differential diagnosis of SRS include the following:
- Cerebral palsy (CP). CP is a heterogeneous group of disorders arising from multiple genetic and environmental etiologies. In some individuals the phenotype overlaps that of SRS. Shared features can include seizures, osteoporosis, scoliosis, and developmental delay.
- Prader-Willi syndrome (PWS). Neonatal hypotonia, developmental delay, osteoporosis, and scoliosis are also features of PWS. Unlike individuals with SRS, those with PWS have metabolic syndrome, obesity, and severe behavior problems. PWS is caused by abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR) on chromosome 15. The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
- Urban syndrome, described in two teenage males, in one family, is characterized by intellectual disability, osteoporosis, and short stature [Urban et al 1979]. Unlike SRS, affected males were obese with normal muscle tone. The molecular basis of Urban syndrome is unknown.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Snyder-Robinson syndrome (SRS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Snyder-Robinson Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Development | Developmental assessment |
|
| Constitutional | Weight, length/height, & head circumference | Assess for evidence of short stature, macrocephaly. |
| Cleft palate | Clinical evaluation incl feeding assessment | |
| Musculoskeletal | Bone density assessment by DEXA scan | To determine degree of osteoporosis & need for calcium supplements or bisphosphonates 1 |
| Clinical evaluation for kyphoscoliosis | Consider radiographic scoliosis survey based on clinical suspicion & referral for orthopedic surgery as appropriate. | |
| Neurologic | Neurologic evaluation |
|
| Genitourinary | Renal ultrasound | To assess for renal abnormalities (rare) |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
DEXA = dual-energy x-ray absorptiometry
- 1.
Bisphosphonates have been used for osteoporosis in general; their efficacy in Snyder-Robinson syndrome has not been demonstrated, and initial evidence of efficacy is controversial.
Treatment of Manifestations
Table 5.
Treatment of Manifestations in Individuals with Snyder-Robinson Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| DD/ID | Speech therapy, PT, &/or OT | Some individuals have performed appropriately in special education programs, learned to follow commands, & held simple jobs [Arena et al 1996]; others showed no improvement of psychomotor skills w/special education [Becerra-Solano et al 2009]. |
| Cleft palate | Standard surgical treatment per craniofacial team | |
| Osteoporosis | Calcium supplementation |
|
| Kyphoscoliosis | Standard management as recommended by orthopedist | |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist 1 |
|
AEDs = antiepileptic drugs; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Surveillance
Table 6.
Recommended Surveillance for Individuals with Snyder-Robinson Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| DD/ID | Monitor developmental progress & educational needs | At each visit |
| Osteoporosis |
| When medically indicated |