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 DXA 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.

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 lymphoblasts
  Note: 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 (or likely pathogenic) variant in SMS (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, 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).

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.

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 dilatation 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.

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.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Snyder-Robinson syndrome (SRS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the SMS pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the SMS pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. There are no data regarding frequency or possibility of germline mosaicism in SRS.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo SMS pathogenic variant, in which case the mother is not a carrier. Of the 20 published cases reported to date, two individuals were shown to have SRS as the result of a de novo pathogenic variant.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an SMS 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 heterozygotes (carriers). In the families reported to date, features of SRS have not been observed in heterozygous females.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the SMS pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males are not known to reproduce.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being carriers for the pathogenic variant or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the pathogenic variant in the family.

Note: Females are heterozygotes for this X-linked disorder; hypothetically, they could develop clinical findings related to the disorder secondary to partial loss of SMS function or skewing of X-chromosome inactivation. To date, no identified heterozygotes have had signs or symptoms attributable to their SMS pathogenic variant.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the SMS pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Polyamines are small organic molecules containing at least two amino groups, which play a wide range of regulatory functions in the cell thereby ensuring normal cell growth, differentiation, and survival [Murray-Stewart et al 2018]. SMS encodes spermine synthase (SMS), which catalyzes the production of spermine, a polyamine, from spermidine and decarboxylated S-adenosylmethionine (dcSAM). Pathogenic variants in SMS lead to an almost total loss of enzymatic activity which in turn leads to a lack of spermine and an increase in spermidine. Therefore, Snyder-Robinson syndrome is a polyamine deficiency syndrome [Cason et al 2003].

Mechanism of disease causation. Loss of function

Author History

Jessica Albert, PhD; National Human Genome Research Institute (2013-2020)
Cornelius F Boerkoel, MD, PhD; National Human Genome Research Institute (2013-2020)
Mary Jo Kutler, MD (2020-present)
Angela Peron, MD (2020-present)
Roger E Stevenson, MD; Greenwood Genetic Center (2013-2020)
Charles E Schwartz, PhD (2013-present)

Revision History

• 13 February 2020 (sw) Comprehensive update posted live
• 27 June 2013 (me) Review posted live
• 28 January 2013 (ja) Original submission

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