Alternative titles; symbols
SNOMEDCT: 702416008; ORPHA: 3063; DO: 0060802;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.11 | Intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type | 309583 | X-linked recessive | 3 | SMS | 300105 |
A number sign (#) is used with this entry because the Snyder-Robinson type of X-linked syndromic intellectual developmental disorder (MRXSSR) is caused by mutation in the spermine synthase gene (SMS; 300105) on chromosome Xp22.
Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia (summary by Zhang et al., 2013).
Snyder and Robinson (1969) reported a family in which affected males had a form of nonspecific X-linked mental retardation with hypotonia and unsteady gait. Eleven males in 4 generations were affected. Arena et al. (1992, 1996) reevaluated the family, defining the disorder as a specific syndrome with the following features: mild to moderate mental retardation; asthenic body build (marfanoid habitus); diminished muscle bulk; osteoporosis; kyphoscoliosis; long, thin face; slight facial asymmetry with a prominent lower lip; nasal voice; high, narrow, or cleft palate; and long, thin fingers and toes. Carrier females were clinically normal. Arena et al. (1996) redefined the entity as an X-linked mental retardation syndrome. In a follow-up of the same family, Cason et al. (2003) reported that some affected males had an unsteady gait, nonspecific movement disorder, and seizures. Two of 4 affected males had an abnormal EEG.
De Alencastro et al. (2008) reported a second family with genetically- confirmed Snyder-Robinson syndrome (300105.0002). At age 12 years, the proband had profound mental retardation, seizures, no speech development, and was unable to stand alone or walk. He had short stature and mild facial dysmorphism, with mild hypertelorism, exophthalmia, short philtrum, thickened lower lip, slight high-arched palate, mandibular prognathism, and ears with prominent antihelices and hypoplastic lobules. Other features included high myopia, pectus carinatum, cryptorchidism, severe kyphoscoliosis, camptodactyly without arachnodactyly, and muscular hypotonia.
Kesler et al. (2009) performed brain MRI studies on 2 affected males with Snyder-Robinson syndrome reported by Cason et al. (2003), at ages 13 and 39 years, respectively. IQ measurements were 36 and 54, respectively. Both had dysmorphic facial features; the younger patient had myoclonic seizures. Total brain volumes of both patients were somewhat enlarged and affected gray, white, and CSF volumes equally. The younger patient had disproportionately decreased cerebellar volume, and both had disproportionately decreased hippocampal and red nucleus volumes. Kesler et al. (2009) postulated that spermine deficiency may result in an imbalance between cell growth and pruning mechanisms during neurodevelopment.
Becerra-Solano et al. (2009) reported 2 adult Mexican brothers with Snyder-Robinson syndrome. Clinical features included mental retardation, multiple childhood fractures associated with decreased bone density, thin body habitus with poor muscle bulk and long thin limbs, pectus excavatum with widely-spaced nipples, and kyphoscoliosis. Dysmorphic facial features included brachycephaly, asymmetric facies, slanted upper palpebral fissures, sparse eyebrows, synophrys, right palpebral ptosis, high nasal bridge, bulbous nasal tip, anteverted nares, smooth philtrum, prominent lower lip, high palate, overcrowded teeth, asymmetric ears, and short webbed neck. Both also had areas of patchy skin hyperpigmentation. Family history was notable for a spontaneous abortion in the mother during the first trimester.
Zhang et al. (2013) reported a family in which 4 males in 3 generations had Snyder-Robinson syndrome. The proband was reported in detail: he had delayed psychomotor development, delayed language, IQ of 74, thin build, low-set ears, small mouth, kyphoscoliosis, and long fingers and toes. He did not have facial asymmetry, or abnormal gait or other neurologic symptoms. He had good social interaction and attended a special school. His maternal uncle also went to a special school and worked in a sheltered environment. Zhang et al. (2013) noted that the phenotype in these patients was relatively mild compared to that reported in other patients with this disorder.
Peron et al. (2013) reported a boy from Italy with Snyder-Robinson syndrome characterized by a thin habitus with decreased muscle mass, unsteady gait, osteoporosis, kyphoscoliosis, dysmorphic facial features, cognitive impairment, and nasal speech. In addition to features typically seen in Snyder-Robinson syndrome, the patient also had an ectopic right kidney and early onset of epilepsy. Seizure activity was first observed in the first year of life and he was diagnosed with atypical West syndrome; at age 6 years, he developed myoclonus and focal motor seizures. The finding of a mutation in the SMS gene (see MOLECULAR GENETICS) confirmed the diagnosis of MRXSSR.
By linkage analysis of 17 members of an affected family, Arena et al. (1996) found a maximum lod score of 4.7 at markers DXS41 and DXS989 on Xp21.3-p22.12, distal to the 3-prime end of the DMD gene (300377).
In affected members of the family originally reported by Snyder and Robinson (1969), Cason et al. (2003) identified a mutation in the SMS gene (300105.0001).
In 2 Mexican brothers with Snyder-Robinson syndrome, Becerra-Solano et al. (2009) identified a mutation in the SMS gene (V132G; 300105.0003).
Zhang et al. (2013) reported a patient and his uncle with a mild form of Snyder-Robinson syndrome who carried a missense mutation in the SMS gene (Y328C; 300105.0004).
In a boy from Italy with Snyder-Robinson syndrome who had originally been diagnosed with West syndrome, Peron et al. (2013) identified a missense mutation in the SMS gene (300105.0005). In the patient's lymphoblastoid cells, no spermine synthase activity above baseline was detected, and the spermine/spermidine ratio was abnormal, consistent with Snyder-Robinson syndrome. The patient's mother was heterozygous for the mutation, and X-inactivation analysis showed mild skewing.
Arena, J. F., Schwartz, C., McClurkin, C., Miller, M., Stevenson, R., Garza, J., Nance, M., Lubs, H. A. Gene localization and clinical redefinition of the Snyder-Robinson syndrome. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A181 only, 1992.
Arena, J. F., Schwartz, C., Ouzts, L., Stevenson, R., Miller, M., Garza, J., Nance, M., Lubs, H. X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12. Am. J. Med. Genet. 64: 50-58, 1996. [PubMed: 8826448] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<50::AID-AJMG7>3.0.CO;2-V]
Becerra-Solano, L. E., Butler, J., Castaneda-Cisneros, G., McCloskey, D. E., Wang, X., Pegg, A. E., Schwartz, C. E., Sanchez-Corona, J., Garcia-Ortiz, J. E. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. Am. J. Med. Genet. 149A: 328-335, 2009. [PubMed: 19206178] [Full Text: https://doi.org/10.1002/ajmg.a.32641]
Cason, A. L., Ikeguchi, Y., Skinner, C., Wood, T. C., Holden, K. R., Lubs, H. A., Martinez, F., Simensen, R. J., Stevenson, R. E., Pegg, A. E., Schwartz, C. E. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Europ. J. Hum. Genet. 11: 937-944, 2003. [PubMed: 14508504] [Full Text: https://doi.org/10.1038/sj.ejhg.5201072]
de Alencastro, G., McCloskey, D. E., Kliemann, S. E., Maranduba, C. M. C., Pegg, A. E., Wang, X., Bertola, D. A., Schwartz, C. E., Passos-Bueno, M. R., Sertie, A. L. New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome. (Letter) J. Med. Genet. 45: 539-543, 2008. [PubMed: 18550699] [Full Text: https://doi.org/10.1136/jmg.2007.056713]
Kesler, S. R., Schwartz, C., Stevenson, R. E., Reiss, A. L. The impact of spermine synthase (SMS) mutations on brain morphology Neurogenetics 10: 299-305, 2009. [PubMed: 19277733] [Full Text: https://doi.org/10.1007/s10048-009-0184-2]
Peron, A., Spaccini, L., Norris, J., Bova, S. M., Selicorni, A., Weber, G., Wood, T., Schwartz, C. E., Mastrangelo, M. Snyder-Robinson syndrome: a novel missense mutation in spermine synthase and expansion of the phenotype. Am. J. Med. Genet. 161A: 2316-2320, 2013. Note: Erratum: Am. J. Med. Genet. 164A: 1083 only, 2014. [PubMed: 23897707] [Full Text: https://doi.org/10.1002/ajmg.a.36116]
Snyder, R. D., Robinson, A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities: report of a family. Clin. Pediat. 8: 669-674, 1969. [PubMed: 5823961] [Full Text: https://doi.org/10.1177/000992286900801114]
Zhang, Z., Norris, J., Kalscheuer, V., Wood, T., Wang, L., Schwartz, C., Alexov, E., Van Esch, H. A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. Hum. Molec. Genet. 22: 3789-3797, 2013. [PubMed: 23696453] [Full Text: https://doi.org/10.1093/hmg/ddt229]