SNOMEDCT: 73284007; ORPHA: 561; DO: 0050858;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.13 | Marshall-Smith syndrome | 602535 | Autosomal dominant | 3 | NFIX | 164005 |
A number sign (#) is used with this entry because Marshall-Smith syndrome (MRSHSS) is caused by heterozygous mutation in the NFIX gene (164005) on chromosome 19p13.
The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).
Marshall et al. (1971) described 2 infants with a syndrome characterized by accelerated skeletal maturation, failure to thrive, and dysmorphic facial features. Sperli et al. (1993) reviewed 20 reported cases.
Chatel et al. (1998) reported an unusually severe form of Marshall-Smith syndrome characterized by neonatal death. Accelerated osseous maturation is a feature of all cases. Diab et al. (2003) emphasized osseous fragility as a clinically significant problem in Marshall-Smith syndrome.
Butler (2004) provided a follow-up on the patient with Marshall-Smith syndrome reported by Summers et al. (1999). This child also had osteopenia and fractures without known trauma. His sclerae were blue (a feature typical of patients with Marshall-Smith syndrome) and the eyes were prominent. Skeletal survey at the age of 1 month had shown an estimated bone age of 3 to 4 years in the wrists, elbows, and femoral epiphyses; bone age at 15 months was estimated at 10 years, and at 3.5 years of age, his bone age was 11 years.
Adam et al. (2005) commented on the study of Roodhooft et al. (1988) in which a patient with features of Marshall-Smith syndrome was found to have overall small muscle fibers with particularly striking hypoplasia of type IIa and IIb fibers by light microscopy. The patient exhibited persistent gait problems with frequent episodes of fatigue and poor appetite, which prompted the muscle biopsy. Although CT scans of the neck did not detect any muscular abnormalities, the appearance of the bones and spinal cord was not described. The clinical description of weak tendon reflexes, however, did not suggest a diagnosis of cervical spinal stenosis with spinal cord impingement.
Cullen et al. (1997) estimated that 24 cases of Marshall-Smith syndrome had been described. Adam et al. (2005) found an additional 9 patients. They summarized the natural history of the disorder on the basis of 5 new cases and reviewed the clinical findings in 3 previously reported children, with special emphasis on skeletal and connective tissue manifestations. An increased rate of nontraumatic fractures and other bony and connective tissue abnormalities supported the hypothesis that the condition should be classified as an osteochondrodysplasia.
Adam et al. (2005) noted that most patients with Marshall-Smith syndrome reported in the literature to that time had died in the neonatal period or early infancy, most commonly from respiratory compromise. Sperli et al. (1993) reported long survival of a patient who did not have respiratory complications, and Williams et al. (1997) reported a 3-year-old child whose failure to thrive had been successfully treated, with significant upper airway obstruction but no life-threatening respiratory complications. Adam et al. (2005) concluded that long-term survival is possible if respiratory problems are expectantly and aggressively managed.
Shaw et al. (2010) reported 15 new patients with Marshall-Smith syndrome, provided an update on 4 previously reported patients (Williams et al., 1997; Dernedde et al., 1998; Adam et al., 2005; Deshpande et al., 2006), and compared these patients to 43 patients with Marshall-Smith syndrome or a very similar phenotype described in the literature. The primary clinical features were moderate to severe developmental delay with absent or limited speech, unusual behavior such as playing in a repetitive or stereotypic manner with a favorite toy, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Characteristic facial features included high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum were common. Mortality from respiratory complications was high, but Shaw et al. (2010) noted that airway support increasingly allowed survival into adulthood.
The heterozygous mutations in the NFIX gene that were identified in patients with Marshall-Smith syndrome by Malan et al. (2010) occurred de novo.
Based on an Nfix-deficient mouse model with a phenotype similar to that in Marshall-Smith syndrome, Malan et al. (2010) screened 9 individuals with MRSHSS for NFIX mutations and found heterozygosity for 7 independent frameshift mutations (164005.0002-164005.0008) and 2 different mutations within the donor splice site of exon 6 (164005.0009-164005.0010). All of the mutations occurred de novo and were not found in 300 control chromosomes. RT-PCR analysis of RNA from skin fibroblasts of 3 patients detected both normal and mutated alleles, suggesting that the mutated RNAs escape nonsense-mediated decay surveillance. Malan et al. (2010) suggested that the splice site mutations have a dominant-negative effect and result in a severe phenotype.
Schanze et al. (2014) analyzed the NFIX gene in 17 patients with a clinical diagnosis of MRSHSS and identified heterozygous mutations in all, confirming that MRSHSS is a genetically homogeneous mendelian disorder. Frameshift or splicing mutations were present in 10 patients (see, e.g., 164005.0013), 5 patients carried almost-identical deletions of exons 6 and 7 (see, e.g., 164005.0014), and 2 patients had smaller deletions involving exon 6 (see, e.g., 164005.0015). The authors noted that predicted MRSHSS-associated mutant NFIX proteins all have a preserved DNA binding and dimerization domain, whereas they vary widely in their C-terminal portion, supporting the hypothesis that MRSHSS-associated mutations encode dysfunctional proteins that act in a dominant-negative manner. The patients exhibited a consistent phenotype, with no obvious correlation between phenotype and specific alterations of the C-terminal portion of the NFIX protein.
Martinez et al. (2015) reported 5 de novo mutations in the NFIX gene, including 2 frameshift mutations and a recurrent splicing mutation (164005.0010) in 3 patients with MRSHSS, and 2 missense mutations in the DNA-binding/dimerization domain in 2 patients with a Sotos-like syndrome, Malan syndrome (MALNS; 614753). The authors reviewed previously reported NFIX mutations and concluded that MRSHSS-associated mutations are scattered through exons 6 to 10 of the gene, whereas most point mutations causing MALNS are clustered in exon 2.
Adam, M. P., Hennekam, R. C. M., Keppen, L. D., Bull, M. J., Clericuzio, C. L., Burke, L. W., Ormond, K. E., Hoyme, H. E. Marshall-Smith syndrome: natural history and evidence of an osteochondrodysplasia with connective tissue abnormalities. Am. J. Med. Genet. 137A: 117-124, 2005. [PubMed: 16086394] [Full Text: https://doi.org/10.1002/ajmg.a.30580]
Butler, M. G. Marshall-Smith syndrome: follow-up report of a four and a half year old male. (Letter) Am. J. Med. Genet. 126A: 329-330, 2004. [PubMed: 15054853] [Full Text: https://doi.org/10.1002/ajmg.a.20603]
Chatel, C., Maazoul, F., Sigaudy, S., Fredouille, C., Ayme, S., Philip, N. Neonatal death in Marshall-Smith syndrome. Genet. Counsel. 9: 15-18, 1998. [PubMed: 9555581]
Cullen, A., Clarke, T. A., O'Dwyer, T. P. The Marshall-Smith syndrome: a review of the laryngeal complications. Europ. J. Pediat. 156: 463-464, 1997. [PubMed: 9208244] [Full Text: https://doi.org/10.1007/s004310050640]
Dernedde, G., Pendeville, P., Veyckemans, F., Verellen, G., Gillerot, Y. Anaesthetic management of a child with Marshall-Smith syndrome. Can. J. Anaesth. 45: 660-663, 1998. [PubMed: 9717599] [Full Text: https://doi.org/10.1007/BF03012097]
Deshpande, C., Forrest, M., Russell-Eggitt, I., Hall, C. M., Mehta, R., Paterson, J. Visual impairment and prolonged survival in a girl with Marshall-Smith syndrome. Clin. Dysmorph. 15: 111-113, 2006. [PubMed: 16531739] [Full Text: https://doi.org/10.1097/01.mcd.0000194408.30794.2f]
Diab, M., Raff, M., Gunther, D. F. Osseous fragility in Marshall-Smith syndrome. Am. J. Med. Genet. 119A: 218-222, 2003. [PubMed: 12749068] [Full Text: https://doi.org/10.1002/ajmg.a.10173]
Fitch, N. The syndromes of Marshall and Weaver. J. Med. Genet. 17: 174-178, 1980. [PubMed: 7401127] [Full Text: https://doi.org/10.1136/jmg.17.3.174]
Fitch, N. Update on the Marshall-Smith-Weaver controversy. (Letter) Am. J. Med. Genet. 20: 559-562, 1985. [PubMed: 3993681] [Full Text: https://doi.org/10.1002/ajmg.1320200318]
Malan, V., Rajan, D., Thomas, S., Shaw, A. C., Louis dit Picard, H., Layet, V., Till, M., van Haeringen, A., Mortier, G., Nampoothiri, S., Puseljic, S., Legeai-Mallet, L., Carter, N. P., Vekemans, M., Munnich, A., Hennekam, R. C., Colleaux, L., Cormier-Daire, V. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am. J. Hum. Genet. 87: 189-198, 2010. [PubMed: 20673863] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.001]
Marshall, R. E., Graham, C. B., Scott, C. R., Smith, D. W. Syndrome of accelerated skeletal maturation and relative failure to thrive: a newly recognized clinical growth disorder. J. Pediat. 78: 95-101, 1971. [PubMed: 4321601] [Full Text: https://doi.org/10.1016/s0022-3476(71)80269-x]
Martinez, F., Marin-Reina, P., Sanchis-Calvo, A., Perez-Aytes, A., Oltra, S., Rosello, M., Mayo, S., Monfort, S., Pantoja, J., Orellana, C. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes. Pediat. Res. 78: 533-539, 2015. [PubMed: 26200704] [Full Text: https://doi.org/10.1038/pr.2015.135]
Roodhooft, A. M., Van Acker, K. J., Van Thienen, M. N., Martin, J. J., Ceuterick, C. Marshall-Smith syndrome: new aspects. Neuropediatrics 19: 179-182, 1988. [PubMed: 3205374] [Full Text: https://doi.org/10.1055/s-2008-1052441]
Schanze, D., Neubauer, D., Cormier-Daire, V., Delrue, M.-A., Dieux-Coeslier, A., Hasegawa, T., Holmberg, E. E., Koenig, R., Krueger, G., Schanze, I., Seemanova, E., Shaw, A. C., Vogt, J., Volleth, M., Reis, A., Meinecke, P., Hennekam, R. C. M., Zenker, M. Deletions in the 3-prime part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome. Hum. Mutat. 35: 1092-1100, 2014. [PubMed: 24924640] [Full Text: https://doi.org/10.1002/humu.22603]
Shaw, A. C., van Balkom, I. D. C., Bauer, M., Cole, T. R. P., Delrue, M.-A., Van Haeringen, A., Holmberg, E., Knight, S. J. L., Mortier, G., Nampoothiri, S., Puseljic, S., Zenker, M., Cormier-Daire, V., Hennekam, R. C. M. Phenotype and natural history in Marshall-Smith syndrome. Am. J. Med. Genet. 152A: 2714-2726, 2010. [PubMed: 20949508] [Full Text: https://doi.org/10.1002/ajmg.a.33709]
Sperli, D., Concolino, D., Barbato, C., Strisciuglio, P., Andria, G. Long survival of a patient with Marshall-Smith syndrome without respiratory complications. J. Med. Genet. 30: 877-879, 1993. [PubMed: 8230168] [Full Text: https://doi.org/10.1136/jmg.30.10.877]
Summers, D. A., Cooper, H. A., Butler, M. G. Marshall-Smith syndrome; case report of a newborn male and review of the literature. Clin. Dysmorph. 8: 207-210, 1999. [PubMed: 10457856]
Williams, D. K., Carlton, D. R., Green, S. H., Pearman, K., Cole, T. R. P. Marshall-Smith syndrome: the expanding phenotype. J. Med. Genet. 34: 842-845, 1997. [PubMed: 9350818] [Full Text: https://doi.org/10.1136/jmg.34.10.842]