The Marshall-Smith syndrome 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
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.
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.
Because there is no genetic testing available for Marshall-Smith syndrome, all individuals have been diagnosed through a careful physical examination and study of their medical history. Advanced skeletal age can be seen on x rays of the patient's hands and wrists, since this is the typical way to assess bone age. A full x ray survey of the body is a good way to assess age of other bones as well. Advanced bone age is always seen in Marshall-Smith syndrome, but it may also be present in other genetic syndromes. Sotos syndrome involves similar skeletal findings, but individuals are generally larger than usual and can have mental delays. Weaver syndrome includes advanced skeletal maturation, but individuals are often larger than usual and have other specific facial characteristics (such as very narrow, small eyes). These and other conditions can be ruled out if the respiratory complications and facial characteristics seen in MSS are not present.
Marshall-Smith syndrome is considered a childhood condition because affected individuals do not typically survive past childhood. There is no long-term research on the disease due to it being rare and not typically present in adults. Most children with MSS die in early infancy, often by three years of age, largely due to severe respiratory complications, and infections that may result from them. There have been reports of children surviving until age seven oreight, but these children did not have severe respiratory problems. These children give hope that the condition is variable, and not every person diagnosed with the condition will have a severely shortened life span.