Marshall-Smith Syndrome

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.

Sotos syndrome-2 (SOTOS2; 614753) is also caused by heterozygous mutation in the NFIX gene.

Description

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 (Adam et al., 2005).

Clinical Features

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.

Molecular Genetics

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.