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Less than 60 cases have been reported in the literature to date.

Marshall-Smith syndrome was originally considered as an overgrowth condition based on advanced bone maturation. It is characterized by a dysostosis with skeletal anomalies including progressive kyphoscoliosis, postnatal failure to thrive in weight, short stature, and osteopenia with fractures. Wide bullet-shaped phalanges as well as large hands and feet are observed. Neonates and infants usually manifest with feeding difficulties and upper airway obstruction with respiratory distress due to glossoptosis, laryngomalacia and/or choanal stenosis. The majority of patients die in the neonatal period or early infancy from respiratory compromise. Respiratory infections are frequent. Patients surviving infancy also have developmental delay, moderate to severe intellectual disability and behavioral abnormalities such as anxiety and stereotyped movements. Brain MRI may show corpus callosum anomalies, macrogyria, pachygyria, delayed myelination, ventricular dilatation, hydrocephalus and periventricular leukomalacia. Characteristic facial features include high forehead, proptosis, blue sclerae, midface hypoplasia, short nose, depressed nasal bridge, anteverted nostrils and retrognathia. Vision impairment may occur as a result of optic nerve hypoplasia. Hypertrichosis, umbilical hernia, connective tissue, endocrine and cardiovascular anomalies may be associated. In a single case a concomitant Wilms tumor had developed, otherwise an increased risk of neoplasm development is not known.

Marshall-Smith syndrome is cause by heterozygous de novo variants in the NFIX (Nuclear Factor I X; 19p13.13) gene. NFIX variants escape nonsense-mediated mRNA decay leading to abnormal proteins with an abnormal C-terminus (dominant-negative mechanism). The NFIX gene acts as the transcription factor in the nuclear factor I family, and is implicated in replication, signal transduction, and transcriptional processes, with, currently not fully elucidated mechanisms.

The syndrome is clinically recognizable. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in the NFIX gene. Most of the variants have been identified in exons 6-10 of the gene.

The differential diagnoses for Marshall-Smith syndrome are Sotos syndrome, Malan overgrowth syndrome, Weaver syndrome, and bone fragility disorders. Radiological findings distinguish them based on skeletal findings.

Prenatal diagnosis is possible if the disease-causing variant has been identified in the family. The recent implementation of prenatal whole exome sequencing could lead to molecular diagnostics during pregnancy.

Marshall-Smith syndrome is inherited in an autosomal dominant manner. All known pathogenic variants have occurred de novo, and in these cases the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%).

Management of Marshall-Smith syndrome required a multidisciplinary approach with appropriate specialists. Patients need symptomatic treatment for airway obstruction, respiratory infections, and feeding difficulties, as well as specific management for bone fragility.

The prognosis is poor and most patients will die in the neonatal period or early infancy due to respiratory compromise. A few cases of prolonged survival have been reported in patients without respiratory complications.

Last update: December 2020 - Expert reviewer(s): Pr Valérie CORMIER-DAIRE - Dr Valérie MALAN | ITHACA*

* European Reference Network