Marshall-Smith syndrome

Page most recently updated 7 September 2026

This page focuses on the reported psychiatric associations, which may be the initial presenting manifestation, and on other clinical features that may assist the psychiatrist or primary care physician in identifying the underlying diagnosis, considered through the lenses of the diagnostic lenses framework.

Marshall-Smith syndrome is a rare genetic disorder. It is generally caused by a de novo pathogenic variant, so absence of a relevant family history is expected. A distinctive presentation may include the combination of advanced skeletal maturation, shallow orbits with proptosis, broad middle phalanges, and severe respiratory difficulties

It can present with psychiatric features such as anxiety, stereotyped behaviors, and behavioral abnormalities. However, the neuropsychiatric phenotype is less well characterized than in many other neurodevelopmental syndromes, in part because severe respiratory disease results in death during infancy in many affected individuals. Developmental delay and moderate-to-severe intellectual disability may occur, with speech and language impairment potentially being substantial.

From a morphologic lens perspective, other features include (but are not limited to):

  • Macrocephaly

  • Prominent forehead

  • Micrognathia

  • Proptosis

  • Depressed nasal bridge

  • Short nose

Other characteristic features include osteopenia and skeletal abnormalities, including kyphoscoliosis and fractures. Respiratory manifestations are often prominent and may include upper airway obstruction, laryngomalacia, choanal stenosis, glossoptosis, respiratory distress, and recurrent respiratory infections. Neurologic manifestations may include hypotonia and structural brain abnormalities, including corpus callosum abnormalities, ventriculomegaly, hydrocephalus, and abnormalities of cortical development. Additional reported features include feeding difficulties, visual impairment including optic nerve hypoplasia, hypertrichosis, umbilical hernia, cryptorchidism, and occasional cardiovascular abnormalities.

Early diagnosis is important to identify and manage potentially life-threatening respiratory and feeding complications, recognize developmental and intellectual impairment early, monitor skeletal and ophthalmologic complications, and institute tailored multidisciplinary supportive care.

Selected references and further reading — Morphologic lens

Jones KL, Jones MC, del Campo M. Smith's recognizable patterns of human malformation. 8th ed. Philadelphia: Elsevier; 2021.

Reardon W. The bedside dysmorphologist: a guide to identifying and assessing congenital malformations. 2nd ed. Oxford: Oxford University Press; 2016.

Allanson JE, Biesecker LG, Carey JC, Hennekam RCM. Elements of morphology: introduction. Am J Med Genet A. 2009;149A(1):2-5. doi:10.1002/ajmg.a.32601.

Hennekam RCM, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, Carey JC; Elements of Morphology Consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A. 2013;161A(11):2726-2733. doi:10.1002/ajmg.a.36249.