Marshall-Smith Syndrome

Clinical Definition and Features

an infant with Sotos syndrome Figure X-1 | Photo courtesy of Marshall-Smith Syndrome Research Foundation Opens in new window

Marshall-Smith syndrome is an overgrowth congenital condition characterized by advanced skeletal maturation of prenatal onset with the bone age at birth often exceeding that of a 2-year-old. Patients often fail to thrive and manifest increased skeletal radiodensity, craniofacial disproportion, slender tubular bones, and broad middle phalanges.

In 1971, Marshall et al first described this disorder; reported that it is characterized by accelerated skeletal maturation, mental and somatic retardation, failure to thrive with chronic respiratory distress and early death, a characteristic small face with a prominent forehead and eyes, and remarkable skeletal alterations.

Although it is described as an overgrowth syndrome, this disorder probably involves unknown defects of the cartilage, bone, and connective tissue rather than a generalized or localized cellular hyperplasia.

Perhaps it represents a new lethal dominant mutation. Findings have been summarized below.

  1. Growth, Performance, and Natural History

Moderate to severe respiratory distress accompanied by noisy stridor may necessitate intubation. There is failure to thrive, and death due to pneumonia which occurs almost always within months. However, a few children have survived for up to 7 years.

The child will often lie with the head extended due to laryngeal hypoplasia Opens in new window. Speech is poor and frequently the child is hypotonic. Psychomotor delay is common. Partial growth hormone deficiency was found by Roodhooft et al.

  1. Craniofacial Features

The forehead is prominent with frontal ridging, while the supraorbital ridges are flattened in 85%. The eyes bulge or are proptosed in nearly all affected and there may be megalocornea Opens in new window.

The sclerae are blue in 60%. Optic atrophy has been found. The eyebrows are bushy with synophrys.

The nose is small with a low nasal bridge and anteverted nostrils in essentially all patients. Unilateral or bilateral choanal stenosis or atresia has been reported.

The helices of the pinnae are often folded with hypoplastic cartilages, and the ears may be low-set. The mandible is small in 85%. The mouth is small and the palate may be highly arched.

Stridor appears to be related to both glossoptosis (documented in 35%), rudimentary epiglottis, and hypoplastic larynx. Hearing loss may be part of the syndrome.

  1. Musculoskeletal System

The hands and feet and/or digits are often stated to be long. Radiographically, carpal and tarsal bone age is markedly advanced.

At birth, the phalangeal epiphyses, femoral heads, and patellae are usually ossified, suggesting a bone age of 4 years or more. The frontal bone is prominent and the calvaria thickened and prominent.

The orbits are shallow and the facial bones small or hypoplastic. The mandibular rami are underdeveloped with absence of the angle.

Long bones tend to be thin. The proximal and middle phalanges of the hands are remarkably thick. The former are rectangular; the latter are bullet-shaped.

The terminal phalanges are greatly reduced in size. The metacarpals are also widened distally and are poorly modeled. Scoliosis has been noted in a few cases.

Severe spinal stenosis and instability at the craniocervical junction have been documented. Increased fractures has also been observed.

  1. Other Abnormalities

Umbilical hernia or omphalocele is present in approximately 35%. Generalized hypertrichosis occurs in about 50%.

Pachygyria of the occipital and temporal areas of the brain has been documented in some instances.

Only a few children have had cardiovascular defects and these have included PDA, ASD, and hypertrophy of the pulmonary arteries.


The cause of this syndrome is unknown, although it appears to be sporadic in the families reported. The male:female ratio is 1:1.


The diagnosis is suspected in babies with markedly accelerated skeletal maturation, particular facial anomalies, and failure to thrive.

The estimated bone age in the wrist, elbow, and femoral epiphysis may be 3–6 years in relationship to a chronologic age of under 6 months. Radiographic studies are import for diagnosis.

Differential Diagnosis

Comparison is sometimes made with Weaver syndrome Opens in new window, but except for accelerated osseous maturation, the phenotypes are distinct. Differences have been well reviewed by Fitch.

In Sotos syndrome Opens in new window, phalangeal age is ahead of carpal age, but in Marshall-Smith syndrome the opposite is the case.


Careful attention to attention to airway anatomy should be given. Infants with this condition may have repeated episodes of low oxygen saturation due to choanal atresia and upper airway obstruction requiring supplemental oxygen.

Respiratory complications is a major component of this syndrome, as are anatomic abnormalities of the respiratory tract, including choanal atresia/stenosis, laryngeal malacia, unusual laryngeal positioning, and defects of the vocal cords. Intubation may be difficult because of laryngeal positioning. Tracheostomy is frequently required to maintain the airway.

See also:
  1. Charon A et al: The Marshall-Smith syndrome. Eur J Pediatr 150:54-55, 1990.
  2. Chatel C et al: Neonatal death in Marshall-Smith syndrome. Genet Couns 9:15-18, 1998.
  3. Cullen A et al: The Marshall-Smith syndrome: A review of the laryngeal complications. Eur J Pediatr 156:463, 1997.
  4. Eich GF et al: Marshall-Smith syndrome: New radiographic, clinical, and pathologic observations. Radiology 181:183-188, 1991.
  5. Fitch N: The syndromes of Marshall and Weaver. J Med Genet 17:174-178, 1980.
  6. Fitch N: Update on the Marshall-Smith-Weaver controversy. Am J Med Genet 20:559-562, 1985.
  7. Hassan M et al: The syndrome of accelerated bone maturation in the newborn infant with dysmorphism and congenital malformations. Pediatr Radiol 5:53-57, 1976.
  8. Hoyme HE et al: The Marshall-Smith syndrome: Further evidence of an osteochondrodysplasia in long term survivors. Proc Greenwood Genet Ctr 12:70, 1993.
  9. Johnson JP, Carey JC, Glassy FJ, et al. Marshall-Smith syndrome: two case reports and a review of pulmonary manifestations. Pediatrics 71:219-224, 1983.
  10. Seidahmed MZ, Rooney DE, Salih MA, et al. Case of partial trisomy 2q3 with clinical manifestations of Marshall-Smith syndrome. Am J Med Genet85:185-188, 1999.