Sotos Syndrome

Clinical Definition and Features

Figure X-1 | Photo courtesy of Kidspot Opens in new window

Sotos syndrome (also called cerebral gigantism), first described by Sotos et al in 1965, is an overgrowth syndrome characterized by increased birth length, increased birth weight, excessive growth during the first four years of life, advanced bone age, and distinctive facial features including flat face, hyperteloric eyes and prominent jaw. Also, the cranium has a circumference above two standard deviations and is dolichocephalic.

The Sotos syndrome, often occurring sporadically, is relatively common among overgrowth syndromes and appears to occur ten times more frequently than Weaver syndrome Opens in new window.

Identical twins have been discordant for the syndrome; and several reported families have been consistent with autosomal dominant inheritance Opens in new window.

Schrander-Stumpel found a balanced translocation: t(3;6)(p21;p21). Breaking point mapping has been carried out on this patient. This is in part supported by the observation of Cole et al that there is loss of heterozygosity at 3p21 in small cell lung carcinoma that has been found in Sotos syndrome.

The syndrome is associated with developmental delay and children tend to be clumsy. Main clinical findings are discussed below.

Clinical Manifestations

1. Growth and Skeletal Findings

Overgrowth is commonly manifested in the newborn, birth weight averaging 4200 g in males and 4000 g in females.

• Birth length, birth weight, and head circumference are, respectively, 3.2, 1.0, and 1.8 standard deviations above the mean.

• Excessive growth is particularly pronounced during the first four years of life.
• Bone age is advanced and gradually increases until the fifth year, after which the difference between bone age and chronological age stabilizes.
• From four years onward, growth curves usually remain above the 97th centile.
• Midparental height of affected individuals is similar to the normal mean midparental height.
• A small percentage of affected individuals have more extreme final height attainment.
• Early feeding problems are observed in 35%.
• The hands and feet are large.
• Disharmonic maturation and abnormal sequences in the appearance of carpal bones occur in some affected individuals.
• A characteristic metacarpophalangeal pattern has been reported.
• Joint laxity is frequent with pes planus especially common.
• Rarely, there is significant scoliosis.

2. Performance and CNS Abnormalities

Most patients have nonprogressive neurologic dysfunction manifested by unusual clumsiveness which improves with age.

Cole and Hughes reported a mean DQ/IQ of 78 with a range of 40–129 (n = 23), but indicated that their figures probably underestimated ability in Sotos syndrome because some children from regular schools could not be formally assessed.

Delay in expressive language and motor development during infancy is particularly common and in some instances may be followed by attainment of normal or near normal intelligence Opens in new window.

Cole and Hughes have observed that patients with Sotos syndrome tend to improve as they get older.

• Delay in walking until after 15 months of age and speech delay until after two and one half years are usual.
• Autism has been seen.
• Seizures  Opens in new window and respiratory and feeding problems have been noted in about 20%.
• Often drooling is observed.
• Attention deficit may also be a component in some instances.

Occasionally, other neurological signs have been reported, including nystagmus, strabismus, increased deep tendon reflexes, hypotonia, and muscle weakness. Dilatation of the cerebral ventricles is seen in 70%–100%.

Other abnormalities include absent corpus callosum, prominent cortical sulci, cavum septum pellucidum, and cavum velum interpositi.

Schaefer et al in a neuroimaging study of 40 patients, found prominence of the trigone in 90%, prominence of the occipital horns in 75%, and ventriculomegaly in 63%.

3. Craniofacial Features

Dolichocephaly and marked frontal bossing are accentuated by frontoparietal balding.

• The head circumference is usually well above the 97th centile.
• Narrow temples make the eyes appear wide-set, but true ocular hypertelorism is not found.
• Strabismus is noted in 40%.
• The cheeks are full.

Although the mandible is long and narrow inferiorly, squared, or pointed, true prognathism is rare. The palate is highly arched, and prematurely erupted deciduous teeth are observed in more than 50% of cases. Cephalometric analyses are available.

4. Neoplasms

Cohen critically reviewed neoplasms reported to occur with Sotos syndrome. Retrospective literature review suggests a tumor frequency of about 3.9%.

• Tumors have included Wilms tumor,
• hepatocellular carcinoma,
• neuroblastoma,
• vaginal epidermoid carcinoma,
• small cell carcinoma of lung,
• sacrococcygeal teratoma,
• giant cell granuloma of the mandible, and
• acute lymphatic leukemia.

5. Laboratory Findings

A 14% frequency of glucose intolerance has been demonstrated in Sotos syndrome by numerous investigators.

6. Other Findings

Congenital heart defects have been discussed by Keneko et al, Cole and Hughes, Noreau et al, and Tsukahara et al. Many low-frequency abnormalities have been reported, including, among others,

• juvenile macular degeneration,
• optic disc pallor,

• glaucoma,
• bones in the anterior fontanelle,
• vertebra plana,
• kyphoscoliosis,
• brittle nails,
• syndactyly,
• functional megacolon, and
• autonomic failure with persistent fever.

Diagnosis and Differential Diagnosis

Most patients can be diagnosed by craniofacial gestalt accompanied by significant overgrowth.

However, enlarged head circumference may be seen in several other conditions including hydrocephalus, neurofibromatosis, achondroplasia, autosomal dominant macrocephaly, and so on.

Occasional patients have been confused as having Weaver syndrome Opens in new window. Still other patients cannot be confidently diagnosed as having either syndrome.

Opitz et al suggested that the many similarities between Sotos syndrome and Weaver syndrome may possibly indicate allelic rather than locus heterogeneity.

Boys with fragile X may overlap phenotypically with those having Sotos syndrome.

Although some syndromes occur with overgrowth and others are associated with macrocephaly Opens in new window, Sotos syndrome is a distinctive condition.

Several syndromes have been confused with Sotos syndrome. Cole and Hughes evaluating 79 patients, found that 50% were misdiagnosed.

Cole and Hughes and others proposed that autosomal dominant macrocephaly, obesity, unusual facies, delayed bone age, mental retardation and autism is a distinct entity. This has come to known as Cole-Hughes macrocephaly syndrome.