Sotos syndrome

Definition

Sotos syndrome is a genetic condition causing excessive growth and a distinctive head and facial appearance. It has in the past been known as cerebral gigantism. It is often accompanied by delayed development, low muscle tone, and impaired speech.

Description

Sotos syndrome was first described in 1964 and is primarily classified as an overgrowth syndrome, which means that the individual affected with it experiences rapid growth. A number of different symptoms occur in Sotos syndrome; however, it primarily results in rapid growth beginning in the prenatal period and continuing through the infancy and toddler years and into the elementary school years. It is also strongly associated with the bones developing and maturing more quickly (advanced bone age), a distinctive appearing face, and developmental delay.

The excessive prenatal growth often results in the newborn being large with respect to length and head circumference; weight is usually average. The rapid growth continues through infancy and into the youth years with the child's length/height and head circumference often being above the 97th percentile, meaning that out of 100 children of the same age, the child is longer/taller and has a larger head than 97 others. The rate of growth appears to decrease in later childhood and adolescence and final heights tend to be within the normal ranges.

The facial features of individuals with Sotos syndrome change over time. In infants and toddlers, the face is round with the forehead being prominent and the chin small. As the child grows older and becomes an adolescent, the face becomes long with the chin being more prominent, usually with a pointed or square shape. In adults, faces are usually long and thin. The head remains large from birth through adulthood.

Hypotonia is present at birth in nearly every child with Sotos syndrome. Hypotonia means that there is significantly less tone in the muscles. Bodies with hypotonia are sometimes referred to as "floppy." Muscle tone improves as the child grows older, but even in adults, it is still present to some degree. Hypotonia affects many aspects of the baby's development. It can cause difficulty in sucking and swallowing, and many babies are diagnosed with failure to thrive in the newborn period. This, however, usually lasts for about three to four months and then goes away. Hypotonia makes attaining fine motor skills (grasping, playing with toys, babbling) and gross motor skills (rolling, crawling, walking) difficult and these developmental milestones are usually delayed. Speech is also affected by hypotonia but as the child grows older and the hypotonia resolves or goes away, speech improves. Although the child may have delayed development, intellect typically is borderline to normal. Special attention may be needed in certain subjects, such as reading comprehension and arithmetic. Severe mental retardation is rarely seen.

There are a number of other features that have been associated with Sotos syndrome, including jaundice in the newborn period, coordination problems, and a tendency for clumsiness. Behavioral problems and emotional immaturity are commonly reported. About half of the children with Sotos syndrome will experience a seizure associated with fever. Dental problems such as early eruption of teeth, excessive wear, discoloration, and gingivitis are common. Teeth may also be aligned incorrectly due to changes in the facial structure.

Infections tend to develop in the ear, upper respiratory tract, and urinary tract. In some children, hearing may be disrupted due to recurrent ear infections and in these situations, a referral to an otolaryngologist (a doctor specializing in the ear, nose, and throat) may be necessary for assessment of hearing. Urinary tract infections occur in about one out of five children with Sotos syndrome. These have been associated with structural problems of the bladder and ureters; consequently, if urinary tract infections occur, the child should undergo further evaluations.

Congenital heart problems and development of tumors have been reported in individuals with Sotos syndrome. However, the information regarding the actual risks of these problems is not definitive and medical screening for these conditions is not routinely recommended.

Genetic profile

Sotos syndrome is for the most part a sporadic condition, meaning that a child affected by it did not inherit it from a parent. In a very few families, autosomal dominant inheritance has been documented, which means that both a parent and his/her child is affected by Sotos syndrome. The cause of Sotos syndrome is not known and the gene(s) that are involved in it have not been identified.

Demographics

Sotos syndrome is described by different groups as being both "fairly common" and "rare." A 1998 article in the American Journal of Medical Genetics states that over 300 cases of Sotos syndrome have been published and probably many more are unpublished. As of 2001, incidence numbers had not been determined. Sotos syndrome occurs in both males and females and has been reported in several races and countries.

Signs and symptoms

A variety of clinical features are associated with Sotos syndrome.

• Newborns are large with respect to length and head circumference; weight is usually average. The rapid growth continues through infancy and into childhood with the child's length/height and head circumference often being above the 97th percentile. The rate of growth appears to decrease in later childhood and adolescence.
• Respiratory and feeding problems (due to hyoptonia) may develop in the neonatal period.
• Infants have a round face with prominent forehead and small chin. As the child grows into adolescence and then adulthood the face becomes long and thin, and the chin becomes more prominent.
• Hypotonia is present at birth. This affects the development of fine and gross motor skills, and developmental milestones are usually delayed. Speech is also affected by hypotonia but as the child grows older and the hypotonia resolves or goes away, speech improves.
• Intellect typically is borderline to normal.
• Behavioral problems and emotional immaturity are commonly reported.
• Dental problems such as early eruption of teeth, excessive wear, discoloration, and gingivitis are common.

Diagnosis

Diagnosis of Sotos syndrome is based upon clinical examination, medical history, and x ray data. There are no laboratory tests that can provide a diagnosis. The clinical criteria that are considered to be diagnostic for Sotos syndrome are excessive growth during the prenatal and postnatal period, advanced bone age, developmental delay, and a characteristic facial appearance. It should be noted that although features suggestive of Sotos syndrome may be present at birth or within 6-12 months after birth, making a diagnosis in infancy is not clear cut and may take multiple evaluations over several years.

There are many conditions and genetic syndromes that cause excessive growth; consequently, a baby and/or child who has accelerated growth needs to be thoroughly examined by a physician knowledgeable in overgrowth and genetic syndromes. The evaluation includes asking about health problems in the family as well as asking about the growth patterns of the parents and their final height. In some families, growth patterns are different and thus may account for the child's excessive growth. The child will also undergo a complete physical examination. Additional examination of facial appearance, with special attention paid to the shape of the head, width of the face at the level of the eyes, and the appearance of the chin and forehead is necessary as well. Measurement of the head circumference, arm length, leg length, and wing span should be taken. Laboratory testing such as chromosome analysis (karyotype) may be done along with testing for another genetic syndrome called fragile-X. A bone age will also be ordered. Bone age is determined by x rays of the hand. If the child begins to lose developmental milestones or appears to stop developing, metabolic testing may be done to evaluate for a metabolic condition.

Treatment and management

There is no cure or method for preventing Sotos syndrome. However, the symptoms can be treated and managed. In the majority of cases, the symptoms developed by individuals with Sotos syndrome are treated and managed the same as in individuals in the general population. For example, physical and occupational therapy may help with muscle tone, speech therapy may improve speech, and behavioral assessments may assist with behavioral problems.

Managing the health of a child with Sotos syndrome includes regular measurements of the growth parameters, i.e., height, head circumference, and weight, although excessive growth is not treated. Regular eye and dental examinations are also recommended. Medical screening for congenital heart defects and tumors is not routinely recommended, although it has been noted that symptoms should be evaluated sooner rather than later.

Prognosis

With appropriate treatment, management, and encouragement, children with Sotos syndrome can do well. Adults with Sotos syndrome are likely to be within the normal range for height and intellect. Sotos syndrome is not associated with a shortened life span.

Resources

BOOKS

Anderson, Rebecca Rae, and Bruce A. Buehler. Sotos Syndrome: A Handbook for Families. Omaha, NB: Meyer Rehabilitation Institute, 1992.

Cole, Trevor R.P. "Sotos Syndrome." In Management of Genetic Syndromes, edited by Suzanne B. Cassidy and Judith E. Allanson. New York: Wiley-Liss, 2001, pp. 389–404.

PERIODICALS

Sotos Syndrome Support Association Quarterly Newsletter.

ORGANIZATIONS

Sotos Syndrome Support Group. Three Danda Square East #235, Wheaton, IL 60187. (888) 246-SSSA or (708) 682-8815. http://www.well.com/user/sssa/.

WEBSITES

Genetic and Rare Conditions Site. http://www.kumc.edu/gec/support/.

The Family Village. http://www.familyvillage.wisc.edu/index.htmlx.

Cindy L. Hunter, CGC

A syndrome of unknown cause characterized by large size at birth and an accelerated growth rate in infancy and early childhood without a like increase in serum growth hormone levels, acromegalic features, moderate mental retardation, and impaired coordination.

Sotos syndrome
Classification and external resources
ICD-10	Q87.3
ICD-9	759.89
OMIM	117550
DiseasesDB	29134

Sotos syndrome (also known as cerebral gigantism) is a rare genetic disorder characterized by excessive physical growth during the first 2 to 3 years of life. The disorder may be accompanied by mild mental retardation, delayed motor, cognitive, and social development, hypotonia (low muscle tone), and speech impairments. Children with Sotos syndrome tend to be large at birth and are often taller, heavier, and have larger heads (macrocrania) than is normal for their age. Signs of the disorder, which vary among individuals, include a disportionately large and long head with a slightly protrusive forehead, large hands and feet, hypertelorism (an abnormally increased distance between the eyes), and downslanting eyes. Clumsiness, an awkward gait, and unusual aggressiveness or irritability may also occur. Although most cases of Sotos syndrome occur sporadically, familial cases have also been reported.

Contents 1 Epidemiology 2 Signs and symptoms 3 Genetics 4 Treatment 5 Prognosis 6 References 7 External links

Epidemiology

Incidence is approximately 1 in 14,000 births.

Signs and symptoms

Characterized by overgrowth and advanced bone age. Affected individuals are dysmorphic with macrodolichocephaly, downslanting palpebral fissures and a pointed chin. The facial appearance is most notable in early childhood. Affected infants and children tend to grow quickly; they are significantly taller than their siblings and peers and have an unusually large head. Adult height is usually in the normal range, however.

People with Sotos syndrome often have intellectual impairment, and most also have behavioral problems. Frequent behavioral issues include attention deficit hyperactivity disorder (ADHD), phobias, obsessions and compulsions, tantrums, and impulsive behaviors. Problems with speech and language are also common. Affected individuals often have problems with sound production, stuttering, and a monotone voice. Additionally, weak muscle tone (hypotonia) may delay other aspects of early development, particularly motor skills such as sitting and crawling.

Other signs and signs of Sotos syndrome can include an abnormal side-to-side curvature of the spine (scoliosis), seizures, heart or kidney defects, hearing loss, and problems with vision. Some infants with this disorder experience yellowing of the skin and whites of the eyes (jaundice) and poor feeding. A few people with Sotos syndrome have developed cancer, most often in childhood, but no single form of cancer has been associated with this condition. It remains uncertain whether Sotos syndrome increases the risk of specific types of cancer. If people with this disorder have any increased cancer risk, their risk is only slightly greater than that of the general population.

Genetics

Mutations in the NSD1 gene cause Sotos syndrome.^[1] The NSD1 gene provides instructions for making a protein that is involved in normal growth and development. The function of this protein is unknown, however. In the Japanese population, the most common genetic change leading to Sotos syndrome deletes genetic material from the region of chromosome 5 containing the NSD1 gene. In other populations, small mutations within the NSD1 gene occur more frequently. Genetic changes involving the NSD1 gene prevent one copy of the gene from producing any functional protein. It is unclear how a reduced amount of this protein during development leads to learning disabilities, overgrowth, and the other features of Sotos syndrome.

About 95 percent of Sotos syndrome cases occur in people with no history of the disorder in their family. Most of these cases result from new mutations involving the NSD1 gene. A few families have been described with more than one affected family member. These cases helped researchers determine that Sotos syndrome has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder.

Treatment

There is no standard course of treatment for Sotos syndrome. Treatment is symptomatic.

Prognosis

Sotos syndrome is not a life-threatening disorder and patients may have a normal life expectancy. The initial abnormalities of Sotos syndrome usually resolve as the growth rate becomes normal after the first few years of life. Developmental delays may improve in the school-age years, however, coordination problems may persist into adulthood.

References

1. ^ Melchior L, Schwartz M, Duno M (March 2005). "dHPLC screening of the NSD1 gene identifies nine novel mutations--summary of the first 100 Sotos syndrome mutations". Ann. Hum. Genet. 69 (Pt 2): 222–6. doi:10.1046/j.1529-8817.2004.00150.x. PMID 15720303. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0003-4800&date=2005&volume=69&issue=Pt%202&spage=222. 

External links

• Information related to orphan diseases and orphan drugs - site is in French
• sotos at NIH/UW GeneTests

v • d • e Congenital abnormality · multiple abnormalities (Q87, 759.7) Craniofacial Acrocephalosyndactylia (Apert syndrome/Pfeiffer syndrome, Saethre-Chotzen syndrome, Carpenter syndrome, Sakati-Nyhan-Tisdale syndrome) other: Möbius syndrome · Goldenhar syndrome · Cyclopia Short stature Aarskog-Scott syndrome · Cockayne syndrome · Cornelia de Lange Syndrome · Dubowitz syndrome · Noonan syndrome · Robinow syndrome · Silver-Russell dwarfism · Seckel syndrome · Smith-Lemli-Opitz syndrome-Turner syndrome Limbs Adducted thumb syndrome · Holt-Oram syndrome · Klippel-Trénaunay-Weber syndrome · Nail-patella syndrome · Rubinstein-Taybi syndrome Gastrulation/mesoderm: Caudal regression syndrome · ectromelia (Sirenomelia) · VACTERL association Overgrowth Beckwith-Wiedemann syndrome · Sotos syndrome · Weaver syndrome Laurence-Moon-Bardet-Biedl Bardet-Biedl syndrome · Laurence-Moon syndrome Combined/other, known locus 3 (Zimmerman-Laband syndrome) · 4/13 (Fraser syndrome) · 8 (Branchio-oto-renal syndrome) · 12 (Keutel syndrome, Timothy syndrome) · 15 (Marfan syndrome) · 19 (Donohue syndrome) Combined/other, unknown locus Ablepharon macrostomia syndrome · Fountain syndrome · Urban-Rogers-Meyer syndrome · Yunis-Varon syndrome

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