Overgrowth syndromes in children constitute a group of rare disorders that are typical of tissue hypertrophy. Individual overgrowth syndromes have been shown to overlap with regard to clinical and radiologic features. The details of the genetic bases of these syndromes are unfolding. Any of the three embryonic tissue layers may be involved.The syndromes may manifest in localized or generalized tissue overgrowth. Latitudinal and longitudinal growth may be affected. Nevertheless, the musculoskeletal features are central to the diagnosis of some syndromes such as Proteus syndrome. The time of presentation of children with overgrowth syndromes is an important contributor to the differential diagnosis. Children with some overgrowth syndromes such as Klippel-Trenaunay-Weber syndrome can be readily detectable at birth. In contrast other overgrowth syndromes such as Proteus syndrome usually present in the postnatal period characteristically between the 2nd and 3rd year of life. In general, children with overgrowth syndromes are at increased risk of embryonic tumor development.

Examples of overgrowth syndromes include; Beckwith-Wiedemann syndrome, Proteus syndrome, Sotos syndrome, neurofibromatosis, Simpson-Golabi-Behmel syndrome, Weaver syndrome, Sturge–Weber syndrome, Macrocephaly-capillary malformation, CLOVES syndrome, fragile X syndrome and Klippel-Trenaunay-Weber syndrome.

Bannayan–Riley–Ruvalcaba syndrome is associated with enlarged head and benign mesodermal hamartomas (multiple hemangiomas, and intestinal polyps). Dysmorphy as well as delayed neuropsychomotor development can also be present. The head enlargement does not cause widening of the ventricles or raised intracranial pressure; these individuals have a higher risk of developing tumors, as the gene involved in BRRs is phosphatase and tensin homologue.

Some individuals have thyroid issues consistent with multinodular goiter, thyroid adenoma, differentiated non-medullary thyroid cancer,

most lesions are slowly growing. Visceral as well as intracranial involvement may occur in some cases, and can cause bleeding and symptomatic mechanical compression

The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. Afflicted patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement. Patients can also exhibit hyperthyroidism of the skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized.

Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels.

Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome. The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to deep vein thrombosis and pulmonary embolism caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs, arthritis and muscle pain may also be symptoms — as is the case for Mandy Sellars, a woman who has been diagnosed with a form of Proteus syndrome (but see "Notable Cases" below). Further risks may occur due to the mass of extra tissue.

The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among sufferers of Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance. In addition, the presence of visible deformity may have a negative effect on the social experiences of the sufferer, causing cognitive and social deficits.

Afflicted individuals are at increased risk for developing certain tumors including unilateral Ovarian cystadenomas, testicular tumors, meningiomas, and monomorphic adenomas of the parotid gland.

Hemimegalencephaly is often found to be associated.

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth syndrome and hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. The disease is inherited in an autosomal dominant manner.

The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz–Jeghers syndrome, juvenile polyposis and Cowden syndrome. Mutation of the PTEN gene underlies this syndrome, as well as Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, these four syndromes are referred to as PTEN Hamartoma-Tumor Syndromes.

Most children with BWS do not have all of these five features. In addition, some children with BWS have other findings including: nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, genitourinary anomalies (enlarged kidneys), cardiac anomalies, musculoskeletal abnormalities, and hearing loss. Also, some premature newborns with BWS do not have macroglossia until closer to their anticipated delivery date.

Given the variation among individuals with BWS and the lack of a simple diagnostic test, identifying BWS can be difficult. In an attempt to standardize the classification of BWS, DeBaun et al. have defined a child as having BWS if the child has been diagnosed by a physician as having BWS and if the child has at least two of the five common features associated with BWS (macroglossia, macrosomia, midline abdominal wall defects, ear creases/ear pits, neonatal hypoglycemia). Another definition presented by Elliot et al. includes the presence of either three major features (anterior abdominal wall defect, macroglossia, or prepostnatal overgrowth) or two major plus three minor findings (ear pits, nevus flammeus, neonatal hypoglycemia, nephromegaly, or hemihyperplasia).

While most children with BWS do not develop cancer, children with BWS do have a significantly increased risk of cancer. Children with BWS are most at risk during early childhood and should receive cancer screening during this time.

In general, children with BWS do very well and grow up to become adults of normal size and intelligence, usually without the syndromic features of their childhood.

Beckwith–Wiedemann syndrome (; abbreviated BWS) is an overgrowth disorder usually present at birth, characterized by an increased risk of childhood cancer and certain congenital features.

Common features used to define BWS are:

- macroglossia (large tongue),

- macrosomia (above average birth weight and length),

- microcephaly

- midline abdominal wall defects (omphalocele/exomphalos, umbilical hernia, diastasis recti),

- ear creases or ear pits,

- neonatal hypoglycemia (low blood sugar after birth).

- Hepatoblastoma

CLOVES syndrome is an extremely rare overgrowth syndrome, with complex vascular anomalies. CLOVES syndrome affects people with various symptoms, ranging from mild fatty soft-tissue tumors to vascular malformations encompassing the spine or internal organs. CLOVES syndrome is closely linked to other overgrowth disorders like proteus syndrome, Klippel–Trénaunay syndrome, Sturge–Weber syndrome, and hemihypertrophy, to name a few.

'CLOVES' is an acronym for:

- C is for congenital.

- L is for lipomatous, which means pertaining to or resembling a benign tumor made up of mature fat cells. Most CLOVES patients present with a soft fatty mass at birth, often visible on one or both sides of the back, legs and/or abdomen.

- O is for overgrowth, because there is an abnormal increase in the size of the body or a body part that is often noted at birth. Patients with CLOVES may have affected areas of their bodies that grow faster than in other people. Overgrowth of extremities (usually arms or legs) is seen, with large wide hands or feet, large fingers or toes, wide space between fingers, and asymmetry of body parts.

- V is for vascular malformations, which are blood vessel abnormalies. Patients with CLOVES have different venous, capillary, and lymphatic channels - typically capillary, venous and lymphatic malformations are known as "slow flow" lesions. Some patients with CLOVES have combined lesions (which are fast flow) and some have aggressive vascular malformation known as arteriovenous malformations (AVM). The effect of a vascular malformation varies per patient based on the type, size, and location of the malformation, and symptoms can vary.

- E is for Epidermal naevi, which are sharply-circumscribed chronic lesions of the skin, and benign. These are often flesh-colored, raised or warty.

- S is for Spinal/Skeletal Anomalies or scoliosis. Some patients with CLOVES have tethered spinal cord, vascular malformations in or around their spines, and other spinal differences. High-flow aggressive spinal lesions (like AVM) can cause serious neurological deficits/paralysis.

The syndrome was first recognised by Saap and colleagues who recognised the spectrum of symptoms from a set of seven patients. In this initial description the syndrome is named CLOVE syndrome. It is believed that the first description of a case of CLOVES syndrome was written by Hermann Friedberg, a German physician, in 1867.

One of the most prominent and visible symptoms of Nevo Syndrome is the prenatal overgrowth, which continues into the infant and toddler stage. This excessive weight gain can be attributed to the low concentrations of growth hormone and insulin growth factor that are normally present to regulate weight gain. Other common symptoms associated with Nevo Syndrome are the outward wrist-drop, edema in hands and feet, undescended testes, low-set ears, hypotonia, the presence of low muscle tone in children, and long tapered fingers, and a highly arched palate.

Perlman syndrome shares clinical overlaps with other overgrowth disorders, with similarities to Beckwith–Wiedemann syndrome and Simpson-Golabi-Behmel syndrome having been particularly emphasized in scientific study. Similarities with Beckwith-Wiedemann syndrome include polyhydramnios, macrosomia, nephromegaly and hypoglycaemia. It is the distinctive facial dysmorphology of Perlman, including deep-set eyes, depressed nasal bridge, everted upper lip, and macrocephaly which allows the two conditions to be distinguished from one another. Diagnosis of Perlman syndrome also overlaps with other disorders associated with Wilms tumor, namely, Sotos syndrome and Weaver syndrome.

Children with Weaver syndrome tend to look similar and have distinctive physical and craniofacial characteristics, which may include several, but not all of the following features:

- Macrocephaly

- Large bifrontal diameter

- Flattened occiput

- Long philtrum

- Retrognathia

- Round face in infancy

- Prominent chin crease

- Large ears

- Strabismus

- Hypertelorism

- Epicanthal folds

- Downslanting palpebral fissures

Other features may include loose skin, thin deep-set nails, thin hair, short ribs, limited elbow and knee extension, camptodactyly, and a coarse, low-pitched voice. Delayed development of motor skills such as sitting, standing, and walking are commonly exhibited in early childhood. Patients with Weaver syndrome typically have mild intellectual disability with poor coordination and balance. They also have some neurological abnormalities such as speech delay, epilepsy, intellectual disability, hypotonia or hypertonia, and behavioral problems.

Perlman syndrome (PS) (also called renal hamartomas, nephroblastomatosis and fetal gigantism) is a rare overgrowth disorder present at birth. It is characterized by polyhydramnios and fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms' tumor at an early age. The prognosis for Perlman syndrome is poor and it is associated with a high neonatal mortality.

This syndrome is 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 skull and large head. Adult height is usually in the normal range, although Broc Brown has the condition and was named the world's tallest teenager. As of late 2016, he was 7'8" and still growing.

Individuals with Sotos syndrome often have intellectual impairment, and most also have behavioral problems. Frequent behavioral impairments include attention deficit hyperactivity disorder (ADHD), phobias, obsessive compulsive disorder, tantrums, and impulsive behaviors (impulse control disorder). Problems with speech and language are also common. Affected individuals may often have stuttering, difficulty with sound production, or 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 include scoliosis, seizures, heart or kidney defects, hearing loss, and problems with vision. Some infants with this disorder experience jaundice and poor feeding. A small number of patients 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 persons with this disorder have any increased cancer risk, their risk is only slightly greater than that of the general population.

Beare–Stevenson cutis gyrata syndrome is a rare genetic disorder characterized by craniosynostosis (premature fusion of certain bones of the skull, sometimes resulting in a characteristic 'cloverleaf skull'; further growth of the skull is prevented, and therefore the shape of the head and face is abnormal) and a specific skin abnormality, called cutis gyrata, characterized by a furrowed and wrinkled appearance (particularly in the face and on the palms and soles of the feet); thick, dark, velvety areas of skin (acanthosis nigricans) are sometimes found on the hands and feet and in the groin.

Additional signs and symptoms of Beare–Stevenson cutis gyrata syndrome can include a blockage of the nasal passages (choanal atresia), overgrowth of the umbilical stump, and abnormalities of the genitalia and anus. The medical complications associated with this condition are often severe and may well be life-threatening in infancy or early childhood.

There are two types of SGBS, each found on a different gene:

SGBS is also considered to be an overgrowth syndrome (OGS). OGS is characterized by a 2-3 standard deviation increase in weight, height, or head circumference above the average for sex and age. One of the most noted features of OGS is the increased risk of neoplasms in certain OGSs. SGBS in particular has been found to have a 10% tumor predisposition frequency with 94% of cases occurring in the abdominal region, most being malignant. It is common for tumors to be embryonal in type and appear before the age of 10.

There are five different types of tumors that patients with SGBS might develop, all intra-abdominal: Wilms tumor, Hepatoblastoma, Hepatocarcinoma, Gonadoblastoma, and Neuroblastoma.

The most common types of tumors developed in patients are the Wilms tumor and hepatoblastoma.

Parkes Weber Syndrome (PWS) is a congenital disorder of the vascular system. It is an extremely rare disease with only 0.3% of the world's population known to have this syndrome. In 1907, a British dermatologist, Frederick Parkes Weber first described this syndrome and hence this disease was named Parkes Weber Syndrome. In the body, vascular system consists of arteries, veins and capillaries. When abnormalities such as: vascular malformation, capillary arteriovenous malformations (AVMs), arteriovenous fistulas (AVFs) and overgrowth of a limb occur together in combination and disturb the complex network of blood vessels of the vascular system -it is known as PWS. The capillary malformations and AVFs are known to be present from the birth. In some cases PWS is a genetic condition where RASA1 gene is mutated and displays autosomal dominant inheritance pattern. If PWS is genetic then most patients show multiple capillary malformations. Patients that do not have multiple capillary malformations most likely did not inherit PWS and do not have RASA1 mutations. In such cases the cause of PWS is often unknown and is sporadic as most cases often are.

Often times PWS is mixed up with Klippel–Trénaunay syndrome (KTS). These two diseases are similar but they are not quite the same. PWS occurs because of vascular malformation that may or may not be because of genetic mutations, where as Klippel-Trenaunay syndrome is a condition in which blood vessels and or lymph vessels do not form properly. PWS and KTS almost have the same symptoms except PWS patients are seen with both AVMs and AVFs occur together along with lymph hypertrophy.

Nevo Syndrome is a rare autosomal recessive disorder that usually begins during the later stages of pregnancy. Nevo Syndrome is caused by a NSD1 deletion, which encodes for methyltransferase involved with chromatin regulation. The exact mechanism as to how the chromatin is changed is unknown and still being studied. Nevo Syndrome is an example of one of about twelve overgrowth syndromes known today. Overgrowth syndromes are characterized with children experiencing a significant overgrowth during pregnancy and also excessive postnatal growth. Studies concerning Nevo Syndrome have shown a similar relation to Ehlers-Danlos syndrome, a connective tissue disorder. Nevo Syndrome is associated with kyphosis, an abnormal increased forward rounding of the spine, joint laxity, postpartum overgrowth, a highly arched palate, undescended testes in males, low-set ears, increased head circumference, among other symptoms.

Weaver syndrome (also called Weaver-Smith syndrome) is an extremely rare congenital disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years. It is characterized by advanced osseous maturation, and distinctive craniofacial, skeletal, and neurological abnormalities. It was first described by Dr. David Weaver in 1974. It is similar to Sotos syndrome.

Major symptoms of PWS include:

Birthmarks: Effected PWS patients suffer from large, flat, pink staining on the skin. This staining is a result of the capillary malformations that have the tendency to increase the blood flow near the surface of the skin causing the staining. Because of the staining color they are sometimes referred to as “port-wine stains”. “Port-wine stain” or discoloration of the skin due to vascular malformation is also referred as Nevus flammeus.

Hypertrophy: Hypertrophy refers to excessive growth of the bone and soft tissue. In PWS patients a limb is overgrown and hypertrophy is usually seen in the affected limb.

Multiple arteriovenous fistulas: PWS patients also suffer from multiple AVFs that occur in conjunction with capillary malformations. AVFs occur because of abnormal connections between arteries and veins. Normally, blood flows from arteries to capillaries then to veins. But for AFV patients, because of the abnormal artery and vein connections, blood flows directly from arteries into the veins completely bypassing the capillaries. These irregular connections affect the blood circulation and may lead to life-threatening complications such as abnormal bleeding and heart failure. AVFs can be identified by: large, purplish bulging veins, swelling in limbs, decreased in blood pressure, fatigue and heart failure.

Capillary arteriovenous malformations: Vascular system disorder is the cause of the capillary malformations. Here, the capillaries are enlarged and increase the blood flow towards the surface of the skin. Because of the capillary malformations, the skin has multiple small, round, pink or even red dots. For most of the affected individuals, these malformations occur on the face, arms and or legs. The spots may be visible right from birth itself or they may develop during childhood years. If capillary malformations occur by themselves, it is not a huge threat to life. But when these occur in conjunction with AVFs then it is a clear indicator of PWS and may be serious depending on the severity of the malformations.

The Human Phenotype Ontology (HPO) reports of additional symptoms in PWS patients. HPO is an active database that collects and researches on the relationships between phenotypic abnormalities and biochemical networks. This is an useful database as it has information and data on some of the rarest diseases such as PWS. According to HPO, the symptoms which are reported very frequently in PWS patients include: abnormal bleeding, hypertrophy of the lower limb, hypertrophy of the upper limb, nevus flammeus or staining of the skin, peripheral arteriovenous fistula, telangiectasia of the skin. Frequent to occasional symptoms include: varicose veins, congestive heart failure, glaucoma and headache.

Abnormal bleeding: some skin lesions are prone to bleed easily.

Peripheral arteriovenous fistula: abnormal communication between artery and vein that is a direct result of the abnormal connection or wiring between the artery and vein.

Telangiectasia of the skin: Telangiectasia is a condition where tiny blood vessels become widened and form threadlike red lines and or patterns on the skin. Because of their appearance and formation of web-like patterns they are also known as spider veins. These patterns are referred as telangiectases.

Varicose veins: Enlarged, swollen and twisted veins.

Congestive heart failure: This is a condition in which the heart’s ability to meet the requirements of the body is diminished. The cardiac output is decreased and the amount of blood pumped is not adequate enough to keep the circulation from the body and lungs going.

Glaucoma: Glaucoma is a combination of diseases that cause damage to the optic nerve and may result in vision loss and blindness.

Headache: pain in the head.

Along with the four aspects of the disorder that give it its name, there are also other common symptoms:

- A downward slant of the forehead

- Delayed bone maturation

- Mental retardation

The ocular abnormalities are generally retinal coloboma and nystagmus.

Detection usually begins with a routine doctor visit when the fundal height is being measured or during an ultrasound examination. When large for gestational age fetuses (LGA) are identified, there are two common causes: maternal diabetes or incorrect dates. However, if these two causes can be ruled out, an ultrasound is performed to detect for overgrowth and other abnormalities. At this point, it becomes essential for a clinical geneticist to assist in the correct selection of tests and possible diagnosis.

First signs of SGBS may be observed as early as 16 weeks of gestation. Aids to diagnosing might include the presence of macrosomia, polyhydramnios, elevated maternal serum-α-fetoprotein, cystic hygroma, hydrops fetalis, increased nuchal translucency, craniofacial abnormalities, visceromegaly, renal abnormalities, congenital diaphragmatic hernia, polydactyly, and a single umbilical artery.

If there is a known mutation in the family, prenatal testing is available. Prenatal testing is also possible by looking for evidence of the mild SGBS phenotype in the mother and the positive SGBS phenotype in male family members. Family members who are positive of SGBS may undergo mutational analysis of genes GCP3, GCP4, and CXORF5. Genomic balance in Xp22 and Xq26 may also be analyzed through array comparative genomic hybridization.

Due to the high percentage of male deaths during the neonatal period, early detection of tumors is crucial. In order to detect the presence of tumors, screening in SGBS patients should include abdominal ultrasound, urinalysis, and biochemical markers that screen for embryonic tumors.

Once the infant is born, possibility of hypoglycemia must be assessed along with cardiac, genitalia, liver, and adrenal evaluations. Such tests include chest radiographs, electrocardiogram, echocardiogram, renal sonography, and abdominal sonography to test for possible abnormalities.

Beare–Stevenson cutis gyrata syndrome is so rare that a reliable incidence cannot be established as of yet; fewer than 20 patients with the condition have been reported.

Sotos syndrome (cerebral gigantism or Sotos-Dodge syndrome) is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild intellectual disability, 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 relatively large skulls (macrocephaly) than is normal for their age. Signs of the disorder, which vary among individuals, include a disproportionately large skull with a slightly protrusive forehead, large hands and feet, large mandible, hypertelorism (an abnormally increased distance between the eyes)(large inter-pupillary distance), 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. It is similar to Weaver syndrome.

Diagnosis is usually based on clinical observation. Various sets of criteria have been suggested to identify the disorder in an individual patient, all of which include macrocephaly and a number of the following: somatic overgrowth, cutis marmorata, midline facial birthmark, polydactyly/syndactyly, asymmetry (hemihyperplasia or hemihypertrophy), hypotonia at birth, developmental delay, connective tissue defect and frontal bossing. Currently no consensus exists about which diagnostic criteria are definitive and so evaluation by a medical geneticist or other clinician with familiarity with the syndrome is usually needed to provide diagnostic certainty. It is not clear if there are some features which are mandatory to make the diagnosis, but macrocephaly appears essentially universal though may not be congenital. The distinctive vascular abnormalities of the skin often fade over time, making the diagnosis challenging in older children with this condition.

The brain can be affected in several ways in this syndrome. Some children are born with structural brain anomalies such as cortical dysplasia or polymicrogyria. While developmental delay is nearly universal in this syndrome it is variable in severity, with the majority having mild to moderate delays and a minority having severe cognitive impairment. Some patients are affected with a seizure disorder. White matter abnormalities on magnetic resonance imaging (MRI), suggesting a delay in white matter myelination, is commonly seen in early childhood. Some patients may have asymmetry of the brain, with one side being noticeably larger than the other.

One interesting phenomenon that seems very common in this syndrome is the tendency for disproportionate brain growth in the first few years of life, with crossing of percentiles on the head circumference growth charts. A consequence of this disproportionate brain growth appears to be a significantly increased risk of cerebellar tonsillar herniation (descent of the cerebellar tonsils through the foramen magnum of the skull, resembling a Chiari I malformation neuroradiologically) and ventriculomegaly/hydrocephalus. Such cerebellar tonsil herniation may occur in up to 70% of children with M-CM.

The medical literature suggests that there is a risk of cardiac arrhythmias in early childhood. The cause for this is unknown. In addition, a variety of different congenital cardiac malformations have been reported in a small number of patients with this disorder.

Like other syndromes associated with disproportionate growth, there appears to be a slightly increased risk of certain types of childhood malignancies in M-CM (such as Wilms' tumor). However, the precise incidence of these malignancies is unclear.

The syndrome is a rare clinical disorder.

- Physical

- Overgrowth

- Accelerated skeletal maturation

- Dysmorphic facial features

- Prominent eyes

- Bluish sclerae

- Coarse eyebrows

- Upturned nose

- Radiologic examination

- Accelerated osseous maturation

- Phalangeal abnormalities

- Tubular thinning of the long bones

- Skull abnormalities

- Mental

- Often associated with intellectual disability (of variable degree)