Overgrowth Syndromes: an Overview
by Beth A. Pletcher, MD, May 1999

Probably the most recognized of the overgrowth syndromes seen in pediatrics is Beckwith-Wiedemann syndrome (BWS), clinically associated with polyhydramnios (often leading to prematurity), pre and postnatal overgrowth, advanced bone age, macroglossia, unusual ear lobe creases, umbilical hernia and/or omphalocele. Neonatal hypoglycemia is seen in 1/3 to 1 /2 of affected infants and is a serious cause of morbidity if it goes undetected and untreated. Polycythemia may also be seen in the neonatal period and may or may not require medical intervention. Abdominal ultrasound in infancy may reveal persistent fetal lobulations in the kidneys with or without hepatomegaly. Hemihypertrophy can be seen in some children with BWS and during early childhood, screening for Wilms' tumor and/or hepatoblastoma is warranted because of an increased risk for these malignancies. A renal sonogram as well as measurement of serum alpha-fetoprotein every 6 months has been advocated by some as a means of screening for these tumors through age 6 years.

The genetics of BWS turns out to be quite complex and several different mechanisms have been attributed to this condition. Over the past few years a number of genes (all residing on the short arm of chromosome 11) have been associated with this clinical entity. Although for many affected individuals the precise molecular defect has not yet been defined, more and more patients are being identified with specific yet different molecular defects all resulting in a similar phenotypic picture. This particular chromosomal region appears to be heavily imprinted which suggests that certain genes inherited from a mother or a father may be preferentially turned on (expressed) or turned off (silenced). Under normal circumstances a certain growth factor (IGF2) seems to be selectively active on the paternally inherited chromosome #11 whereas a tumor suppressor gene (H19) appears to be active only on the maternally inherited chromosome #11.

Even though the majority of individuals with BWS represent new mutations or genetic event in the family, there are a number of reports of autosomal dominant transmission of this disorder. Because chromosomal duplications, cytogenetic translocations as well as monozygotic twins discordant for BWS have all been seen, it is clear that this is genetically heterogeneous and can occur post-zygotically resulting in somatic mosaicism (some cells with the BWS mutation and some without). In fully 10-20% of patients with BWS, molecular studies demonstrate paternal uniparental disomy (UPD) which suggests that there are two paternal #11 chromosomes and no maternal contribution. In all of these cases identified thus far mosaicism has been seen which suggests a post-zygotic error during cell division.

Point mutations in three genes so far have been shown to cause BWS. First, mutations in p57kip2, a cyclin dependent kinase inhibitor, have been seen in: sporadic cases, many maternally transmitted BWS and a much smaller percentage of paternally transmitted BWS. This gene in particular has a high association with omphalocele and cleft palate. IGF2 the growth factor alluded to above, is normally only active on the paternally inherited chromosome #11. The activation of a second copy of this growth factor on the maternal chromosome, presence of two active copies due to paternal UPD as discussed previously or presence of two paternal genes due to duplication of this chromosomal region on the paternal chromosome have all been postulated as causes of BWS with excellent molecular proof. Although the duplication form of BWS is relatively rare, it has a strong association with mental retardation which is not very common in BWS in general. Apparently balanced translocations involving chromosome 11p have been reported at least 15 times and so far have all been maternally inherited. It is postulated that the translocation in these patients disrupts an important imprinting center gene leading to activation of a normally inactive region of the maternal chromosome. Over time as these many causes of BWS are elucidated, molecular and cytogenetic studies may become even more helpful in confirming diagnoses and also highlighting individual medical risks for long term sequelae.

Simpson-Golabi- Behmel syndrome(SGBS), clinically similar to BWS, is inherited as an X-linked recessive condition, therefore typically affecting only boys. Clinical similarities with BWS include: pre and postnatal overgrowth, variable mental retardation with many of normal intelligence, advanced bone age in early childhood, macroglossia and cleft palate. Unlike BWS, boys with SGBS may have coarse facies, down-slanting palpebrae, a broad nasal bridge, unusual groove on the midline lower lip, cleft lip, supernumerary nipples, vertebral segmentation defects, polydactyly, syndactyly, broad thumbs and great toes, intracardiac defects and cardiac conduction defects. Although umbilical hernias may be seen in SGBS, omphaloceles are rare as are neonatal hypoglycemia or polycythemia. SGBS is caused by a mutation in or a deletion of the glypican 3 (GPC3) gene on the long arm of the X chromosome. Female carriers of SGBS may have mild manifestations with a tremendous spectrum in the clinical features in affected males. Up to _ of reported cases of SGBS have died within the first 6 months of life although this is likely to be an over estimate due to ascertainment bias. The GPC3 gene product is postulated to be a growth factor co-receptor and may modulate growth of embryonic mesodermal tissues. As a result, boys with SGBS appear to be at increased risk for the development of embryonal tumors, but the precise risks are not as clearly defined as in BWS.

Weaver syndrome is also an overgrowth syndrome of prenatal onset associated with macrocephaly, mild hypertonia and advanced bone age. Typical facial features may include: frontal bossing, flat occiput, hypertelorism, epicanthal folds, strabismus, down-slanting palpebrae, large ears, a long philtrum and mild micrognathia. Unusual hand findings include: broad thumbs, deep set nails, camptodactyly (contractures of the fingers) and prominent finger tip pads. Contractures of the elbows and knees are also reported as well as talipes equinovarus and metatarsus adductus. Learning difficulties or mild mental retardation is more common in this condition with neurologic findings of dysarthria, progressive spasticity or a low-pitched voice seen in late infancy or childhood. The genetic cause of Weaver syndrome has yet to be elucidated and most cases represent sporadic events. However, several cases of mildly affected mothers having severely affected sons raises the possibility that some cases may be due to an X-linked recessive gene or an autosomal dominant gene with expression limited primarily to males. Quite recently a number of children have been described with features of both Weaver syndrome and neurofibromatosis, raising the possibility of a contiguous gene syndrome on chromosome 17 resulting in both conditions due to a deletion of a small piece of DNA containing genes for both disorders. No molecular explanation for this co-occurrence has been found but should become clear in the next few years.

Sotos syndrome, also known as cerebral gigantism, is the most common diagnosis made in children with macrocephaly, overgrowth and developmental delay. In addition to pre and postnatal overgrowth and advanced bone age, children with Sotos syndrome tend to have hypotonia, hyperreflexia and motor delay early in life. Dolicocephaly is a common finding as are down-slanting palpebrae, a prominent jaw, a high arched palate, facial flushing, premature dental eruption, large hands and feet, pes planus, genu valgum and a CT/MRI finding of ventriculomegaly. The majority of cases of Sotos syndrome are sporadic although reports of five families with parent to child transmission raises the possibility of an autosomal dominant gene.