Panel testing recommended at Breda Genetics for this conditions:
Complete or partial somatic overgrowth in infancy, childhood or adolescence (sometimes referred to also as macrosomia) is a genetically determined condition, often accompanied by other clinical signs (overgrowth syndromes). Mutations in a bunch of genes have been so far identifed, although genetic heterogeneity is certainly wide and some genes are yet to be identified. Overgrowth syndromes are most commonly inherited in an autosomal dominant fashion, although autosomal recessive inheritance is also reported. The most famous overgrowth syndromes are Sotos syndrome and Beckwith-Weidemann syndrome, but many other can be included in this chapter of Medical Genetics.
Detailed clinical description
While considerable overlap in presentation sometimes exists, advances in molecular genetics are of help in determining the specific diagnosis. Somatic growth is dependent on an increase in both cell size and number. Overgrowth is defined by extreme physical size and stature including tall stature or generalized/localized overgrowth of tissues and/or inceased head circumference (macrocephaly). Tall stature is caused by epiphyseal growth plates remaining open. Since some acquired and genetic endocrinological (hormonal) disorders may also increase the rate of growth and body size (e.g. pituitary gigantism, which is caused by excess of growth hormone), overgrowth syndrome are by definition non-hormonal. A degree of mental retardation may also be present, as well as some associated dysmorphisms, although intelligence may be normal.
Sotos syndrome (less commonly known also as cerebral gigantism), shows prenatal onset in utero and is characterized in vast majority of patients (90%) by the triad of 1. excessive growth resulting in tall stature and macrocephaly, 2. distinctive craniofacial features, and 3. developmental delay.
Postnatal growth becomes unequivocally evident from around 6 years of life, with height always above the 97th percentile. However, the final adult height is usually within the upper normal range due to accompanied bone age advancement. High and broad forehead, sparse fronto-temporal hair, malar flushing, down-slanted palpebral fissures and a pointed chin are the most common facial traits. Macrocephaly is present as head circumference above the 97th percentile. Most patients show mild to moderate intellectual retardation, although QI is reportedly varying from 30 to more than 100.
Neonatal jaundice and feeding difficulty, cardiac and renal anomalies, seizure, scoliosis, strabismus, ADHD (attention deficit hyperactivity disorder), ventriculomegaly and corpus callosum hypoplasia have been frequently reported, in association to an increased risk for neoplasia.
Sotos syndrome 1 is caused by mutation in the NSD1 gene (autosomal dominant inheritance), Sotos syndrome 2 is caused by mutations in the NFIX gene (autosomal dominant), Sotos syndrome 3 is thought to be caused by mutation in the APC2 gene.
Beckwith-Wiedemann syndrome is actually the most common genetic overgrowth syndrome. It is less commonly known as exomphalos-macroglossia-gigantism syndrome (EMG syndrome). The clinical presentation is highly variable, since some patients lack the hallmark features of exomphalos, macroglossia, and gigantism, and because of this there are no absolute criteria for a clinical diagnosis to date. Like Sotos syndrome, overgrowth starts prenatally during the latter half of pregnancy, being accompanied by polyhydramnios. Also in this case, adult heights are generally in the normal range. Abnormal growth may also manifest as hemihypertrophy and/or macroglossia (increased size of the tongue). Hyperinsulinemic hypoglycemia is reported in 30 to 50% of newborns.
Abdominal wall defects (omphalocele, umbilical hernia, and diastasis recti), cleft palate and visceromegaly of the liver, spleen, pancreas, kidneys, or adrenals can be often diagnosed. Fetal adrenocortical cytomegaly is pathognomonic. Kidney anomalies may include malformations, medullary dysplasia, nephrocalcinosis, and nephrolithiasis. Like in Sotos syndrome, there is an increased risk for malignancies. These are mostly of the embryonal type, such as Wilms tumor and hepatoblastoma, and are a clinical priority, since tumor surveillance and early diagnosis may reduce treatment-related morbidities.
Intelligence is usually normal, although mild to moderate mental retardation can be seen, being neonotal hypoglicemia and airway problems predisposing factors.
Beckwith-Wiedemann syndrome is caused by mutation or deletion of imprinted genes within the chromosome 11p15.5 region. More in details, the syndrome is caused by:
- Loss of methylation on the maternal chromosome at imprinting center 2 (IC2) (50% of cases).
- Maternally inherited heterozygous mutation in the CDKN1C gene (40% of familial cases and 5%-10% of cases with no family history of the syndrome).
- Paternal uniparental disomy for chromosome 11p15 (20% of cases).
- Gain of methylation on the maternal chromosome at imprinting center 1 (IC1) (5% of cases).
- Cytogenetically detectable abnormalities involving chromosome 11p15 (fewer than 1% of cases).
Other overgrowth syndromes
TCF20-related overgrowth syndrome. Recently, de novo truncating heterozygous mutations have been reported in the TCF20 gene. TCF20-related overgrowth syndrome is characterized by mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia and possibly autism spectrum diosrder.
CLOVE syndrome, somatic. CLOVE is acronym for Congenital Lipomatous Overgrowth, Vascular malformations, and Epidermal nevi. Progressive, complex, and mixed primarily truncal vascular malformations, dysproportionate and abnormal distribution of body fat, varying degrees of scoliosis, and enlarged, but not severely distorted, bony structures without progressive overgrowth. The presence of scoliosis lead some authors to refer to this syndrome as CLOVES. Occasionally, cranial asymmetry, emimegalencephaly, dysgenesis of the corpus callosus, ptosis, horizontal nystagmus, bilateral cataracts, wide feet and hands, macrodactyly, wide sandal gap and neurological manifestations such as epilepsy have been reported. CLOVE syndrome can be caused by somatic mosaicism for postzygotic activating mutations in the PIK3CA gene. Patients with CLOVE syndrome have a low rate of malignant transformation, likely due to the limited number of cells hyperexpressing PIK3CA because of somatic mosaicism. Somatic PIK3CA mutations have also been seen in patients diagnosed with Klippel-Trenaunay-Weber syndrome, an overgrowth syndrome with features overlapping those of CLOVE syndrome.
Megalencephaly–polymicrogyria–polydactyly–hydrocephalus syndrome. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) is caused by heterozygous mutation in the PIK3R2 gene (both germline and somatic mutations can be found – please note: PIK3R2 and not PIK3CA). Besides PIK3R2 mutations (MPPH1), mutations in other genes can cause other genetic subtypes: MPPH2 is caused by mutation in the AKT3 gene and MPPH3 is caused by mutation in the CCND2 gene. MPPH syndrome is characterized by megalencephaly, hydrocephalus, and polymicrogyria. Polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (see below).
Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic. Megalencephaly-capillary malformation syndrome (MCAP) is caused by somatic mutations in the PIK3R2 gene. MCAP is a polymalfomative syndrome characterized by a spectrum of anomalies including cutaneous capillary malformations, primary megalencephaly, prenatal overgrowth, brain and body asymmetry, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria.
Proteus syndrome, somatic. Proteus syndrome is a highly variable disorder of asymmetric and disproportionate overgrowth of body parts, cerebriform connective tissue nevus, epidermal nevi, dysregulated adipose tissue with lipomas, thin limbs, lung cysts and vascular malformations. The syndrome is severe and is caused by a somatic activating mutation in the AKT1 gene (specifically the activating E17K [p.Glu17Lys] mutation). Elattoproteus syndrome is consdiered an inverse form of Proteus syndrome, where reduced tissue growth prevails on overgrowth.
Sturge-Weber syndrome. Sturge-Weber syndrome is characterized by capillary malformation, glaucoma, leptomeningeal vascular anomalies, and variable facial overgrowth due to soft-tissue and skeletal overgrowth, with lip and maxilla being the most commonly enlarged structures of the face. Sturge-Weber syndrome can be caused by somatic mosaic mutation in the GNAQ gene.
Smith-Kingsmore syndrome. Smith-Kingsmore syndrome is a rare autosomal dominant syndrome characterized by intellectual disability, macrocephaly with tall forehead and frontal bossing, seizures, umbilical hernia, and facial dysmorphic features. Overgrowth is limited to the head, as rhizomelic shortening is observed in limbs. The syndrome is caused by heterozygous mutation in the MTOR gene.
Kosaki overgrowth syndrome. Kosaki overgrowth syndrome is characterized by a prominent forehead, proptosis, downslanting palpebral fissures, wide nasal bridge, thin upper lip, and pointed chin. Patients are tall, with an elongated lower segment, hands, and feet. Hyperelastic and fragile skin is seen, whereas white matter lesions cause progressive neurologic deterioration. Kosaki overgrowth syndrome (KOGS) is caused by heterozygous mutation in the PDGFRB gene.
Tenorio syndrome. Tenorio syndrome is characterized by overgrowth, macrocephaly, and intellectual disability. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome. Additional inconstant signs can be seen from patient to patient, from Raynaud phenomena to keratitis, conjunctivitis, limbitis, serous otitis, and pneumonia. Tenorio syndrome is caused by heterozygous mutation in the RNF125 gene.
Simpson-Golabi-Behmel syndrome. Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, and other congenital abnormalities, which shows phenotypic similarities to Beckwith-Wiedemann syndrome. Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutation in the GPC3 gene. Simpson–Golabi-Behmel syndrome type 2 (SGBS2) is caused by mutation in the OFD1 gene.
Costello syndrome. Costello syndrome is characterized by polyhydramnios and fetal overgrowth and macrocephaly which can be seen on prenatal ultrasound examination. Costello syndrome patients are at an increased risk of developing certain cancerous and noncancerous tumors.
Genetic testing strategy
Panel testing recommended at Breda Genetics for this conditions:
References: PMC 4027072, OMIM 117550, OMIM 614753, OMIM 617169, OMIM 130650, Genereviews NBK1394, PMID 27436265, OMIM 612918, OMIM 185300, OMIM 616638, PMID 19182685, OMIM 616260, OMIM 616592, OMIM 312870.