Genetics: Mutations in the NSD1 gene cause Sotos syndrome.
More than 100 mutations in the NSD1 gene have been identified in people with Sotos syndrome.
Sotos syndrome is reported to occur in 1 in 10,000 to 14,000 newborns. Many cases of this disorder are not diagnosed, however, so the true incidence may be closer to 1 in 5,000.
Increased intrauterine growth, edema at birth lymphedema), hympotonia, contractures, clumsiness, long head, malformed ears, enlarged extremities, abnormal curvature of digits, retarded motor development, retarded speech development, scoliosis, micrognatia/retrognatia, eye anomalies, myopia, blepharophimosis/short palp. fissures, long/large/bulbous nose, high vaulted/narrow palate, hip anomalies, knee anomalies, foot anomalies, undescended/ectopic testes.
Any of these may or may not be present:
Behavioral patterns including phobias, aggression, obsessions, adherence to routine, autistic-like behavior, attention deficit disorder, above-average memorization skills.
Enlarged ventricles of the brain, hydrocephalus (rare), abnormal EEG's and seizures (with at least 1/3 of seizures being fever-related).
Frequent ear infections and upper respitory infections, asthma, and allergies. Constipation, megacolon.
Delayed toilet training, urogenital anomalies; Congenital heart anomalies; Nystagmus, strabismus; Increased sweating; Hyperthyroidism, hypothyroidism; Possible increased risk of tumors.
Complications of lymphedema include infections such as cellulitis, lymphangitis, erysipelas, Draining wounds that leak lymphorrea, Loss of Function due to the swelling and limb changes, psychological, Deep venous thrombosis, Sepsis Gangrene, Possible amputation of the limb, Pleural effusions, dry skin, splitting, plaques and nodules, susceptibility to fungus and bacterial infections, chronic localized inflammations, lymphatic cancers, pain, skin complications, debilitating joint problems.
There is no generalized treatment for Sotos syndrome, rather treatment is based on the symptoms present.:
Treatment might include surgery for the physical anomolies, therapy for the motor development complications and the establishment of a lymphedema mangement program.
Because Sotos syndrome is not a life threatening condition, patient may have a normal life span.
June 25, 2008
Alternative titles; symbols CEREBRAL GIGANTISMGene map locus 5q35
A number sign (#) is used with this entry because Sotos syndrome is caused by mutation in the NSD1 gene (606681).
Sotos et al. (1964) described 5 children with a disorder characterized by excessively rapid growth, acromegalic features, and a nonprogressive cerebral disorder with mental retardation. High-arched palate and prominent jaw were noted in several of them. Birth length was between the 90th and 97th centiles in all. Bone age was advanced in most.
Hook and Reynolds (1967) reported that affected children have large hands and feet from birth. Growth is rapid in the first years of life but final height may not be excessive. Bone age is advanced. The skull is large with moderate prognathism. Mild dilation of the cerebral ventricles, nonspecific EEG changes, and seizures have been observed. Poor coordination and mental retardation are features. In 2 patients, Bejar et al. (1970) found abnormal dermatoglyphics, normal growth hormone levels, and high levels of valine, isoleucine and leucine in the blood. The glycine-to-valine ratio seemed particularly useful in distinguishing patients from controls.
Ruvalcaba et al. (1980) found hamartomatous polyps of the intestine and melanin spots of the penis in 2 males with the Sotos syndrome. Halal (1983) reported that the older of the boys she reported with cerebral gigantism had pigmented spots on the genitalia and that the father had been found to have a rectal polyp–findings like those in the 2 unrelated adult males reported by Ruvalcaba et al. (1980).
Kaneko et al. (1987) found congenital heart defects in 5 of 10 patients with typical Sotos syndrome. Noreau et al. (1998) found that 3 of 14 Sotos syndrome patients had congenital heart defects. In a literature review, they found another 17 patients with variable cardiac defects, mostly closure defects, making an overall incidence of approximately 8%.
Goldstein et al. (1988) described 2 unrelated children with macrocephaly, excessive growth, strabismus, hypotonia and developmental delay, and improvement with age.
In a review, Cole and Hughes (1990) emphasized that the handicaps in Sotos syndrome are fewer than previously believed and tend to improve with age. The latter feature makes identification of affected adults difficult. Cole and Hughes (1994) clinically assessed 79 patients with a provisional diagnosis of Sotos syndrome and evaluated their photographs between ages 1 and 6 years. These photographs, together with photographs of first-degree relatives, also at ages 1 to 6 years, were reviewed by 4 clinical geneticists. In 41 probands, but no first-degree relatives, the facial gestalt was thought to be characteristic of Sotos syndrome. Comparison of anthropometric measurements, bone age, and developmental delay in these 41 probands showed marked differences between them and the remaining 38 probands. Length was identified as the most significantly increased prenatal parameter. In childhood, occipitofrontal head circumference (OFC), height, and weight were all increased. OFC remained above the 97th percentile in all but one case throughout childhood and adulthood, whereas height and weight had a tendency to return toward the mean. This 'normalization' was more pronounced in females and was probably related to their early puberty. Early developmental delay and an advanced bone age were seen in 100% and 84% of cases, respectively. Cole and Hughes (1994) suggested that facial gestalt, growth pattern, bone age, and developmental delay are the major diagnostic criteria. Using these criteria, no affected first-degree relatives were identified.
Scarpa et al. (1994) described a sister and brother with macrocrania and coarse face (frontal bossing, highly arched palate, prognathism, pointed chin, large ears). Psychomotor development of the sister, who also had advanced osseous maturation, improved significantly at the age of 7 years. Accelerated growth with normal bone age, optic atrophy, renal agenesis with contralateral double kidney, and significant mental retardation (IQ, 45) were shown in the brother at 3.5 years of age. The father of these children was tall, with macrocrania and large hands and feet. He had had learning difficulties in school and was a manual laborer.
Scarpa et al. (1994) suggested that these children and their father showed different manifestations of Sotos syndrome. Allanson and Cole (1996) presented anthropometric evaluation of the head in 45 patients with Sotos syndrome between age 1 and 25 years. With increasing age, the face lengthens and the chin becomes more striking.
Opitz et al. (1998) reported affected mother and daughter. The mother was described as a large infant and 'as tall as her teacher in school.' Her adult height was 185.4 cm, and she had mandibular prognathism and a prominent pointed chin. The daughter showed a prominent forehead with sparseness of frontal hair and a 'ruddy' or flushed complexion, especially of the nose and perioral area. She had prominent features of the congenital hypotonia/lymphedema sequence with hypermobile joints, especially at the knees and ankles, lymphedema nails (especially toenails), and a high total ridge count (TRC) of the fingertip dermatoglyphics. The mother also had a high TRC and a receding frontal hairline.
Robertson and Bankier (1999) reported 3 children with anthropometric and dysmorphologic features of classic Sotos syndrome in association with redundant skin folds, joint hypermobility, and, in 2 of the 3, vesicoureteric reflux. Robertson and Bankier (1999) thought the associated features suggested a coexisting connective tissue disorder. All the patients had a normal bone age. Although Sotos syndrome in its classically described form was not present, Robertson and Bankier (1999) concluded that this entity might reflect a related, perhaps allelic, condition. Tumor Formation
Maldonado et al. (1984) reported the association of malignant tumors in Sotos syndrome. Nance et al. (1990) described a 15-month-old child with Sotos syndrome and a paraspinal neuroblastoma. From this and other evidence, they concluded that children with this disorder may be at an increased risk for developing tumors. Gorlin et al. (1990) estimated a risk of 3.9% of benign or malignant tumors in Sotos syndrome. The same excess of neoplasms is present in other overgrowth syndromes. Le Marec et al. (1999) reported that one of a monozygotic twin pair, both of whom had Sotos syndrome, developed a diffuse gastric carcinoma containing signet ring cells at the age of 26. The young age of occurrence of this gastric carcinoma suggested a genetic factor. Leonard et al. (2000) reported 2 children with Sotos syndrome who had benign sacrococcygeal teratomas. Given that Sotos syndrome and sacrococcygeal teratoma are rare events, the authors suggested that these tumors may be due to the effects of overgrowth on tumor development.
Opitz et al. (1998) discussed the differentiation of 2 overgrowth syndromes, Sotos syndrome and Weaver syndrome (277590), and the question of whether the similarities are sufficient to consider them 1 entity. They noted that vertebrate development is constrained into only a very few final or common developmental pathways; therefore, no developmental anomaly seen in humans is unique to ('pathognomonic of') one syndrome. Possible phenotypic differences between the syndromes of Sotos and Weaver pointed out by Opitz et al. (1998) were the following: the Sotos syndrome may be a cancer syndrome, whereas the Weaver syndrome is not (although a neuroblastoma had been reported in the latter disorder). In Sotos syndrome there is remarkably advanced dental maturation; this is rarely commented on in Weaver syndrome. In Weaver syndrome, there are more conspicuous contractures and a facial appearance that experts find convincingly different from that in Sotos syndrome. Opitz et al. (1998) favored allelic heterogeneity as the explanation for the similarities between Sotos and Weaver syndromes. They suggested that mapping and isolation of the causative gene or genes would settle the issue.
Schaefer et al. (1997) concluded that neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal.
Fryns (1988) referred to cases of the fragile X syndrome (309550) in which Sotos syndrome had been diagnosed; he therefore suggested that this disorder be designated the Sotos sequence or the mental retardation-overgrowth sequence.
Most reported cases of Sotos syndrome have been sporadic and may represent new dominant mutations. Hook and Reynolds (1967) reported a concordant set of affected identical twins. Hooft et al. (1968) described cerebral gigantism in 2 first cousins. Nevo et al. (1974) described affected brother and sister and their affected double first cousin in an inbred Arab family in Israel. Two of the 3 showed generalized edema and flexion contractures of the feet at birth. This may represent a distinct disorder; see Nevo syndrome (601451). Hansen and Friis (1976) described affected mother and child. Zonana et al. (1976) described affected mother and 2 children (male and female). The mother's father may have been affected. Zonana et al. (1977) reported 3 families showing vertical transmission and equal severity in males and females; no male-to-male transmission was observed. As an addendum, they commented on a fourth instance of affected mother and son. Smith et al. (1981) observed affected mother and daughter–the presumed fifth instance of dominant inheritance. The mother had primary hypothyroidism due to Hashimoto disease. Halal (1982) reported a family in which the father and 2 of his sons were affected. She knew of no other instance of documented male-to-male transmission. Winship (1985) described a 'Cape Coloured' family with affected father and 4 children by 2 different, unrelated wives. Presumed Sotos syndrome was described in a mother and 2 daughters by Bale et al. (1985). They suggested that instances of seemingly autosomal recessive inheritance may be examples of incomplete penetrance, gonadal mosaicism, or genetic heterogeneity. Minor changes in 2 mothers of 2 unrelated affected infants reported by Goldstein et al. (1988) suggested dominant inheritance of a Sotos sequence. Brown et al. (1998) described a pair of 5-year-old male monozygotic twins who were discordant for Sotos syndrome. The possibility of uniparental disomy in Sotos syndrome was investigated by Smith et al. (1997). Using 112 dinucleotide repeat DNA polymorphisms, they examined parental inheritance of all autosomal pairs, except chromosome 15, in 29 patients with Sotos syndrome. All informative cases showed biparental inheritance and no cases of UPD were found.
In a study of the metacarpophalangeal pattern profile (MCPP) in Sotos syndrome, Butler et al. (1985) found no evidence of heterogeneity and developed a diagnostic tool using MCPP variables, which they suggested may be useful.
Schrander-Stumpel et al. (1990) described a 6-year-old boy with Sotos syndrome who also had a de novo, apparently balanced translocation, t(3;6)(p21;p21). They suggested that the autosomal dominant gene for the Sotos syndrome may be located either at 3p21 or 6p21. Tsukahara and Kajii (1991) could find no abnormality in high resolution-banded chromosomes from 5 patients. Involvement of genes at 3p21 was also suggested by the case reported by Cole et al. (1992); a 22-year-old female with Sotos syndrome, a nonsmoker, died of small cell lung carcinoma (182280) for which genetic determinants in the 3p21 region are suggested by loss-of-heterozygosity studies. Maroun et al. (1994) reported the case of a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between 5q and 15q: 46,XX,t(5,15)(q35;q22). They thus suggested 5q35 or 15q22 as the site of an autosomal dominant gene determining Sotos syndrome.
Faivre et al. (2000) reported a child with apparent Sotos syndrome and mosaicism for partial duplication of the short arm of chromosome 20 (46,XY,dup(20)(p12.1-p11.2)/46,XY). The somatostatin receptor-4 (SSTR4; 182454) gene is located at 20p11.2, encompassed by the duplication. The authors proposed that a dosage effect of this gene might be responsible for some of their patient's clinical findings.
Imaizumi et al. (2002) described a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8, 46,XX,t(5;8)(q35;q24.1), in a 15-month-old girl with a typical Sotos syndrome phenotype. They proposed that a gene responsible for this disorder is located in the distal long arm region of chromosome 5.
In patients with Sotos syndrome harboring a chromosomal translocation, Kurotaki et al. (2002) isolated the NSD1 (606681) gene from the 5q35 breakpoint. They identified 1 nonsense, 3 frameshift, and 20 submicroscopic deletion mutations of NSD1 among 42 sporadic cases of Sotos syndrome. The results indicated that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.
To the 42 cases of Sotos syndrome reported by Kurotaki et al. (2002), Kurotaki et al. (2003) added 70 more cases, 53 of whom were Japanese. Among the 112 total cases, they identified 50 microdeletions (45%) and 16 point mutations (14%). They noted a large difference between Japanese and non-Japanese patients in the frequency of microdeletions, which occurred in 49 (52%) of the 95 Japanese but in only 1 (6%) of the 17 non-Japanese. Most of the microdeletions were confirmed to be identical by FISH analysis. Kurotaki et al. (2003) identified highly homologous sequences, i.e., possible low copy repeats, in regions flanking proximal and distal breakpoints of the common deletion. This suggested that low copy repeats may mediate the deletion. The frequency of such low copy repeats seemed to vary in different populations, and thus the differences in frequency of microdeletions between Japanese and non-Japanese cases may have been caused by patient selection bias.
In a Finnish father and son with Sotos syndrome, Hoglund et al. (2003) identified a heterozygous mutation in the NSD1 gene (606681.0009). The authors noted that the findings in this family confirm that familial Sotos syndrome is caused by mutation in the NSD1 gene.
Beckwith-Wiedemann syndrome (BWS; 130650) is, like Sotos syndrome, an overgrowth syndrome. Deregulation of imprinted growth regulatory genes within the 11p15 region is the major cause of BWS. Similarly, defects of the NSD1 gene account for more than 60% of cases of Sotos syndrome. Owing to the clinical overlap between the 2 syndromes, Baujat et al. (2004) investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and 2 NSD1 mutations (606681.0011-606681.0012) were identified in a series of 52 patients with BWS. The results suggested that the 2 disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the 11p15 region. Turkmen et al. (2003) screened the NSD1 gene for mutations in 20 patients and 1 familial case with Sotos syndrome, 5 patients with Weaver syndrome, 6 patients with unclassified overgrowth and mental retardation, and 6 patients with macrocephaly and mental retardation. They identified 19 mutations, 17 previously undescribed, in 18 Sotos patients and the familial case (90%). The best correlation between the molecular and clinical findings was for facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. Turkmen et al. (2003) found no mutations of the NSD1 gene in the patients with Weaver syndrome or other overgrowth phenotypes and concluded that the great majority of patients with Sotos syndrome have mutations in NSD1.
Boman and Nilsson (1980); Dodge et al. (1983); Stephenson et al. (1968)
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Edit History wwang : 1/17/2008 terry : 1/3/2008 carol : 11/27/2006 wwang : 9/21/2006
Nicita F, Ruggieri M, Polizzi A, Mauceri L, Salpietro V, Briuglia S, Papetti L, Ursitti F, Grosso S, Tarani L, Segni M, Savasta S, Parisi P, Verrotti A, Spalice A.
Child Neurology Division, Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Roma, Italy Department of Formative Processes, University of Catania, Catania, Italy National Center for Rare Diseases, Superior Institute of Health, Rome, Italy Health Care Center for Obstetrics and Gynecology “Lucina,” Catania, Italy Unit of Genetics and Immunology, Department of Pediatrics, University of Messina, Messina, Italy Department of Pediatrics, Gynecology, Obstetrics, and Reproductive Medicine, Pediatric Neurology Section, University of Siena, Siena, Italy Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy Department of Pediatrics, University of Pavia, Pavia, Italy Department of Pediatrics, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy; Department of Pediatrics, University of Chieti, Chieti, Italy.
Keywords: Sotos syndrome; Seizures; Epilepsy; Cerebral gigantism; Overgrowth syndrome
Sotos syndrome (SS) is an overgrowth syndrome characterized by typical facial appearance, learning disability, and macrocephaly as cardinal diagnostic features. Febrile (FS) and afebrile seizures are reported in 9-50% of cases. There is no evidence that patients with SS and FS later develop epilepsy, and no studies have investigated the electroclinical features and the long-term outcome in epileptic SS patients. The authors report a series of 19 SS patients with FS and/or epilepsy during childhood and a long-term follow-up. More than half of FS evolved to epilepsy. Temporal lobe seizures were recorded in 40% of patients with SS. Seizures were easy to control with common antiepileptic drugs in almost all patients. A careful neurologic evaluation is useful for SS patients, since seizures are an important finding among people with this overgrowth syndrome.
Juneja A, Sultan A.
Department of Pediatric and Preventive Dentistry, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, India. firstname.lastname@example.org
Sotos syndrome is a well-defined childhood overgrowth syndrome characterized by pre- and postnatal overgrowth, developmental delay, advanced bone age, and a typical facial gestalt including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing. This report presents a case of Sotos syndrome in a 5½-year-old child.
Am J Med Genet A. 2008 May
Thomas A, Lemire EG. IWK Health Centre, Maritime Medical Genetics Service, Halifax, Nova Scotia, Canada.
Keywords Sotos syndrome • maternal serum screen • polyhydramnios • fetal macrosomia • macrocephaly
There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements. This is the first report of an elevated Down syndrome risk in a pregnancy with confirmed Sotos syndrome. Sotos syndrome should be included in the differential diagnosis of newborns with a normal karyotype where the pregnancy has demonstrated an increased risk for Down syndrome by maternal serum screening, especially in the presence of supportive ultrasound findings.
Kessler H, Kraft S. Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum des Saarlandes. email@example.com
Sotos syndrome, or cerebral gigantism, is a rare genetic syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial gestalt and learning difficulties. It is caused by mutations or deletions of the NSD-1 gene. Most cases are sporadic. Apart from a number of physical abnormalities that are commonly present, a high prevalence of cognitive, emotional and behavioural problems in children with Sotos syndrome can be assumed. However, there has been almost no literature about psychiatric symptoms in adults with Sotos syndrome so far; one case of psychosis was reported. In the present case, the authors present psychopathological features of an adult patient with Sotos syndrom who developed - among other things - psychotic symptoms.
Pediatr Dermatol. 2008 Jan-Feb
Gilaberte Y, Ferrer-Lozano M, Oliván MJ, Coscojuela C, Abascal M, Lapunzina P. Department of Dermatology, Hospital San Jorge, Huesca, Spain. firstname.lastname@example.org
Cerebral giantism or Sotos syndrome consists of a pre- and postnatal overgrowth whose genetic basis are mutations and deletions of the nuclear receptor-binding SET domain containing protein gene. These patients have an increased risk of developing neoplasms, especially in adulthood. We report a 9-year-old boy, diagnosed with familial Sotos syndrome, who had two pilomatrixoma, symmetrically located on both sides of the neck, measuring 4 cm in diameter. Genetic study of the tumor tissue showed deletion of exon 22 of the NSD1 gene, whereas beta-catenin gene mutations were not detected. To the best of our knowledge, presentation of multiple pilomatricomas with Sotos syndrome has never been reported. Therefore their association probably is incidental. Nevertheless, the unusual size of our patient's pilomatricomas could be due to deletion of the NSD1 gene, which characterizes Sotos syndrome.
Hirai N, Matsune K, Ohashi H. Source Department of Pediatric Dentistry, Nihon University Graduate School of Dentistry at Matsudo, Chiba, Japan. email@example.com. Abstract Sotos syndrome is a well-known overgrowth syndrome caused by haploinsufficiency of NSD1 gene located at 5q35. There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). We investigated detailed craniofacial, dental, and oral findings in five patients with deletion type, and three patients with mutation type Sotos syndrome. All eight patients had a high palate, excessive tooth wear, crowding, and all but one patient had hypodontia and deep bite. Hypodontia was exclusively observed in the second premolars, and there were no differences between the deletion and mutation types in the number of missing teeth. Another feature frequently seen in common with both types was maxillary recession. Findings seen more frequently and more pronounced in deletion-type than in mutation-type included mandibular recession, scissors or posterior cross bite, and small dental arch with labioclination of the maxillary central incisors. It is noteworthy that although either scissors bite or cross bite was present in all of the deletion-type patients, neither of these was observed in mutation-type patients. Other features seen in a few patients include enamel hypoplasia (two deletion patients), and ectopic tooth eruption (one deletion and one mutation patients). Our study suggests that Sotos syndrome patients should be observed closely for possible dental and oral complications especially for malocculusion in the deletion-type patients.
Kasnauskiene J, Cimbalistiene L, Ciuladaite Z, Preiksaitiene E, Kučinskienė ZA, Hettinger JA, Sismani C, Patsalis PC, Kučinskas V. Source Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Lithuania. firstname.lastname@example.org Abstract We report on a girl with developmental delay and a de novo 264 kb interstitial duplication in the region of Sotos syndrome at 5q35.3 in the immediate vicinity of critical NSD1 gene, but manifesting the phenotype, of overgrowth both prenatal stage and postnatal, macrocephaly, developmental delay, and resembling that of Sotos syndrome, rather than the recently reported syndrome of reciprocal duplication. The duplication is located right downstream from the NSD1 gene, a region which appears critical for the expression of the gene as regulatory elements might be disrupted or the expression of a not amplified critical gene might be otherwise affected by the duplicated region. Thus,in the process of evaluating identified CNVs attention should be drawn to the possible influence of chromosomal rearrangement on distant genes, which could add additional diversity to genomic disorders. Our case demonstrates that evaluation of the size of chromosomal alteration and gene content are not sufficient for assessment of CNV's pathogenicity and the context of adjacent genes should be considered.
NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome. Pasillas MP, Shah M, Kamps MP. Source Department of Pathology, University of California at San Diego School of Medicine, La Jolla, USA. Abstract Sotos syndrome is a human developmental and cognitive disorder caused by happloinsufficiency of transcription factor NSD1. Similar phenotypes arise from NSD1 gene deletion or from point mutations in 9 of 13 NSD1 domains, including all 6 PHD domains, indicating that each NSD1 domain performs an essential role. To gain insight into the biochemical basis of Sotos syndrome, we tested the ability of each NSD1 PHD domain to bind histone H3 when methylated at regulatory sites Lys4, Lys9, Lys27, Lys36, and Lys79, and histone H4 at regulatory Lys20, and determined whether Sotos point mutations disrupted methylation site-specific binding. NSD1 PHD domains 1, 4, 5, and 6 bound histone H3 methylated at Lys4 or Lys9. Eleven of 12 Sotos mutations in PHD4, PHD5, and PHD6 disrupted binding to these methylated lysines, and 8 of 9 mutations in PHD4 and PHD6 severely compromised binding to transcription cofactor Nizp1. One mutation in PHD1 did not alter binding to specific methylated histone H3, and one mutation in PHD4 did not alter binding to either methylated histone or Nizp1. Our data suggests that Sotos point mutations in NSD1 PHD domains disrupt its transcriptional regulation by interfering with its ability to bind epigenetic marks and recruit cofactors.
May 2008 PubMed
Nov 2007 Full Text BioMed
May 2007 J-Stage
Nov. 11, 2011
Sotos Syndrome Support Group (Australia)
Eltern-Initiative Sotos-Syndrom (EISS), Germany, auf Deutsch
Q87 Other specified congenital malformation syndromes affecting multiple systems
Q87.0 Congenital malformation syndromes predominantly affecting facial appearance Acrocephalopolysyndactyly Acrocephalosyndactyly [Apert] Cryptophthalmos syndrome Cyclopia Syndrome: Goldenhar · Moebius · oro-facial-digital · Robin Whistling face
Q87.1 Congenital malformation syndromes predominantly associated with short stature Syndrome: · Aarskog · Cockayne · De Lange · Dubowitz · Noonan · Prader-Willi · Robinow-Silverman-Smith · Russell-Silver · Seckel · Smith-Lemli-Opitz
Excludes: Ellis-van Creveld syndrome ( Q77.6 )
Q87.2 Congenital malformation syndromes predominantly involving limbs Syndrome: · Holt-Oram · Klippel-Trénaunay-Weber · nail patella · Rubinstein-Taybi · sirenomelia · thrombocytopenia with absent radius [TAR] · VATER
Q87.3 Congenital malformation syndromes involving early overgrowth Syndrome: · Beckwith-Wiedemann · Sotos · Weaver
2008 ICD-9-CM Diagnosis 759.89
Congenital malformation syndromes affecting multiple systems, NEC