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O que é Sotos syndrome?
Sotos syndromeé uma doença genética caracterizada por crescimento excessivo em indivíduos com síndromes.
Esse crescimento excessivo geralmente começa na infância (mas casos pré-natais foram documentados) e dura até a adolescência. Freqüentemente, é acompanhada por idade óssea avançada.
O síndromes ocorre em 1 em 14,000 nascidos vivos e afeta homens e mulheres de forma semelhante.
Quais mudanças genéticas causam Sotos syndrome?
Em 90% dos casos, a síndromes ocorre devido a mutações no gene NSD1. Embora pesquisas adicionais sugiram mutações no gene NFIX e APC2 também podem ser causas contribuintes.
No caso de herança autossômica dominante, apenas um dos pais é o portador da mutação do gene e eles têm 50% de chance de transmiti-la a cada um de seus filhos. As síndromes herdadas em uma herança autossômica dominante são causadas por apenas uma cópia da mutação do gene.
Quais são os principais sintomas de Sotos syndrome?
O principal sintomas do Sotos syndrome pode variar entre os indivíduos e também pode variar na extensão de sua gravidade.
O síndromesAs características faciais típicas incluem cabeça grande, rosto longo e estreito e testa alta. Bochechas coradas e um queixo pontudo e olhos bem espaçados, palato saliente e recuo da linha do cabelo são características comuns do síndromes.
Outro potencial sintomas incluem defeitos cardíacos congênitos, embora raramente sejam graves, convulsões e escoliose em 40% dos casos.
Deficiência intelectual e atraso no desenvolvimento também são comuns entre os indivíduos diagnosticados com síndromes, particularmente o atraso na fala.
Problemas de equilíbrio e mobilidade também são comuns sintomas.
Possíveis traços / características clínicas:
Ansiedade, maturação esquelética acelerada, escoliose, deficiência intelectual, rosto comprido, rosto estreito, herança autossômica dominante, crescimento excessivo
Como alguém faz o teste de Sotos syndrome?
O teste inicial para Sotos syndrome pode começar com a triagem de análise facial, por meio do FDNA Telehealth plataforma telegenética, que pode identificar os principais marcadores do síndromes e delineia a necessidade de mais testes. Seguirá uma consulta com um conselheiro genético e, em seguida, um geneticista.
Com base nesta consulta clínica com um geneticista, as diferentes opções para testes genéticos serão compartilhadas e o consentimento será solicitado para testes adicionais.
Informações médicas sobre Sotos syndrome
Sotos syndrome 1 combines early overgrowth with a characteristic facial appearance (macrocephaly, broad and prominent forehead, downslanting palpebral fissures, long chin) and sometimes intellectual disability. Advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, and joint hyperlaxity are common. The syndrome is caused by heterozygous mutations in the NSD1 gene or by deletions in the 5q35 region (Kurotaki et al., (2002), Imaizumi et al., (2002)).
Familial cases have been reported (Bale et al., 1985; Scarpa et al., 1994; Smith et al., 1980; Winship et al., 1985; Opitz et al., 1998).
Cole et al., (1992) reported a 22-year-old woman who developed a small cell carcinoma of the lung.
Hersh et al., (1992) concluded that the childhood malignancy risk is ""probably lower than 2.2%"" from a questionnaire survey of geneticists.
Corsello et al., (1996) reported one case with non-Hodgkin lymphoma and one with an acute lymphoblastic leukemia, although from the clinical photographs the diagnosis was not absolutely typical of Sotos - see also the comments by Cole and Allanson (1998), Corsello and Giuffre (1998), and Cohen (1999). Leonard et al., (2000) reported two cases with sacrococcygeal teratomas. The patient reported by Deardorff et al., (2004) had a ganglioglioma.
Reported malignancies include Wilms tumor, hepatocarcinoma, neuroblastoma, and leukemias (Martinez-Glez and Lapunzina, 2007).
Cole and Hughes (1994) provide a good review of the clinical features. Features can be very variable - see family reported by Donnelly et al., (2011).
The face is characterized by macrocephaly, a high prominent forehead, downslanting palpebral fissures, a long pointed chin, and a high-arched palate. The birth weight may be increased with an enlarged head circumference. In childhood, height is excessive, with an advanced bone age and large hands and feet, although the final adult height may not be increased (Agwu et al., 1999).
The cerebral ventricles may appear mildly dilated on CT scan (Schaefer et al., 1997). The authors also noted that hypoplasia of the corpus callosum and cavum septum pellucidum are common.
Noreau et al., (1998) and Tsukahara et al., (1999) reported cases with congenital heart disease (note that left ventricular noncompaction might occur - Martinez et al., (2011). These were present in 30-40% of Japanese patients but apparently a lower percentage in other ethnic groups.
Robertson and Bankier (1999) reported three children with features of Sotos syndrome but with a normal bone age, together with cutis laxa, joint hypermobility and vesicoureteric reflux. The facies seemed typical for Sotos syndrome, but again this may be a separate subgroup. Mutations in NSD1 have now been found in this family (Hood et al., 2016), so that profound joint laxity and aortic dilatation is part of Sotos syndrome.
Melo et al., (2000) review the neuroimaging and echocardiographic findings in Sotos syndrome.
Amiel et al., (2002) report five unrelated cases with facial features of Sotos but with more severe developmental delay than expected.
Sweeney et al., (2002) reported two patients with severe scoliosis.
Tatton-Brown et al., (2005) reported the results of a multicenter genotype-phenotype study of 266 patients. Although there was an ascertainment bias in this study, Sotos syndrome was clinically diagnosed in 99% of patients with a mutation. Of the clinically diagnosed patients, a mutation (83%) or 5q35 microdeletion (10%) was found in 93%. Clinically, 10% of cases did not have an enlarged skull circumference or height. Patients with a microdeletion had less prominent overgrowth and more learning difficulties. Otherwise, there was no correlation between deletion size and clinical phenotype. The number of familial cases was small, possibly indicating reduced reproductive fitness in Sotos syndrome.
Nagai et al., (2003) looked at the clinical features of five patients with intragenic NSD1 mutations predicted to form a truncated NSD1 protein and in 21 patients with a fairly common ~2.2 Mb deletion involving the entire NSD1 gene. Overgrowth and advanced maturation in infancy to early childhood, intellectual disability, hypotonia, hyperreflexia, and characteristic minor anomalies were present in patients with mutations and deletions, whereas major anomalies in the central nervous system (agenesis or hypoplasia of the corpus callosum), cardiovascular system (patent ductus arteriosus and atrial septal defect), and urinary system (vesicoureteric reflux, hydronephrosis, and small kidney) were exclusively exhibited by patients with deletions.
Rio et al., (2003) studied 39 patients with childhood overgrowth. The series included typical Sotos patients (23), Sotos-like patients (10), and Weaver patients (6). They identified six NSD1 deletions and 16 intragenic mutations in Sotos or Sotos-like patients, and intragenic mutations in 3/6 Weaver patients. However, Tatton-Brown et al., (2005) mentioned that two of the Weaver cases were in fact typical Sotos cases, and the third was thought to have possible Sotos syndrome. Intellectual disability was consistently more severe in patients with NSD1 deletions.
Douglas et al., (2003) studied 75 patients with childhood overgrowth. Of the 37 patients with typical Sotos syndrome, 28 (76%) had a NSD1 mutation. In 13 patients with a Sotos-like syndrome but with atypical features, four mutations were found. Fifty-nine patients with congenital overgrowth (24 with classical facial features of Sotos, nine who were Sotos-like, two with Weaver and 24 with non-specific overgrowth) were looked at by Cecconi et al., (2005). Seventeen mutations were found, and these were all in the Sotos group. Heart defects (especially an ASD) were prominent. The occasional patient had neither macrocephaly nor advanced bone-age.
Turkmen et al., (2003) studied 20 cases of Sotos syndrome and found mutations in 18 (six nonsense, eight frameshifts, three splice site, one missense, one in-frame deletion). Further mutations were reported by Kamimura et al., (2003).
Hoglund et al., (2003) reported a father and son with a 1 bp deletion in the NSD1 gene.
The condition in those with a NSD1 mutation is well-reviewed by Tatton-Brown and Rahman (2004).
There are also families with non-syndromic overgrowth and NSD1 mutations (van Haelst et al., 2005). Note the child reported by Kanemoto et al., (2006) who had features of Nevo but had a Sotos (NSD1) mutation.
A duplication of the insulin-like growth factor on 15q26 might cause a Sotos-like phenotype and should be considered in those without a NSD1 mutation (Kant et al., 2007).
A mother and her two children all had normal intelligence and NSD1 mutations (Zechner et al., 2009). Two had bronchial asthma, and one had diabetes and massive accumulation of fat and fluid under the skin of the limbs and ankles.
Hypodontia of the mandibular premolars, enamel problems, and excessive wearing of the teeth are common features (Kotilainen et al., 2009).
A three-generation family (eight affected) was reported by Donnelly et al., (2011).
A duplication was reported by Kasnauskiene et al., (2011).
Two cases with subpleural blebs resulting in pneumothorax were reported by Balasubramanian et al., (2014).
Some patients with an overgrowth syndrome resembling Sotos may have NFIX mutations - see under Marshall-Smith syndrome.
A Brazilian cohort (Vieira et al., 2015) showed considerable molecular heterogeneity with only 19% found to have NSD1 mutations. One had a PTEN mutation.
There is an infrequent association with hypo- or hyper-thyroidism and with hyperinsulin hypoglycemia (Matsuo et al., 2013, Nakamura et al., 2015). Hyperinsulinemic hypoglycemia in the neonatal period might be a clue to the diagnosis (Salas et al., 2016).
A patient reported by McClelland et al., (2016) had a low birth weight and generalized lymphedema.
Sio et al., (2017) described a 2-year-old patient with Sotos syndrome and Hirschsprung disease.
Laccetta et al., (2017) described a family with heterozygous missense mutations in the NSD1. The proband exhibited full Sotos syndrome, whereas his mother and grandfather only had tall stature.
Abdalla et al., (2017) described an Egyptian boy with Sotos syndrome, who presented with lack of social interaction, attention deficit, absent speech and marked hypotonia. Audiogram showed severe bilateral sensorineural hearing loss. Brain MRI showed an arachnoid cyst. The authors identified heterozygous 1.9 Mb deletion (hg19, 5:175,460,087-177,400,270) in 5q35 region with three deleted genes (SLC34A1, NSD1, and F12). In addition, they identified a 0.3 Mb duplicated region in 5q35.3 (177,482,505-177,810,677) including two genes (NHP2 and AGXT2L2)."
* This information is courtesy of the L M D.
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