Silver-Russell syndrome (SRS)

O que é Silver-Russell syndrome (SRS)?

Silver-Russell síndromes é uma doença genética rara caracterizada por crescimento limitado antes e depois do nascimento, conhecida como restrição de crescimento intrauterino. Os bebês que nascem com a doença apresentam baixo peso ao nascer. Muitas vezes é referido como um distúrbio de crescimento congênito.

Sintomas variam de leve a grave, dependendo das mutações genéticas envolvidas no caso de cada indivíduo afetado.

Síndromes Sinônimos:
RSS Russel-Silver Síndromes Russell-silver Síndromes; Rss Silver-russell Anão Silver-Russell síndromes SRS

Quais mudanças genéticas causam Silver-Russell syndrome (SRS)?

Em 60-70% dos casos, a síndromes é causada por mutações no gene (um) SRS2 no cromossomo 7 e ICR1 e IGF2 no cromossomo 11. Mas HMGA2 no cromossomo 12 e PLAG1 no cromossomo 8 também foram associados à síndrome de Silver-Russell.

Em alguns casos, uma síndrome genética pode ser o resultado de uma mutação de novo e o primeiro caso em uma família. Neste caso, trata-se de uma nova mutação gênica que ocorre durante o processo reprodutivo.

Em alguns casos, a síndrome pode ser herdada em um padrão autossômico dominante ou autossômico recessivo.


Herança autossômica recessiva significa que um indivíduo afetado recebe uma cópia de um gene mutado de cada um de seus pais, dando-lhes duas cópias de um gene mutado. Os pais que carregam apenas uma cópia da mutação do gene geralmente não apresentam sintomas, mas têm uma chance de 25% de passar as cópias das mutações do gene para cada um de seus filhos.

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 Silver-Russell syndrome (SRS)?

O principal sintomas do síndromes são a restrição do crescimento intra-uterino (baixo peso ao nascer) e deficiência no crescimento após o nascimento.

Características físicas do síndromes incluem uma cabeça grande em relação ao tamanho do corpo, uma testa larga, face triangular, queixo pequeno e estreito, curvatura do mindinho no dedo anular e marcas de nascença cor café com leite. Assimetria facial e de membros também são comuns sintomas.

Atraso motor e de fala também pode se apresentar com o síndromes dependendo da gravidade do caso.

Possíveis traços / características clínicas:
Deficiência de hormônio do crescimento, Atraso de desenvolvimento global, Carcinoma hepatocelular, Falange média curta do 5 º dedo, Falange distal curta do 5 º dedo, Hipospádia, Retardo de crescimento intrauterino, Nefroblastoma, Micrognatia, Mancha café-com-leite, Esclera azul, Anormalidade do tamanho do crânio, Anormalidade do sistema cardiovascular, Anormalidade do pé, Anormalidade do ureter, Esporádica, Face triangular, Seminoma testicular, Bossa frontal, Craniofaringioma, Fechamento de sutura craniana atrasada, Maturação esquelética retardada, Clinodactilia do 5 dedo, Válvula uretral posterior congênita, Desproporção craniofacial, Hipoglicemia de jejum, Pequeno para a idade gestacional, Cantos da boca voltados para baixo, Sindactilia

Como alguém faz o teste de Silver-Russell syndrome (SRS)?

O teste inicial para a síndromes de Silver-Russell pode começar com uma triagem de análise facial, por meio da plataforma de telegenética FDNA Telehealth, que pode identificar os principais marcadores da síndrome e delinear 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 Silver-Russell Síndromes

A characteristic facial appearance, prenatal growth retardation and asymmetry of the limbs are the main features of this condition. The head circumference is relatively normal, which gives the impression of 'pseudohydrocephalus'. The face is small and triangular with frontal bossing, blue sclerae, thin lips with downturned corners, and micrognathia. Minor abnormalities include increased sweating, clinodactyly of the 5th fingers and cafe au lait patches. Intelligence has been thought to be normal, however Lai et al., (1994) studied 25 cases in detail and found that 32% had an IQ below 70 and 40% were reading at least 24 months below their chronological age. The average IQ was 86. Price et al., (1999) studied 57 cases and found that in those above school age, about a third had special educational needs. Most cases are sporadic - although there is a possibility that this syndrome is autosomal dominant in some families (Duncan et al., 1990; Zanchetta et al., 1990) many of the cases in these reports do not have classical features. Possibly affected sibs have also been reported (Callaghan, 1970; Robichaux et al., 1981; Teebi, 1992). Bailey et al., (1995) reported monozygous twins where one had some features of the condition. Two other sets of discordant monozygotic twins from the literature were reviewed (Nyhan and Sakati, 1977; Samn et al., 1990). Sibs were reported by Ounap et al., (2004). There was asymmetry in one, but the features were fairly convincing. Uniparental disomy was not found.
Ramirez-Duenas et al., (1992) reported an 8-year-old girl with the condition who had a paternally derived (17;20)(q25;q13) apparently balanced translocation. Midro et al., (1993) also reported a possible case with a balanced 1;17 translocation with a breakpoint at 17q25.3. Eggermann et al., (1998) reported a case with a paternally derived 17q22-q24 deletion where the chorionic somatomammotrophin hormone 1 (CSH1 gene) was deleted. Tamura et al., (1993) reported a possible case with a ring chromosome 15 who was deleted for insulin-like growth factor 1receptor gene (IGFIR). Harada et al., (2002) refined the critical region to a 4Mb interval in this case and also the case reported by Kato et al., (2001) (see below). Rogan et al., (1996) also noted similarities to the Russell-Silver phenotype in ring 15 cases but found no evidence of chromosome 15 deletion or disomy in five classical Russell-Silver cases. However Abu-Amero et al., (1997) found no evidence for hemizygousity of the IGFIR gene in 33 cases of Russell-Silver syndrome. Schinzel et al., (1994) reported a girl with an 8q11-q13 deletion and some features of the syndrome. The patient reported with a 1q32.1-q42.1 deletion by van Haelst et al., (2002) seems unconvincing. Dupont et al., (2002) reported a 10-year-old girl with features of Russel-Silver syndrome who had maternal heterodisomy for chromosome 7 secondary to a (7;16) (q21;q24) reciprocal translocation.
Kotzot et al., (1995) studied 35 patients with either the Russell-Silver syndrome or primordial growth retardation. They found maternal uniparental disomy (UPD) for chromosome 7 in four (three with isodisomy). Preece et al., (1997) reported three cases with maternal UPD for chromosome 7 out of 37 families studied. Some of these cases might be reported in the paper by Price et al., (1999) where four out of 42 subjects had uniparental disomy. These cases were noted to have a generally milder phenotype. Hannula et al., (2001) also noted that patients with maternal UPD7 had a milder phenotype. The face was only mildly triangular, and the corners of the mouth did not turn down. They also noted strikingly poor feeding throughout childhood, and excessive sweating without evidence of hypoglycaemia. Miyoshi et al., (1999) reported a child with a maternal UPD for part of chromosome 7 secondary to a paternal ring 7 chromosome. This appeared to rule out the putative imprinting region form 7p13 to 7q11. However see the comments of Wakeling et al., (2000). Two further cases with a Russell-Silver phenotype and UPD7 were reported by Bernard et al., (1999). Ayala-Madrigal et al., (1996) found no cases of uniparental disomy for chromosome 7, 8, 11, 17 or 20 out of seven patients studied.Sonnappa et al., (2005) reported a fascinating patient with cystic fibrosis and Russell-Silver with maternal isodisomy of chromosome 7.
Willems et al., (1988) reported a patient with ketoaciduria and dicarboxylic aciduria who had mild hypoglycaemia and ketosis. Cazgan et al., (1994) reported four cases with metabolic abnormalities. These consisted of fasting-induced hypoglycaemia and ketonaemia. One case had dicarboxylic aciduria and elevated serum long-chain fatty acids. Alvarenga et al., (1995) reported evidence for type II renal tubular acidosis in 14 out of 33 patients.
Stanhope et al., (1991) presented data to suggest that biosynthetic growth hormone treatment gives an initial growth response, but might not affect final height. Rakover et al., (1996) presented similar evidence of an improvement in height over three years of treatment during childhood, but could not assess the long term benefit in adulthood. Eggermann et al., (1997) found 3 cases of uniparental disomy in 7 out of 37 cases. No evidence for uniparental disomy for chromosome 2, 9, 14 or 16 was found.
Joyce et al., (1999) reported a mother and daughter with features of the condition who had a 7p12-p13 duplication. They had mild to moderate learning difficulties. Monk et al., (2000) reported a five year old girl with a duplication of 7p11.2-p13 including the GRB10 gene and IGFBP1 and -3, of maternal origin, who was said to have features of the condition, however the clinical photographs were unconvincing. Yoshihashi et al., (2000) and Hitchins et al., (2001) demonstrated that the GRB10 gene is monoallelically expressed in human fetal brain tissues and is transcribed from the maternally derived allele in somatic-cell hybrids. However, Martinez et al., (2001) studied 11 patients with Russell-Silver syndrome and could find no evidence of dup(7)(p11.2-p13) by molecular means. Mergenthaler et al., (2001) studied 32 cases of Russell-Silver syndrome by molecular means and could not demonstrate 7p duplications. 58 patients were studied by Yoshihashi et al., (2000) with Russell-Silver syndrome and a P95S substitution was found in two patients. The mutant allele was inherited from the mother. The GRB10 gene codes for a growth factor receptor-bound protein that interacts with either the IGF-I receptor or the GH receptor. Hitchins et al., (2001) studied 18 non-mUPD7 Russell-Silver cases and found no GRB10 mutations. Hannula et al., (2001) narrowed down the region of maternal uniparental disomy to 7q31-qter in a patient with convincing features of the condition. Maternal uniparental disomy for 7q21 has been reported in myoclonus-dystonia (see in LNDB) along with features of Silver-Russell syndrome (Guettard et al., 2008). Kobayashi et al., (2001) could find no evidence of PEG1/MEST mutations in 15 patients with Russell-Silver syndrome. Eggermann et al., (2001) screened 68 patients for UPD of 7q32-qter. No cases of segmental UPD7q were found. Kato et al., (2001) reported a patient with partial trisomy 7q and monosomy 15q who had glaucoma. He was also claimed to have a Russell-Silver phenotype, but this was not totally convincing. The phenotype of 7q trisomy was reviewed. Hitchins et al., (2001) provide a comprehensive review of the data on chromosomal location and imprinting. An unusual patient with a severe Russell-Silver phenotype was reported by Li et al., (2004). She was mosaic 45X/46XX, but intestingly, skin fibroblast culture showed 45X/46XX on the side with severe limb hypotrophy and 45X on the normal side. The relationship of the chromosomal findings to the phenotype was a problem to explain.
Maternal duplication of 11p15, might be responsible for severe intrauterine and postnatal growth retardation (Eggermann et al., 2005). Gicquesl et al., (2005) described demethylation in the telomeric imprinting center region ICR1 of the 11p15 region in several Russell-Silver patients. Mosaic uniparental disomy 11 was reported by Bullman et al., (2008). In general, the Russell-Silver phenotype might be less pronounced in 11p cases than in maternal UPD (7q) - Eggermann et al., (2008). These authors reported 2 cases of segmental UPD7q. The case reported by Fuke-Sato (2012) with mosaic upd7 mat was also mild. For a review, see Abu-Amero et al., (2010). Mutations in CDKN1C at 11p15 have also been reported (Brioude et al., 2013)Microdeletions of 12q14 can have features of Russell-Silver syndrome (Spengler et al., (2010) as can 22q11.2 distal microdeletion (Garavelli et al., 2011). The condition is expertly reviewed by Wakeling (2011).
De Crescenzo et al. (2015) identified a heterozygous 7bp intronic deletion eliminating the 3' AG-splicing site in HMGA2 gene in the proband and her mother both displaying the typical features of Silver-Russel syndrome. The affected girl had intrauterine growth retardation and relative macrocephaly, postnatal growth retardation, triangular face, broad and prominent forehead, thin upper lip, micrognathia, Vth finger clinodactyly, II-III toe syndactyly and clitoral hypertrophy. Her mother also presented low stature (-3.87 SDS) and triangular face with prominent forehead and Vth finger brachydactyly.
Habib et al. (2016) analyzed 234 Silver-Russell patients with confirmed 11p15 H19/IGF2:IG-DMR/ICR1 hypomethylation. He found deletions on paternal allele of the 11p15 ICR1 in 1% of the cases of Silver-Russell syndrome. The clinical features observed in these patients included short birth length and low birth weight, short stature, low weight during infancy, prominent forehead, feeding difficulties and body asymmetry. Two cases were sporadic and the third was familial (paternal transmission).
Inoue et al. (2017) described five patients with Silver-Russell-like phenotype caused by pathogenic number copy variations outside the Silver-Russell region. Copy number variations included a 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, a 3.77–4.00 Mb deletion in 19q13.11-12, and a 1.41–1.97 Mb deletion in 7q11.23 in two patients. Clinical characteristics were IUGR, relative macrocephaly at birth, developmental delay, short stature, feeding difficulties, protruding forehead, triangular face, and fifth finger brachydactyly.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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