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Silver-Russell syndrome (SRS)
Was ist Silver-Russell syndrome (SRS)?
Silver-Russell syndrome is a rare genetic disorder characterized by limited growth both before and after birth known as intrauterine growth restriction. Babies born with the condition have a low weight at birth. It is often referred to as a congenital growth disorder.
Symptoms vary from mild to severe depending on the genetic mutations involved in each affected individual’s case.
RSS Russel-Silver Syndrome Russell-silver Syndrome; Rss Silver-russell Dwarfism Silver-Russell syndrome SRS
Was Genveränderungen verursachen Silver-Russell syndrome (SRS)?
In 60-70% der Fälle wird das Syndromes durch Mutationen im Gen (eins) SRS2 auf Chromosom 7 und ICR1 und IGF2 auf Chromosom 11 verursacht. HMGA2 in Chromosom 12 und PLAG1 in Chromosom 8 wurden jedoch auch mit dem Silver-Russell-Syndrom in Verbindung gebracht.
In einigen Fällen kann ein genetisches Syndrom das Ergebnis einer De-novo-Mutation und der erste Fall in einer Familie sein. In diesem Fall handelt es sich um eine neue Genmutation, die während des Fortpflanzungsprozesses auftritt.
In einigen Fällen kann das Syndrom in einem autosomal dominanten oder autosomal rezessiven Muster vererbt werden.
Autosomal-rezessive Vererbung bedeutet, dass eine betroffene Person von jedem ihrer Elternteile eine Kopie eines mutierten Gens erhält, wodurch sie zwei Kopien eines mutierten Gens erhält. Eltern, die nur eine Kopie der Genmutation tragen, zeigen im Allgemeinen keine Symptome, haben jedoch eine 25% ige Chance, die Kopien der Genmutationen an jedes ihrer Kinder weiterzugeben.
Im Fall einer autosomal dominanten Vererbung ist nur ein Elternteil der Träger der Genmutation, und sie haben eine 50% ige Chance, sie an jedes ihrer Kinder weiterzugeben. Syndrome, die in einer autosomal dominanten Vererbung vererbt werden, werden durch nur eine Kopie der Genmutation verursacht.
Was sind die wichtigsten symptome von Silver-Russell syndrome (SRS)?
The main symptoms of the syndrome are intrauterine growth restriction ( a low birth weight) and a failure to thrive once born.
Physical features of the syndrome include a large head in relation to the size of the body, a wide forehead, triangular face, small and narrow chin, curving of the pinky into the ring finger and cafe-au-lait coloured birthmarks. Facial and limb asymmetry are also common symptoms.
Motor and speech delay may also present with the syndrome depending on the severity of the case.
Possible clinical traits/features:
Growth hormone deficiency, Global developmental delay, Hepatocellular carcinoma, Short middle phalanx of the 5th finger, Short distal phalanx of the 5th finger, Hypospadias, Intrauterine growth retardation, Nephroblastoma, Micrognathia, Cafe-au-lait spot, Blue sclerae, Abnormality of skull size, Abnormality of the cardiovascular system, Abnormality of the foot, Abnormality of the ureter, Sporadic, Triangular face, Testicular seminoma, Frontal bossing, Craniopharyngioma, Delayed cranial suture closure, Delayed skeletal maturation, Clinodactyly of the 5th finger, Congenital posterior urethral valve, Craniofacial disproportion, Fasting hypoglycemia, Small for gestational age, Downturned corners of mouth, Syndactyly
Wie wird jemand getestet? Silver-Russell syndrome (SRS)?
Die ersten Tests für das Silver-Russell-
Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.
Medical information on Silver-Russell Syndrome
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.
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