Silver-Russell syndrome
| Classification according to ICD-10 | |
|---|---|
| Q87.1 | Congenital malformation syndromes that are predominantly associated with short stature - Silver-Russell syndrome |
| ICD-10 online (WHO version 2019) | |
The Silver-Russell-Syndrome ( SRS ) is a form of the intrauterine short stature . The incidence of the disease is estimated at around 1-3 in 100,000 births worldwide, making it a rare disease . Intrauterine short stature is the collective term for those developmental peculiarities that arise in children in the womb (= intrauterine) and are particularly noticeable due to nutritional deficiency and growth deficit in the child at birth . The causes of Silver-Russell syndrome are not yet fully understood. In English-speaking countries, Silver-Russell Syndrome ( SRS ) is mostly commonCalled Russell-Silver Syndrome ( RSS ).
History & Genetics
The first time was syndrome 1953 / 1954 by Henry Russell (England) and Alexander Silver (USA) described a scientific point. Since then, over 360 cases have been published, most of which, according to current knowledge, have occurred sporadically, although a few familial clusters and sibling cases have also become known. For this reason, a genetic cause is suspected.
So far, a maternal uniparental disomy 7 (UPD (7) mat) has been found in around 10 out of 100 people with SRS . This means that the child inherited two copies of the number 7 chromosome from its biological mother and not, as usual, one copy from the mother and one from the father, which speaks for imprinting . The copy of paternal chromosome 7 is either absent or damaged in people with SRS. In around 40% of SRS patients, a DNA methylation disorder on chromosome 11 can be detected today (2010) . In this case, the paternal (paternal) allele of the H19-DMR (ICR1 - differentially methylated region or imprinted control region) in 11p15 is hypomethylated. H19 codes for a non-translated RNA, i.e. an RNA that is not translated into a protein.
The H19 gene is under the control of an "imprinting control region" or DMR (differentially methylated region), which is methylated in the paternal chromosome and unmethylated in the maternal chromosome. If DMR1 is methylated, embryonic growth factor IGF2 is formed, which, together with H19, is under the control of ICR1. This is the case with the paternal allele. In the unmethylated maternal allele, the RNA of H19 is expressed instead of the growth factor IGF2. The binding of the zinc finger protein CTCF is important for this . The addition of CTCF to the DNA in ICR1 causes an “isolation” of the IGF2 gene from the promoter / enhancer area, which is upstream of the DNA. This means that only H19 can be expressed. If the ICR1 is methylated (paternal chromosome), CTCF cannot bind and IGF2 is produced instead of H19.
Other chromosomal structural features have been found in some people with SRS, e.g. B. an elongation on the short arm of chromosome 7 (remodeling in 7p), shortenings on the long arm of chromosome 17 (region 17q23-25) or breaks on chromosome X (one of the sex chromosomes ). With modern karyotyping methods (SNP arrays) it was also possible to show microdeletions in Silver-Russell patients. An uneven occurrence of the SRS in identical twins speaks against a uniform genetic cause .
diagnosis
Based on these findings, it can be assumed that there is no uniform genetic pattern for SRS and that various chromosome peculiarities can be the cause.
This in turn would explain the sometimes quite high variability in clinical symptoms , which is regularly used to make a diagnosis . Several symptoms must always be proven in a child in order to be able to deduce the diagnosis of SRS. Family peculiarities (partial symptoms without typical full-screen expression, e.g. with regard to body size, face shape, etc.) must be taken into account.
If SRS is suspected in a child, the first step should be to examine the methylation status of the H19-DMR. This is done either by a Southern blot or, due to the better detection rate, by an MS-MLPA (methylation sensitive - multiplex ligation dependent probe amplification). At the same time, testing for a maternal UPD of chromosome 7 (uniparental disomy 7 (UPD (7) mat) is carried out using MS-PCR (methylation-sensitive PCR) at the MEST and GRB10 loci.If these tests do not result, it is advisable to carry out a Molecular cariotyping via a DNA array (chip) should be considered, sometimes a clear diagnosis is not possible (initially).
Symptoms
Over time, some specifics have been documented that are very common in people with SRS. Not all characteristics occur in all people with SRS or can be found to the same extent. Apart from genetic characteristics, the most common or existing characteristics are:
- Deficient birth (a comparatively small and underweight child, even with a timely delivery , the birth weight is usually less than two kilograms)
- a large head compared to the body that develops according to age (i.e., intrauterine brain growth has been least affected)
- comparatively high, bulging forehead
- triangular face shape
- ears set comparatively low and set far back on the head
- Crease in the eyes
- pointed chin
- small mouth with drooping corners, micrognathia
- Tooth misalignment , microdontics
- comparatively thin skin
- sparse fat deposits under the skin, little muscle mass
- whitish or brownish spots on the skin ( hyperpigmentation )
- Misalignment of the fingers and / or toes
- Clinodactyly (curvature of the fifth fingers, sometimes with shortening)
- significantly delayed bone maturation , which means that the growth in length is always below the average for the respective age group
- more or less clearly uneven growth (general or local lateral asymmetry , especially of the extremities )
- Adult height below average in two out of three people, as usual in one in three; In the growth phase, 90 out of 100 children are stunted in growth compared to their peers
- Persistent underweight in relation to body size (partly due to the frequent peculiarities of drinking and eating behavior in small children)
- normal to slightly reduced cognitive performance / intelligence
- in some children is a cleft palate before
- partly hearing impairment
- often comparatively high ( squeaky ) voice
- premature puberty
- Tendency to hypoglycemia (= hypoglycaemia, in which the blood sugar level drops to values below about 40 to 50 mg / dl )
- Keratoconus (a disease of the cornea)
Others
Since the cognitive performance of people with SRS is not or not particularly restricted, almost all children can attend regular kindergarten and school. Adults can learn and practice a regular job. From a medical point of view, people with SRS are normally not medically restricted in their way of life and in their quality of life.
therapy
Growth hormone treatment aimed at becoming an adult approximately equal to parental height is still under investigation. In some children, the administration of hormones shows clear improvements in length growth, while in others a corresponding therapy shows little or no success.
Because of the propensity for hypoglycemia , avoiding hypoglycaemia is important.
Differential diagnosis
The following special features can be used as a differential diagnosis to the SRS:
- embryo-fetal alcohol syndrome (FAS)
- Floating Harbor Syndrome
- other forms of congenital short stature such as B. the SHORT syndrome .
Individual evidence
- ↑ Emma L. Wakeling, Frédéric Brioude, Oluwakemi Lokulo-Sodipe, Susan M. O'Connell, Jennifer Salem: Diagnosis and management of Silver – Russell syndrome: first international consensus statement . In: Nature Reviews Endocrinology . tape 13 , no. 2 , February 2017, ISSN 1759-5037 , p. 105–124 , doi : 10.1038 / nrendo.2016.138 ( nature.com [accessed May 31, 2020]).
- ↑ U. Thelen, H. Busse, G. Kurlemann, H. Gerding: Silver-Russel syndrome with keratoconus. (No longer available online.) In: dog.org. German Ophthalmological Society, archived from the original on May 4, 2007 ; accessed on May 1, 2017 . at the Internet Archive
- ↑ Ute Moog, Olaf Rieß: Components of the clinical-genetic examination. In: thieme-connect. Thieme, accessed on May 1, 2017 .
literature
- Possibility to order an information folder on the Silver-Russel Syndrome
- T. Eggermann, K. Eggerman, S. Mergenthaler and others: Silver-Russel-Syndrome (SRS) - state of research and indication for the examination of uniparental disomy 7 (UPD7). In: Medical Genetics . Volume 12, 2000, pp. 348-352.
- Karl-Heinz Klingebiel , Hartmut A. Wollmann: Intrauterine growth retardation and Silver-Russell syndrome. Palatium-Verlag, Mannheim 2002, ISBN 3-920671-45-7 .
- R. Witkowski, O. Prokop, E. Ullrich, G. Thiel: Lexicon of the syndromes and malformations. 7th edition. 2003, ISBN 3-540-44305-3 .
- T. Eggermann, K. Eggermann, N. Schönherr: Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome. In: Trends Genet . Volume 24, 2008, pp. 195-204.
- Sabrina Spengler, Nadine Schönherr, Gerhard Binder, Hartmut Wollmann, Susanne Fricke-Otto, Reinhard Mühlenberg, Bernd Denecke, Michael Baudis, Thomas Eggermann: Submicroscopic chromosomal imbalances in idiopathic Silver-Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome. In: J Med Genet. Volume 47, No. 5, May 2010, pp. 356-360. doi: 10.1136 / jmg.2009.070052
