Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM_003483.6:c.138_141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2-q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations.

Silver-Russell syndrome (SRS, OMIM, 180860) is a rare genetic disorder with a wide spectrum of symptoms. The most common features are intrauterine growth retardation (IUGR), poor postnatal development, macrocephaly, triangular face, prominent forehead, body asymmetry, and feeding problems. The diagnosis of SRS is based on a combination of clinical features. Up to 60% of SRS patients have chromosome 7 or 11 abnormalities, and <1% show abnormalities in IGF2 signaling pathway genes (IGF2, HMGA2, PLAG1 and CDKN1C). The underlying genetic cause remains unknown in about 40% of cases (idiopathic SRS). We report a novel IGF2 variant c.[-6-2A>G] (NM_000612) in a child with severe IUGR and clinical features of SRS and confirm the utility of targeted exome sequencing in patients with negative results to common genetic analyses. In addition, we report that long-term growth hormone treatment improves height SDS in this patient.

BACKGROUND: Nonallelic homologous recombination (NAHR) of segmental duplications or low copy repeats (LCRs) result in DNA gain/loss and play an important role in the origin of genomic disorders.
METHODS: A 3-year- old boy was referred for genetic analysis. Comparative genomic hybridization array analysis revealed a loss of 3776 kb in the 4p16.3 chromosomal region and a gain of 3201 kb in the 11p15.5p15.4 chromosomal region.
CONCLUSIONS: Genomic imbalances caused by NAHR in LCRs result in deletion and duplication syndromes.

SRS is classified as a rare syndrome with an estimated incidence of 1 in 30.000/100.000 [Christoforidis A. et al., 2005]. It\'s a clinically and genetically heterogeneous disorder that presents a very wide phenotypic range. Due to its heterogeneity, SRS diagnosis is difficult, and the disease is probably underdiagnosed [Eggermann T. et al., 2009].
M., a 7-year-old patient affected by SRS syndrome, comes to the first visit with a history of pain in the upper retroincisive gum due to the deep bite (gingival impingement). The pain prevents the correct chewing during meals and makes the orthodontic treatment necessary.
The elaboration of a personal orthodontic treatment plan allows the patient to recover the correct masticatory function and improve her facial aesthetic.

[This corrects the article DOI: 10.3389/fgene.2023.1198821.].

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The IGF2 and adjacent H19 are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer\'s cramps, depression, and bipolar disorder. Trio-WES identified a VPS16 heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent IGF2 deficit and VPS16 alteration.

BACKGROUND: Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.
METHODS: We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl\'s mother, great-grandmother, and grandmother\'s brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband\'s mother, great-grandmother, and grandmother\'s brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found.
CONCLUSIONS: Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants.

Optical genome mapping (OGM) appears as a new tool for matching standard cytogenetic methods (karyotype and microarray) into a single assay. The chromosomal region 11p15.5 harbours two differentially methylated regions, the imprinting centre regions 1 and 2 (ICR1, ICR2). Disturbances in both regions alter human growth and are associated with two imprinting disorders, Beckwith-Wiedemann (BWS) and Silver-Russell syndromes. Herein, we present a prenatal case with a triplication in 11p15.5, including the H19/IGF2 imprinted region, detected by microarray and OGM. A 30-year-old pregnant woman of 17 weeks of gestation was referred for prenatal karyotype and microarray study because of increased nuchal translucency, short femur, megabladder, hyperechogenic bowel, and renal ectasia. Microarray, OGM, and MS-MLPA were performed, and a tandem cis-triplication in 11p15.5 and hypermethylation of the ICR1 region, compatible with BWS was detected. OGM, with its power to detect all classes of structural variants, including copy number variants, at a higher resolution than traditional cytogenetic methods can play a significant role in prenatal care and management as a next-generation cytogenomic tool. This study further supports the hypotheses that the amplification/duplication-triplication of the H19/IGF2 region could be related to BWS if it is of paternal origin.

BACKGROUND: Silver-Russell syndrome (SRS) is a rare condition, affects one in 100,000 births. Turner syndrome (TS) is a chromosomal disorder, with an incidence of one in 2,500 females. Patient with SRS and mosaic 45, X/46,X,del(X) karyotypes can have a wide range of phenotypic manifestations. The aim of this article is to present a case report of a patient with an extremely rare and not reported so far genetically confirmed diagnose of Silver-Russell syndrome and Turner syndrome.
METHODS: The patient is a 9-years old girl who had a karyotype of 45,X on prenatal amniocytes. After delivery she was small for gestational age and her phenotype was quite consistent with Russell-Silver syndrome: characteristic dimorphic facial skeleton with a triangular face with prominent forehead, thin nose, hypotonia and hemihyperthrophy. The girl was admitted to hospital due to short stature and deep body weight deficiency. Skin fibroblast and DNA analysis showed mosaic karyotype 45,X[14]/46,X,del(X)(p21.2) and hypomethylation of a gene H19 located on chromosome 11p15. At present the patient is treated with growth hormone in our clinic with good therapeutic results.
CONCLUSIONS: The diagnosis of one genetic disorder does not rule out the possibility of a second genetic disease. Early diagnosis of coexistence of two different genetic syndromes, although very difficult, may help with quickly, appropriate therapy for patients and prevent them from developing serious complications.
UNASSIGNED: Zespół Silvera-Russella (SRS) jest rzadką chorobą, występującą z częstością 1 na 100 000. Zespół Turnera (TS) jest zaburzeniem chromosomalnym, który dotyka 1 na 2500 kobiet. Pacjentka z SRS i mozaikowym kariotypem TS 45,X/46,X,del(X) może prezentować szeroki zakres zmian fenotypowych. Celem niniejszego artykułu jest przedstawienie opisu przypadku pacjentki z niezwykle rzadką i nieopisaną do tej pory koicydencją genetycznie potwierdzonych SRS i TS.
UNASSIGNED: Pacjentka to 9-letnia dziewczynka z kariotypem 45,X w prenatalnym badaniu amniocytów. Po porodzie stwierdzono niedobór masy ciała w stosunku do wieku ciążowego oraz fenotyp zbliżony do fenotypu SRS: charakterystyczną dymorficzną trójkątną twarzoczaszkę z wydatnym czołem, cienkim nosem oraz hipotonię i przerost połowiczy. Dziewczynka została przyjęta do kliniki z powodu niskiego wzrostu i głębokiego niedoboru masy ciała. Analiza fibroblastów skóry i DNA wykazała mozaikowy kariotyp 45,X[14]/46,X,del(X)(p21.2) oraz hipometylację genu H19 zlokalizowanego na chromosomie 11p15. Obecnie pacjentka leczona jest hormonem wzrostu z dobrym wynikiem terapeutycznym.
UNASSIGNED: Rozpoznanie jednego zaburzenia genetycznego nie wyklucza możliwości występowania drugiej choroby genetycznej. Wczesne rozpoznanie współistnienia dwóch różnych zespołów genetycznych, choć bardzo trudne, może pomóc w szybkim, odpowiednim leczeniu pacjentów i uchronić ich przed poważnymi powikłaniami.

\"Characterized by both intrauterine and postnatal growth retardation, and consequent small stature, Silver–Russell syndrome is associated with typical minor anomalies (relative macrocephalia, protruding forehead, downturned corners of mouth, micrognathia, low set ears, facial, skeletal and limb asymmetry) and findings involving mainly the endocrine system. The molecular background of the syndrome is complex, but it is most often caused by the involvement of critical regions of chromosome 11 and/or chromosome 7. Beside the molecular diagnosis, the Netchine–Harbison clinical scoring system aims to contribute to the successful diagnosis of Silver–Russell syndrome. Although Silver–Russell syndrome is mostly sporadic, in our case report we present an extremely rare familial accumulation, where three of four siblings are affected by Silver–Russell syndrome. Early diagnosis is important to initiate adequate feeding and nutritional guidance, enhance early development and start growth hormone therapy as soon as possible. We would like to emphasize that management and long-term follow-up is crucial to prevent potential complications and treat specific issues appropriately.\"
A Silver–Russell-szindróma jellegzetes minor anomáliák mellett (relatív macrocephalia, kiemelkedő homlok, kék sclera, lefelé ívelő szájzug, micrognathia, alacsonyan ülő fülek, illetve arc-, skeletalis és végtagi aszimmetria) súlyos, méhen belüli és születést követő növekedési zavarral jár. Az endokrin rendszert érintő eltérések is kiemelt jelentőségűek. Kialakulásának molekuláris háttere összetett, de a leggyakrabban a 11-es kromoszóma és/vagy a 7-es kromoszóma Silver–Russell-szindróma szempontjából kritikus régióinak érintettsége okozza. A molekuláris géndiagnosztika mellett a Netchine–Harbison-féle klinikai diagnosztikai pontrendszer segíti a diagnózis felállítását. Bár a tünetegyüttes többnyire sporadikus megjelenésű, rendkívül ritka familiáris halmozódást bemutató esetünkben a négy testvérből három gyermeknél Silver–Russell-szindróma került felismerésre. A Silver–Russell-szindróma korai, lehetőleg már újszülöttkori diagnosztizálása kulcsfontosságú a megfelelő táplálásvezetés, a korai fejlesztés, majd a növekedésihormon-kezelés időben történő elkezdése szempontjából. A betegek gondozása és megfelelő utánkövetése kiemelkedő jelentőségű a szindrómához társuló potenciális szövődmények időben történő felismerése és megfelelő kezelése céljából. Orv Hetil. 2022; 163(45): 1775–1781.