Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

Paternal 132 bp deletion affecting KCNQ1OT1 in 11p15.5 is associated with growth retardation but does not affect imprinting.

BACKGROUND: The chromosomal region 11p15.5 harbours two imprinting centres (H19/IGF2:IG-DMR/IC1, KCNQ1OT1:TSS-DMR/IC2). Molecular alterations of the IC2 are associated with Beckwith-Wiedemann syndrome (BWS), whereas only single patients with growth retardation and Silver-Russell syndrome (SRS) features have been reported. CNVs in 11p15.5 account for less than 1% of patients with BWS and SRS, and they mainly consist of duplications of both ICs either affecting the maternal (SRS) or the paternal (BWS) allele. However, this correlation does not apply to smaller CNVs, which are associated with diverse clinical outcomes. METHODS AND RESULTS: We identified a family with a 132 bp deletion within the KCNQ1OT1 gene, associated with growth retardation in case of paternal transmission but a normal phenotype when maternally inherited. Comparison of molecular and clinical data with cases from the literature helped to delineate its functional relevance. CONCLUSION: Microdeletions within the paternal IC2 affecting the KCNQ1OT1 gene have been described in only five families, and they all include the differentially methylated region KCNQ1OT1:TSS-DMR/IC2 and parts of the KCNQ1 gene. However, these deletions have different impacts on the expression of both genes and the cell-cycle inhibitor CDKN1C. They thereby cause different phenotypes. The 132 bp deletion is the smallest deletion in the IC2 reported so far. It does not affect the IC2 methylation in general and the coding sequence of the KCNQ1 gene. Thus, the deletion is only associated with a growth retardation phenotype when paternally transmitted but not with other clinical features in case of maternal inheritance as observed for larger deletions.

New euchromatic variant dup(11)(p15.3p15.1) transmitted through two generations defined by low coverage whole genome sequencing.

We report on a 14-year old boy, his father, and his paternal uncle, all three carriers of a duplication of chromosomal region 11p15.3-p15.1. The aberration was transmitted by the grandmother, who is carrier of a balanced insertion 46,XX,ins(14;11)(q32.1;p15.3p15.1). In order to determine the precise molecular basis of this structural variant, we performed low-coverage whole genome sequencing on the boy's father. This approach allowed precise determination of the genomic breakpoints and revealed a duplication of 6.9 Mb, centromeric to the Beckwith-Wiedemann/Silver-Russell syndrome critical region in 11p15.5, that inserted in inverse orientation into 14q32.12 (according to HGVS nomenclature: NC_000014.8:g.92871000_92871001ins[NC_000011.9:g.12250642_19165928inv;T]). To our knowledge, this is the first report of a duplication of 11p15.3-p15.1 involving more than 40 genes and transmitted through two generations without apparent clinical effects.

Further heterogeneity in Silver-Russell syndrome: PLAG1 deletion in association with a complex chromosomal rearrangement.

Silver-Russell syndrome (SRS) is a rare genetic condition primarily characterized by growth restriction and facial dysmorphisms. While hypomethylation of H19/IGF2:IG-DMR (imprinting control region 1 [IC1]) located at 11p15.5 and maternal uniparental disomy of chromosome 7 (upd[7]mat) are the most common genetic mechanisms responsible for SRS, the expanding body of literature describing alternative causative variants suggests SRS is a highly heterogeneous condition, also involving variation in the HMGA2-PLAG1-IGF2 pathway. We report a familial PLAG1 deletion in association with a complex chromosomal rearrangement. We describe two siblings with differing unbalanced chromosomal rearrangements inherited from a mother with a 5-breakpoint balanced complex rearrangement involving chromosomes 2, 8, and 21. The overlapping but diverse phenotypes in the siblings were characterized by shared SRS-like features, underlined by a PLAG1 whole gene deletion. Genetic analysis and interpretation was further complicated by a meiotic recombination event occurring in one of the siblings. This family adds to the limited literature available on PLAG1-related SRS. We have reviewed all currently known cases aiming to define the associated phenotype and guide future genetic testing strategies. The heterogeneity of SRS is further expanded by the involvement of complex cytogenomic abnormalities, imposing requirements for a comprehensive approach to testing and genetic counseling.

A boy with Silver-Russell syndrome and Sotos syndrome.

Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth deficiency. It is most often caused by hypomethylation of the paternal imprinting center 1 of chromosome 11p15.5. In contrast, Sotos syndrome is an overgrowth syndrome that results either from pathogenic NSD1 gene variants or copy number variations affecting the NSD1 gene. Here, we report on a 6 month-old boy with severe short stature, relative macrocephaly, severe feeding difficulties with underweight, muscular hypotonia, motor delay, medullary nephrocalcinosis, bilateral sensorineural hearing impairment and facial dysmorphisms. SNP array revealed a 2.1 Mb de novo interstitial deletion of 5q35.2q35.3 encompassing the NSD1 gene. As Sotos syndrome could not satisfactorily explain his symptoms, diagnostic testing for SRS was initiated. It demonstrated hypomethylation of the imprinting center 1 of chromosome 11p15.5 confirming the clinically suspected SRS. We compared the symptoms of our patient with the typical clinical features of individuals with SRS and Sotos syndrome, respectively. To our knowledge, this is the first study reporting the very unusual coincidence of both Sotos syndrome and SRS in the same patient.

Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood.

BACKGROUND: Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%-10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS. METHODS: A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped. RESULTS: The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤-2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS. CONCLUSION: Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.

upd(20)mat is a rare cause of the Silver-Russell-syndrome-like phenotype: Two unrelated cases and screening of large cohorts.

Silver-Russell syndrome (SRS) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly, feeding difficulties and body asymmetry. Recently, upd(20)mat has been identified in few patients with SRS-like features, suggestive of a new imprinting disorder characterized by prenatal and postnatal growth failure. Here, we describe two male patients with upd(20) and feeding difficulties, prenatal and postnatal growth retardation and normal cognitive development. During pregnancy, confined placental mosaicism for trisomy 20 was detected in one of the patients but was not investigated further until identification of upd(20)mat in the neonatal period. To evaluate whether upd(20)mat should be part of the first trier genetic diagnostic in patients with growth retardation, we screened a large cohort of patients (n = 673) referred to our laboratories for SRS-testing without detecting any upd(20). Our results, along with the existing evidence, indicate that upd(20)mat is a very rare cause of growth retardation, but should be followed up when confined placental mosaicism for trisomy 20 mosaicism is observed during pregnancy.

Heterogeneous phenotypes in families with duplications of the paternal allele within the imprinting center 1 (H19/IGF2:TSS-DMR) in 11p15.5.

The clinical impact of duplications affecting the 11p15.5 region is difficult to predict, and depends on the parent-of-origin of the affected allele as well as on the type (deletion, duplication), the extent and genomic content of the variant. Three unrelated families with inheritance of duplications affecting the IC1 region in 11p15.5 through two generations but different phenotypes (Beckwith-Wiedemann and Silver-Russell syndromes, normal phenotype) are reported. The inconsistent phenotypic patterns of carriers of the same variant strongly indicate the impact of cis- and/or trans-acting modifiers on the clinical outcome of IC1 duplication carriers.

Patient with an autosomal-recessive MBTPS1-linked phenotype and clinical features of Silver-Russell syndrome.

Pathogenic variants in the MBTPS1 gene encoding the Site 1 protease have been described so far only in one growth retarded patients with skeletal deformities, large ears, a triangular face reminiscent to Silver-Russell syndrome (SRS), and elevated blood lysosomal enzymes. We now report on the identification of a second adult patient homozygous for one of the two published pathogenic MBTPS1 variants (p.Asp365Gly) by Whole Exome Sequencing (WES), and a comparable phenotype. With this case, the association of pathogenic variants in MBTPS1 with a recognizable disorder could be confirmed, and the autosomal recessive inheritance is further established. As the variant was identified after a long diagnostic odyssey of the family, this example illustrates the need to apply WES in the diagnostic workup in case of growth retardation as early as possible. By compiling the clinical data of this new patient with those of the already reported patient, a better prognosis for future patients with MBTPS1 variants can be issued, and clinical management can be adjusted.

Maternal UPD of chromosome 7 in a patient with Silver-Russell syndrome and Pendred syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss. METHODS: Karyotyping analysis was performed to investigate any chromosomal abnormalities. Whole-genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next-generation sequencing on all known deafness-causing genes. RESULTS: The proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919-2A > G of SLC26A4; both mutated alleles were inherited from his mother. CONCLUSION: This is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences.

BACKGROUND: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex. OBJECTIVES: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations. METHODS: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain. RESULTS: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. CONCLUSIONS: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver-Russell syndrome phenotypes.

Genomic imprinting affects a subset of genes in mammals, such that they are expressed in a monoallelic, parent-of-origin-specific manner. These genes are regulated by imprinting control regions (ICRs), cis-regulatory elements that exhibit allele-specific differential DNA methylation. Although genomic imprinting is conserved in mammals, ICRs are genetically divergent across species. This raises the fundamental question of whether the ICR plays a species-specific role in regulating imprinting at a given locus. We addressed this question at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, the misregulation of which is associated with the human imprinting disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). We generated a knock-in mouse in which the endogenous H19/Igf2 ICR (mIC1) is replaced by the orthologous human ICR (hIC1) sequence, designated H19(hIC1) We show that hIC1 can functionally replace mIC1 on the maternal allele. In contrast, paternally transmitted hIC1 leads to growth restriction, abnormal hIC1 methylation, and loss of H19 and Igf2 imprinted expression. Imprint establishment at hIC1 is impaired in the male germ line, which is associated with an abnormal composition of histone posttranslational modifications compared with mIC1. Overall, this study reveals evolutionarily divergent paternal imprinting at IC1 between mice and humans. The conserved maternal imprinting mechanism and function at IC1 demonstrates the possibility of modeling maternal transmission of hIC1 mutations associated with BWS in mice. In addition, we propose that further analyses in the paternal knock-in H19(+/hIC1) mice will elucidate the molecular mechanisms that may underlie SRS.

Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome.

The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of specific gene alterations. Some genetic alterations suggest a role for increased dosage of the imprinted CYCLIN DEPENDENT KINASE INHIBITOR 1C (CDKN1C) gene, often mutated in IMAGe Syndrome and Beckwith-Wiedemann Syndrome (BWS). Cdkn1c encodes a potent negative regulator of fetal growth that also regulates placental development, consistent with a proposed role for CDKN1C in these complex childhood growth disorders. Here, we report that a mouse modelling the rare microduplications present in some SRS patients exhibited phenotypes including low birth weight with relative head sparing, neonatal hypoglycemia, absence of catch-up growth and significantly reduced adiposity as adults, all defining features of SRS. Further investigation revealed the presence of substantially more brown adipose tissue in very young mice, of both the classical or canonical type exemplified by interscapular-type brown fat depot in mice (iBAT) and a second type of non-classic BAT that develops postnatally within white adipose tissue (WAT), genetically attributable to a double dose of Cdkn1c in vivo and ex-vivo. Conversely, loss-of-function of Cdkn1c resulted in the complete developmental failure of the brown adipocyte lineage with a loss of markers of both brown adipose fate and function. We further show that Cdkn1c is required for post-transcriptional accumulation of the brown fat determinant PR domain containing 16 (PRDM16) and that CDKN1C and PRDM16 co-localise to the nucleus of rare label-retaining cell within iBAT. This study reveals a key requirement for Cdkn1c in the early development of the brown adipose lineages. Importantly, active BAT consumes high amounts of energy to generate body heat, providing a valid explanation for the persistence of thinness in our model and supporting a major role for elevated CDKN1C in SRS.

A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome.

BACKGROUND: Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype. SUBJECTS AND METHODS: Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤-2SDS, (2) postnatal growth retardation (height ≤-2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤-2SDS in toddlers; (6) protruding forehead at the age of 1-3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data. RESULTS: The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion. CONCLUSIONS: This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.

Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C.

We report duplications of maternally derived chromosome 11p15 involving CDKN1C encoding a negative regulator for cell proliferation in three Japanese patients (cases 1 and 2 from family A and case 3 from family B) with Silver-Russell syndrome (SRS) phenotype lacking hemihypotrophy. Chromosome analysis showed 46,XX,der(16)t(11;16)(p15.3;q24.3)mat in case 1, 46,XY,der(16)t(11;16)(p15.3;q24.3)mat in case 2 and a de novo 46,XX,der(17)t(11;17)(p15.4;q25.3) in case 3. Genomewide oligonucleotide-based array comparative genomic hybridization, microsatellite analysis, pyrosequencing-based methylation analysis and direct sequence analysis revealed the presence of maternally derived extra copies of the distal chromosome 11p involving the wild-type CDKN1C (a ~7.98 Mb region in cases 1 and 2 and a ~4.43 Mb region in case 3). The results, in conjunction with the previous findings in patients with similar duplications encompassing CDKN1C and in those with intragenic mutations of CDKN1C, imply that duplications of CDKN1C, as well as relatively mild gain-of-function mutations of CDKN1C lead to SRS subtype that usually lack hemihypotrophy.

Pure Choriocarcinoma of the Ovary in Silver-Russell Syndrome.

Pure ovarian choriocarcinoma is an extremely rare malignancy that can be gestational or non-gestational in origin. Silver-Russell syndrome (SRS) is a rare congenital developmental disorder characterized by pre- and postnatal growth failure, relative macrocephaly, a triangular face, hemihypotrophy, and fifth-finger clinodactyly. We report a rare case of pure ovarian choriocarcinoma occurring in a 19-year-old woman with SRS. Following surgery, multiple chemotherapy courses were effective and she was free of disease at the 10-month follow-up.

12q14 microdeletion syndrome and short stature with or without relative macrocephaly.

Patients with 12q14 microdeletion can present with short stature with or without relative macrocephaly. When associated with relative macrocephaly, the phenotype resembles Silver-Russell syndrome (SRS). Short stature is attributable to haploinsufficiency of HMGA2, but a patient with a deletion at the HMGA2 locus only did not have macrocephaly. Hence, the presence of a separate locus for a relative macrocephaly phenotype was suggested. Herein, we present a girl with a 12q14 microdeletion involving the HMGA2 locus who had short stature but did not have macrocephaly. Inclusion and exclusion mappings based on a quantitative review of the degree of relative macrocephaly and the extent of the deletions in previously reported patients with a 12q14 microdeletion demonstrated a presumptive interval for relative macrocephaly spanning a few megabases. These results confirm that a deletion spanning both HMGA2 and this presumptive interval locus would cause an SRS-like phenotype.

17p13.1 microduplication in a boy with Silver-Russell syndrome features and intellectual disability.

Many deletions of chromosome 17p13.1 have been described, but very few 17p13.1 duplications have been reported yet. Here, we describe the genotype and phenotype of a boy with a duplication of this region. The main clinical features are mild intellectual deficiency, growth retardation, and a typical Silver-Russell syndrome (SRS) appearance with small triangular face, prominent forehead, micrognathia, low-set ears, and clinodactyly. Array-CGH revealed a 586 kb duplication containing many genes with a high neuronal expression. Interestingly, this region covers the minimal critical region including all candidate genes suggested to explain the 17p13.1 microdeletion syndrome. In the neighboring region 17p13.3, deletions and duplications of the same region are each responsible of a specific phenotype. Future case descriptions will show if a similar mechanism applies to the region 17p13.1. The 17p13.1 region contains interesting putative candidate genes that might be involved in the SRS etiology. Additional data are needed to verify the significance of this aberration.

Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation.

Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver-Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype. Detailed clinical analysis confirmed the molecular finding in the patient indicating that the 14q32 epimutation was clinically preponderant. The parallel occurrence of upd(7q)mat and a DLK1/GTL2 hypomethylation in the same patient is a unique finding. Indeed, both disturbances might have occurred coincidentally, but it can also be hypothesized that the upd(7q)mat as the initial genomic mutation represents a trans-acting mutation causing an aberrant methylation in 14q32.

Type 1 collagenopathy presenting with a Russell-Silver phenotype.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern of inheritance. Six other genes, CRTAP, LEPRE1, FKBP10, PP1B, SP7/Osterix (OSX), and SERPINH1, are associated with autosomal recessive forms of OI. However, other, rare phenotypes have also been described. There are many differential diagnoses of the short, syndromic child, including chromosomal, single gene, and multifactorial causes. However, one condition of particular relevance in the context of this report is the Russell-Silver syndrome (RSS). As originally described, the RSS is a very specific condition. However, it has subsequently become an umbrella term for a heterogeneous group of conditions presenting with short stature and triangular shape to the face. A significant proportion of these are now believed to be due to imprinting defects at 11p15. However, the cause in many cases remains unknown. We describe two cases with a phenotypic overlap between OI and RSS who both have COL1A1 mutations. Thus, a type 1 collagenopathy should be considered in the differential diagnosis of syndromic short stature.