Case report: Long term response to growth hormone in a child with Silver-Russell syndrome-like phenotype due to a novel paternally inherited IGF2 variant.

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.

The effects of 3-year growth hormone treatment and body composition in Polish patients with Silver-Russell syndrome.

INTRODUCTION: Silver-Russell syndrome (SRS) is characterized by clinical and genetic heterogeneity. SRS is the only disease entity associated with (epi)genetic abnormalities of 2 different chromosomes: 7 and 11. In SRS, the 2 most frequent molecular abnormalities are hypomethylation (loss of methylation) of region H19/IGF2:IG-DMR on chromosome 11p15.5 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Therapy with recombinant human growth hormone (rhGH) is implemented to increase body height in children with SRS. The effect of the administered rhGH on height, weight, body mass index (BMI), body composition, and height velocity in patients with SRS during 3 years of rhGH therapy was analysed. MATERIAL AND METHODS: 31 SRS patients (23 with 11p15 LOM, 8 with upd(7)mat) and 16 patients small for gestational age (SGA) as a control group were diagnosed and followed up in The Children's Memorial Health Institute. Patients were eligible for the 2 Polish rhGH treatment programmes [for patients with SGA or with growth hormone deficiency (GHD)]. Anthropometric parameters were collected in all patients. Body composition using bioelectrical impedance was measured in 13 SRS and 14 SGA patients. RESULTS: Height, weight, and weight for height (SDS) at baseline of rhGH therapy were lower in SRS patients than in the SGA control group: -3.3 ± 1.2 vs. -2.6 ± 06 (p = 0.012), -2.5 vs. -1.9 (p = 0.037), -1.7 vs. -1.1 (p = 0.038), respectively. Height SDS was increased from -3.3 ± 1.2 to -1.8 ± 1.0 and from -2.6 ± 0.6 to -1.3 ± 0.7 in the SRS and SGA groups, respectively. Patients with 11p15 LOM and upd(7) mat achieved similar height, 127.0 ± 15.7 vs. 128.9 ± 21.6 cm, and -2.0 ± 1.3 vs. -1.7 ± 1.0 SDS, respectively. Fat mass percentage decreased in SRS patients from 4.2% to 3.0% (p < 0.05) and in SGA patients from 7.6% to 6.6% (p < 0.05). CONCLUSIONS: Growth hormone therapy has a positive influence on the growth of SRS patients. Regardless of molecular abnormality type (11p15 LOM vs. upd(7)mat), height velocity was similar in SRS patients during 3 years of rhGH therapy.

Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment.

OBJECTIVE: Silver-Russell syndrome (SRS) causes short stature. Growth hormone (GH) treatment aims to increase adult height. However, data are limited on the long-term outcomes of GH in patients with molecularly confirmed SRS. This study evaluated height, body mass index (BMI) and GH treatment in molecularly confirmed SRS. DESIGN: An observational study with retrospective data collection. PATIENTS: Individuals with molecularly confirmed SRS aged ≥13 years. MEASUREMENTS: Data were collected on height, height gain (change in height standard deviation score [SDS] from childhood to final or near-final height), BMI and gain in BMI (from childhood to adulthood) and previous GH treatment. RESULTS: Seventy-one individuals (40 female) were included. The median age was 22.0 years (range 13.2-69.7). The molecular diagnoses: H19/IGF2:IG-DMR LOM in 80.3% (57/71); upd(7)mat in 16.9% (12/71) and IGF2 mutation in 2.8% (2/71). GH treatment occurred in 77.5% (55/71). Total height gain was greater in GH-treated individuals (median 1.53 SDS vs. 0.53 SDS, p = .007), who were shorter at treatment initiation (-3.46 SDS vs. -2.91 SDS, p = .04) but reached comparable heights to GH-untreated individuals (-2.22 SDS vs. -2.74 SDS, p = .7). In GH-treated individuals, BMI SDS was lower at the most recent assessment (median -1.10 vs. 1.66, p = .002) with lower BMI gain (2.01 vs. 3.58, p = .006) despite similar early BMI SDS to GH-untreated individuals (median -2.65 vs. -2.78, p = .3). CONCLUSIONS: These results support the use of GH in SRS for increasing height SDS. GH treatment was associated with lower adult BMI which may reflect improved metabolic health even following discontinuation of therapy.

Silver-Russell syndrome and Turner syndrome in a girl with short stature treated with growth hormone - case report.

INTRODUCTION: 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. CASE REPORT: 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.

To increase body height and muscle strength - one medicine for two diseases? Case report of a boy with Silver-Russell syndrome and Duchenne muscular dystrophy.

The coexistence of 2 genetic diseases can mutually modify their course. We describe the case of a 10-year-old boy with Sliver-Russell syndrome (SRS) and Duchenne muscular dystrophy (DMD). The patient's short stature, which is part of the clinical picture of both diseases, has been additionally aggravated by the steroid therapy, which is necessary to delay the progression of DMD. From the age of 9 years, the patient was treated with recombinant human growth hormone (rhGH) for 18 months. The following study discusses whether rhGH therapy in a child with SRS and DMD may alleviate or worsen the course of DMD, and how it affects carbohydrate metabolism disorders.

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum.

BACKGROUND: (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes. SUBJECTS AND METHODS: To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis. RESULTS: These 249 patients with SGA-SS were classified into the "SRS-compatible group" (n = 148), the "non-SRS with normocephaly or relative macrocephaly at birth group" (non-SRS group) (n = 94), or the "non-SRS with relative microcephaly at birth group" (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the "SRS-compatible group," 21.3% of patients in the "non-SRS group," and 14.3% in the "non-SRS with microcephaly group" had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the "SRS-compatible group" and in 13.8% of patients in the "non-SRS group." CONCLUSION: We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome.

BACKGROUND: Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver-Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. RESULTS: Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine-Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency. CONCLUSIONS: In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

Sleep disordered breathing in Silver-Russell syndrome patients: a new outcome.

OBJECTIVE: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy. METHODS: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy. RESULTS: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 µg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6). CONCLUSION: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB.

Gonadal function and pubertal development in patients with Silver-Russell syndrome.

STUDY QUESTION: Is gonadal function affected in males and females with Silver-Russell Syndrome (SRS)? SUMMARY ANSWER: Sertoli cell dysfunction is more common in males with SRS, with 11p15 LOM, but gonadal function seems to be unaffected in females with SRS. WHAT IS KNOWN ALREADY: Males with SRS have an increased risk for genital abnormalities such as cryptorchidism and hypospadias, which could be associated with reproductive problems in later life. In SRS females, an association has been described with Mayer-Rokitansky-Küster-Hauser syndrome, which might compromise their reproductive function. STUDY DESIGN, SIZE, DURATION: Longitudinal follow-up study, involving 154 subjects, over a time period of 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty-one SRS patients (14 males) and 123 non-SRS patients born at same gestational age (SGA; 65 males). All received growth hormone and 27.3% received additional gonadotropin-releasing hormone analog treatment (GnRHa). MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at onset of puberty was 11.5 years in SRS males versus 11.6 years in non-SRS males (P = 0.51), and 10.5 years in SRS females versus 10.7 years in non-SRS females (P = 0.50). Four of the 14 SRS males had a post-pubertal inhibin-B level below the fifth percentile compared to healthy controls, and two of them an FSH above the 95th percentile, indicating Sertoli cell dysfunction. One of them had a history of bilateral cryptorchidism and orchiopexy. All SRS females had AMH, LH and FSH levels within the reference range. Pubertal duration to Tanner stage five was similar in SRS and non-SRS. Pubertal height gain was better in SRS patients who additionally received GnRHa (P < 0.01). Mean age at menarche was 13.1 years in SRS versus 13.3 years in non-SRS (P = 0.62). One SRS female had primary amenorrhea due to Müllerian agenesis. LIMITATIONS, REASONS FOR CAUTION: As this is a rare syndrome, the SRS group had a small size. WIDER IMPLICATIONS OF THE FINDINGS: As gonadal function is not affected in females with SRS, it is likely that reproductive function is also not affected. Sertoli cell dysfunction in males with SRS could cause impaired reproductive function and should be assessed during pubertal development. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. The authors have no conflicts of interest.

Effect of Cyproheptadine on Weight and Growth Velocity in Children With Silver-Russell Syndrome.

OBJECTIVES: Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS. METHODS: Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment. RESULTS: The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [P = 0.01]) and body mass index (-3.4 vs -2.4 SDS [P = 0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS. CONCLUSIONS: Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results.

Adrenarche in Silver-Russell Syndrome: Timing and Consequences.

Objectives: Premature adrenarche has been reported to be frequent in Silver-Russell syndrome (SRS), but systematic studies are lacking. Here, we studied the prevalence of early adrenarche in SRS, potential predictors, and consequences based on cases with long-term follow-up. Design and Setting: This retrospective longitudinal single-center study included 62 patients with SRS (34 boys) with documented age at adrenarche and positive Netchine-Harbison clinical score who were seen during the past 20 years with a median follow-up of 12.8 years. Clinical and biochemical characteristics were collected from patient records. Adrenarche was defined by reaching a serum dehydroepiandrosterone concentration >500 ng/mL. Results: Boys reached adrenarche at a median age of 9.2 years (quartiles: 7.6, 10.9 years) and pubarche at a median age of 11.7 years (quartiles: 10.7, 12.8 years). Girls reached adrenarche at a median age of 8.1 years (quartiles: 6.6, 10.1 years) and pubarche at a median age of 9.8 years (quartiles: 8.3, 10.8). Premature adrenarche occurred in 13% of the patients. Multiple linear regression analysis revealed that early adrenarche was associated with early initiation of recombinant human growth hormone (rhGH) treatment (P = 0.0024 in boys; P = 0.0195 in girls), but not with the Netchine-Harbison clinical score (P > 0.25). Response to rhGH treatment (median dose, 50 µg/kg/d) and adult height (n = 43) were not compromised by early adrenarche. Conclusions: Early or premature adrenarche was more frequent in SRS than in the general population and was associated with early age at initiation of rhGH treatment. Response to rhGH treatment and adult height were not compromised by early adrenarche.

Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient's intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7 Mb duplication at 15q11.2-q13.1 encompassing the Prader-Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS.

Metabolic Health and Long-Term Safety of Growth Hormone Treatment in Silver-Russell Syndrome.

Context: Children with Silver-Russell syndrome (SRS) are born small for gestational age (SGA) and remain short. Growth hormone (GH) treatment improves height in short SGA children, including those with SRS. Data on metabolic health and long-term safety of GH treatment in SRS are lacking. Objective: To investigate metabolic health in SRS patients during and until 2 years after discontinuation of GH treatment. Design: Metabolic health was assessed longitudinally at GH-start, GH-stop, 6 months, and 2 years thereafter. Patients: Twenty-nine SRS patients vs 171 non-SRS subjects born SGA. Main Outcome Measures: Lean body mass (LBM), fat mass percentage (FM%), insulin sensitivity (Si), ß-cell function, blood pressure, and serum lipids. Results: At GH-start [mean age (standard deviation) 5.4 (2.1) years in SRS and 6.7 (2.0) years in non-SRS (P = 0.003)], blood pressure, serum lipids, glucose, and insulin levels were similar and within normal ranges in SRS and non-SRS. LBM standard deviation score (SDS) and FM% SDS were lower than average in both groups. During treatment, LBM SDS remained stable whereas FM% SDS increased in both groups. During the 2 years after GH-stop, LBM decreased and FM% increased, whereas Si and ß-cell function improved. At 2 years after GH-stop (mean age 18 years), all parameters were similar and within normal ranges in SRS and non-SRS. None of the SRS patients developed metabolic syndrome, diabetes mellitus type 2, or adverse events. Conclusion: GH-treated SRS patients have a similar metabolic health and safety profile as non-SRS subjects born SGA, both during and until 2 years after GH-stop.

The effects of growth hormone therapy on the somatic development of a group of Polish children with Silver-Russell syndrome.

OBJECTIVE: Silver-Russell Syndrome is both clinically and genetically a heterogeneous syndrome. Among the most important dysmorphic features of this condition are: a triangular shaped face with a small mandible, a prominent frontal eminence, a thin vermilion border with downward-pointing lip corners, clino- and brachydactyly of the 5th fingers as well as body asymmetry. The most well-known genetic mutations in this syndrome are: the 11p15 epimutation (20-60% patients) and the maternal uniparental chromosome 7 disomy present in 7% to 15% of patients. Children with SRS have severely impaired physical growth - intrauterine and after birth. This, together with the aforementioned dysmorphic features, forms the main diagnostic criteria. MATERIAL AND METHODS: The study group consisted of 12 children treated with growth hormone, aged 2 to 17 (8.9±4.0 years), therein, all of whom met the phenotype diagnostic criteria by Wollmann and Price. The effects of growth hormone therapy on somatic development of these children are also presented. RESULTS: Height and weight improved as a result of growth hormone treatment, but the effects were significantly worse than in children with IUGR. Children from the study group presented also a smaller an improvement in growth velocity than children from the control group, but the difference was statistically insignificant. CONCLUSIONS: Growth hormone therapy accelerates the growth of children with SRS but to a smaller extent than the growth of children born with intrauterine growth retardation without dysmorphic features.

Long-Term Results of GH Treatment in Silver-Russell Syndrome (SRS): Do They Benefit the Same as Non-SRS Short-SGA?

CONTEXT: Silver-Russell syndrome (SRS) is a genetically heterogeneous syndrome characterized by low birth weight, severe short stature, and variable dysmorphic features. GH treatment is a registered growth-promoting therapy for short children born small for gestational age, including SRS, but there are limited data on the GH response in SRS children and on differences in response among the (epi)genetic SRS subtypes (11p15 aberrations, maternal uniparental disomy of chromosome 7 [mUPD7], and idiopathic SRS). OBJECTIVES: To compare growth and adult height between GH-treated small for gestational age children with and without SRS (non-SRS), and to analyze the difference in GH response among SRS genotypes. DESIGN AND SETTING: A longitudinal study. PARTICIPANTS: Sixty-two SRS and 227 non-SRS subjects. INTERVENTION: All subjects received GH treatment (1 mg/m(2)/d). MAIN OUTCOME MEASURES: Adult height and total height gain. RESULTS: The SRS group consisted of 31 children with 11p15 aberrations, 11 children with mUPD7, and 20 children with idiopathic SRS. At the start of GH treatment, mean (SD) height standard deviation score [SDS] was significantly lower in SRS (-3.67 [1.0]) than in non-SRS (-2.92 [0.6]; P < .001). Adult height SDS was lower in SRS (-2.17 [0.8]) than in non-SRS (-1.65 [0.8]; P = .002), but the total height gain SDS was similar. There was a trend toward a greater height gain in mUPD7 than in 11p15 (P = .12). CONCLUSION: Children with SRS have a similar height gain during GH treatment as non-SRS subjects. All (epi)genetic SRS subtypes benefit from GH treatment, with a trend toward mUPD7 and idiopathic SRS having the greatest height gain.

Adult height and epigenotype in children with Silver-Russell syndrome treated with GH.

AIMS: To compare adult heights of GH-treated and GH-untreated patients with Silver-Russell syndrome (SRS) who were epigenotyped. METHODS: This was a nonrandomized retrospective study with matched controls at a single center. Molecular analysis of 32 out of 37 GH-treated patients (16 females) revealed IGF2-H19 epimutations in 12 and maternal uniparental disomy of chromosome 7 (matUPD7) in 5 patients; 15 were negative. At start of GH, mean age was 7.2 years and mean height -3.34 standard deviation score (SDS). Mean GH dose used was 51 µg/kg·day, mean duration of therapy was 5.6 years. Puberty was blocked by GnRH analogs in 16 patients. The untreated group comprised 13 individuals (5 females, mean age 6.8 years and mean height -3.34 SDS). End points were adult height and overall height gain. RESULTS: GH-treated patients reached an adult height of -2.12 ± 0.98 SDS gaining 1.22 SDS in comparison to baseline. Adult height SDS of the untreated was -3.13 ± 1.37 SDS. The matched treated patients were significantly taller than their untreated counterparts. Outcome was dependent on height at start of GH and duration of therapy. Height gain was highest in the shortest patients. CONCLUSIONS: GH improved adult height in SRS to a comparable degree as reported in nonsyndromic SGA children. A trend toward a better outcome in matUPD7 needs confirmation in larger cohorts.

Bloom syndrome in short children born small for gestational age: a challenging diagnosis.

BACKGROUND: GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. OBJECTIVE: We report 2 patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH. CASES: Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. CONCLUSION: Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF-1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels.