Hartmut A. Wollmann

Growth and symptoms in Silver-Russell syndrome: Review on the basis of 386 patients

The spontaneous growth of 386 patients (163 girls and 223 boys) with Silver-Russell syndrome (SRS) was analysed in a mixed longitudinal and cross-sectional manner. One hundred and twenty patients were seen in the two centres between 1970 and 1993, additional definite cases were added from the literature. Mean (± SD) length of full-term babies with SRS at birth was 43.1±3.7 cm (n=102) in both sexes. Mean weight at birth was 1940±353 g in boys and 1897±325 g in girls. During the first 3 years of life there was poor growth with a further loss in height. Between ages 4 and 10 years there was constant growth in parallel to the 3rd percentile with a mean height SDS of −4.3. The pubertal growth spurt was reduced in the whole group. Bone age development paralleled growth, retardation increased during the first years, remained constant during prepubertal time and caught up in early puberty. Mean adult height was 151.2±7.8 cm in males and 139.9±9.0 cm in females. Head circumference for age was in the lower normal range (mean SDS for 156 prepubertal boys −1.8; mean SDS for 97 prepubertal girls ≈2.2).ConclusionNormative data on spontaneous growth of children with Silver-Russell syndrome are described, allowing a better counselling of patients as well as the judgement of the effects of growth promoting therapies.

The centromeric 11p15 imprinting centre is also involved in Silver–Russell syndrome

Silver–Russell syndrome (SRS) is a heterogeneous disorder characterised by severe intrauterine and postnatal growth retardation, limb and body asymmetry, a typical facial appearance and less common dysmorphisms. Recently, epimutations and maternal duplications affecting the short arm of chromosome 11 have been shown to have a crucial role in the aetiology of the disease. Disturbances in the same genomic region cause the overgrowth disorder Beckwith–Wiedemann syndrome (BWS). In BWS, mutations in the telomeric as well as in the centromeric imprinting centres (ICR1 and ICR2) in 11p15 can be observed. In SRS, methylation defects in the imprinted region in 11p15 were considered to be restricted to the telomeric ICR1. They can be detected in about 30% of patients. This article reports on the first patient with SRS with a cryptic duplication restricted to the centromeric ICR2 domain in 11p15. The maternally inherited duplication in this patient included a region of 0.76–1 Mbp and affected the genes regulated by the ICR2, among them CDKN1C and LIT1. This study provides evidence for a role for this imprinting centre in the aetiology of SRS and shows that SRS presents a picture genetically opposite to that of BWS.

Is maternal duplication of 11p15 associated with Silver- Russell syndrome?

Background: Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS—with an opposite phenotype to BWS—might also be caused by genomic disturbances in 11p15. Methods: A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis. Results: Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15. Conclusions: We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.

Pelvic ultrasonography: Early differentiation between isolated premature thelarche and central precocious puberty

We examined 55 girls with isolated premature thelarche between the ages of 0.3 and 7.3 years (group A), 20 children with central precocious puberty between 2.1 and 7.7 years of age and 101 age-matched controls. The children with precocious puberty were divided according to distribution of pubic hair into group B (Tanner stages PH1, B2–3;n=11), representing an early stage of the disorder, and group C (stages PH2–3, B3–4;n=9), representing an advanced stage. Uterine and ovarian volumes were measured sonographically, peak serum levels of luteinizing hormone and folliclestimulating hormone were determined after intravenous administration of luteinizing hormone-releasing hormone. The mean uterine and ovarian volumes were significantly greater in children with precocious puberty than in controls (group B: uterine volume: 3.8±2.0 ml vs 0.9±0.3 ml for controls,P<0.001; ovarian volume: 2.2±1.3 ml vs 0.6±0.2 ml for controls,P<0.01; group C: uterine volume: 8.0±4.4 ml vs 1.0±0.3 ml for controls,P<0.01; ovarian volume: 2.6±1.3 ml vs 0.4±0.1 ml,P<0.01). No significant differences were found between children with premature thelarche and the control group. As a diagnostic method for the early detection of central precocious puberty, ultrasound measurement of uterine volume had a sensitivity and specificity of 100% (cut-off value, 1.8 ml), while ultrasound determination of ovarian volume had a sensitivity of 82% and a specificity of 95% (cut-off value, 1.2 ml). In contrast, as a diagnostic criterion the ratio of levels of luteinizing hormone to follicle-stimulating hormone as determined following stimulation with luteinizing hormone releasing hormone had a sensitivity of 33% and a specificity of 100% (cut-off value, 1.0). Conclusion: ultrasonographic measurement of uterine and ovarian volume offers a reliable means of distinguishing between isolated premature thelarche and early stages of central precocious puberty.

Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain

Introduction: Silver-Russell syndrome (SRS; also know as Russell-Silver syndrome) is a heterogeneous syndrome which is characterised by severe intrauterine and postnatal growth retardation and typical dysmorphic features. Recently, the first SRS patients with (epi)genetic mutations in 11p15 affecting the telomeric imprinting domain have been identified. Interestingly, opposite mutations are associated with Beckwith-Wiedemann syndrome (BWS). However, the general significance of epigenetic mutations in 11p15 for the aetiology of SRS remained unclear. Methods: We screened a cohort of 51 SRS patients for epimutations in ICR1 and KCNQ1OT1 by methylation sensitive Southern blot analyses. Results: ICR1 demethylation could be observed in 16 of the 51 SRS patients, corresponding to a frequency of approximately 31%. Changes in methylation at the KCNQ1OT1 locus were not detected. Discussion: Combining these data with those on maternal duplications in 11p15, nearly 35% of SRS cases are associated with detectable (epi)genetic disturbances in 11p15. We now have to also consider a general involvement of 11p15 alterations in growth retarded patients with only minor or without further dysmorphic features. SRS and BWS may now be regarded as two diseases caused by opposite (epi)genetic disturbances of the same chromosomal region displaying opposite clinical pictures.

Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients

The association of uniparental disomy (UPD) and short stature has been reported for different chromosomes and in several conditions. Therefore, we investigated a cohort of 21 patients referred because of intrauterine and postnatal growth retardation for UPD of chromosomes 2, 7, 9, 14, 16, and 20. Typing of short tandem repeats showed maternal UPD(14) and maternal UPD(20) in two cases. In the first case, an interstitial UPD(14) was detected and the growth retarded newborn showed some additional clinical signs in common with the putative “maternal UPD(14) syndrome”. The maternal UPD(20) patient showed minor features. However, since it is only the second maternal UPD(20) case it is too early to delineate a specific syndrome and the role of this constitution in growth remains to be investigated. Our data suggest that searching for UPD in growth retarded patients is a helpful approach to getting more information on the role of UPD in growth retardation. Based on our results, general considerations and indications for UPD testing are discussed.

Spontaneous Adult Height in Idiopathic Short Stature

Two hundred and thirty-six patients with idiopathic short stature (ISS) (184 m, 52 f) who presented at a mean age of 12.2 (range 2.8-17.5) years, a mean height of -2.16 standard deviation score (SDS), a mean target height (THT) of -0.27 SDS (m = f), were reinvestigated at a mean age of 20.5 (range 18-24) years. 182(142 m, 37 f) (67%) had reached normal adult height (AHT) while 54 (39 m, 15 f) (23%) had not. However, only 23 (17 m, 6 f) did not reach a height within their familial target. Patients were subdivided into 2 groups according to deviation from familial height target: 60(44 m, 16 f) were considered adequate for their families (group 1), while 176 (140 m, 39 f) were smaller (group 2). Children in group 1 were younger and bone age (BA) was less retarded. Patients in group 1 reached their THT, this was not the case in group 2. Young age, low THT and low predicted adult height (PAH) at presentation were the factors associated with poor stratural outcome, but AHT could not be predicted in individuals. In boys, PAH (Bayley-Pinneau) (0.0 SDS) exceeded AHT (-0.7 SDS), in girls, both were almost identical (-0.79, -0.77 SDS). Since most children with ISS reach an AHT within the normal range, attempts to improve AHT by means of growth-promoting therapies appear to be justified only in a minority of selected patients with ISS. Methods to improve the accuracy of individual height prognoses are needed.

Use of multiplex ligation-dependent probe amplification increases the detection rate for 11p15 epigenetic alterations in Silver-Russell syndrome.

Silver–Russell syndrome (SRS) describes a malformation syndrome with severe intrauterine and postnatal growth retardation. Currently, two major (epi)mutations have been described: while approximately 10% of patients carry a maternal uniparental disomy of chromosome 7 (UPD7), 35–60% show a hypomethylation at the H19 differentially methylated regions (DMRs) in 11p15. Until recently, a Southern‐blot based test was routinely used to identify epimutation carriers. Nevertheless, this test was time consuming and hampered by the huge amount of genomic DNA needed. With the methylation‐specific multiplex ligation‐dependent probe amplification assay (MLPA) for SRS, a PCR‐based test is now available, allowing the analysis also of small amounts of DNA. Probes in this assay hybridize to the H19 DMRs but do not cover the genomic target of the Southern‐blot probe. We now screened 72 patients with SRS by MLPA. Hypomethylation of the H19 DMRs was confirmed in all patients analyzed by Southern blot. In addition, we identified six individuals with hypomethylation of the H19 DMR who had previously normal blot results. This discrepancy can be explained by the observed generally lower degree of demethylation in this group, possibly not detectable by the less sensitive Southern‐blot method but also with a varying degree of methylation at different DMRs in the same individual. Apart from hypomethylation in the H19 DMR, we observed a slight demethylation for one of the IGF2 probes. The total detection rate of 11p15 hypomethylation is now increased to >38%. Considering maternal UPD7 and chromosomal aberrations, (epi)genetic alterations now account for more than 50% of SRS patients. In summary, MLPA represents an easy, low cost and reliable system in the molecular diagnostics of SRS.

Major determinants of height development in Turner syndrome (TS) patients treated with GH: Analysis of 987 patients from KIGS.

Little is known about factors determining height outcome during GH treatment in Turner syndrome (TS). We investigated 987 TS children within the Kabi International Growth Study (KIGS) who had reached near adult height (NAH) after >4 y GH treatment (including >1 y before puberty). Through multiple regression analysis we developed a model for NAH and total gain. Our results were as follows (median): 1) At start, age 9.7 yrs, height (HT) 118.0 cm (0.0 TS SDS), projected adult height 146.1 cm, GH dose 0.27 mg/kg wk; 2) NAH HT 151.0 cm (1.5 TS SDS); 3) Prepubertal gain 21.2 cm (1.6 TS SDS); 4) Pubertal gain 9.4 cm (0.0 TS SDS). NAH correlated (r2 = 0.67) with (ranked) HT at GH start (+), 1st year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (−), and dose (+). The same factors explained (R2 = 0.90) the total HT gain. However, HT at GH start correlated negatively. Karyotype had no influence on outcome. Evidently, height at GH start (the taller, the better), age at GH start (the younger, the better), the responsiveness to GH (the higher, the better) and age at puberty (the later, the better) determine NAH.

Health-related quality of life of children and adolescents with growth hormone deficiency or idiopathic short stature - part 2: available results and future directions.

Research on the health-related quality of life (HrQoL) impact of short stature and its treatment in children and adolescents has developed recently. Based on a PubMed literature search, studies addressing this issue were identified and considerable methodological problems mainly related to the HrQoL instruments used and conflicting results are discussed in this mini review. Additionally, this mini review identifies a need for further research and indicates potential directions.