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Hartmut A Wollmann

Publications and source records attributed to Hartmut A Wollmann.

12 recordsLinked to original sources
PubMed2007

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 (r = 0.67) with (ranked) HT at GH start (+), 1 year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (-), and dose (+). The same factors explained (R = 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.

Adolescent↗
PubMed2006

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.

Abnormalities, Multiple↗
PubMed2006

Supernumerary marker chromosome 7 and maternal uniparental disomy 7 in a boy with growth retardation and triangular face.

We report on a 12-month-old boy with pre and post-natal growth retardation, triangular face and mild psychomotor retardation. Karyotyping revealed a supernumerary marker chromosome (SMC) in 36% of cells. Using fluorescence in situ hybridization and BAC clones, the supernumerary marker chromosome was found to be a highly deleted chromosome 7 with breakpoints within the pericentric euchromatin (partial trisomy 7). Microsatellite typing indicated maternal uniparental disomy of chromosome 7 (matUPD7). The patient showed only few signs of the Silver-Russell syndrome. He therefore reflects the mild end of the phenotypic spectrum in patients with matUPD7. The case supports the argument that karyotyping is warranted in patients with short stature and only few additional features, and that UPD studies are required in patients with a SMC(7). Considering that the SMC(7) contributed very little, if any, to the phenotype of this boy, we propose that UPD7 studies should be carried out in children with pre- and postnatal growth retardation of unknown cause even in the absence of a SMC.

Chromosome Deletion↗
PubMed2005

IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age.

BACKGROUND: A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. METHODS: Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters. RESULTS: Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. CONCLUSIONS: IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.

Body Height↗
PubMed2005

Diagnostic proceeding in Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by pre- and postnatal growth restriction (<3rd percentile) and a typical craniofacial gestalt. The basic defect of SRS is currently unknown, and the number of meaningful genetic tests available is therefore limited. Different chromosomal aberrations have been identified, including in the chromosomal region 7p12-p14. Detailed analyses of numerous candidate genes have not revealed any relevant insights with respect to the etiology of the disease.However, maternal uniparental disomy (UPD) of chromosome 7 (matUPD7), the inheritance of both homologues of chromosome 7 only from the mother, is observed in approximately 10% of SRS patients. Here, we report on our experiences of UPD testing in patients referred to our laboratory with the clinical diagnosis of SRS. A diagnostic algorithm for SRS is suggested. METHODS: Eighty-six patients with the clinical diagnosis of SRS were screened for matUPD7 by microsatellite typing. In 13 cases, the clinical data were consistent with the diagnosis of SRS. The other 73 patients were referred for UPD testing with the suspected diagnosis of SRS, but clinical data were scarce. RESULTS: In total, we identified three new cases of matUPD7: one patient belonged to the cohort of 13 clinically characterized patients; the other two patients were referred with the suspected diagnosis of SRS but initially without detailed reports. DNA studies revealed uniparental heterodisomy 7 in two patients, while the results in the third case were consistent with uniparental isodisomy. CONCLUSIONS: MatUPD7 is predominantly detectable in patients showing SRS features, and testing should therefore be restricted to this group of growth-restricted patients. Generally, a combination of cytogenetic and molecular genetic tests can be offered in SRS, aiming at the detection of chromosomal rearrangements and matUPD7 in >10% of SRS patients.

Abnormalities, Multiple↗
PubMed2004

Searching for genomic variants in IGF2 and CDKN1C in Silver-Russell syndrome patients.

Silver-Russell syndrome (SRS) is a heterogeneous syndrome with evidence for a substantial role of genetic factors in its etiology. Apart from other specific clinical features, severe intrauterine and postnatal growth retardation are the dominant characteristics of SRS. Therefore, studies on the genetic basis of the disease focus on genes involved in growth and its regulation. Another key for the identification of (a) SRS gene(s) is the finding of chromosomal disturbances in SRS patients: recently, four growth retarded patients carrying duplications in 11p15 of maternal origin have been described, two of these cases presented SRS-like features. The same region includes IGF2 and CDKN1C and is well known to harbour alterations in patients suffering from Beckwith-Wiedemann syndrome. We therefore decided to perform an extensive search for variants in the IGF2 and CDKN1C genes; mutations in these genes cause growth disturbances. More than 40 SRS patients were screened for mutations by different detection strategies, allele frequencies were compared between patients and controls. In both genes, we did not detect any obvious pathogenic mutation. In case of IGF2, slight differences in the allelic distribution of specific polymorphisms between SRS patients and controls were observed. In CDKN1C, several variants could be identified in both cohorts with similar frequencies, but only one patient showed a so far unknown variant not detectable in controls.

Base Sequence↗
PubMed2004

Cognitive development in Silver-Russell syndrome: a sibling-controlled study.

This study examined cognitive development in Silver-Russell syndrome (SRS), a condition with intrauterine growth retardation, persisting short stature, and specific stigmata. Neuropsychological function and cognitive abilities were assessed in a sample of 36 children with SRS (21 males, 15 females; mean age 7 years 6 months, SD 2 years 8 months; age range 3 to 12 years) and 25 normally developing siblings (mean age 8 years 6 months, SD 2 years 7 months; age range 3 to 12 years) using the Kaufman Assessment Battery for Children. Special measures were taken to control for confounding factors and sample bias. Mean overall IQ score in the total SRS sample (95.7, SD 10.63), as measured by the Mental Processing Composite Scale, was significantly reduced (p=0.021) compared with test norms (IQ 100, SD 15), indicating a moderate cognitive impairment. Subscale analysis revealed some specific deficiencies. However, these cannot be attributed to an established category of specific learning disorder. The mean score in the Achievement Scale (91.25, SD 14.92), which is more sensitive to educational influences, showed stronger deficits (p=0.001). The sibling control group achieved a slightly better mean IQ score (104.20, SD 12.32) than test norms (p=0.10). Direct analysis of paired differences between the subsample of children with SRS and a sibling among the control group (n=25) revealed a significant mean difference of 8.08 IQ points (p=0.011). Risk factor analysis revealed that cognitive development is not associated with birth length (p=0.404), birthweight (p=0.820), growth hormone therapy (p=0.810), phenotypic severity (p=0.828), or sex (p=0.880). Two children with maternal uniparental disomy for the entire chromosome 7 had markedly lower IQ scores (81 and 84 respectively). In contrast to the few previous findings, children with SRS show only moderate, but significant, impairments in cognitive outcome, which are more striking in our sample when compared with siblings than with test norms.

Adolescent↗
PubMed2003

Characterization of genomic variants in CSH1 and GH2, two candidate genes for Silver-Russell syndrome in 17q24-q25.

Silver-Russell syndrome (SRS) is a syndrome of severe pre- and postnatal growth retardation and typical dysmorphic features. Rare chromosomal aberrations have been reported in SRS; among these are two balanced translocations involving 17q24-q25. Recently, we described a patient with a paternally inherited heterozygous deletion of the chorionic somatomammotropin hormone 1 (CSH1) gene. The CSH1 gene is member of the growth hormone (GH) gene cluster on 17q, which consists of two growth hormone genes and three CSH genes. Genomic alterations in the GH cluster are well known, causing different phenotypes depending on the size of the deletion and the genes involved. By screening 63 SRS cases with marker D17S254, we have detected 2 further patients with a heterozygous deletion in the GH cluster. Quantitative analysis using restriction assays confirmed these findings. Additionally, in a cohort of 17 patients with isolated intrauterine and postnatal growth retardation, we detected a further patient to be carrier of a CSH1 deletion. Screening of 141 unrelated controls revealed hemizygosity in one person for which data on growth were not available. We additionally analyzed our cohort of SRS patients for mutations in CSH1 and its 3' neighbour GH2. However, analyses failed to reveal any pathogenic mutation. While the central role of GH1 in human growth is well established, the physiological roles of CSH1 and other components of the cluster are unclear. The increased prevalence of hemizygosity of CSH1 in our population in comparison to controls indicates a role for CSH1 haploinsufficiency in the etiology of growth retardation. Investigation of CSH1 deletions in further SRS and growth retarded patients will enable us to establish under which circumstances haploinsufficiency of CSH1 is likely to result in clinical changes.

Abnormalities, Multiple↗
PubMed2002

Uniparental disomy: clinical indications for testing in growth retardation.

UNLABELLED: Growth is a complex process which is in part genetically determined. Among other genetic causes, uniparental disomy (UPD), the exceptional inheritance of two homologous chromosomes from only one parent, may occasionally be detected. Recent insights have revealed that the molecular basis for the clinical features of UPD are specific human genes that are only monoallelically active, depending on whether they are located on the paternal or maternal chromosome. UPD will lead to an imbalanced expression of these imprinted genes and cause abnormal development. Meanwhile, specific syndromes have been found to be associated with UPD, these include Prader-Willi syndrome (maternal UPD15/mUPD15), Angelman syndrome (paternal UPD15/pUPD15), (transient) neonatal diabetes mellitus (pUPD6), Silver-Russell syndrome (mUPD7), Beckwith-Wiedemann syndrome (pUPD11) and the mUPD14 syndrome. Among other features, most of these syndromes are also characterised by growth restriction. Additionally, UPDs of further chromosomes have been described in growth restricted patients without additional phenotypic abnormalities; however, a conclusive association between the UPD and the clinical features remains to be investigated. CONCLUSION: in this review we propose a set of reasons for testing of specific uniparental disomies other than 15 in growth restricted patients.

Female↗
PubMedDate not supplied

Screening for insulin-like growth factor-I receptor mutations in patients with Silver-Russell syndrome.

Individuals with a deletion of 15q26.1-->qter which contains the insulin-like growth factor-I (IGF-I) receptor gene exhibit phenotypical similarities to patients with Silver-Russell syndrome (SRS) who represent a group of short children affected by pre- and postnatal growth failure and several dysmorphic features. The genetic basis of SRS is presumably heterogeneous. The IGF-I receptor gene is a good SRS candidate gene because the biological effects of the major growth factors IGF-I and -II are transmitted through the IGF-I receptor during pre- and postnatal growth. All 12 patients studied exhibited the classical SRS phenotype with low birth weight, connatal macrocephaly, typical facial features and short stature at presentation. Klinodactyly of the fifth finger was found in ten patients, and skeletal asymmetry in seven. Chromosomal analysis gave normal results. Uniparental disomy of chromosome 7 was excluded. After reverse transcription of RNA, 19 overlapping cDNA fragments encompassing the whole IGF-I receptor coding sequence were PCR-amplified and screened for mutations by single strand conformation analysis (SSCP). In eight of 12 patients studied, we detected four SSCP polymorphisms which were directly sequenced. All single base exchanges (C948A, C2343T, G3174A and G3915A) were silent variants of the IGF-I receptor gene, two of which were also present in control individuals. In conclusion, for the first time, the complete coding region of the IGF-I receptor gene was screened for mutations in patients with SRS. Our data do not support the suggestion that the IGF-I receptor is frequently involved in the pathogenesis of SRS.

Abnormalities, Multiple↗