The authors present the case of a boy with congenital pseudoarthrosis of the right clavicle who met all clinical and auxologic criteria of Prader-Willi's syndrome. Poor cooperation due to mental retardation was the reason for the primary conservative treatment. During this, deformity of the middle clavicle progressed, but without development of subjective complaints and functional deficit. At his 16 years, this cosmetic defect became unacceptable for his parents and, later than it is usually recommended, resection of pseudoarthrosis with plate osteosynthesis and autologous spongioplasty was indicated. The sufficient skeletal maturation and size of both fragments allowed us to perform stable osteosynthesis with the use of a contoured reconstruction plate, without the risk of insufficient osteosynthesis or clavicle fracture after the removal of osteosynthetic material.
- MeSH
- Clavicle pathology surgery MeSH
- Humans MeSH
- Prader-Willi Syndrome complications MeSH
- Child, Preschool MeSH
- Pseudarthrosis complications congenital pathology surgery MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Case Reports MeSH
Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.
- MeSH
- Child MeSH
- Adult MeSH
- Intracellular Signaling Peptides and Proteins cerebrospinal fluid deficiency MeSH
- Humans MeSH
- Adolescent MeSH
- Neuropeptides cerebrospinal fluid deficiency MeSH
- Orexins MeSH
- Prader-Willi Syndrome cerebrospinal fluid physiopathology MeSH
- Sleep Stages physiology MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Names of Substances
- HCRT protein, human MeSH Browser
- Intracellular Signaling Peptides and Proteins MeSH
- Neuropeptides MeSH
- Orexins MeSH
INTRODUCTION: Prader-Willi syndrome (PWS) is primarily caused by a paternal microdeletion of the 15q11-q13 region, maternal uniparental disomy (mUPD) or unbalanced translocations. The MKRN3 gene, located within 15q11-q13, is a master regulator of pubertal initiation. We aimed to compare variant pubertal onset and progression with recent normative data and to correlate it with abnormal MKRN3 gene status. METHODS: Age at pubarche, gonadarche, subsequent pubertal progression and bone age (BA) at gonadarche were investigated in 37 PWS patients (18 females) who already entered pubarche and/or gonadarche with median age 11.1 (95% CI: 6.4 - 18.8) years. All patients were re-tested to confirm genetic subtypes of PWS. The MKRN3 gene was analyzed using single gene sequencing. RESULTS: Out of 37 subjects, 22 had microdeletion and 15 mUPD. Regardless of genetic subtypes and MKRN3 gene status, no correlation between genotypes and the pubertal pattern was found. They initiated pubarche early - girls at 7.4 (95%CI:6.4-8.4), and boys at 9.2 (8.2-10.2) years. The subsequent progression from PH2 to PH4 (pubic hair development) was prolonged to 3.7 years in girls (1.5-5.9;p<0.05), and 2.9 in boys (2.2-3.6;p<0.001). The age at gonadarche was adequate - 10.0 years in girls (8.8-11.2), and 11.0 in boys (9.8-12.1). Progression rate of breast development from B2 to B4 was 3.9 (0.2-7.5) years in girls and of testicular volume from 4 ml to 15ml was 3.8 (0.0-8.1) years in boys. The BA at gonadarche is advanced by 0.6 ± 1.1 years (p<0.001). CONCLUSIONS: Children with PWS, regardless of the genetic subtype and/or MKRN3 status, had an early pubarche and normally timed gonadarche. Pubarche progression was slower. Advanced BA was significantly correlated with gonadarche.
- Keywords
- MKRN3 gene, Prader-Willi syndrome puberty, bone age, gonadarche, pubarche, puberty,
- MeSH
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Prader-Willi Syndrome * genetics physiopathology MeSH
- Disease Progression MeSH
- Puberty * physiology genetics MeSH
- Ribonucleoproteins genetics MeSH
- Ubiquitin-Protein Ligases genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- MKRN3 protein, human MeSH Browser
- Ribonucleoproteins MeSH
- Ubiquitin-Protein Ligases MeSH
OBJECTIVES: Subsequent to early life feeding issues, children with Prader-Willi syndrome (PWS) develop hyperphagia and severe obesity. Growth hormone (GH) therapy has been approved in PWS to improve growth, body composition, and BMI. We aimed to clarify the role of age at GH therapy onset on growth and BMI trajectories in children with PWS. METHODS: We analyzed height and BMI in 114 patients (58 boys) from REPAR - Czech national GH registry. From them, 69 started GH therapy prior to 2 y/o (age 0.8 ± 0.4 years; mean ± SD; early-onset group [EO]), and 45 later (age 7.1 ± 4.1 years; late-onset group [LO]). RESULTS: Height-SDS before therapy was similar in all (EO: -1.9 ± 1.2 [mean ± SD]; LO: -1.7 ± 1.1). After the first year of GH therapy, height-SDS in the EO group increased to -1.0 ± 1.2, in the LO group to -0.9 ± 1.1. After 5 years, height fully normalized in all (-0.1 ± 1.1 SDS). The LO children were already obese at treatment initiation (BMI-SDS: 2.9 ± 2.2), and their BMI-SDS decreased after 1 year of GH therapy by 0.9 (p=0.003). The weight in EO children was below average before GH treatment (BMI-SDS: -0.9 ± 1.2) and their BMI-SDS increased to the overweight range of 1.3 ± 2.2 (p<0.001) within the oncoming 3 years. Albeit BMI-SDS was around the obesity limit in most children after 5 years on GH therapy, the highest lifetime BMI-SDS was lower in EO (2.2 ± 2.6) than in LO (3.7 ± 2.2; p<0.001). CONCLUSIONS: GH treatment in PWS normalizes body height. After 5 years of GH therapy, BMI-SDS in EO and LO groups are similar; however, the EO group is exposed to lower maximal BMI-SDS values.
- Keywords
- BMI, Prader–Willi syndrome, growth, growth hormone treatment, obesity,
- MeSH
- Child MeSH
- Body Mass Index MeSH
- Infant MeSH
- Humans MeSH
- Human Growth Hormone * therapeutic use MeSH
- Obesity, Morbid * prevention & control etiology MeSH
- Follow-Up Studies MeSH
- Pediatric Obesity * prevention & control MeSH
- Prader-Willi Syndrome * drug therapy complications MeSH
- Child, Preschool MeSH
- Prognosis MeSH
- Body Height drug effects MeSH
- Age of Onset MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic epidemiology MeSH
- Names of Substances
- Human Growth Hormone * MeSH
OBJECTIVES: In contrast to most human autosomal genes which are expressed biallelically, the expression of imprinted genes depends on the parental origin of the allele. Prader-Willi syndrome is a neurobehavioral disorder in which the expression of active paternal alleles of imprinted genes from chromosomal region 15q11-q13 is abolished by deletions, maternal uniparental disomy or imprinting defects. We report an unusual case of maternal uniparental disomy of chromosome 15 due to a balanced translocation t(8;15)(q24.1;q21.2) leading to Prader-Willi syndrome in a 3-year-old girl. METHODS AND RESULTS: Cytogenetic investigation revealed a balanced translocation t(8;15)(q24.1;q21.2) in the patient and subsequently also in her unaffected mother. Fluorescence in situ hybridization analysis did not reveal any deletion of the PWS critical region, but methylation analysis of the SNRPN gene showed an abnormal methylation pattern indicating the absence of paternal chromosome 15. Microsatellite analysis of multiple loci and methylation-specific MLPA analysis confirmed maternal uniparental heterodisomy of chromosome 15 as the cause of PWS in the patient. CONCLUSIONS: This example emphasizes the importance of uniparental disomy testing in pregnancies of carriers of chromosomal aberrations with participation of chromosomes carrying imprinted genes involved in human diseases.
- MeSH
- Cytogenetic Analysis MeSH
- In Situ Hybridization, Fluorescence MeSH
- Humans MeSH
- Chromosomes, Human, Pair 15 MeSH
- Chromosomes, Human, Pair 8 MeSH
- DNA Methylation MeSH
- Microsatellite Repeats MeSH
- Prader-Willi Syndrome genetics MeSH
- Child, Preschool MeSH
- Translocation, Genetic * MeSH
- Uniparental Disomy genetics MeSH
- Check Tag
- Humans MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Prader-Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11-q13, but the specific contributions of individual genes remain unknown. Most paternal PWS deletions are bracketed by recurrent breakpoints BP1 or BP2 and BP3. Atypical deletions are very rare. In the present work, we describe the molecular analysis of two patients with atypical deletions using microsatellite analysis, methylation-specific MLPA, and microarray CGH. A deletion of about 2 Mb in Patient 1 started at BP2 and ended in the middle of the typically deleted region within the UBE3A gene. The deletion in Patient 2 started 1.3 Mb distal from BP2 within the C15ORF2 gene, extended over 9.5 Mb, and ended within the AVEN gene in proximal 15q14. In Patient 1 both deletion breakpoints involved repetitive regions, which precluded cloning of the junction and pointed to non-allelic homologous recombination as a possible mechanism of this rearrangement. The breakpoints in Patient 2 were sequenced, and their structure suggested non-homologous end joining as the most likely cause of this deletion. The phenotype of both patients did not depart significantly from the typical clinical picture of PWS, although some symptoms in Patient 2 were also reminiscent of the phenotype of individuals with the recently described 15q13.3 microdeletion syndrome. Our findings support previous observations of relatively mild phenotypic effects resulting from deletions that extend distally from the PWS region and observations of the modest effects of different types of genetic defects on the spectrum and severity of symptoms in PWS.
- MeSH
- Chromosome Deletion * MeSH
- Phenotype MeSH
- Cloning, Molecular MeSH
- Humans MeSH
- Chromosomes, Human, Pair 15 * MeSH
- DNA Methylation MeSH
- Microsatellite Repeats MeSH
- Adolescent MeSH
- Molecular Sequence Data MeSH
- Prader-Willi Syndrome genetics MeSH
- Base Sequence MeSH
- Oligonucleotide Array Sequence Analysis MeSH
- Chromosome Breakage MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctive diseases with severe impairment of psychomotoric development and behaviour. Both syndromes are caused by the loss of paternal (PWS) or maternal (AS) gene expression of chromosomal region 15q11-13. The work reveals the various causes of this loss. The choice of the most suitable method for screening of the genome mutations in the patients suspected of PWS and AS is another purpose of the work. METHODS AND RESULTS: The methyl specific analysis (MS PCR) in locus SNRPN, short tandem repeat (STR) analysis and fluorescent in situ hybridization (FISH) were used. In the group of 55 patients tested for PWS and AS only maternal allele was present in 11 patients and only paternal allele was present in 1 patient in the locus SNRPN: 10 microdeletions 15q11-13, 1 UPD(15)mat and 1 UPD(15)pat. CONCLUSIONS: MS PCR seems to be the most profitable method for the first step of selection of PWS patients. In positive cases is inevitable to use also additional tests of molecular diagnosis to distinguish the particular mechanism leading to the disorders. In AS patients is also MSPCR recommended as the first step although it is necessary to exclude mutation in UBE3A gene in case of MS PCR negativity.
- MeSH
- Angelman Syndrome genetics MeSH
- Autoantigens MeSH
- Chromosome Deletion MeSH
- Child MeSH
- Adult MeSH
- In Situ Hybridization, Fluorescence MeSH
- snRNP Core Proteins MeSH
- Infant MeSH
- Humans MeSH
- Chromosomes, Human, Pair 15 MeSH
- DNA Methylation MeSH
- Adolescent MeSH
- Infant, Newborn MeSH
- Polymerase Chain Reaction MeSH
- Prader-Willi Syndrome genetics MeSH
- Child, Preschool MeSH
- Ribonucleoproteins, Small Nuclear genetics MeSH
- Tandem Repeat Sequences MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Autoantigens MeSH
- snRNP Core Proteins MeSH
- Ribonucleoproteins, Small Nuclear MeSH
- SNRPN protein, human MeSH Browser
- MeSH
- Glycogen Storage Disease complications MeSH
- Infant MeSH
- Humans MeSH
- Prader-Willi Syndrome complications MeSH
- Child, Preschool MeSH
- Muscle Hypotonia etiology MeSH
- Syndrome MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
Animal models and family studies led to the identification ofcases of rare monogenic forms of human obesity. Rare Mendelian syndromes as Prader-Willi syndrome and Bardet-Biedl syndrome represent cases of genetically determined obesity. Genome wide linkage and classical candidate gene studies were in general unsuccessful concerning the identification of genes of common obesity. On the other hand, genome-wide association studies (GWAS) were found to be effective, as also variants with only a minor effect have been detected. Seventeen polygenic variants influencing body weight regulation were clearly confirmed. It is assumed that more of these variants exist and therefore they might be identified in near future by GWAS. It is possible that the size effect of some variants can be within few grams of body weight. In order to detect variants with small effect there is a need of meta-analyses based on hundreds of thousands of individuals. Newly identified variants result in an increase of 0.06-0.33 kg/m2 of BMI per allele. In an adult of an average height of 170cm, it corresponds to 173-954 g per risk allele. It was estimated that subjects carrying 13 or more risk alleles were on average 1.46 body mass index units heavier (representing 3.7-4.7 kg) than carriers of less than three risk alleles. Further research should be focused on a gene-gene interaction. An interaction ofgene and environment should be statistically analyzed in adequate proband cohorts. If we are able to identify a large number of risk variants, the predisposition to a certain disease could be predicted. Currently a detailed family history has more predictive power.
- MeSH
- Alstrom Syndrome genetics MeSH
- Bardet-Biedl Syndrome genetics MeSH
- Genome-Wide Association Study MeSH
- Epigenesis, Genetic MeSH
- Genetic Predisposition to Disease MeSH
- Humans MeSH
- Obesity epidemiology genetics MeSH
- Prader-Willi Syndrome genetics MeSH
- Body Weight genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Review MeSH
