Prader-Labhart-Willi syndrome (PWS)-char-acterized by severe obesity, short stature, hypogonadism... more Prader-Labhart-Willi syndrome (PWS)-char-acterized by severe obesity, short stature, hypogonadism, and muscle hypotonia-appears to be an interesting model for body-composition abnormalities. Twenty-seven PWS patients (15 males and 12 females) aged 6-22 y underwent total-body analysis by dual-energy X-ray photon absorptiometry (DXA). For each PWS patient two age- and sex-matched control subjects were studied: one obese subject with a relative body weight (RBW> 120%) and body mass index (BMI) similar to that of the patient and one normal-weight subject (RBW < 120%). Percentage body fat was significantly greater in PWS patients than in obese subjects (47.4 ± 7.2 % compared with 41.9 ± 9.9%, P < 0.0001) and the same difference was evident for arms and legs but not for the trunk. Lean mass was significantly lower in PWS patients (26.4 ± 8.2 kg) than in normal-weight subjects (32.9 ± 10.2 kg) and even
Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Pr... more Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Prader-Willi Syndrome (PWS). Depending on age, PWS patients present genital hypoplasia and delayed or incomplete gonadal maturation. Nevertheless, only a few evaluations have been made of these findings in this syndrome; in the cases previously reported the diagnosis of PWS has often been based only on clinical criteria and not confirmed by genetic analysis. In this paper we describe both external genital findings and spontaneous pubertal development in 84 patients aged from 2.1 to 35.4 (42 males, 42 females) affected by PWS. Diagnosis was made using the Holm and Cassidy criteria and was confirmed by genetic analysis (methylation test and/or FISH). We evaluated the presence of cryptorchidism, scrotal development, length of penis and volume of testis in males and outlook of labia minora and/or clitoris, age of menarche and features of menses (when present) in females; in both sexes we also evaluated the onset of puberty. All recruited males showed cryptorchidism, which was bilateral in 36 out of 42 patients (86%); 38 patients (90%) underwent orchidopexy. Small testes and scrotal hypoplasia were present in 76% and 69% of cases, respectively. In 76% of females, hypoplasia or absence of labia minora and/or clitoris was described. Spontaneous menarche occurred only in 14/32 cases (44%) over the age of 15 years, but menstrual cycles were often a periodical vaginal spotting. Primary amenorrhea was diagnosed in 56% of cases. Isolated premature pubarche was present in six males and in six females (14% of cases) while one male and two females were affected by precocious puberty (3.6%). Hypogonadism represents a common clinical feature in PWS, confirming the importance of such a major diagnostic criterion. Cryptorchidism was consistently present in all our cases. Patients with PWS commonly fail to spontaneously complete puberty, although some patients may have early pubarche or, more rarely, precocious puberty. In older subjects, hormonal replacement therapy is not always necessary and it must be reserved for selected patients.
Prader-Labhart-Willi syndrome (PWS)-characterized by severe obesity, short stature, hypogonadism,... more Prader-Labhart-Willi syndrome (PWS)-characterized by severe obesity, short stature, hypogonadism, and muscle hypotonia-appears to be an interesting model for bodycomposition abnormalities. Twenty-seven PWS patients (15 males and 12 females) aged 6-22 y underwent total-body analysis by 773 g) subjects (P < 0.0001); this difference was most pronounced in the limb region. Bone mineral density (BMD) in PWS patients (0.993 ± 0.116 g/cm2) did not differ significantly from that of normal-weight subjects (1.033 ± 0.147 g/cm2) but was significantly lower than that of obese subjects (1.154 ± 0.139 g/cm2). The influence of age on body composition was assessed by comparing two age subgroups (< 12 y, n = 10; and 12 y, n = 17). The older PWS patients had higher adiposity, lower BMC, and dramatically lower BMD. Also, the lean mass deficit increased with age so that the ratio of fat mass to lean mass was close to 1. In conclusion, PWS patients showed a peculiar body composition, to some extent similar to that found in subjects deficient in growth hormone or even to sedentary and elderly people. These results suggest the importance of an accurate analysis of body composition in PWS patients.
Nutrition Metabolism and Cardiovascular Diseases, 2011
Background and aims: PradereWilli syndrome (PWS), the most frequent syndromic obesity, is associa... more Background and aims: PradereWilli syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status. Methods and results: A cross-sectional study was performed in 109 PWS children aged 2e 18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2. Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p Z 0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p Z 0.001) and high triglycerides (7% vs 23% and 16%, p Z 0.026).
Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized... more Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATPsensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11, but to date only twenty mutations have been identified in KCNJ11, most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.
American Journal of Physiology-Endocrinology and Metabolism, 2006
Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively ... more Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively the IHF content of obese adolescents to ascertain whether it is associated with insulin resistance and abnormal energy homeostasis. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured using localized hepatic 1H-MRS, indirect calorimetry, fasting-derived and 3-h-OGTT-derived surrogate indexes (HOMA2 and WBISI), and DEXA, respectively, in 54 obese adolescents (24 female and 30 male, age 13 ± 2 yr, BMI >99th percentile for their age and sex). NAFLD (defined as IHF content >5% wet weight) was found in 16 individuals (30%) in association with higher ALT ( P < 0.006), Hb A1c ( P = 0.021), trunk fat content ( P < 0.03), and lower HDL cholesterol ( P < 0.05). Individuals with NAFLD had higher fasting plasma glucose (89 ± 8 vs. 83 ± 9 mg/dl, P = 0.01) and impaired insulin sensitivity (HOMA2 and WBISI, P < 0.05). Meanwhile, paramete...
Inter-and Intrachromosomal Rearrangements Are priate informed consent, from the patient, both par... more Inter-and Intrachromosomal Rearrangements Are priate informed consent, from the patient, both parents, and paternal grandparents. DNA was isolated by use of Both Involved in the Origin of 15q11-q13 Deletions in Prader-Willi Syndrome a QIAamp blood kit (Qiagen). We employed markers D15S541 and D15S542, both mapping to YAC To the Editor: A124A3, proximal to the deletion region, and markers Prader-Willi syndrome (PWS) is due to an interstitial de D15S165 and D15S1048, both mapping distal to the novo deletion at 15q11-q13 in Ç70% of cases. The common deletion region (Hudson et al. 1995). In addideletion spans a region of Ç4 Mb and invariably intion, marker ATC3C11, mapping õ1 Mb from the disvolves the paternally derived homologue (Robinson et tal deletion breakpoint (S. L. Christian and D. H. Ledal. 1991). For most patients the distal breakpoint apbetter, unpublished data), was used. PCR assays were pears to be located within a single YAC (Kuwano et al. performed as described elsewhere (Christian et al. 1995; 1992), whereas two consistent breakpoint hot spots Hudson et al. 1995). The results of the microsatellite have been identified on the proximal side; one (class I) analysis are shown in table 1, and examples of the analylies in the region between the centromere and D15S541/ sis performed on two independent families are shown D15S542, and the other (class II) lies between in figure 1. D15S541/D15S542 and D15S543, with each account-Three patients were deleted for the D15S541/D15S542 ing for approximately half of the deletions (Christian markers, thus being classified as class I-deletion patients. et al. 1995). This finding was consistent with the known frequency The relatively high frequency of deletions, significant of the class I breakpoints among PWS patients. The lack clustering of the breakpoints in PWS deletion patients, of a proximal marker on the deleted allele in these paand the finding of a similar location for the breakpoints tients precluded assessment of the haplotype for the rein small inv dup(15) has led to the hypothesis that small gion comprising the deletion. Of the seven class II paregions in proximal 15q may contain sequences leading tients, five demonstrated a paternal recombination event to instability (Knoll et al. 1993; Huang et al. 1997). between the markers flanking the common deletion re-Recently, preliminary data for a low-copy repeat associgion. The genetic distance between marker D15S541 and ated with a novel evolutionarily conserved gene family marker D15S165 has been estimated as 17.2 cM in males spanning the proximal and distal breakpoint regions has (Robinson and Lalande 1995). Marker D15S1048 maps been reported (Ji et al. 1996). 2 cM proximal to D15S165 (Hudson et al. 1995). ThereIn order to analyze the mechanism underlying delefore, when the genetic distance between D15S541 and tions in PWS, we genotyped 10 three-generation families D15S165 in male meiosis is taken into account, the idenof PWS-deletion patients, using microsatellite markers tification, in five of seven cases, of a different grandparenflanking the common deletion region. Each patient was tal origin for the alleles flanking the deletion is signifiknown to be deleted for the interval from D15S11 to cantly different from the expected frequency (x 2 GABRB3, by FISH and/or other molecular techniques. Å 12.438, P Å .0004). This finding is highly suggestive of an unequal crossover occurring in the paternal meio-Peripheral blood samples were obtained, with appro
During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because ... more During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because the syndrome is expressed mainly by severe hypotonia at this age and the typical clinical features of later life are not yet present. Aim: To identify all the PWS clinical markers in severe hypotonic newborns, which could facilitate an early diagnosis of the syndrome. Methods: Twenty-one PWS newborns (14 males and 7 females) with severe hypotonia at birth were evaluated. Paediatricians skilled in syndromology carried out a careful clinical examination. Fluorescent in situ hybridization (FISH) analysis and/or a methylation test was used to confirm the PWS clinical diagnosis. Results: The clinical diagnosis of PWS was reached at a mean age of 7.4 mo with genetic confirmation at 11 mo of life. In 12 newborns at least 3 craniofacial features were present (57%), suggesting the diagnosis of PWS. Two craniofacial dysmorphic characteristics were described in 6 newborns and only 1 in 3 cases. Cryptorchidism was monolateral in 6 and bilateral in 7 patients; in one newborn both testes were in scrotum. A micropenis was described in one patient and hypoplasia of the labia minora was reported in two females. Diagnosis by means of dysmorphologic evaluation is difficult in the neonatal period. The presence of severe hypotonia should always induce neonatologists to perform specific genetic tests in order to obtain an early diagnosis of PWS.
Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of ... more Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of chromosome 15, in which obesity is common. However, there is limited information on the underlying physiological mechanisms promoting obesity in this population. We tested whether there was a significant positive association between leptin and total body fat (TBF) in subjects with PWS, and whether this association was stronger among subjects with than without PWS. Research Methods and Procedures: We studied 21 PWS patients and 64 non-PWS controls on whom we measured serum leptin, total body fat, glucose, insulin, and resting energy expenditure. We tested whether the slope of the regression line between leptin and TBF (in kg), measured by dual energy X-ray absorptiometry, was the same for PWS patients and Qon-PWS controls. Results: Regression analyses indicated that the leptin-TBF association was significantly stronger among PWS patients. In contrast, the slope of the leptin-body mass index association did not significantly differ between PWS patients and non-PWS controls. None of the other outcome variables showed associations with leptin. Discussion: Results suggest that the role of leptin in promoting obesity may be greater among subjects with PWS than among non-PWS controls.
Prader–Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal menta... more Prader–Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal mental and physical development. PWS patients have a deletion in an imprinted region on paternal chromosome 15 (15q11–13), maternal disomy for this segment, or rarely, a chromosomal imprinting center deletion that gives rise to suppression of the equivalent paternal genes. Within the affected segment of chromosome 15 are genes
Prader-Labhart-Willi syndrome (PWS)-char-acterized by severe obesity, short stature, hypogonadism... more Prader-Labhart-Willi syndrome (PWS)-char-acterized by severe obesity, short stature, hypogonadism, and muscle hypotonia-appears to be an interesting model for body-composition abnormalities. Twenty-seven PWS patients (15 males and 12 females) aged 6-22 y underwent total-body analysis by dual-energy X-ray photon absorptiometry (DXA). For each PWS patient two age- and sex-matched control subjects were studied: one obese subject with a relative body weight (RBW> 120%) and body mass index (BMI) similar to that of the patient and one normal-weight subject (RBW < 120%). Percentage body fat was significantly greater in PWS patients than in obese subjects (47.4 ± 7.2 % compared with 41.9 ± 9.9%, P < 0.0001) and the same difference was evident for arms and legs but not for the trunk. Lean mass was significantly lower in PWS patients (26.4 ± 8.2 kg) than in normal-weight subjects (32.9 ± 10.2 kg) and even
Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Pr... more Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Prader-Willi Syndrome (PWS). Depending on age, PWS patients present genital hypoplasia and delayed or incomplete gonadal maturation. Nevertheless, only a few evaluations have been made of these findings in this syndrome; in the cases previously reported the diagnosis of PWS has often been based only on clinical criteria and not confirmed by genetic analysis. In this paper we describe both external genital findings and spontaneous pubertal development in 84 patients aged from 2.1 to 35.4 (42 males, 42 females) affected by PWS. Diagnosis was made using the Holm and Cassidy criteria and was confirmed by genetic analysis (methylation test and/or FISH). We evaluated the presence of cryptorchidism, scrotal development, length of penis and volume of testis in males and outlook of labia minora and/or clitoris, age of menarche and features of menses (when present) in females; in both sexes we also evaluated the onset of puberty. All recruited males showed cryptorchidism, which was bilateral in 36 out of 42 patients (86%); 38 patients (90%) underwent orchidopexy. Small testes and scrotal hypoplasia were present in 76% and 69% of cases, respectively. In 76% of females, hypoplasia or absence of labia minora and/or clitoris was described. Spontaneous menarche occurred only in 14/32 cases (44%) over the age of 15 years, but menstrual cycles were often a periodical vaginal spotting. Primary amenorrhea was diagnosed in 56% of cases. Isolated premature pubarche was present in six males and in six females (14% of cases) while one male and two females were affected by precocious puberty (3.6%). Hypogonadism represents a common clinical feature in PWS, confirming the importance of such a major diagnostic criterion. Cryptorchidism was consistently present in all our cases. Patients with PWS commonly fail to spontaneously complete puberty, although some patients may have early pubarche or, more rarely, precocious puberty. In older subjects, hormonal replacement therapy is not always necessary and it must be reserved for selected patients.
Prader-Labhart-Willi syndrome (PWS)-characterized by severe obesity, short stature, hypogonadism,... more Prader-Labhart-Willi syndrome (PWS)-characterized by severe obesity, short stature, hypogonadism, and muscle hypotonia-appears to be an interesting model for bodycomposition abnormalities. Twenty-seven PWS patients (15 males and 12 females) aged 6-22 y underwent total-body analysis by 773 g) subjects (P < 0.0001); this difference was most pronounced in the limb region. Bone mineral density (BMD) in PWS patients (0.993 ± 0.116 g/cm2) did not differ significantly from that of normal-weight subjects (1.033 ± 0.147 g/cm2) but was significantly lower than that of obese subjects (1.154 ± 0.139 g/cm2). The influence of age on body composition was assessed by comparing two age subgroups (< 12 y, n = 10; and 12 y, n = 17). The older PWS patients had higher adiposity, lower BMC, and dramatically lower BMD. Also, the lean mass deficit increased with age so that the ratio of fat mass to lean mass was close to 1. In conclusion, PWS patients showed a peculiar body composition, to some extent similar to that found in subjects deficient in growth hormone or even to sedentary and elderly people. These results suggest the importance of an accurate analysis of body composition in PWS patients.
Nutrition Metabolism and Cardiovascular Diseases, 2011
Background and aims: PradereWilli syndrome (PWS), the most frequent syndromic obesity, is associa... more Background and aims: PradereWilli syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status. Methods and results: A cross-sectional study was performed in 109 PWS children aged 2e 18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2. Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p Z 0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p Z 0.001) and high triglycerides (7% vs 23% and 16%, p Z 0.026).
Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized... more Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATPsensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11, but to date only twenty mutations have been identified in KCNJ11, most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.
American Journal of Physiology-Endocrinology and Metabolism, 2006
Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively ... more Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively the IHF content of obese adolescents to ascertain whether it is associated with insulin resistance and abnormal energy homeostasis. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured using localized hepatic 1H-MRS, indirect calorimetry, fasting-derived and 3-h-OGTT-derived surrogate indexes (HOMA2 and WBISI), and DEXA, respectively, in 54 obese adolescents (24 female and 30 male, age 13 ± 2 yr, BMI >99th percentile for their age and sex). NAFLD (defined as IHF content >5% wet weight) was found in 16 individuals (30%) in association with higher ALT ( P < 0.006), Hb A1c ( P = 0.021), trunk fat content ( P < 0.03), and lower HDL cholesterol ( P < 0.05). Individuals with NAFLD had higher fasting plasma glucose (89 ± 8 vs. 83 ± 9 mg/dl, P = 0.01) and impaired insulin sensitivity (HOMA2 and WBISI, P < 0.05). Meanwhile, paramete...
Inter-and Intrachromosomal Rearrangements Are priate informed consent, from the patient, both par... more Inter-and Intrachromosomal Rearrangements Are priate informed consent, from the patient, both parents, and paternal grandparents. DNA was isolated by use of Both Involved in the Origin of 15q11-q13 Deletions in Prader-Willi Syndrome a QIAamp blood kit (Qiagen). We employed markers D15S541 and D15S542, both mapping to YAC To the Editor: A124A3, proximal to the deletion region, and markers Prader-Willi syndrome (PWS) is due to an interstitial de D15S165 and D15S1048, both mapping distal to the novo deletion at 15q11-q13 in Ç70% of cases. The common deletion region (Hudson et al. 1995). In addideletion spans a region of Ç4 Mb and invariably intion, marker ATC3C11, mapping õ1 Mb from the disvolves the paternally derived homologue (Robinson et tal deletion breakpoint (S. L. Christian and D. H. Ledal. 1991). For most patients the distal breakpoint apbetter, unpublished data), was used. PCR assays were pears to be located within a single YAC (Kuwano et al. performed as described elsewhere (Christian et al. 1995; 1992), whereas two consistent breakpoint hot spots Hudson et al. 1995). The results of the microsatellite have been identified on the proximal side; one (class I) analysis are shown in table 1, and examples of the analylies in the region between the centromere and D15S541/ sis performed on two independent families are shown D15S542, and the other (class II) lies between in figure 1. D15S541/D15S542 and D15S543, with each account-Three patients were deleted for the D15S541/D15S542 ing for approximately half of the deletions (Christian markers, thus being classified as class I-deletion patients. et al. 1995). This finding was consistent with the known frequency The relatively high frequency of deletions, significant of the class I breakpoints among PWS patients. The lack clustering of the breakpoints in PWS deletion patients, of a proximal marker on the deleted allele in these paand the finding of a similar location for the breakpoints tients precluded assessment of the haplotype for the rein small inv dup(15) has led to the hypothesis that small gion comprising the deletion. Of the seven class II paregions in proximal 15q may contain sequences leading tients, five demonstrated a paternal recombination event to instability (Knoll et al. 1993; Huang et al. 1997). between the markers flanking the common deletion re-Recently, preliminary data for a low-copy repeat associgion. The genetic distance between marker D15S541 and ated with a novel evolutionarily conserved gene family marker D15S165 has been estimated as 17.2 cM in males spanning the proximal and distal breakpoint regions has (Robinson and Lalande 1995). Marker D15S1048 maps been reported (Ji et al. 1996). 2 cM proximal to D15S165 (Hudson et al. 1995). ThereIn order to analyze the mechanism underlying delefore, when the genetic distance between D15S541 and tions in PWS, we genotyped 10 three-generation families D15S165 in male meiosis is taken into account, the idenof PWS-deletion patients, using microsatellite markers tification, in five of seven cases, of a different grandparenflanking the common deletion region. Each patient was tal origin for the alleles flanking the deletion is signifiknown to be deleted for the interval from D15S11 to cantly different from the expected frequency (x 2 GABRB3, by FISH and/or other molecular techniques. Å 12.438, P Å .0004). This finding is highly suggestive of an unequal crossover occurring in the paternal meio-Peripheral blood samples were obtained, with appro
During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because ... more During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because the syndrome is expressed mainly by severe hypotonia at this age and the typical clinical features of later life are not yet present. Aim: To identify all the PWS clinical markers in severe hypotonic newborns, which could facilitate an early diagnosis of the syndrome. Methods: Twenty-one PWS newborns (14 males and 7 females) with severe hypotonia at birth were evaluated. Paediatricians skilled in syndromology carried out a careful clinical examination. Fluorescent in situ hybridization (FISH) analysis and/or a methylation test was used to confirm the PWS clinical diagnosis. Results: The clinical diagnosis of PWS was reached at a mean age of 7.4 mo with genetic confirmation at 11 mo of life. In 12 newborns at least 3 craniofacial features were present (57%), suggesting the diagnosis of PWS. Two craniofacial dysmorphic characteristics were described in 6 newborns and only 1 in 3 cases. Cryptorchidism was monolateral in 6 and bilateral in 7 patients; in one newborn both testes were in scrotum. A micropenis was described in one patient and hypoplasia of the labia minora was reported in two females. Diagnosis by means of dysmorphologic evaluation is difficult in the neonatal period. The presence of severe hypotonia should always induce neonatologists to perform specific genetic tests in order to obtain an early diagnosis of PWS.
Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of ... more Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of chromosome 15, in which obesity is common. However, there is limited information on the underlying physiological mechanisms promoting obesity in this population. We tested whether there was a significant positive association between leptin and total body fat (TBF) in subjects with PWS, and whether this association was stronger among subjects with than without PWS. Research Methods and Procedures: We studied 21 PWS patients and 64 non-PWS controls on whom we measured serum leptin, total body fat, glucose, insulin, and resting energy expenditure. We tested whether the slope of the regression line between leptin and TBF (in kg), measured by dual energy X-ray absorptiometry, was the same for PWS patients and Qon-PWS controls. Results: Regression analyses indicated that the leptin-TBF association was significantly stronger among PWS patients. In contrast, the slope of the leptin-body mass index association did not significantly differ between PWS patients and non-PWS controls. None of the other outcome variables showed associations with leptin. Discussion: Results suggest that the role of leptin in promoting obesity may be greater among subjects with PWS than among non-PWS controls.
Prader–Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal menta... more Prader–Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal mental and physical development. PWS patients have a deletion in an imprinted region on paternal chromosome 15 (15q11–13), maternal disomy for this segment, or rarely, a chromosomal imprinting center deletion that gives rise to suppression of the equivalent paternal genes. Within the affected segment of chromosome 15 are genes
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