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We present an infant girl with a de novo interstitial deletion of the chromosome 15q11q14 region, larger than the typical deletion seen in PraderWilli syndrome PWS. She presented with features seen in PWS including hypotonia, a poor suck, feeding problems, and mild micrognathia. She also presented with features not typically seen in PWS such as preauricular ear tags, a higharched palate, edematous feet, coarctation of the aorta, a PDA, and a bicuspid aortic valve. Gbanded chromosome analysis showed a large de novo deletion of the proximal long arm of chromosome 15 confirmed using FISH probes D15511and GABRB3. Methylation testing was abnormal and consistent with the diagnosis of PWS. Because of the large appearing deletion by karyotype analysis, an array comparative genomic hybridization aCGH was performed. A 12.3 Mb deletion was found which involved the 15q11q14 region containing approximately 60 protein coding genes. This rare deletion was approximately twice the size of the typical deletion seen in PWS and involved the proximal breakpoint BP1 and the distal breakpoint was located in the 15q14 band between previously recognized breakpoints BP5 and BP6. The deletion extended slightly distal to the AVENgene including the neighboring CHRM5gene. There is no evidence that the genes in the 15q14 band are imprinted; therefore, their potential contribution in this patients expanded PWS phenotype must be a consequence of dosage sensitivity of the genes or due to altered expression of intact neighboring genes from a position effect. © 2010 WileyLiss, Inc.

Prader–Willi syndrome (PWS) is due to loss of paternally expressed genes in the 15q11–q13 region generally from a paternal 15q11–q13 deletion. The proximal deletion breakpoint in the 15q11–q13 region occurs at one of two sites located within either of two large duplicons allowing for identification of two typical deletion subgroups. The larger type I (TI) deletion involving breakpoint 1 (BP1) is nearer to the centromere and located proximal to the microsatellite marker D15S1035, while the smaller type II (TII) deletion involves breakpoint 2 (BP2) and distal to D15S1035. Breakpoint 3 (BP3) is located at the distal end of the 15q11–q13 region and common to both typical deletion subgroups. Using high resolution aCGH, BP1 spanned a region from 18.683 to 20.220 Mb, BP2 from 20.812 to 21.357 Mb and BP3 from 25.941 to 27.286 Mb. The TI deletion ranged in size from 5.721 to 8.147 Mb (mean 6.583) and the type II deletion from 4.770 to 6.435 Mb (mean 5.330). A subset of the TI subjects showed larger deletions including the loss of at least three genes/transcripts (i.e., LOC283755, POTE5, OR4N4) in addition to the four genes between BP1 and BP2 (i.e., GCP5, CYFIP1, NIPA1, NIPA2). Interestingly, four PWS subjects had duplications of the 15q11 region in addition to the typical deletion. Furthermore, most PWS subjects had copy number variation (CNV) of 50 kb or larger in other chromosome regions; most common were deletions and duplications of 8p and 3q, previously recognized sites of CNV in the human genome. © 2008 Wiley‐Liss, Inc.

No Abstract.

SPONASTRIME dysplasia (SD) is an autosomal recessive skeletal dysplasia of the spondyloepimetaphyseal dysplasia (SEMD) type. The name was derived from “spondylar and nasal alterations with striated metaphyses” [Fanconi et al. 1983; Helv Paediat Acta 38: 267–280]. We follow two previously reported patients with SD [Patients 3, 4 in Langer et al. 1996; Am J Med Genet 63: 20–27]. Since the original publication, additional findings were identified in these patients. © 2008 Wiley‐Liss, Inc.

No Abstract.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM. © 2007 Wiley‐Liss, Inc.

Prader–Willi syndrome (PWS) is an obesity syndrome characterized by rapid weight gain and excessive food intake. Food intake is regulated by the hypothalamus but directly influenced by gastrointestinal peptides responding to the nutritional status and body composition of an individual. Ghrelin, derived from preproghrelin, is secreted by the stomach and increases appetite while obestatin, a recently identified peptide derived post‐translationally from preproghrelin, works in opposition to ghrelin by decreasing appetite. The objective of this study was to measure fasting obestatin and ghrelin levels in peripheral blood of subjects with PWS and compare to age and gender matched control subjects. Plasma obestatin and ghrelin levels were measured in subjects with PWS (n = 16, mean age = 16.0 ± 13.3 years; age range 1–44 years) and age and gender matched control subjects (n = 16). Significantly higher obestatin levels were seen in the 16 PWS subjects (398 ± 102 pg/ml) compared with 16 controls (325 ± 109 pg/ml; matched t‐test, P = 0.04), particularly in 5 young (≤3 years old) PWS subjects (460 ± 49 pg/ml) compared with 5 young controls (369 ± 96 pg/ml; matched t‐test, P = 0.03). No significant difference in ghrelin levels was seen between the PWS and comparison groups. No significant correlation was observed for either peptide when compared with body mass index but a significant negative correlation was seen for ghrelin and age in PWS subjects. Our observations suggest that obestatin may be higher in infants with PWS compared to comparison infants. The possibility that obestatin may contribute to the failure to thrive which is common in infants with PWS warrants further investigation. © 2007 Wiley‐Liss, Inc.

Prader–Willi syndrome (PWS) is caused by loss of function of paternally expressed genes in the 15q11‐q13 region and a paucity of data exists on transcriptome variation. To further characterize genetic alterations in this classic obesity syndrome using whole genome microarrays to analyze gene expression, microarray and quantitative RT‐PCR analysis were performed using RNA isolated from lymphoblastoid cells from PWS male subjects (four with 15q11‐q13 deletion and three with UPD) and three age and cognition matched nonsyndromic comparison males. Of more than 47,000 probes examined in the microarray, 23,383 were detectable and 323 had significantly different expression in the PWS lymphoblastoid cells relative to comparison cells, 14 of which were related to neurodevelopment and function. As expected, there was no evidence of expression of paternally expressed genes from the 15q11‐q13 region (e.g., SNRPN) in the PWS cells. Alterations in expression of serotonin receptor genes (e.g., HTR2B) and genes involved in eating behavior and obesity (ADIPOR2, MC2R, HCRT, OXTR) were noted. Other genes of interest with reduced expression in PWS subjects included STAR (a key regulator of steroid synthesis) and SAG (an arrestin family member which desensitizes G‐protein‐coupled receptors). Quantitative RT‐PCR for SAG, OXTR, STAR, HCRT, and HTR2B using RNA isolated from their lymphoblastoid cells and available brain tissue (frontal cortex) from separate individuals with PWS and control subjects and normalized to GAPD gene expression levels validated our microarray gene expression data. Our analysis identified previously unappreciated changes in gene expression which may contribute to the clinical manifestations seen in PWS. © 2007 Wiley‐Liss, Inc.

No Abstract.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder characterized by hypotonia, suck and feeding difficulties, hypogonadism, small hands and feet, developmental delay, hyperphagia and early childhood obesity and a particular facial appearance. The obesity associated with PWS is the result of a chronic imbalance between energy intake and energy expenditure (EE) due to hyperphagia, decreased physical activity, reduced metabolic rate and an inability to vomit. EE is affected by body composition as well as exercise. Individuals with PWS have a lower lean body mass (LBM) compared with controls which may contribute to reduced basal level EE. To determine the relationship among body composition, activity levels and metabolic rates, dual energy X‐ray absorptiometry (DEXA) and a whole‐room respiration chamber were used to measure body composition, total EE (TEE), resting EE (REE), physical activity, and mechanical work (MW) during an 8 hr monitoring period. The chamber consisted of a live‐in whole‐room indirect calorimeter equipped with a force platform floor to allow simultaneous measurement of EE, physical activity, and work efficiency during spontaneous activities and standardized exercise. Participants with PWS (27 with 15q11–q13 deletion and 21 with maternal disomy 15 with an average age of 23 years) had significantly decreased TEE by 20% and reduced LBM compared to 24 obese subjects. Similarly, REE was significantly reduced by 16% in the individuals with PWS relative to the comparison subjects. Total MW performed during the 8 hr monitoring period was significantly reduced by 35% in the PWS group. The energy cost of physical activity is related to the duration, intensity and type of activity and the metabolic efficiency of the individual. After adjusting group differences in LBM by analysis of variance, TEE and REE were no longer different between the two groups. Our data indicate that there is a significant reduction of EE in individuals with PWS resulting from reduced activity but also from lower energy utilization due to reduced LBM which consists primarily of muscle. © 2006 Wiley‐Liss, Inc.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11‐q13 region generally due to a paternally‐derived deletion of the 15q11‐q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non‐disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X‐chromosome inactivation was calculated to determine whether non‐random skewing of X‐inactivation is present indicating a small pool of early embryonic cells. We studied X‐chromosome inactivation in 25 females with PWS‐UPD, 35 with PWS‐deletion, and 50 controls (with similar means, medians, and age ranges) using the polymorphic androgen receptor (AR) gene assay. A significant positive correlation (r = 0.5, P = 0.01) was seen between X‐chromosome inactivation and age for only the UPD group. Furthermore, a significantly increased level (P = 0.02) of extreme X‐inactivation skewness (>90%) was detected in our PWS‐UPD group (24%) compared to controls (4%). This observation could indicate that trisomy 15 occurred at conceptus with trisomy rescue in early pregnancy leading to extreme skewness in several PWS‐UPD subjects. Extreme X‐inactivation skewness may also lead to additional risks for X‐linked recessive disorders in PWS females with UPD and extreme X‐chromosome skewness. © 2006 Wiley‐Liss, Inc.

Prader–Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11‐q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IC) deletion (PWS IC deletion). These mice die generally within 2–3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5‐fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro‐opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 7B). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription‐PCR (RT‐PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS. © 2006 Wiley‐Liss, Inc.

Prader–Willi syndrome (PWS) is the most common known syndromic cause of life‐threatening obesity, yet few studies have examined the causes of death in PWS. The objective of this study was to examine the contribution of choking leading to mortality in PWS. In 1999, a brief survey was made available from the Prader–Willi Syndrome Association (USA) bereavement program, which documented demographic data and causes of death. Families were subsequently offered the opportunity to fill out a detailed questionnaire and additional forms to release medical records. Demographic information was available on 178 deceased individuals with PWS, and cause of death available on 152 individuals. Fifty‐four families completed questionnaires. Of the deceased individuals with completed questionnaires, 34% reported a history of choking. Choking was listed by familial report as the cause of death in 12 (7.9%) of 152 subjects with an average age of 24 years (range 3–52 years; median 22.5 years) at death from choking. Only two of these individuals were less than 8 years of age. The data suggest that risks associated with choking are different in the PWS population compared with others. Potential causes of increased choking in PWS include poor oral/motor coordination, poor gag reflex, hypotonia, hyperphagia, decreased mastication, and voracious feeding habits. We recommend implementation of preventive measures and education for families and group home care providers for all individuals with PWS including the Heimlich maneuver, supervised meals, better food preparation, and diet modification to avoid high‐risk choking items. © 2006 Wiley‐Liss, Inc.

No Abstract.

We describe a 9‐year‐old male referred for genetic evaluation for Prader‐Willi syndrome (PWS). PWS is the most common genetically defined cause of life‐threatening obesity and results from a functional loss of paternally expressed genes from the chromosome 15q11‐q13 region. The patient presented with pervasive developmental disorder, delayed speech, and rapid onset of obesity at age 4 years, all features similar to PWS. However, chromosome 15q11‐q13 methylation testing and fragile X studies were normal. GTG‐banding and fluorescence in situ hybridization (FISH) with whole chromosome 3 paint probe (WCP3) and a chromosome 3p subtelomeric probe suggested a duplication of 3p25.3p26.2, a finding supported by comparative genomic hybridization (CGH). This region of chromosome 3p contains genes which contribute to obesity and behavioral problems, most notably, ghrelin (GHRL), an oxytocin receptor (OXTR), solute carrier family six members (gamma‐aminobutyric acid (GABA) neurotransmitter transporters, SLC6A1 and SLC6A11), and peroxisome proliferator‐activated receptor gamma (PPARG). To characterize these obesity and behavior related genes in our subject, we performed quantitative RT‐PCR and compared expression levels with similarly aged male subjects (four non‐obese males, four obese males, and four PWS males—two with 15q11‐q13 deletions and two with maternal disomy 15). Our studies suggest increased expression of several genes in the 3p duplication region, including GHRL and PPARG, which may contribute to the phenotypic features in our 3p duplication subject. © 2006 Wiley‐Liss, Inc.

Maladaptive behaviors among 65 people with Prader–Willi syndrome were assessed using the Reiss Screen for maladaptive behaviors. Young adults in their twenties were more likely to display aggressive behavior than adolescents and older adults. Differences in maladaptive behaviors between the typical deletion and uniparental disomy (UPD) subtypes were evaluated. The typical deletion subtype had higher self‐injury and stealing scores than the UPD subtype. Subject characteristics were differentially related to maladaptive behavior among the typical deletion and UPD subtypes. Differences in maladaptive behavior were also examined between the typical deletion type I and type II subtypes. The type I deletion subtype had greater physical depression scores than the type II deletion subtype. The Reiss Screen cut‐off scores were used to determine whether differences occurred between the subtypes at a clinically significant level. These findings offer insight into the health care needs of people with PWS. © 2005 Wiley‐Liss, Inc.

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial respiratory chain and an important scavenger of reactive oxygen species. Low levels are found in individuals with reduced energy expenditure, cardiac and skeletal muscle dysfunction, and mitochondrial disorders, many of these manifestations are seen in individuals with Prader-Willi syndrome (PWS). In addition, CoQ10 supplementation frequently is given to individuals with this syndrome. To determine if CoQ10 levels are decreased in PWS, we studied plasma CoQ10 levels in 16 subjects with PWS, 13 with obesity of unknown cause, and 15 subjects without obesity but of similar age and compared with body composition. Plasma CoQ10 levels were significantly decreased (P < 0.05), using several statistical approaches in subjects with PWS (0.45 ± 0.16 μg/ml), compared to subjects without obesity (0.93 ± 0.56 μg/ml), but not different from subjects with obesity (0.73 ± 0.53 μg/ml). When plasma CoQ10 was normalized relative to cholesterol, triglyceride, and creatinine levels and fat and lean mass [determined by dual energy X-ray absorptiometry (DEXA)] in the subjects with either PWS or obesity, no significant differences were observed. However, a lower muscle mass was found in the PWS subjects. © 2003 Wiley-Liss, Inc.

We report a nine-month-old Caucasian male with features seen in oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia sequence (FND) born to normal, non-consanguineous parents and review the literature. His malformations included a left pre-auricular skin tag, severely hypoplastic right pinna without an external canal, severely everted and hypoplastic left upper eyelid, bilateral cleft lip and palate, bifid broad nasal tip, ocular hypertelorism, micrognathia, hypoplastic mandible, an extra cervical rib on the left, hemivertebrae at T3–4, agenesis of the posterior corpus callosum with a midline lipoma, and an extra renal pelvis. This constellation of anomalies is consistent with the diagnosis of oculoauriculofrontonasal syndrome (OAFNS) which appears to be a distinct condition from either OAVS or FND but with overlapping features. © 2001 Wiley-Liss, Inc.

Bone density, anthropometric data, and markers of bone turnover were collected on 21 subjects diagnosed with Prader-Willi syndrome (PWS) and compared with 9 subjects with obesity of unknown cause. In addition, urinary N-telopeptide levels were obtained in all subjects. N-telopeptides are the peptide fragments of type I collagen, the major bone matrix material. During periods of active bone degradation or high bone turnover, high levels of N-telopeptides are excreted in the urine. However, no significant difference was detected in the urinary N-telopeptide levels when corrected for creatinine excretion (raw or transformed data) between our subjects with obesity or PWS and the observed effect size of the between-group difference was small. Although N-telopeptide levels were higher but not significantly different in the subjects with PWS compared with obese controls, the subjects with PWS had significantly decreased total bone and spine mineral density and total bone mineral content (all P < 0.001). No differences in N-telopeptide levels or bone mineral density were observed between subjects with PWS and chromosome 15q deletion or maternal disomy. Thus, decreased bone mineral density in subjects with PWS may relate to the lack of depositing bone mineral during growth when bones are becoming more dense (e.g., during adolescence), possibly because of decreased production of sex or growth hormones and/or long-standing hypotonia. It may not be caused by loss, or active degradation, of bone matrix measurable by the methods described in this study further supporting the possible need for hormone therapy during adolescence. © 2001 Wiley-Liss, Inc.

The cardinal feature of individuals with Prader-Willi syndrome (PWS) is severe hyperphagia-mediated obesity resulting from a faulty satiety mechanism. PWS is the most common genetic cause of marked obesity. Cholecystokinin (CCK) is a 33-amino-acid peptide found in high levels in the gut and brain involved in mediating the satiety response to meals. Free fatty acids (FFA) are responsible for the stimulation of CCK release after a fatty meal, and CCK and plasma FFA levels rise in tandem in normal individuals. Fasting plasma CCK levels were measured by radio-immunoassay in 33 PWS subjects with a mean age of 22.2 years ± 8.1 years and 24 obese control subjects without a known cause of their obesity with a mean age of 28.7 years ± 12.9 years. Consistent with previous findings, neither fasting plasma FFA levels (617.5 versus 486.8 μm/mL) or CCK levels (21.0 versus 19.1 pg/mL) were significantly different in PWS or control subjects, respectively. However, there was a significant correlation between fasting plasma FFA and CCK levels in obese subjects (r = 0.64, P < 0.01), this correlation was completely lacking in PWS subjects (r = −0.06, P = 0.79). This difference in correlation coefficients constitutes a large effect. There were no significant effects observed for genetic subtypes (15q11-q13 deletion or maternal disomy 15), body mass index, percentage of fat, plasma levels of insulin, C-peptide, glucagon or leptin, age, or gender on CCK levels in our PWS subjects. These results suggest that differences in the peripheral CCK response to FFA levels may be a factor contributing to the altered satiety response in PWS subjects. Am. J. Med. Genet. 95:67–70, 2000. © 2000 Wiley-Liss, Inc.

Metacarpophalangeal pattern (MCPP) analysis is an application of an anthropometric technique that provides a quantitative assessment of the amount and direction of abnormality in the hand skeleton. MCPP analysis was undertaken on 15 individuals (9 males, 6 females) with Noonan syndrome ranging in age from 0.1 to 36 years with a mean age at 11.6 years. The overall average Z score for the MCPP variables was −2.1 and the range was −2.5 (for metacarpal two) and −1.5 (for middle phalanx 5). The average hand pattern variability index, a measure of hand bone length relationships, was abnormal. A Pearsonian correlation analysis was used to assess similarity between the mean pattern and each of the 15 individual patterns. Nine (60%) of the fifteen individuals with Noonan syndrome had significant positive correlations (P < 0.05), indicating homogeneity or similarity in the hand patterns. A stepwise discriminant analysis was performed on Z score data from the individual hand bone measurements on the 15 subjects with Noonan syndrome and 41 healthy controls (24 females, 17 males; mean age = 13.1 years with age range of 9.6 to 18 years). This analysis produced a discriminant function with two MCPP variables (metacarpal 1 and middle phalanx 3) entering into the function and producing a correct classification rate of 93%. The two MCPP variables contributed to the overall difference between individuals with Noonan syndrome and the normative sample. The hand pattern variability index was outside of the normal range, indicating an abnormal MCPP with multivariate analysis. The MCPP analysis may be useful as a tool for diagnosis in screening subjects for Noonan syndrome. Am. J. Med. Genet. 92:128–131, 2000. © 2000 Wiley-Liss, Inc.

SPONASTRIME (SPOndylar and NAsal changes, with STRIations of the MEtaphyses) dysplasia is a rare, autosomal recessive bone disorder first described by Fanconi et al. [1983: Helv Paediatr Acta 38:267–280]. Radiographic findings include abnormal vertebral bodies with age-dependent changes, and striations of the metaphyses, scoliosis, and retarded ossification of the carpal bones. Physical features include severe short stature, lumbar lordosis, midface hypoplasia, frontal bossing, and a depressed nasal root. To date, 12 patients from 6 families have been reported. Four additional patients have been reported with a variant of this condition, which includes mental retardation. We report on an 11-year-old boy with features consistent with SPONASTRIME dysplasia. Height was 106.1 cm (−6 SD). He had a coarse appearing face with a depressed nasal bridge, short, upturned nose, and midface hypoplasia. Intelligence was normal. A clinical evaluation at 6 years of age suggested the diagnosis of spondyloepiphyseal dysplasia (SED). However, genetics evaluation at 11 years of age with repeat radiologic studies revealed delayed carpal ossification (−4 to −5 SD), metaphyseal irregularities and striations most notably in the distal femurs and the proximal tibias, lumbar lordosis, narrow interpedicular distances of the lumbar spine, and pear-shaped vertebral bodies. These findings were most consistent with the diagnosis of SPONASTRIME dysplasia, and not SED. Although radiographic findings of SPONASTRIME dysplasia are distinguishable from SED, the physical appearance may be similar. Many bone dysplasias have overlapping radiographic findings and clinical presentation but with different recurrence risks, making genetic counseling a challenge. Am. J. Med. Genet. 92:33–39, 2000. © 2000 Wiley-Liss, Inc.

Brunner et al. [1993: Am J Hum Genet 52:1032–1039; 1993: Science 262:578–580] described males with an MAO-A deficiency state resulting from a premature stop codon in the coding region of the MAOA gene. This deficiency state was associated with abnormal levels of amines and amine metabolites in urine and plasma of affected males, as well as low normal intelligence and apparent difficulty in impulse control, including inappropriate sexual behavior. In the present study, disruption of the MAOA gene was evaluated in males with mental retardation with and without a history of sexually deviant behavior, as well as normal controls, healthy males, and patients with other diseases (Parkinson disease, Lesch-Nyhan syndrome). When available, plasma samples were evaluated first for levels of 3-methoxy, 4-hydroxyphenolglycol (MHPG), a metabolite of norepinephrine which serves as the most sensitive index of MAO-A activity in humans. Blood DNA from individuals with abnormally low MHPG, and from other individuals for whom metabolite levels were not available, were screened for nucleotide variations in the coding region of the MAOA gene by single-strand conformational polymorphism (SSCP) analysis across all 15 exons and splice junctions, and by sequencing, when indicated by either altered metabolites or SSCP shifts. No evidence for mutations disrupting the MAOA gene was found in 398 samples from the target populations, including institutionalized mentally retarded males (N = 352) and males participating in a sexual disorders clinic (N = 46), as well as control groups (N = 75). These studies indicate that MAOA deficiency states are not common in humans. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:25–28, 1999. © 1999 Wiley-Liss, Inc.

No abstract.

The Prader-Willi syndrome (PWS) usually results from a paternal deletion of 15q11-q13 or maternal disomy for chromosome 15. Reduced pigmentation of skin, hair, and eyes is common in PWS and was suggested previously to be associated with the 15q11-q13 deletion. The P gene, located in this same region, is associated with OCA2, an autosomal recessive disorder that is the most frequent form of tyrosinase-positive oculocutaneous albinism. We studied 28 individuals with PWS and found that hemizygosity for the P gene was significantly correlated with the occurrence of hypopigmentation among PWS patients. However, we found little or no relationship between the occurrence of hypopigmentation and the polymorphism haplotype of the intact P allele. Thus, our results indicate that hypopigmentation is likely the result of deletion of the P gene in the context of PWS but do not support the linked hypothesis that hypopigmentation results from hemizygosity for variant P alleles with reduced function. Am. J. Med. Genet. 71:57–62, 1997. © 1997 Wiley-Liss, Inc.

The holoprosencephaly (HPE) sequence is a malformation complex with abnormal midline cleavage of the embryonic forebrain. HPE is genetically heterogeneous with at least 6 different chromosome regions containing genes involved in the expression of the phenotype. HPE3, recently identified as the human Sonic hedgehog gene, is localized to 7q36. We have used fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) amplification in 5 cell lines from patients with HPE (3 cases), HPE and sacral agenesis (1 case), and microcephaly (1 case) to further define the structural rearrangements of the long arm of chromosome 7 in each case. All cell lines demonstrated loss of material in the critical region of HPE3 at band 7q36, which includes the Sonic hedgehog gene. We report here the analysis of these patient cell lines. Am. J. Med. Genet. 76:51–57, 1998. © 1998 Wiley-Liss, Inc.

Prader-Willi syndrome (PWS) is characterized by early childhood obesity, mental deficiency, hypogonadism, hypotonia, hypopigmentation, short stature, small hands and feet, and a characteristic face. It is the most common genetic cause of obesity and obesity is the most significant health problem for PWS patients. Ob protein (leptin), which is produced by adipose tissue, is thought to play a significant role in obesity; thus, unusually low plasma leptin levels, or relative loss of sensitivity to leptin in PWS subjects, could be an important factor in their obesity. We measured plasma leptin levels in 19 obese and 14 non-obese PWS patients [mean body mass index (BMI) 37.2 and 22.0, respectively] and compared these levels to those of 28 obese controls (mean BMI 35.5) and 16 non-obese control individuals (mean BMI 21.6). The mean plasma leptin concentration (ng/ml) for obese PWS subjects was 33.4 and 23.6 for non-obese PWS subjects. Obese control leptin was 36.2 ng/ml and non-obese control was 9.9. Among the control groups, leptin levels in females were significantly higher than those in males; the obese males and females had significantly higher leptin than their respective non-obese counterparts. These differences did not hold true for the PWS subjects. Leptin levels in obese PWS males and females were similar, and the same was true of the non-obese PWS males and females. The differences between obese and non-obese PWS subjects of both sexes were small and not significant. Comparing control groups with their PWS counterparts revealed no significant differences, with one exception: circulating plasma leptin levels in non-obese PWS males were nearly five times higher than in non-obese control males with similar BMI. This difference may reflect a more female pattern of fat distribution and hypogonadism, which are characteristic of PWS males. Leptin levels in PWS patients were not obviously correlated with the chromosome 15 finding seen in the patients. Am. J. Med. Genet. 75:7–12, 1998. © 1998 Wiley-Liss, Inc.

We report on a relatively large survey of Prader-Willi syndrome, Angelman syndrome, and control subjects with the newly described methylation polymerase chain reaction (PCR) method to determine its usefulness for molecular diagnosis. Sixty-one Prader-Willi syndrome (PWS) individuals (26 men and 35 women), 9 Angelman syndrome (AS) patients (5 men and 4 women), and 58 other individuals were studied with methylation PCR following sodium bisulfite treatment of genomic DNA. In addition, multiple tissues, including fetal tissue, were studied from several individuals to determine the effects of various tissues on methylation PCR results. The expected methylation PCR result was observed in each case. This PCR-based assay evaluates the methylation status of the CpG island of the SNRPN gene and allows for rapid molecular diagnosis of PWS or AS with less labor than Southern hybridization for methylation analysis. The PCR results were identical to those achieved by Southern hybridization in those individuals studied. Am. J. Med. Genet. 80:263–265, 1998. © 1998 Wiley-Liss, Inc.