Nutrient intake and body composition variables in Prader-Willi syndrome--effect of growth hormone supplementation and genetic subtype.

UNLABELLED: In patients with Prader-Willi syndrome (PWS), limited information exists on the effects of growth hormone (GH) therapy, gender and genetic subtype on nutrient intake and body composition. We therefore compared GH-treated and nontreated patients, taking into account Tanner stage, gender, and genetic form. PATIENTS AND METHODS: In 37 individuals with PWS (20/17 M/F; 21/16 GH+/GH-), dietary intake and body composition (BMI, DEXA) were assessed. RESULTS: Older GH-treated children (Tanner stage 3-4) displayed improved body composition variables (BMI, total and percentage fat mass, truncal fat) (p < 0.05), despite dietary intake similar to non-treated patients; younger children (Tanner stage 1-2) displayed a different pattern, despite greater total caloric and fat intake (p < 0.05) with GH treatment, with only minor differences in body composition. Genetic form and gender had no intrinsic effect on nutrient intake or body composition. CONCLUSION: In 37 patients with PWS, GH treatment selectively affected body composition (BMI, fat mass), and dietary fat intake based on patients' developmental status, while these variables were unaffected by gender or genetic subtype.

Prader-Willi and Angelman syndromes. Disorders of genomic imprinting.

Prader-Willi and Angelman syndromes are 2 clinically distinct disorders associated with multiple anomalies and mental retardation. They are only discussed together because they share a similar and uncommon genetic basis: they involve genes that are located in the same region in the genome and are characterized by genetic imprinting. This normal process has contributed to these 2 complex and severe conditions through inactivation of 1 copy of the genes relevant to each disorder: the maternally derived copy of genes for Prader-Willi syndrome in proximal 15q are normally silent, and a paternally derived copy of 1 gene for Angelman syndrome in 15q is normally silent. For both disorders, when the normally active copy of the gene or genes is missing, abnormality results. Since the genes for these 2 disorders are located very close together, and since the center involved in inactivating the genes involved in imprinting may be the same, both these disorders usually result from the same chromosomal deletion; which disorder results depends on the parent of origin of the chromosome 15 that becomes deleted. Both Prader-Willi and Angelman syndrome can also occur as a result of having both members of the chromosome 15 pair derived from 1 parent, a condition known as uniparental disomy. Both can also result from a structural abnormality of the imprinting center, known as an imprinting mutation. In addition, Angelman syndrome can be caused by a mutation in the gene that causes it; a comparable cause is not present in Prader-Willi syndrome since it results from abnormality in more than 1 gene. Finally, despite the complexity of possible causes, all but the single gene mutation of the Angelman syndrome gene can be detected through methylation-sensitive DNA probes, since DNA methylation is the process by which the genes for these 2 disorders are imprinted. This unusual property of specific areas of the DNA holds promise for future treatment of these and other disorders related to imprinting through reversal of the imprinting process.

Methylphenidate therapy for aggression in a man with ring 22 chromosome. Report and literature review.

A 28-year-old mentally retarded man with ring 22 chromosome [r(22)] had deterioration of mood and behavior, decreased speech, bradykinesia, and decline of fine motor skills over a three-year period, which were further exacerbated by treatment with phenothiazines. A trial of methylphenidate hydrochloride resulted in rapid improvement of mood, behavior, and to a small extent, motor function. This finding suggests that dopamine depletion may play a role in the behavioral deterioration seen in this disorder. The possibility that genes that control dopamine metabolism may be present on chromosome 22 is raised. The phenotype of this patient is compared with the 25 reported cases of r(22).

An evaluation of autonomic nervous system function in patients with Prader-Willi syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder in which many cardinal features may have a neurologically based pathophysiology involving both the central and peripheral components of the autonomic nervous system. Autonomic nervous system function was studied noninvasively in a group of subjects with PWS and control subjects to determine whether autonomic nervous system dysfunction exists as part of the PWS. DESIGN/SETTING: This cross-sectional study was performed in the neurophysiology laboratory at a tertiary care facility. METHODS: Evaluation included anthropometric measurements and calculation of a body mass index (BMI). Simultaneous electrocardiography and serial recordings of pulse rate and systolic/diastolic mean arterial blood pressures during orthostatic maneuvers were taken. Pupillary response to the instillation of dilute pilocarpine and measurements of plasma norepinephrine at rest and after standing were also obtained. Results were analyzed using two-tailed t tests, Fisher exact test, analysis of variance, and analysis of covariance adjusting for age, gender, and BMI. PATIENTS: There were 14 subjects with PWS (8 female, 6 male; aged 4 to 40 years, mean age 16 years) and 8 control subjects (4 female, 4 male; aged 5 to 37 years, mean age 19 years). RESULTS: Abnormal findings were obtained only in subjects with PWS. Analysis of covariance adjusting for age, gender, and BMI revealed a trend for subjects with PWS to have lower resting diastolic blood pressure (P < .09) and significantly less change in diastolic blood pressure after standing (P < .02). Subjects with PWS had significantly greater BMI than did control subjects (P < .001), which correlated significantly with all pulse rate measurements where the greater the BMI the higher the pulse rate at rest (r = .25, P < .04) and the lower the pulse rate after arising from lying to standing at both 15 and 30 seconds (r = .17, P < .1; r = .55, P < .08 respectively). Pupillary constriction of 2 mm or more was seen in 7 of 14 subjects with PWS and in no control subjects (P < .004). The 30:15 R-R interval ratio was abnormal in 6 of 14 subjects with PWS and in no control subjects (P < .03). CONCLUSIONS: These results suggest that patients with PWS have a detectable underlying autonomic dysfunction characterized principally by diminished parasympathetic nervous system activity.

Prader-Willi syndrome: consensus diagnostic criteria.

The diagnosis of Prader-Willi syndrome (PWS) is based on clinical findings that change with age. Hypotonia is prominent in infancy. Obesity, mild mental retardation or learning disability, and behavior problems, especially in association with food and eating, result in a debilitating physical and developmental disability in adolescence and adulthood. No consistent biological marker is yet available for PWS in spite of recent research activity in cytogenetics and molecular genetics. Diagnostic criteria for PWS were developed by consensus of seven clinicians experienced with the syndrome in consultation with national and international experts. Two scoring systems are provided: one for children aged 0 to 36 months and another one for children aged 3 years to adults. These criteria will aid in recognition of the syndrome in hypotonic infants and in obese, mildly retarded, behaviorally disturbed adolescents and adults. They will also ensure uniform diagnosis for future clinical and laboratory research in PWS.

Hand and foot length in Prader-Willi syndrome.

Small hands and feet (acromicria) are often cited as manifestations in the Prader-Willi syndrome (PWS), but it has been our experience that these are not universal findings. To address this issue, we obtained longitudinal and cross-sectional data, retrospectively and prospectively, including height, hand length, and foot length, on 56 patients with PWS who are followed in the multidisciplinary PWS clinic at the University of Connecticut Health Center. Hand and foot lengths were plotted using two published sets of normative data. In addition, height age was calculated on each measurement of stature so that the corresponding hand and foot measurements could be compared to those expected for height, rather than age, as many PWS individuals are short. Foot length was proportionately smaller than hand length in all individuals; this difference was more striking in females. By age 12 years, almost all individuals had a foot length less than 25th centile for chronological age and less than 50th centile for height age. Female hand length was also less than 25th centile for chronological by age 12 years and less than 50th centile for height age in almost all cases. Male hand length data appeared to fall more within the normal range until adulthood, although fewer data were available. Black individuals with PWS had relatively larger hands and feet than their Caucasian counterparts. Many people with PWS had hand and foot lengths which fell within the normal range, particularly those under the age of 12 years and those whose height was greater than 50th centile for age.(ABSTRACT TRUNCATED AT 250 WORDS)

New syndrome of macrocephaly, hypertelorism, short limbs, hearing loss, and developmental delay.

We describe a boy with an apparently unique constellation of anomalies, including macrocephaly, short stature, relatively short limbs, hearing loss, developmental delay, sparse anterior scalp hair, hypertelorism, downslanting palpebral fissures, and a short nose with a broad, flat nasal bridge and anteverted nares. Chromosomes were normal and radiographs failed to show a bone dysplasia. We conclude that this represents a new syndrome.

Hydrolethalus syndrome: report of an apparent mild case, literature review, and differential diagnosis.

We present an infant with manifestations of the hydrolethalus syndrome who has survived for over 5 months; previously, the longest survival reported in this condition has been 2 days. The literature is reviewed and the clinical and pathological findings of our patient are compared with those of the 50 previously reported cases. The differential diagnosis of the condition is discussed.

Correlates of maladaptive behavior in children and adults with Prader-Willi syndrome.

Four features of maladaptive behavior were examined in 25 children and 61 adults with Prader-Willi syndrome: age, gender, IQ, and the Body Mass Index (BMI). Among children, older subjects showed increased symptomatology relative to younger subjects, especially in depression and withdrawal. Among adults, maladaptive behaviors seem to show both steady and variable expressions, waxing and waning over time. Boys showed heightened depression relative to girls, findings which were not seen in the adults. No maladaptive behavior differences were found in high vs. low IQ subjects. Thinner adults with lower BMIs had higher maladaptive behavior scores relative to heavier subjects, particularly in internal states involving distressful affect and problems with thinking. Several explanations of these counterintuitive BMI findings are discussed, as is the need for prospective research on maladaptive behavior in children and adults with this syndrome.

New syndrome: mother and son with hypertelorism, downslanting palpebral fissures, malar hypoplasia, and apparently low-set ears associated with joint and scrotal anomalies.

We report on a mother and son with a similar syndrome of hypertelorism and telecanthus, epicanthal folds, downslanting palpebral fissures, ptosis, broad nasal bridge, malar hypoplasia, thin upper lip, smooth philtrum, and apparently low-set prominent ears. The son also has a hypoplastic shawl scrotum, cryptorchidism, and genu valgum. His language development was delayed at 18 months, but subsequently improved and was normal at age 3. The mother has the additional findings of marked cubitus valgus, hyper-extensible joints, dull normal intelligence and a bleeding diathesis. This pattern of multiple congenital anomalies may represent a new syndrome.

Prader-Willi and Angelman syndromes: sister imprinted disorders.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment.

Cephalometric analysis of the Prader-Willi syndrome.

The Prader-Willi syndrome (PWS) is characterized by short stature, mild mental retardation, and a characteristic face. Approximately 75% of all patients have a del (15q). Cephalometric roentgenograms of 20 PWS patients of both sexes (12 adults, 8 children, age 4.5-50.0 years) were analyzed to determine if the facial appearance is reflected in changes in the bony architecture, a characteristic which might be useful in diagnosis and/or dental treatment of these individuals. PWS subjects were compared with chronologic age and sex-matched control individuals derived from the Denver Growth study using 52 point computer analyzed lateral head-plate tracings performed by the same individual (RS). The mean Z-score differences for mandibular and maxillary total length, ramus height, mandibular corpus length, posterior facial height, and mid-facial height were all significantly smaller in greater than 65% of the PWS subjects; this was more evident in the PWS children. The Z-score difference for posterior cranial base was very large in most PWS adults and children whereas lower facial height was small or normal in all subjects. No statistical difference in mean Z-score measurements was found for all these measures in PWS subjects with or without the 15q chromosome deletion. The overall small bony structures contrast with the relatively large soft tissue draping seen especially in obese adults. The data suggest that a characteristic bony model might be created for PWS which could be of use in diagnosis and in the treatment of PWS patients by their orthodontist.

Delayed diagnosis in patients with Prader-Willi syndrome due to maternal uniparental disomy 15.

Prader-Willi syndrome (PWS) results from absence of the normally active paternally inherited genes on proximal 15q, due to del(15)(q11q13) or by maternal uniparental disomy (UPD) 15 in most cases. In addition to a higher frequency of hypopigmentation among deletion patients, minor phenotypic differences between deletion and UPD patients have recently been reported, including lower birth weight in the deletion group, shorter birth length in males with UPD, and shorter course of gavage feeding and later onset of hyperphagia in females with UPD. We previously reported that those with UPD had a less "typical" facial appearance, and they less often had skin picking, skill with puzzles, and high pain threshold. There were no children younger than 3.5 years of age in the UPD group, in contrast to several of them in the deletion group, suggesting a possible diagnostic delay in the UPD group. To assess this possibility and seek reasons for it, we reviewed the charts of 60 PWS patients with complete molecular testing. Mean age at diagnosis of patients with UPD was significantly higher than in the deletion group. Mean percentiles of birth weights and lengths of patients with UPD were significantly lower than in those with deletion. Mean duration of gestation, mean duration of gavage feeding, and mean age at onset of hyperphagia did not differ significantly between groups. Delay in the diagnosis of patients with UPD, which may influence the management and impact of the disorder, might be explained by a lower frequency of typical facial anomalies in this group.

Molecular cytogenetics of a de novo interstitial deletion of chromosome arm 6q in a developmentally normal girl.

Using fluorescence in situ hybridization and microsatellite analysis, we have characterized a de novo interstitial deletion on the long arm of chromosome 6 [46,XX,del(6) (q23.3q24.2)] in a developmentally normal girl with very mild phenotypic abnormalities. The deletion was paternal in origin and was between markers WI-5023 and D6S1042. The size of the deletion was estimated to be approximately 4-5 Mb. The normal phenotype in this patient might be the result of imprinting of paternal copies of genes located in the segment 6q23. 3-q24.2. Alternatively, the genes located in the segment 6q23.3-q24. 2 might not be subject to dosage effects and therefore the haploinsufficiency of genes in this segment might not have phenotypic consequences.

Deletion of chromosome 15 (q11-13) in a Prader-Labhart-Willi syndrome clinic population.

Deletion of the long arm of chromosome 15 has recently been reported in a number of patients with the Prader-Labhart-Willi syndrome who were studied with prometaphase banding. We performed cytogenetic analysis on 12 patients with this disorder in whom the clinical diagnosis was certain. A specific cytogenetic anomaly, del(15q11-13) was found in all of the 12 patients. In nine of the 12, the deletion was noted in all cells examined; in two, there was mosaicism, some cells having the deletion and others being normal; one patient had a 7;15 translocation. No clinical differences were evident between individuals with mosaicism for the translocation and those with the typical deletion in all cells examined. The finding that all of our patients with Prader-Labhart-Willi syndrome have a cytogenetic anomaly, with some patients having mosaicism, distinguishes the results of this study from those of previous reports. Prometaphase chromosome analysis is recommended in all individuals clinically suspected of having Prader-Labhart-Willi syndrome and should be considered in hypotonic infants without a specific diagnosis.

Epiphyseal dysplasia with coxa vara, microcephaly, and normal intelligence in sibs: expanded spectrum of Lowry-Wood syndrome?

We report on a brother and sister with epiphyseal dysplasia and coxa vara, microcephaly, and short stature. This constellation of findings similar to that found in the Lowry-Wood syndrome (Epiphyseal dysplasia, microcephaly, short stature, and mental retardation). In the sibs we describe, mental retardation is not apparent, and they have the additional finding of developmental coxa vara. Despite these 2 exceptions, this family probably represents the same disorder described by Lowry and Wood (Clinical Genetics 8:269-274, 1975), and serves to expand the spectrum of the syndrome to include coxa vara. It is also possible that these sibs represent a previously undescribed syndrome, most likely with autosomal recessive inheritance.

Jarcho-Levin syndrome: unusual survival in a classical case.

Spondylothoracic dysostosis, or Jarcho-Levin syndrome, together with spondylocostal dysostosis, constitute a heterogeneous group of rare disorders characterized by short-neck, short-trunk dwarfism and multiple vertebral anomalies at all levels of the vertebral column. The latter include hemivertebrae, fused, hypoplastic, and "butterfly" vertebrae. In most cases of Jarcho-Levin syndrome, the small size of the thorax causes respiratory death in infancy. This report of a Puerto Rican child with spondylothoracic dysostosis and unusually long survival to 11 years exemplifies the nosologic and prognostic difficulties associated with this syndrome.

Chromosome 7p--syndrome: craniosynostosis with preservation of region 7p2.

Deletion of a portion of the short arm of chromosome 7 is associated with a recognizable phenotype which often includes craniosynostosis. Recent reports have suggested that craniosynostosis occurs only if there is a deletion involving band 7p21 or the segment distal to that band. We report on a boy who had an interstitial deletion of 7p, not involving band 7p21 or the segment distal to that band, who nevertheless had craniosynostosis. Thus, it appears that the determination of craniosynostosis in this syndrome is more complicated than has been suggested previously.

Photoanthropometric study of craniofacial traits of individuals with Prader-Willi syndrome.

A photoanthropometric method, which enables an objective description of facial structures, was used to better delineate the craniofacial characteristics of 37 individuals with Prader-Willi syndrome (PWS; 21 males and 16 females; 22 with 15q11q13 deletions and 15 with normal-appearing chromosome 15s) between the ages of 0 to 12 years. Facial parameters were measured from strict frontal and profile photographic 35 mm slides and compared with other facial measurements from the same face (e.g., palpebral fissure width to bizygomatic diameter). We studied 16 photoanthropometric craniofacial indices following the protocols established by Stengel-Rutkowski et al. [1984: Hum Genet 67:272-295] and Butler et al. [1988: Am J Med Genet 30:165-168]. Based on our measurements of 37 Prader-Willi syndrome individuals, none of the parameters were consistently outside of the normal range when compared with photoanthropometric index standards for age established from white control children [Stengel-Rutkowski et al., 1984]. However, several suggestive findings were documented by our analysis including: narrow palpebral fissure width [particularly in older children (6-12 years)], high midface, broad interalar distance, short back of the nose, prominent high chin, and broad low-set ears. No significant differences were found in craniofacial parameters between deletion or nondeletion Prader-Willi syndrome patients with this methodology. These craniofacial parameters (many not previously evaluated in PWS patients) may become useful for early detection, and aid in the diagnosis and the study of the development of the characteristic face seen in Prader-Willi patients.

7p deletion syndrome: an adult with mild manifestations.

Deletion of 7p results in a wide spectrum of congenital abnormalities and minor facial and hand anomalies, often including craniosynostosis. We report on the oldest recognized patient with this disorder, a 24-year-old woman with an interstitial deletion from p15.3-p21.2 or p21.3. The manifestations in this patient are milder than those of previously described patients, and include borderline mental retardation, short stature, minor facial anomalies, and several skeletal changes. The absence of craniosynostosis in this patient is noteworthy, given previous suggestions that there is a specific locus for this finding in the 7p region. Twelve cases of 7p deletion, in which the missing segment overlaps that of the current case, are reviewed. This case delineates a broader spectrum for patients with 7p deletion syndrome.