Prader-Willi syndrome: endocrine manifestations and management

ABSTRACT Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic dysfunction that can lead to various endocrine changes such as: obesity, growth hormone deficiency, hypogonadism, hypothyroidism, adrenal insufficiency and low bone mineral density. In addition, individuals with PWS have increased risk of developing type 2 diabetes mellitus. This review summarizes and updates the current knowledge about the prevention, diagnosis and treatment of endocrine manifestations associated with Prader Willi syndrome, especially diagnosis of growth hormone deficiency, management and monitoring of adverse effects; diagnosis of central adrenal insufficiency and management in stressful situations; screening for central hypothyroidism; research and treatment of hypogonadism; prevention and treatment of disorders of glucose metabolism. Careful attention to the endocrine aspects of PWS contributes significantly to the health of these individuals. Arch Endocrinol Metab. 2020;64(3):223-34

Análisis de variación del número de copias y de patrones de metilación en la región 15q11-q13 / Variation analysis of the number of copies and methylene patterns in region 15q11-q13

La región q11-q13 del cromosoma 15 humano es proclive a sufrir alteraciones genéticas. Algunos genes de la región presentan expresión parental diferencial monoalélica, regulada por imprinting (EI). Errores en la regulación del EI, disomías uniparentales (DSU), así como también el cambio en el número de copias genómicas (CNV) producidos por sitios susceptibles de quiebre cromosómico (BP), producen alteraciones en esta región. Las enfermedades más frecuentes asociadas son el síndrome de Prader-Willi, el síndrome de Angelman y el síndrome de microduplicación 15q11-q13. En el presente trabajo analizamos la región 15q11-q13 por Methyl specific-multiplex ligation-dependent probe amplification (MS-MLPA) en 181 muestras de ADN derivadas a nuestro servicio de análisis genético molecular. En este trabajo mostramos que, de las 181 muestras, 39 presentaron alteraciones detectables por MS-MLPA. El 61.5% (24/39) de esas alteraciones detectadas fueron deleciones, el 5.1% (2/39) duplicaciones y el 33.3%(13/39) DSU/EI. Los CNV fueron 4 veces más frecuentes que las DSU/EI (OR = 4; IC 95%: 1.56-10.25) consistente con la literatura. Entre los CNV, dos casos atípicos permiten postular posibles sitios BP que no han sido informados en la literatura previamente.

Human chromosome 15q11-q13 region is prone to suffer genetic alterations. Some genes of this region have a differential monoallelic imprinting-regulated expression pattern. Defects in imprinting regulation (IE), uniparental disomy (UPD) or copy number variation (CNV) due to chromosomal breakpoints (BP) in 15q11-q13 region, are associated with several diseases. The most frequent are Prader-Willi syndrome, Angelman syndrome and 15q11-q13 microduplication syndrome. In this work, we analyzed DNA samples from 181 patients with phenotypes which were compatible with the above-mentioned diseases, using Methyl specific-multiplex ligation-dependent probe amplification (MS-MLPA). We show that, of the 181 samples, 39 presented alterations detectable by MS-MLPA. Of those alterations, 61.5% (24/39) were deletions, 5.1% (2/39) duplications and 33.3% (13/39) UPD/IE. The CNV cases were 4 times more frequent than UPD/IE (OR= 4; IC 95%: 1.56-10.25), consistent with the literature. Among the CNVs, two atypical cases allow to postulate new possible BP sites that have not been reported previously in the literature.

A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy

SUMMARY Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS.

Molecular cytogenetic evaluation of chromosomal microdeletions: the experience of a public hospital in Southern Brazil

Introduction: During the past few decades, the number of diseases identified to be caused by chromosomal microdeletions has increased quickly, bringing a new and crucial role for cytogenetics on the diagnosis of these conditions. The purpose of this study was to identify and characterize chromosomal microdeletions associated with malformation syndromes and intellectual disability. Methods: We retrospectively evaluated a consecutive series of samples from a cohort of 598 subjects with clinical symptoms of a microdeletion syndrome, including the deletion of chromosomes 4p16.3, 5p15.2, 5q35, 7q11.23, 8q24.12, 15q11.2, 16p13.3, 17p13.3, 17p11.2,2, and 22q11.2, as investigated by fluorescence in situ hybridization (FISH). Array-based comparative genomic hybridization (array-CGH) was performed on 25 samples with microdeletions. Results: A total of 598 samples were evaluated from patients whose clinical phenotypes were most indicative of 22q11.2 deletion syndrome (29.10%), Prader-Willi syndrome (23.41%), Angelman syndrome (16.89%), and Williams-Beuren syndrome (14.72%). In 142 of the samples (23.75%), a chromosomal imbalance associated with phenotypic abnormalities was found. The deletion of 7q11.23 was the most frequent (8.03%), followed by del22q11.2 (5.68%) and del15q11.2 (5%). Conclusion: Our study reinforces the idea that the effort to improve the capacity to perform molecular cytogenetic investigations associated with a qualified clinical evaluation is crucial for the detection and precise characterization of submicroscopic chromosome deletions, bringing benefits to patients, relatives, and genetic counselors. It also contributes to the continuing education of cytogeneticists and to the knowledge of chromosomal rearrangements associated with genomic disorders.

A clinical follow-up of 35 Brazilian patients with Prader-Willi Syndrome

OBJECTIVE: Prader-Willi Syndrome is a common etiology of syndromic obesity that is typically caused by either a paternal microdeletion of a region in chromosome 15 (microdeletions) or a maternal uniparental disomy of this chromosome. The purpose of this study was to describe the most significant clinical features of 35 Brazilian patients with molecularly confirmed Prader-Willi syndrome and to determine the effects of growth hormone treatment on clinical outcomes. METHODS: A retrospective study was performed based on the medical records of a cohort of 35 patients diagnosed with Prader-Willi syndrome. The main clinical characteristics were compared between the group of patients presenting with microdeletions and the group presenting with maternal uniparental disomy of chromosome 15. Curves for height/length, weight and body mass index were constructed and compared between Prader-Willi syndrome patients treated with and without growth hormone to determine how growth hormone treatment affected body composition. The curves for these patient groups were also compared with curves for the normal population. RESULTS: No significant differences were identified between patients with microdeletions and patients with maternal uniparental disomy for any of the clinical parameters measured. Growth hormone treatment considerably improved the control of weight gain and body mass index for female patients but had no effect on either parameter in male patients. Growth hormone treatment did not affect height/length in either gender. CONCLUSION: The prevalence rates of several clinical features in this study are in agreement with the rates reported in the literature. Additionally, we found modest benefits of growth hormone treatment but failed to demonstrate differences between patients with microdeletions and those with maternal uniparental disomy. The control of weight gain in patients with Prader-Willi syndrome is complex and does not depend exclusively on growth hormone treatment.

Síndrome de Prader-Willi: criterio y guía para la atención odontopediátrica / Prader-Willi syndrome: criteria and guidelines for the pediatric dental care

El síndrome de Prader-Willi (SPW) es una enfermedad rara (incidencia 1:15.000), de causa genética, debido a una deleción del cromosoma 15 paterno en la región 15q 11-q13. Presenta alteraciones a nivel del hipotálamo con manifestaciones clínicas típicas, tales como hipotonía, hipogonadismo, facies típica y retraso mental que permiten su diagnóstico. El pronóstico de esta patología suele ser favorable si existe un adecuado manejo en la alimentación y un ambiente familiar con contención. Los odontólogos cumplen un rol fundamental en el mantenimienot y prevención de la salud bucal. El trabajo de interdisciplina es uno de los pilares fundamentales para un correcto abordaje y tratamiento odontológico, con el objetivo final de lograr la salud bucal que redundará en la salud sistémica de estas personas. En una unidad de atención odontológica especializada para niños portadores de discapacidad y riesgo médico se han atendido 16 pacientes durante los últimos 6 años, habiéndose confeccionado una guía de atención odontológica para pacientes con SPW basada en el plan de tratamiento odontopediátrico personalizado que tendrá en cuenta los signos y sintomatología sistémica y en especial las características bucodentales. De la atención clínica surgió la necesidad de realizar estudios específicos en la saliva de estos niños, por su característica especial, los cuales fueron realizados en interrelación con la universidad relacionada a la unidad de atención de pacientes especiales.

Prader-Willi syndrome: Methylation study or fluorescence in situ hybridization first.

Prader–Willi syndrome (PWS) is neurogenetic disorder involving the imprinting mechanism at 15q11–13 region. We report a 4-year-old girl who was referred to our laboratory to be investigated for clinical obesity, mental deficiency and respiratory problems. The patient was born for non-consanguineous and healthy biological parents. After normal pregnancy, the patient was delivered by cesarean section at full term, with a birth weight of 2500 g, and the height and head circumference were unknown. In neonatal stage, she presented severe hypotonia with feeding problems. Her developmental progress was delayed. She walked and developed speech at the age of 3 years. Since the age of 3 years, she presented severe dental problems. Methylation study had confirmed the diagnosis, and for detecting etiology, fluorescence in situ hybridization using probes for small nuclear ribonucleoprotein polypeptide N (SNRPN), which map inside the chromosomal region 15q11–15q13, was necessary to confirm the 15q11–15q13 deletion of paternal chromosome 15, which is the predominant genetic defect in PWS. In conclusion, we report this case with an objective to reinforce the necessity of analysis of DNA methylation within the 15q11–13 region, which is an important tool for the correct diagnosis among children presenting with neonatal hypotonia, mental deficiency and obesity.

Hipotiroidismo central en pacientes con el síndrome de Prader-Willi durante los 2 primeros años de vida / Central hypothyroidism in patients with Prader-Willi syndrome during the first 2 years of life

Introducción. El síndrome de Prader-Willi SPW) es un trastorno genético causado por la pérdida de expresión de genes de origen paterno en la región cromosómica compleja 15q11-q13. El fenotipo clínico ha sido bien caracterizado, especialmente relacionado con la disfunción hipotalámica. Aunque entre 20 a 30% de los pacientes con SPW tienen hipotiroidismo central (HC), no ha sido bien definida la función tiroidea durante los dos primeros años de vida. Objetivo: evaluar la función hipotalámica-pituitaria-tiroidea en lactantes con SPW. Diseño del estudio: 18 pacientes con SPW entre 0,16 y 2 años de edad fueron incluídos en un estudio prospectivo. El diagnóstico de SPW se basó en los hallazgos clínicos y en el análisis molecular. Se calcularon los escores de desviacion estándar (SDS) de la T4 total (T), T4 libre (L), T3 y TSH en suero en todos los pacientes incluídos en el estudio. Resultados: En 14 de los 18 pacientes con SPW, se encontraron niveles de T4T y/o T4L menores a -2 SDS (44,4 y 55,5%, respectivamente), mientras que solamente en 1 paciente con SPW el nivel de T3 estaba por debajo de -2 SDS. Conclusión: Este estudio muestra que la incidencia de HC es alta en lactantes con SPW. Los pediatras deben tener en cuenta el diagnostico de HC en este período crítico de la acción de la hormona tiroidea en el desarrollo neurológico (AU)

Introduction. Prader-Willi syndrome (PWS) is a genetic disorder caused by the loss of expression of paternally transcribed genes in a highly imprinted region of chromosome 15q11- q13. The clinical phenotype has been well characterized, mostly related to hypothalamic dysfunction. Even though central hypothyroidism (CH) has been documented in 20 to 30% of PWS patients, thyroid function has not been well characterized during the first 2 years of life. Objective: to evaluate hypothalamic-pituitary-thyroid function in infant PWS patients. Study design: Eighteen PWS patients, aged 0.16 to 2 years, were included in a prospective study. PWS diagnosis was based on clinical features and molecular analysis. Serum total (T) T4, free (F) T4, T3 and TSH standard deviation scores (SDS) were calculated in all PWS patients included in the study. Results: In 14 out of 18 PWS patients, serum TT4 and/or FT4 levels less than -2 SDS ( 44.4 and 55.5 %, respectively) were found, while in only 1 PWS patient serum T3 levels was below -2 SDS. Conclusion: This study shows that there is a high incidence of CH in infant PWS patients. Pediatricians should be aware of this diagnosis in this critical period of thyroid hormone action on neurological development (AU)

Comparing Two Diagnostic Laboratory Tests for Several Microdeletions Causing Mental Retardation Syndromes: Multiplex Ligation-Dependent Amplification vs Fluorescent In Situ Hybridization / 대한진단검사의학회지

BACKGROUND: Microdeletion syndromes not detectable by conventional cytogenetic analysis have been reported to occur in approximately 5% of patients with unexplained mental retardation (MR). Therefore, it is essential to ensure that patients with MR are screened for these microdeletion syndromes. Mental retardation syndrome multiplex ligation-dependent probe amplification (MRS-MLPA) is a new technique for measuring sequence dosages that allows for the detection of copy number changes of several microdeletion syndromes (1p36 deletion syndrome, Williams syndrome, Smith-Magenis syndrome, Miller-Dieker syndrome, DiGeorge syndrome, Prader-Willi/Angelman syndrome, Alagille syndrome, Saethre-Chotzen syndrome, and Sotos syndrome) to be processed simultaneously, thus significantly reducing the amount of laboratory work. METHODS: We assessed the performance of MLPA (MRC-Holland, The Netherlands) for the detection of microdeletion syndromes by comparing the results with those generated using FISH assays. MLPA analysis was carried out on 12 patients with microdeletion confirmed by FISH (three DiGeorge syndrome, four Williams syndrome, four Prader-Willi syndrome, and one Miller-Dieker syndrome). RESULTS: The results of MLPA analysis showed a complete concordance with FISH in 12 patients with microdeletion syndromes. CONCLUSIONS: On the basis of these results, we conclude that MLPA is an accurate, reliable, and cost-effective alternative to FISH in the screening for microdeletion syndromes.

Lack of evidence for monosomy 1p36 in patients with Prader-Willi-like phenotype

Monosomy 1p36 is the most common subtelomeric microdeletion syndrome with an incidence rate estimated to be 1 in 5000 births. A hypothesis of a similarity between patients with 1p36 deletion and those with Prader-Willi syndrome and the existence of two different phenotypes for 1p36 microdeletion has been suggested. The main objective of the present study was to determine the existence of 1p36 microdeletion in a sample of patients with mental retardation, obesity and hyperphagia who tested negative by the methylation test for Prader-Willi syndrome. Sixteen patients (7 females, 9 males), 16-26 years old, were evaluated with high-resolution cytogenetic analysis at 550-850 band levels and with 11 polymorphic microsatellite markers located in the 1p36 region. All patients had normal cytogenetic and molecular results. The results obtained by high-resolution cytogenetic methodology were confirmed by the molecular analyses. We did not detect a 1p36 microdeletion in 16 subjects with the Prader-Willi-like phenotype, which reinforces that no correlation seems to exist between Prader-Willi-like phenotype and the 1p36 microdeletion syndrome.

Síndrome de Prader-Willi: a propósito de un caso / Prader-Willi syndrome: a purpose of a case

El Síndrome de Prader-Willi es una alteración genética poco frecuente, cuyo fenotipo es obesidad, baja estatura, retraso mental moderado e hipotonía neonatal. La alteración genética que se observa con mayor frecuencia es la delección intersticial 15q11-q13 en el cromosoma 15 de origen paterno. Su diagnóstico no siempre es fácil debido a que muchos de sus rasgos pueden ser pocos específicos y otros cambian con la edad. Por ello se han desarrollado protocolos con los criterios de diagnóstico clínico. La sospecha clínica de SPW y su confirmación mediante análisis de metilación, proporciona la oportunidad para dirigir y prevenir problemas y complicaciones que puedan ocurrir mas tarde. Se presenta el caso de un escolar masculino de 6 años de edad, quien exhibe las características clínicas y citogenéticas de SPW. Se hace una revisión de la literatura y discusión de hallazgos clínicos y estudios citogenéticos.

Atypical presentation of Prader-Willi syndrome with Klinefelter (XXY karytype) and craniosynostosis

A síndrome de Prader-Willi é afecção genética de deficiência mental associada a hipogonadismo hipogonadotrófico, hiperfagia e obesidade. Descrevemos o caso de menino de 4 anos de idade, filho de casal consangüíneo, apresentando três condições clínicas não relacionadas: síndrome de Prader-Willi, cariótipo 47,XXY (compatível com síndrome de Klinefelter) e craniossinostose coronal. Ao nosso conhecimento, não foi relatado caso semelhante previamente na literatura.

A combination of five short tandem repeats of chromosome 15 significantly improves the identification of Prader-Willi syndrome etiology in the Argentinean population

Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes in the PWS critical region of chromosome 15. Various molecular mechanisms are known to lead to PWS: deletion 15q11-q13 (75% of cases), maternal uniparental disomy (matUPD15) (23%) and imprinting defects (2%). FISH and microsatellite analysis are required to establish the molecular etiology, which is essential for appropriate genetic counseling and care management. We characterized an Argentinean population, using five microsatellite markers (D15S1035, D15S11, D15S113, GABRB3, D15S211) chosen to develop an appropriate cost-effective method to establish the parental origin of chromosome 15 in nondeleted PWS patients. The range of heterozygosity for these five microsatellites was 0.59 to 0.94. The average heterozygosity obtained for joint loci was 0.81. The parental origin of chromosome 15 was established by microsatellite analysis in 19 of 21 non-deleted PWS children. We also examined the origin of the matUPD15; as expected, most of disomies were due to a maternal meiosis I error. The molecular characterization of this set of five microsatellites with high heterozygosity and polymorphism information content improves the diagnostic algorithm of Argentinean PWS children, contributing significantly to adequate genetic counseling of such families.

Caracterización clínico-genético-molecular de 45 pacientes chilenos con Síndrome de Prader Willi / Clinical, genetic and molecular features in 45 patients with Prader-Willi Syndrome

Background: Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by neonatal hypotonia, retarded mental and motor development, hypogonadism, hyperphagia, morbid obesity and dysmorphic facial features. It has an incidence of 1:12.000-15.000 newborns and is caused by abnormalities in genes located in 15q11q13. PWS is one of the most frequent genetic disorders and microdeletion syndromes. It is also the most common cause of obesity from genetic origin and it was the first disease in which imprinting and uniparental disomy were recognized as cause of genetic disorders. Seventy to seventy five percent of PWS cases are due to 15q11q13 deletions, 20-25percent to uniparental disomy and 1percent to mutations in the imprinting center. Aim: To analyze the clinical, genetic and molecular features of patients with PWS, seen at one institution. Patients and methods: Retrospective review of 45 patients (27 males) with PWS seen at the Genetics Outpatient Clinic at INTA. Results: Twenty three (51.1percent) patients had a delection, 13 (28.9percent) patients did not have a deletion. In nine patients, fluorescence in situ hybridization (FISH) study was not performed, therefore the presence of deletion was unknown. The clinical score was 8 points for patients younger than 3 years (n=11) and 11.5 points for patients older than 3 years (n=34); for patients aged 12 months or less, the clinical score was 7 points. Mean clinical score was 11 points for patients with deletion and 10 points for patients without deletion. Conclusions: Most patients with PWS have a deletion; the phenotype depends on age and the clinical score is useful for Chilean patients with PWS .

Low level of mosaicism in atypical Prader Willi syndrome: detection using fluorescent in situ hybridization.

Prader Willi syndrome (PWS) most commonly is due to paternal micro-deletion of 15q11-q13. Although PWS is not a rare condition, mosaic micro-deletion cases are reported rarely. FISH using PWS micro-deletion probe is the most useful method to detect deletion including mosaicism. In this report we describe a female child with clinical features of atypical PWS and FISH analysis showing mosaicism for deletion in the PWS critical region. This is first mosaic deletion case of PWS from Indian subcontinent.

A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity

Diagnosis of patients with Prader-Willi and Angelman Syndromes: the importance of an overall investigation

Seventy-two patients with clinical diagnoses of Prader-Willi (PWS; n = 28 patients) or Angelman syndromes (AS; n = 44 patients) were submitted to chromosome analysis, SNRPN-SNURF exon 1 methylation assay, and microsatellite genotyping. Analysis of the methylation pattern confirmed the PWS diagnosis in 18 out of 28 patients and the AS diagnosis in 20 out of 44 patients. FISH and microsatellite analysis detected a deletion in 30 patients (14 PWS and 16 AS). Eight patients had normal FISH results (4 PWS and 4 AS); microsatellite markers showed that these patients had a uniparental disomy (UPD). Based on this study, we propose a strategy for the routine diagnosis of these syndromes that consists of the following steps: 1) methylation analysis, which does not require parental samples; 2) microsatellite genotyping of patient and parents to differentiate deletions, UPD and imprinting mutations; and 3) FISH for otherwise uninformative cases, and whenever parental samples are not available. Of the 34 patients whose PWS or AS diagnoses were not confirmed by laboratory tests, five presented a small extra marker chromosome, identified in three of them as an inv dup(15). One AS patient carried a balanced t(15;15) translocation associated with paternal UPD. Therefore G-banded chromosome analysis should be performed on all such patients, to detect possible structural rearrangements

Genomic imprinting and human chromosome 15

Genomic imprinting is a reversible phenomenon that affects the expression of genes depending on their parental origin. The best characterized human disorders resulting from an alteration of the imprinting process are Angelman and Prader-Willi syndromes. They are due to the lack of active maternal or paternal genes, respectively, from chromosome region 15q11q13. Most cases arise via interstitial deletions. We review evidence that other common cytogenetic alterations of this region, interstitial and supernumerary duplications, could be the reciprocal products of the deletions and are also affected by the imprinting phenomenon, given the predominance of maternally-derived duplications in patients ascertained due to developmental delays or autistic features.

Genomic imprinting: genetic mechanisms and phenotypic consequences in Prader-Willi and Angelman syndromes

O segmento cromossômico 15q11-q13 é de grande interesse em Genética Humana uma vez que diversos rearranjos estruturais têm sido descritos nessa regiäo (deleçöes, duplicaçöes e translocaçöes) resultando em fenótipos diferentes como os das síndromes de Prader-Willi (PWS) e Angelman (AS), que foram as primeiras doenças humanas a serem relacionadas com a expressäo diferencial de alelos parentais (imprinting genômico). Contrário às leis de Mendel onde a herança parental da informaçäo genética näo influencia a expressäo gênica, o imprinting genômico é caracterizado por modificaçöes no DNA que produzem diferentes fenótipos dependendo da origem parental da mutaçäo. A manifestaçäo clínica da PWS aparece quando ocorre a perda de genes com expressäo exclusivamente paterna, e a AS resulta da perda do gene com expressäo exclusivamente materna. Diferentes mecanismos genéticos podem resultar em PWS ou AS como deleçöes, dissomia uniparental ou mutaçöes no processo de imprinting. Em pacientes com AS existe uma classe adicional de pacientes com mutaçäo no gene UBE3A. Estudos de pacientes com PWS e AS podem ajudar no entendimento do processo de imprinting e, assim, outras regiöes do genoma com características similares podem ser localizadas, e diferentes síndromes podem ter seus mecanismos genéticos elucidados.

Impronta genómica en el síndrome de Prader-Willi y en el síndrome de Angelman / Genetic imprinting in the Prader-Willi and Angelman syndromes

Los síndromes de Angelman y Prader-Willi son desórdenes del neurocomportamiento con manifestaciones clínicas diferentes y constituyen el mejor ejemplo del concepto de impronta genómica. Se encuentran asociados con deficiencias maternas y paternas de una misma región en el cromosoma 15q11-q13, respectivamente. Los pacientes con síndrome de Prader-Willi presentan hipotonía muscular al nacimiento, obesidad, talla baja, retraso psicomotor e hipogonadismo; la facies es peculiar. El síndrome de Angelman se caracteriza por microbraquicefalia, pelo delgado y claro, hipoplasia maxilar, ojos hundidos, boca grande con protrusión lingual y prognatismo; el retraso psicomotor es severo, neurológicamente presentan ataxia, movimientos como ®marioneta¼ y ausencia del lenguaje; la mayoría de los pacientes presenta convulsiones, electroencefalograma anormal y paroxismos de risa. El pronóstico de ambas enfermedades es bueno si se evitan las complicaciones