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

Anestesia locorregional en una paciente adulta con síndrome de Prader-Willi: consideraciones anestésicas / Anesthetic consideration: Regional anesthesia with Prader-Willi

Prader-Willi syndrome (PWS) is a disorder caused by a genetic alteration that causes a multisystem clinic. It can be due mainly to three genetic mechanisms; a paternal deletion of the 15q11-13 region, a maternal uniparental disomy, or an imprinting defect. The paternal deletion is observed in 70% of the patients, the disomy in 25% and the imprinting defect in only 5% of those affected by this syndrome. 1) It is the most common syndromic cause of obesity with an estimated prevalence in the population of 1: 50,000; 2) The clinic is very variable, which is why clinical criteria have been created that, supported by the genetic study, confirm the diagnosis; 3) They have difficulty feeding during lactation, which leads to hyperphagia in childhood that leads to obesity. In the adult stage, in addition to obesity, respiratory pathology, sleep disturbances and psychological disorders stand out; 4) Objective: the aim of the present review was to compile the cases recorded in the scientific literature of patients anesthetized with PWS and the anesthetic options used in said patients.

El síndrome de Prader-Willi (SPW) es un trastorno causado por una alteración genética que provoca una clínica multisistémica. Puede ser debido principalmente a tres mecanismos genéticos; una deleción paterna de la región 15q11-13, una disomía uniparental materna o un defecto de impronta. La deleción paterna se observa en el 70% de los pacientes, la disomía en el 25% y el defecto de impronta en tan solo el 5% de los afectados por este síndrome. 1) Constituye la causa sindrómica más frecuente de obesidad con una prevalencia estimada en la población de 1:50.000; 2) La clínica es muy variable por lo que se han creado unos criterios clínicos que apoyados por el estudio genético confirman el diagnóstico; 3) Presentan dificultad para la alimentación durante la lactancia, que da paso a una hiperfagia en la infancia que deriva en obesidad. En la etapa adulta, además de la obesidad destacan la patología respiratoria, alteraciones del sueño y trastornos psicológicos; 4) Objetivo: el objetivo de la presente revisión fue recopilar los casos registrados en la literatura científica de pacientes anestesiados con SPW y las opciones anestésicas utilizadas en dichos pacientes.

Bariatric surgery in individuals with severe cognitive impairment: report of two cases / Cirurgia bariátrica em indivíduos com déficits cognitivos graves: relato de dois casos

ABSTRACT CONTEXT: Bariatric surgery has become the gold-standard treatment for refractory morbid obesity. Obesity is frequently associated with certain syndromes that include coexisting cognitive deficits. However, the outcomes from bariatric surgery in this group of individuals remain incompletely determined. CASE REPORT: A 25-year-old male with Prader-Willi syndrome, whose intelligence quotient (IQ) was 54, was admitted with a body mass index (BMI) of 55 kg/m2, associated with glucose intolerance. He underwent the Scopinaro procedure for biliopancreatic diversion, with uneventful postoperative evolution, and presented a 55% loss of excess weight one year after the surgery, with resolution of glucose intolerance, and without any manifestation of protein-calorie malnutrition. A 28-year-old male with Down syndrome, whose IQ was 68, was admitted with BMI of 41.5 kg/m2, associated with hypertension. He underwent Roux-en-Y gastric bypass, with uneventful postoperative evolution. He presented a 90% loss of excess weight one year after the surgery, with resolution of the hypertension. CONCLUSION: Bariatric surgery among individuals with intellectual impairment is a controversial topic. There is a tendency among these individuals to present significant weight loss and comorbidity control, but less than what is observed in the general obese population. The severity of the intellectual impairment may be taken into consideration in the decision-making process regarding the most appropriate surgical technique. Bariatric surgery is feasible and safe among these individuals, but further research is necessary to deepen these observations.

RESUMO CONTEXTO: A cirurgia bariátrica tornou-se o tratamento padrão ouro para a obesidade mórbida refratária. A obesidade está frequentemente associada a certas síndromes nas quais também coexistem déficits cognitivos, entretanto, os resultados da cirurgia bariátrica nesse grupo de indivíduos ainda não foram completamente determinados. RELATO DE CASO: Um homem de 25 anos com síndrome de Prader-Willi, cujo quociente de inteligência (QI) era estimado em 54, foi admitido com índice de massa corporal (IMC) de 55 kg/m2, associado com intolerância à glicose. Foi submetido a uma derivação biliopancreática à Scopinaro, com evolução pós-operatória sem complicações significativas. Apresentou perda de 55% do excesso de peso um ano após a cirurgia, com resolução da intolerância à glicose, sem manifestação de desnutrição proteico-calórica. Outro paciente, homem de 28 anos com syndrome de Down, cujo QI era de 68, foi admitido com IMC de 41,5 kg/m2, associado a hipertensão arterial. Foi submetido ao bypass gástrico em Y de Roux, com evolução pós-operatória sem complicações. Apresentou perda de 90% do excesso de peso após um ano e resolução da hipertensão. CONCLUSÃO: A cirurgia bariátrica em indivíduos com déficits intelectuais é um tópico controverso. Existe uma tendência entre esses indivíduos de apresentar perda de peso e controle de comorbidades significativos, porém menores que os observados na população obesa geral. A gravidade do déficit intelectual pode ser considerada no processo de decisão sobre a técnica cirúrgica mais adequada. A cirurgia bariátrica é factível e segura nesse grupo de indivíduos. Porém, mais estudos são necessários para aprofundar estas observações.

Manifestaciones otorrinoloringológicas del síndrome de Prader Willi / Otorhinolaryngologic manifestations of Prader-Willi syndrome / Manifestações otorrinolaringológicas da síndrome de Prader-Willi

El síndrome de Prader-Willi es la causa sindrómica más común de obesidad infantil. Además de la hiperfagia, son característicos la hipotonía, la disfunción hipotalámica y el retraso del desarrollo psicomotor. Esta combinación de signos y síntomas predispone a que estos niños presenten trastornos respiratorios durante el sueño y un mayor riesgo de aspiración de alimentos y asfixia. Describimos las manifestaciones otorrinolaringológicas de este síndrome en la población pediátrica.

Prader-Willi syndrome is the most common syndromic cause of childhood obesity. In addition to hyperphagia, patients suffer from hypotonia, hypothalamic dysfunction and developmental delay. This combination of signs and symptoms predispose these children to sleep-disordered breathing and to an increased risk of food aspiration and asphyxia. We describe otorhinolaryngologic manifestations of this syndrome in the pediatric population.

Síndrome de Prader-Willi é a causa mais comum de sindrômica obesidade infantil. Além hiperfagia, são característicos hipotonia, disfunção hipotalámica e retardo psicomotor. Esta combinação de sinais e sintomas predispõe essas crianças têm distúrbios respiratórios do sono e aumento do risco de aspiração de alimentos e asfixia. Nós descrevemos as manifestações otorrinolaringológicas desta síndrome na população pediátrica.

Falla multiorgánica asociada a hipertermia en una lactante con síndrome de Prader-Willi. caso clínico / Multiorgan failure associated with hyperthermia in an infant with Prader-Willi syndrome. Case report

El golpe de calor es una emergencia médica y se debe entender como una forma de hipertermia asociada a una respuesta inflamatoria sistémica, que ocasiona falla multiorgánica y en la cual la disfunción del sistema nervioso central es predominante. Si no es tratada precozmente, puede ocasionar una alta mortalidad. El síndrome de Prader-Willi es un trastorno genético multisistémico secundario a una anormalidad en el brazo largo del cromosoma 15 (15q11-q13), caracterizado por hipotonía central neonatal, retraso del desarrollo psicomotor, hipogonadismo, hiperfagia y obesidad. Estos pacientes son proclives a presentar problemas de termorregulación. Se comunica el caso de una lactante de 5 meses en quien se estableció el diagnóstico de síndrome de Prader-Willi en el curso de un episodio febril sin foco conocido, que evolucionó con falla multiorgánica y rabdomiólisis secundaria a la hipertermia.

Heat stroke is a medical emergency characterized primarily by an elevated core temperature associated with a systemic inflammatory response, which causes multiple organ dysfunction in which encephalopathy predominates. If it is not early treated has high mortality. The Prader-Willi syndrome is a multisystem genetic disorder secondary to an abnormality in long arm chromosome 15 (15q11-q13), characterized by neonatal central hypotonia, developmental delay, hypogonadism, hyperphagia and obesity. These patients are susceptible to developing thermoregulatory problems. We report the case of a 5-month-old infant, in whom a diagnosis of Prader-Willi syndrome was established in the course of a febrile episode without known focus, who developed multiorganic failure and rhabdomyolysis secondary to hyperthermia.

Percurso e resultados da terapia fonoaudiológica na síndrome de Prader-Willi (SPW): relato de caso / Trajectory and outcomes of speech language therapy in the Prader-Willi syndrome (PWS): case report

O objetivo deste estudo foi descrever o percurso e os resultados da terapia fonoaudiológica na síndrome de Prader-Willi, por meio do estudo longitudinal do caso de uma criança de 8 anos de idade, do gênero masculino, ao longo de quatro anos de terapia fonoaudiológica em uma clínica-escola. Foram realizadas filmagens de sessões de terapia e análise documental de informações dos prontuários referentes à anamnese, avaliação e relatórios terapêuticos fonoaudiológicos e avaliações multidisciplinares. A criança apresentou características típicas da síndrome de Prader-Willi como obesidade, hiperfagia, ansiedade, problemas de comportamento e auto-agressões. Em avaliação fonoaudiológica foram observados hipotonia orofacial, sialorréia, voz hipernasal, alterações cognitivas, dificuldades de compreensão oral, comunicação por meio de gestos e produção de palavras isoladas ininteligíveis. Inicialmente, a terapia fonoaudiológica teve o objetivo principal de promover o desenvolvimento da linguagem com ênfase na interação social por meio de atividades lúdicas. Com a evolução do caso o direcionamento principal passou a ser o desenvolvimento de habilidades conversacionais e narrativas. Foram observadas evoluções quanto à manutenção da atenção, brincadeira simbólica, contato social e comportamento. Além disso, houve aumento do vocabulário, evolução quanto à compreensão oral e desenvolvimento de habilidades narrativas. Dessa maneira, a intervenção fonoaudiológica em caso de síndrome de Prader-Willi foi eficaz em diferentes níveis, no que se refere às habilidades fonológicas, sintáticas, lexicais e pragmáticas da linguagem.

The aim of this study was to describe the trajectory and the outcomes of speech-language therapy in Prader-Willi syndrome through a longitudinal study of the case of an 8 year-old boy, along four years of speech-language therapy follow-up. The therapy sessions were filmed and documental analysis of information from the child's records regarding anamnesis, evaluation and speech-language therapy reports and multidisciplinary evaluations were carried out. The child presented typical characteristics of Prader-Willi syndrome, such as obesity, hyperfagia, anxiety, behavioral problems and self aggression episodes. Speech-language pathology evaluation showed orofacial hypotony, sialorrhea, hypernasal voice, cognitive deficits, oral comprehension difficulties, communication using gestures and unintelligible isolated words. Initially, speech-language therapy had the aim to promote the language development emphasizing social interaction through recreational activities. With the evolution of the case, the main focus became the development of conversation and narrative abilities. It were observed improvements in attention, symbolic play, social contact and behavior. Moreover, there was an increase in vocabulary, and evolution in oral comprehension and the development of narrative abilities. Hence, speech-language pathology intervention in the case described was effective in different linguistic levels, regarding phonological, syntactic, lexical and pragmatic abilities.

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)

Morbid obesity in an adolescent with Prader-Willi syndrome / Obesidad mórbida en una adolescente con síndrome de Prader-Willi

Prader- Willi syndrome is an uncommon multisystem genetic disorder caused by defects of chromosome 15 (15qll-ql3), often due to deletions or uniparental disomy The syndrome is characterized by neonatal hypotonia, dysmorphic facial features, short stature, motor and mental disabilities, behavioral changes, hyperphagia, precocious obesity and hypogonadotropic hypogonadism. We present a 17 year-old woman, with a previous genetic diagnosis of Prader-Willi syndrome and BMI of 74 Kg/m², that was admitted in anasarca, with marked cyanosis, dyspnea and oliguria. She presented high levels ofblood urea, creatinine and aminotransferases, in addition to hyperkalemia and hyperuricemia. She had been in regular use of fluoxetine during the last six months, and evolved with severe high bloodpressure and respiratory failure, which needed intensive care support. Moreover, sequéis and clear signs of recent selfinjuries were observed in her trunk, forearms and hands. The findings of morbid obesity, anasarca, self-injury, hyperuricemia and hypoxemia in Prader- Willi syndrome are emphasized.

El síndrome de Prader-Willi es un desorden multisistémico infrecuente causado por defectos genéticos del cromosoma 15 (15qll-ql3), debido a deleciones o disomía uniparental. Se caracteriza por hipotonía neonatal, dismorfias faciales, baja estatura, incapacidades motoras y mentales, problemas conductuales, hiperfagia, obesidad precoz e hipogonadismo hipogonadotrófico. Presentamos una mujer de 17 años, con IMC de 74 Kg/m² con diagnóstico genético previo del síndrome que ingresó con anasarca, intensa cianosis, disnea y oliguria. Presentaba elevación plasmática de urea, creatinina y aminotransferasas, asociadas con hiperkalemia e hiperuricemia. Había utilizado regularmente ñuoxetina durante los seis meses precedentes y evolucionó con hipertensión arterial severa e insuficiencia respiratoria, que requirieron de cuidados intensivos. Además, se constataron cicatrices y claras señales de automutilación reciente en su tronco, antebrazos y manos. Se destacan los hallazgos de obesidad mórbida, anasarca, automutilación, hiperuricemia e hipoxemia en el síndrome de Prader-Willi.

Abordagem terapêutica da obesidade na Síndrome de Prader-Willi / Therapeutical approach of obesity in Prader-Willi Syndrome

A Síndrome de Prader-Willi (SPW) é uma doença complexa, multissistêmica, caracterizada por hipotonia, retardo mental, características dismórficas, hiperfagia e compulsão alimentar devido à disfunção hipotalâmica. SPW ocorre pela perda de função de genes localizados no cromossomo 15q11-13, região que sofre imprinting genômico. Obesidade é a principal causa de morbidade e mortalidade entre pacientes com SPW. O objetivo desta revisão é analisar as opções terapêuticas disponíveis para o tratamento da obesidade na SPW, incluindo a terapia farmacológica e o tratamento cirúrgico.

Prader-Willi Syndrome (PWS) is a multisystemic genetic disease characterized by hypotonia, mental retardation, characteristic facial appearance, hyperphagia, and compulsive eating due to hypothalamic dysfunction. PWS is caused by loss of function of genes located in chromosome 15q11-q13, an area subject to genomic imprinting. Obesity is a major cause of increased morbidity and mortality among patients with PWS. The objective of this study was to analyze the therapeutic options available for the treatment of the obesity in PWS including pharmacological and surgical strategies.

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.

Syndromes and disorders associated with mental retardation.

This article reviews selective comments on the concept of Mental Retardation (MR) in adolescents. Issues covered include the definition, prevalence, and differential diagnosis of MR. Some of the syndromes and disorders associated with MR in the adolescents are also considered with emphasis on the behavioral concerns that may be present in this age group. Finally, concepts of management by the clinician are reviewed. It is recommended that health care professionals caring for adolescents with MR should help these youths maximize their potential as human beings, helping them achieve meaningful functioning in adulthood.

Síndrome Prader Willi asociado a obesidad mórbida: tratamiento quirúrgico / Surgical treatment of morbid obesity associated to Prader-Willi syndrome: report of 1 case

Prader-Willi Syndrome (PWS) is a multisystemic genetic disease characterized by hypothalamic hypogonadism, mental retardation and compulsive hyperphagia associated with early and severe obesity. Complications of overweight, such as type-2 diabetes Mellitus, dyslipidemia and diffuse atheromatosis are common. We report a 15 years old morbid obese male with PWS, with a body mass index of 57.7 kg/m2, refractory to weight-lowering treatments. He underwent preoperative evaluation and treatment by a multidisciplinary team, and subjected to a 95 percent gastrectomy, leaving a 50 ml remnant pouch and a long limb (120 cm) Y-Roux gastro-jejuno anastomosis. There were no surgical complications, oral feeding was initiated at the 5th day with an hypocaloric diet. During the first postoperative year, the patient lost 70 kg, achieving a body mass index of 30 kg/m2. Surgical treatment can become a therapeutic choice for obesity in PWS patients

Prader-Willi syndrome with sleep disordered breathing: effect of two years nocturnal CPAP.

We report a case of a 3-year-old child with Prader-Willi syndrome who had severe sleep disordered breathing with daytime hypersomnolence. His daytime blood gases showed type II respiratory failure. He was effectively treated with continuous positive airway pressure (CPAP) and has used this form of therapy for 2 years now with improvement in daytime somnolence, improved mental acuity and normalisation of daytime blood gases.