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.

Utilización de la hormona de crecimiento en niños y adolescentes / [Use of growth hormone in children and adolescents].

Growth hormone treatment for children and adolescents with growth disorders has been used for more than five decades. Since 1985 recombinant human growth hormone (rhGH) is the only drug approved for treatment. In most of the countries rhGH is licensed for the treatment of children with growth hormone deficiency, Turner syndrome, Prader-Willi syndrome, chronic renal failure, and children born small for gestational age. The objective of the treatment is to improve the growth of these patients. The efficacy of rhGH treatment based on auxologic parameters has shown that growth response is variable and mostly dependent on each particular indication. Most of the reports on drug safety obtained from different databases that included thousands of patients, have shown that rhGH is a safe drug and that serious adverse events are rare. Regarding new indications to improve height in children, data on efficacy remains controversial, so we believe their ultimate indication must take into account potential risk versus benefits of this treatment.

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.

Uso de hormônio de crescimento na síndrome de Prader-Willi: [revisão] / Growth hormone usage in Prader-Willi syndrome: [review]

A síndrome de Prader-Willi (PWS), com prevalência de 60:1.000.000, é o resultado da perda de parte do cromossomo 15 paterno, em razão da deleção em 56 por cento dos casos, dissomia uniparental materna em 24 por cento dos casos, ou por causa da metilação, fenômeno epigenético, em 18 por cento dos casos. O quadro clínico inicia-se com profunda hipotonia que, especialmente no primeiro ano de vida, torna difícil a alimentação da criança. Conforme melhora a hipotonia, nos primeiros dois anos, por volta do quarto ano de vida, um apetite insaciável advém, o que leva tais crianças à obesidade extrema, com hipoventilação alveolar que põe em risco sua sobrevivência. Dessa forma, paradoxalmente, a PWS ameaça a vida dos pacientes, em um primeiro momento, por inanição e, em uma fase posterior, pelo excesso de peso. O uso de hormônio de crescimento (hrGH) nessas crianças tem por objetivo primário a mudança da composição corpórea e a melhora da atividade física e da qualidade de vida. Por outro lado, muitos pacientes com PWS são, de fato, deficientes em GH, ocorrendo melhora no padrão de crescimento com o tratamento. Tem-se de ser cuidadoso, no entanto, ao iniciar o tratamento com hrGH, com zelosa avaliação da apnéia do sono (polissonografia) e da permeabilidade das vias aéreas, tendo em vista que o tratamento com hrGH pode piorar o padrão respiratório em alguns pacientes.

Prader-Willi syndrome (PWS), with a prevalence of 60:1.000.000, results from the loss of paternal chromosome 15, being 56 percent due to deletion, 24 percent due to uniparental maternal disomy, and 18 percent from methylation, an epigenetic phenomenon. The clinical picture begins with extreme muscular hypotonia, which makes it difficult to feed the child in the first year. As the hypotonia improves, usually in the first two years, around the 4th year of life, an insatiable appetite leads these children to an extreme obesity, with alveolar hypoventilation which endangers their lives. So, paradoxically, PWS threatens the lives of the patients, through inanition in a first phase and, afterwards, through excessive weight gain. The use of growth hormone (hrGH) in these children has a primary goal to change the body composition and improve the physical activity and the quality of life. On the other hand, many PWS patients are indeed GH deficient, and an improvement in the height SDS occurs with treatment. We have to be careful, however. When starting a PWS treatment with a patient on hrGH, a careful evaluation of sleep apnoea (polysomnography) as well as a careful examination of the airways is extremely mandatory, since the treatment may compromise the respiratory pattern of some patients.

Síndrome de Prader-Willi: aspectos metabólicos associados ao tratamento com hormônio de crescimento / Prader-Willi syndrome: metabolic aspects related to growth hormone treatment

OBJETIVOS: Avaliar as alterações metabólicas de crianças e adolescentes portadores da Síndrome de Prader-Willi tratadas com hormônio de crescimento recombinante humano (rhGH). CASUíSTICA E MÉTODOS: Foram estudados sete pacientes: quatro meninos e três meninas, com idades de seis anos e seis meses a 14 anos e 11 meses. Receberam rhGH, 0,1 U/Kg/dia subcutâneo, seis vezes por semana, durante dois anos. Avaliamos dados antropométricos, lípides séricos, glicemia, IGF-I e composição corpórea, no início e após 12 e 24 meses de tratamento com rhGH. RESULTADOS: Todos os pacientes tiveram elevação do IGF-I. Houve diminuição das pregas cutâneas, sendo que a média de perda de massa adiposa foi de 5,0 por cento e a massa magra aumentou em média 7,6 kg nos pré-púberes, e a paciente púbere ganhou 4,8 kg e teve um decréscimo de 5,6 por cento de massa adiposa. Houve ganho de massa óssea de 0,07 g/cm² (7,3 por cento) nos pré-púberes e de 0,02 g/cm² (2,0 por cento) na menina púbere. CONCLUSÃO: Em nosso estudo, o uso do hormônio de crescimento na Síndrome de Prader-Willi melhorou a composição corpórea e demonstrou aumento da massa muscular e massa óssea com melhora dos níveis lipídicos.

AIM: The focus of this study was to evaluate the metabolic profile of Prader-Willi Syndrome (PWS) patients treated with growth hormone. PATIENTS AND METHODS: Seven patients (four boys and three girls) with ages between six years and six months and 14 years and 11 months were treated with GH 0.1 U/kg/day subcutaneous by six times a week, for two years. Anthropometric data, lipids, glucose, IGF-I and body composition were evaluated at baseline and after 12 and 24 months. RESULTS: IGF-I levels increased in all cases. Skin folds decreased. The mean reduction in body fat was 5.0 percent and the mean increased in lean mass was 7.6 kg in the prepubertal patients. The pubescent girl increased 4.8 kg and showed a 5.6 percent decrease in fat mass. A mean gain in the bone mass was 0.07 g/cm² (7.3 percent) in prepubescent cases, and 0.02 g/cm² (2.0 percent) in the pubescent girl. CONCLUSION: In our study GH treatment improved lean body and bone masses and had beneficial effect on lipid values.

Growth hormone therapy.

Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.

Short stature and growth hormone.

Normal growth and development is a prime concern during childhood. Accurate assessment is essential for differentiating between normal and abnormal growth. Increased accessibility to growth hormone has equipped the pediatrician and pediatric endocrinologist to treat and improve growth in many clinical scenarios. At the same time, there is added responsibility to use this tool judiciously. This review summarizes the basics of proper growth assessment, differentiation of normal and abnormal growth causes of and works up of short stature, and delineation of indications for growth hormone treatment.

Síndrome de Prader-Willi: tratamiento con hormona de crecimiento en dos casos / Use of growth hormone in Prader-Willi syndrome: report of 2 cases

Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by the absence or abnormal inactivation of a critical region of the paternal chromosome 15. Clinical manifestations include marked hypotonia at birth, progressive obesity that starts during the second year of life, stunting, hypogonadism and some dysmorphic features. Some of the symptoms and signs can be explained by growth hormone (GH) deficiency. We report two females aged 12 and 13 years old with PWS. Both were very short and obese, showed blunted GH responses to provocative stimuli and had low plasma levels of Insulin Growth Factor-1 (IGF-1). They have been on GH treatment for more than two years, demonstrating a marked growth acceleration, reduction in their fat mass, improvement of their muscular strength and an increase in their IGF-1 levels