查看更多>>摘要：It has been more than 40 years since the cardiologist Jacqueline Noonan gave a detailed description of a patient with distinct facial, auxological and cardiological features. Since then, this symptom complex has been called Noonan syndrome (NS) [1]. It turned out that NS, together with some other overlapping syndromes, such as the cardio-facio-cutaneous, Costello and LEOPARD syndromes, belongs to one of the most frequent monogenic disorders, with an estimated incidence of 1:1,000-2,500 births [2]. Previous work led to the identification of certain genes that are responsible for these disorders. PTPN11 was the first gene recognized in subjects with NS, whereas several members of the Ras-MAPK pathway have been linked to the Noonan complex more recently.
查看更多>>摘要：It has been more than 40 years since the cardiologist Jacqueline Noonan gave a detailed description of a patient with distinct facial, auxological and cardiological features. Since then, this symptom complex has been called Noonan syndrome (NS) [1]. It turned out that NS, together with some other overlapping syndromes, such as the cardio-facio-cutaneous, Costello and LEOPARD syndromes, belongs to one of the most frequent monogenic disorders, with an estimated incidence of 1:1,000-2,500 births [2]. Previous work led to the identification of certain genes that are responsible for these disorders. PTPN11 was the first gene recognized in subjects with NS, whereas several members of the Ras-MAPK pathway have been linked to the Noonan complex more recently.
查看更多>>摘要：Noonan syndrome (NS) is a fairly common (1 per 1,000-2,500 live births) autosomal dominantly inherited disorder and the most common syndromal cause of congenital heart disease after Down's syndrome. The clinical features vary with age, but typical signs of NS include characteristic facial features with hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, chest and spinal deformities, short stature, specific heart defects, learning disabilities and mild mental retardation. This article gives a brief introduction to NS and its basic clinical features using the established and generally accepted NS scoring system based on family history and facial, cardiac, growth, chest wall and other criteria. Aspects discussed include the definition, epidemiology, etiology, diagnosis and genetics of NS, as well as growth, skeletal and gonadal anomalies, pubertal development, ophthalmic and cutaneous abnormalities and the incidence of cancer in patients with NS.
查看更多>>摘要：Noonan syndrome (NS) is a fairly common (1 per 1,000-2,500 live births) autosomal dominantly inherited disorder and the most common syndromal cause of congenital heart disease after Down's syndrome. The clinical features vary with age, but typical signs of NS include characteristic facial features with hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, chest and spinal deformities, short stature, specific heart defects, learning disabilities and mild mental retardation. This article gives a brief introduction to NS and its basic clinical features using the established and generally accepted NS scoring system based on family history and facial, cardiac, growth, chest wall and other criteria. Aspects discussed include the definition, epidemiology, etiology, diagnosis and genetics of NS, as well as growth, skeletal and gonadal anomalies, pubertal development, ophthalmic and cutaneous abnormalities and the incidence of cancer in patients with NS.
查看更多>>摘要：The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.
查看更多>>摘要：The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.
查看更多>>摘要：The current paper introduces concise neuropsychological assessment as an essential tool for studying the contribution of cognition and behavior in the expression of genetic syndromes, like Noonan syndrome (NS). Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level. Language and motor development are often delayed, but no longer dysfunctional in adulthood. Continuing mild problems in selective and sustained attention are noted, as well as suboptimal organization skills and compromised abilities to structure complex information. These problems seem to culminate in learning difficulties, requiring attention for special needs in education. It seems that a complex of psychosocial immaturity, alexithymia and amenable traits is typical of NS patients. Consequently, psychopathology or psychological problems in leading a self-serving life may often remain underreported. This is why the authors advocate the integration of the domain of social cognition and personality in NS assessment.
查看更多>>摘要：The current paper introduces concise neuropsychological assessment as an essential tool for studying the contribution of cognition and behavior in the expression of genetic syndromes, like Noonan syndrome (NS). Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level. Language and motor development are often delayed, but no longer dysfunctional in adulthood. Continuing mild problems in selective and sustained attention are noted, as well as suboptimal organization skills and compromised abilities to structure complex information. These problems seem to culminate in learning difficulties, requiring attention for special needs in education. It seems that a complex of psychosocial immaturity, alexithymia and amenable traits is typical of NS patients. Consequently, psychopathology or psychological problems in leading a self-serving life may often remain underreported. This is why the authors advocate the integration of the domain of social cognition and personality in NS assessment.
查看更多>>摘要：The hypothalamo-pituitary-adrenal axis has not been studied systematically in Noonan syndrome (NS), despite potential concerns about other aspects of hypothalamo-pituitary function. While adrenarche may be delayed in children with constitutional growth of puberty and in isolated GH deficiency, this does not generally seem to be the case in hypergonadotrophic hypogonadism due to Turner syndrome (TS) and this is (anecdotally) the usual hormonal profile in NS children and adults. Precocious or 'exaggerated' adrenarche can be associated with intrauterine growth retardation and is a forerunner of syndrome X. Although NS neonates often have 'normal' birth weights, in some it can be artificially inflated by subcutaneous edema (as in TS, where intrauterine growth retardation is characteristic). Overall, however, a controlling role for adrenarche (whether precocious or delayed) in gonadarche in NS seems unlikely. Neither normally descended testes nor normal (even if delayed) pubertal development implies normal fertility in NS men. Interactions between fetal, neonatal, childhood and pubertal testis development and gonadal axis maturation are complex. There is probably a spectrum of abnormalities in NS, but most commonly primary gonadal failure and hypergonadotrophic hypogonadism - characteristic NS molecular genetic abnormalities - may be important for normal germ cell proliferation, development and migration. The identification of different gene defects facilitates understanding of NS phenotypic diversity and provides opportunities for prospective studies on gonadal and adrenal axes in better defined populations less subject to ascertainment bias. At a clinical level, more longitudinal data are still needed with regard to the natural history of pubertal timing, its tempo of progression and the pattern of pubertal growth.
查看更多>>摘要：The hypothalamo-pituitary-adrenal axis has not been studied systematically in Noonan syndrome (NS), despite potential concerns about other aspects of hypothalamo-pituitary function. While adrenarche may be delayed in children with constitutional growth of puberty and in isolated GH deficiency, this does not generally seem to be the case in hypergonadotrophic hypogonadism due to Turner syndrome (TS) and this is (anecdotally) the usual hormonal profile in NS children and adults. Precocious or 'exaggerated' adrenarche can be associated with intrauterine growth retardation and is a forerunner of syndrome X. Although NS neonates often have 'normal' birth weights, in some it can be artificially inflated by subcutaneous edema (as in TS, where intrauterine growth retardation is characteristic). Overall, however, a controlling role for adrenarche (whether precocious or delayed) in gonadarche in NS seems unlikely. Neither normally descended testes nor normal (even if delayed) pubertal development implies normal fertility in NS men. Interactions between fetal, neonatal, childhood and pubertal testis development and gonadal axis maturation are complex. There is probably a spectrum of abnormalities in NS, but most commonly primary gonadal failure and hypergonadotrophic hypogonadism - characteristic NS molecular genetic abnormalities - may be important for normal germ cell proliferation, development and migration. The identification of different gene defects facilitates understanding of NS phenotypic diversity and provides opportunities for prospective studies on gonadal and adrenal axes in better defined populations less subject to ascertainment bias. At a clinical level, more longitudinal data are still needed with regard to the natural history of pubertal timing, its tempo of progression and the pattern of pubertal growth.
NSTL
Karger