Turner syndrome and neurofibromatosis 1: Rare co-existence with important clinical implications / Journal of the ASEAN Federation of Endocrine Societies

@#A 16.5-year-old Indian female presented with secondary amenorrhoea, cubitus valgus, scoliosis and multiple lentigines on the face. Karyotyping revealed mosaic Turner syndrome (TS) with 45, X/46, X iXq. She also had multiple café-au-lait macules and axillary freckles but no neurofibroma and did not fulfil the classic criteria for diagnosis of Neurofibromatosis-1(NF1). Many of her macules were smaller than 15 mm in diameter, which might be due to her hypoestrogenic state. However, exome-sequencing found a pathologic variant consistent with NF1. She was started on daily oral estrogen, and oral progesterone for 10 days every month with close monitoring for neurofibroma and/or glioma expansion. Co-occurrence of NF1 and TS is extremely rare, TS and NF1 can both affect growth and puberty, cause different cutaneous and skeletal deformities, hypertension, vasculopathy and learning disabilities. Our case highlights the need for genetic testing in some cases with NF1 who do not strictly fulfil the NIH diagnostic criteria. We also emphasize the need for close monitoring during therapy with growth hormone, estrogen and progesterone due to the potential risk of tumour expansion in NF1.

Advances in the pathogenesis and treatment of short stature in Noonan syndrome / 国际儿科学杂志

Noonan syndrome(NS)is an inherited disease involving multiple systems.The main clinical manifestations include distinctive facial features, short stature, heart defects, developmental delay and chest deformity.Short stature, reported in up to 70% of NS patients, is one of the main reasons NS patients seek medical treatment.The pathogenesis is associated with the up-regulation of RAS-mitogen activated protein kinase(RAS-MAPK)signal pathway.Further study is needed for some further specific mechanisms.Recombinant human growth hormone(rhGH)therapy has been approved for NS patients with short stature and has achieved a good therapeutic effect.However, the knowledge of drug dosage, influencing factors, long-term efficacy and risk of rhGH treatment is still insufficient.This paper reviews the pathogenesis and treatment of short stature in NS, providing help for the treatment and management of the disease.

Clinical and mutation analysis of a case of Noonan-like syndrome with loose anagen hair / 中华皮肤科杂志

To report a case of Noonan-like syndrome with loose anagen hair, and to detect gene mutations in the family. A 3-year-old female patient presented with a special facial appearance, short stature, deep palmar and plantar creases, and dark skin. The scalp hair was sparse and thin, dermoscopy showed black spot sign, single-hair follicular units, hair shafts varying in the diameter, upright hair and new vellus hair, and constriction of hair shafts and nodular hair were occasionally observed. Peripheral blood samples were collected from the proband and her parents, and the genomic DNA was extracted for whole-exome sequencing. A heterozygous missense mutation c.4A>G was identified in exon 2 of the SHOC2 gene in the proband, resulting in the substitution of serine by glycine at amino acid position 2 (p.S2G) . The mutation was not identified in either of her parents. Combined with the clinical phenotype and gene mutation, the diagnosis of Noonan-like syndrome with loose anagen hair was confirmed.

Genodermatosis hiperpigmentadas

Introducción: Las genodermatosis son consideradas enfermedades raras, por ser poco frecuentes y afectar un número reducido de individuos. El poco conocimiento sobre ellas en el campo de las ciencias médicas y los pobres recursos terapéuticos disponibles dificulta su diagnóstico, con una alta morbilidad. En Las Tunas representan 22,22 % de las enfermedades genéticas. Entre ellas se pueden citar presentando alteraciones de la pigmentación con hiperpigmentación: incontinencia pigmenti, síndrome de LEOPARD, mastocitosis, la neurofibromatosis, síndrome de Noonan, y con hiper e hipopigmentación están las didimosis. Objetivo: Compilar información actualizada acerca de las características y criterios diagnósticos de las enfermedades genéticas nombradas que faciliten su estudio y seguimiento de los pacientes. Métodos: Revisión de la literatura disponible en SciELO, PubMed Central, Medline Plus, Clinical key, Orphanet y OMIM. Los descriptores utilizados fueron: genética médica, enfermedades dermatológicas genéticas. Durante el proceso de revisión se consultaron 7 libros y 16 artículos publicados en los últimos 5 años. Análisis y síntesis de la información: Se revisó la clasificación de las genodermatosis hiperpigmentarias, y de estas las características clínicas, el tipo de herencia, el gen afectado, los criterios diagnósticos y estudios complementarios. Conclusiones: Conocer las características y criterios diagnósticos de las enfermedades genéticas presentadas permite diagnosticarlas, diferenciarlas entre ellas y favorecer el seguimiento de los pacientes afectados.

Introduction: Genodermatoses are considered rare diseases, as they are rare and affect a small number of individuals. The poor knowledge about them in the field of medical sciences and the poor therapeutic resources available hinder their diagnosis, with high morbidity. In Las Tunas they represent 22.22% of genetic diseases. Among them, can be cited presenting pigmentation alterations with hyperpigmentation: incontinentia pigmenti, LEOPARD syndrome, mastocytosis, neurofibromatosis, Noonan syndrome, and with hyper and hypopigmentation are the didymosis. Objective: To compile updated information about the characteristics and diagnostic criteria of the genetic diseases named to facilitate their study and follow-up of patients. Methods: Literature review available in SciELO, PubMed Central, Medline Plus, Clinical key, Orphanet and OMIM. The descriptors used were: medical genetics, genetic dermatological diseases. During the review process, 7 books and 16 articles published in the last 5 years were consulted. Analysis and synthesis of information: The classification of hyperpigmentary genodermatoses was reviewed, and of these the clinical characteristics, the type of inheritance, the affected gene, the diagnostic criteria and complementary studies. Conclusions: Knowing the characteristics and diagnostic criteria of the genetic diseases presented allows to diagnose them, differentiate them between them and favor the follow-up of the affected patients.

RASopathies: Dermatologists’ viewpoints

Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well- recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.

PTPN11 gene mutation mediated Noonan syndrome in children with idiopathic short stature / 中华内分泌代谢杂志

Objective:To analyze the genetic etiology of idiopathic short stature(ISS) children, and to investigate the clinical characteristics of Noonan syndrome caused by PTPN11 gene mutation, and the response to recombinant human growth hormone(rhGH) as well.Methods:Genomic DNA was extracted from the peripheral blood of 232 ISS patients, and the genome was detected by whole exon sequencing. The gene variation was analyzed according to the guideline of American College of Medical Genetics and Genomics(ACMG), and clinical baseline data and follow-up data of rhGH treatment were collected from PTPN11 gene pathogenic patients.Results:Among 232 ISS patients, 6 were found to have PTPN11 pathogenic gene variants(c.1507G>C, c. 317A>G, c. 923A>G, c. 922A>G, c. 236A>G, c. 922A>G), diagnosed as Noonan syndrome. Together with 3 cases of Noonan syndrome patients(all PTPN11 gene variation C. 1510A>G) previously diagnosed in our hospital, the clinical characteristics of patients were analyzed. Among the 9 Noonan syndrome patients, 7 were boys and 2 were girls. The average age was 10.2(4.5, 14.7) years old, and their height standard deviation score was -3.06 SD(95% CI -2.29 SD--3.94 SD). Among them, 4 patients received rhGH treatment with an average treatment duration of 2.25(1.5, 3.5) years. After treatment, their height increased by 14.3(8.6, 23.9) cm, and the change in height standard deviation score improved by 0.21 SD(95% CI 0.12 SD-0.27 SD). Conclusion:Noonan syndrome has a wide range of clinical phenotypes. For children with short stature, heart defects and cryptorchidism, the possibility of Noonan syndrome should be considered. PTPN11 is the common pathogenic gene for Noonan syndrome, and genetic testing facilitates the early diagnosis, treatment, and follow-up prognosis of Noonan syndrome patients.

Síndrome de Noonan e insuficiencia aórtica severa en un paciente adulto / Noonan Syndrome and Severe Aortic Regurgitation in an Adult Patient

Introducción: El síndrome de Noonan es una enfermedad congénita con una incidencia de 1:1000-2500 recién nacidos vivos. Se encuentra subdiagnosticada en nuestro medio debido a la variabilidad clínica, lo cual no permite un adecuado control y seguimiento para detectar complicaciones consecuentes a los defectos cardiovasculares congénitos. En Perú no existen reportes de casos sobre el síndrome de Noonan y sus complicaciones. Objetivo: Discutir la importancia del examen clínico para su adecuado diagnóstico a partir de las características del síndrome de Noonan en un adulto. Caso clínico: Presentamos el caso de un varón de 33 años con síndrome de Noonan, endocarditis infecciosa e insuficiencia aórtica severa. Conclusiones: Se resalta la importancia del examen físico y el uso de criterios diagnósticos para realizar el diagnóstico del síndrome de Noonan(AU)

Introduction: Noonan syndrome is a congenital disease with an incidence of 1: 1000-2500 live newborns. Due to its clinical variability, it is underdiagnosed in our setting, which does not allow adequate control and follow-up to detect complications resulting from congenital cardiovascular defects. In Peru, there are no case reports on Noonan syndrome and its complications. Objective: To discuss the importance of clinical examination for adequate diagnosis of Noonan syndrome, based on the characteristics of the disease in an adult. Clinical case: We present the case of a 33-year-old male patient with Noonan syndrome, infective endocarditis, and severe aortic regurgitation. Conclusions: The importance of physical examination and the use of diagnostic criteria to diagnose Noonan syndrome are highlighted(AU)

A case of Noonan syndrome with severe blepharophimosis / 中华整形外科杂志

Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, congenital heart disease, short stature, developmental delay, and bleeding diculties. This paper reports a rare Noonan syndrome child who presented chiefly to our institution with severe blepharophimosis. After DAN whole exome sequencing analysis, the patient was diagnosed with the PTPN11 gene c. 1517C> T mutation.

Clinical orofacial and myofunctional manifestations in an adolescent with Noonan Syndrome: a case report / Manifestações clínicas e miofuncionais orofaciais em adolescente com a Síndrome de Noonan: relato de caso

ABSTRACT Noonan syndrome is an autosomal dominant genetic disease with different manifestations, including Speech, Language and Hearing Sciences ones. The authors describe the orofacial and myofunctional manifestations of an adolescent diagnosed with Noonan syndrome, by consulting the Speech, Language and Hearing Sciences record of a 17-year-old male patient, who underwent screening and speech therapy evaluation with a confirmed genetic diagnosis of Noonan syndrome. The results were qualitatively analyzed. The patient had a long facial type, with a disproportion between the lower and middle thirds of the face, ogival palate, and Mallampati class IV. A deficit in mobility and sensitivity of phonoarticulatory organs was also identified, absence of pathological oral and gag reflexes, decreased lip tone and tongue tension, increased speed chewing and inefficient grinding, functional swallowing for assessed consistencies, mild verbal and nonverbal apraxia, and moderate dysarthria. The results confirmed the presence of alterations in the speech-language organs, proving the relevance of the Speech, Language and Hearing Sciences evaluation in Noonan Syndrome, to allow adequate follow-up and treatment.

RESUMO A síndrome de Noonan é uma doença genética autossômica dominante com diferentes manifestações, incluindo as fonoaudiológicas. Os autores descrevem as manifestações miofuncionais orofaciais de um adolescente com diagnóstico de síndrome de Noonan, por meio de consulta ao prontuário fonoaudiológico de um paciente do sexo masculino, dezessete anos, que foi submetido à triagem e avaliação fonoaudiológicas com diagnóstico genético confirmado de síndrome de Noonan. Os resultados foram analisados qualitativamente. O paciente apresentou tipologia facial longa, com desproporção entre os terços inferior e médio da face, palato ogival e Mallampati classe IV. Também foi identificado déficit na mobilidade e sensibilidade dos órgãos fonoarticulatórios, ausência de reflexos orais patológicos e de gag, diminuição de tônus de lábios e de tensão de língua, mastigação com velocidade aumentada e trituração ineficiente, deglutição funcional para as consistências avaliadas, apraxia verbal e não verbal leve, disartria moderada. Os resultados confirmam a presença de alterações morfofuncionais relacionadas aos órgãos fonoarticulatórios, comprovando a relevância da avaliação fonoaudiológica na Síndrome de Noonan, de forma a possibilitar o acompanhamento e tratamento adequados.

Reporte de un caso de síndrome de Noonan diagnosticado en atención primaria / A case report of Noonan syndrome diagnosed in primary healthcare

El síndrome de Noonan es un trastorno genético de herencia autosómica dominante, de expresión fenotípica variable. Pertenece al grupo de las enfermedades conocidas como rasopatías, trastornos producido por las mutaciones en los genes RAS. Los pacientes desarrollan síntomas como dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y discapacidad intelectual. En el presente reporte, se describe un caso de diagnóstico del síndrome de Noonan en un paciente de 14 años, realizado a nivel de atención primaria en Ecuador. El síndrome se identificó mediante diagnóstico clínico, permitiendo su derivación al segundo y tercer nivel de salud para una atención especializada.

Noonan syndrome is an autosomal dominant inherited disorder with variable phenotypic expression. It belongs to the group of diseases known as RASopathies, which are characterized by mutations in the RAS genes. Patients develop symptoms such as facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders and mental retardation. In this article, we report a case of Noonan syndrome in a 14-year-old patient, diagnosed in a primary health center in Ecuador. The syndrome was identified through clinical diagnosis, after which the patient was referred to the secondary and tertiary levels for specialized care.

Caracterización clínica y molecular de niños con síndrome de Noonan y otras RASopatías en Argentina / Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Introducción. Las RASopatías son un conjunto de síndromes fenotípicamente superpuestos causados por mutaciones en genes implicados en la vía RAS/MAPK. La herencia es autosómica dominante, presentan características clínicas comunes, como baja talla, dismorfias craneofaciales, cardiopatia congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1,RAF1, BRAFy HRAS,y comparar las principales características clínicas en pacientes con confirmación molecular. Población y métodos. Se estudiaron niños con diagnóstico clínico de RASopatía evaluados entre agosto de 2013 y febrero de 2017. Resultados. Se identificaron mutaciones en el 71 % (87/122) de los pacientes. El estudio molecular confirmó el diagnóstico en el 73 % de los pacientes con síndrome de Noonan. La mutación más prevalente fue c.922A>G (p.Asn308Asp) en el gen PTPN11. Se detectó una variante no descrita en RAF1, c.1467G>C (p.Leu489Phe). Se confirmó el sindrome cardiofaciocutáneo en el 67 % de los casos con mutaciones en el gen BRAF. El síndrome de Costello y el síndrome de Noonan con múltiples lentigos se confirmaron en todos los casos. Conclusión. La confirmación del diagnóstico clínico permitió un diagnóstico diferencial más preciso. Se determinó la prevalencia de las mutaciones en PTPN11 (el 58 %), SOS1 (el 10 %) y RAF1 (el 5 %) en niños con síndrome de Noonan, en PTPN11 (el 100 %) en el sindrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el sindrome de Costello.

Introduction. RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. Objective. To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. Results. Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. Conclusion. The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 % ), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.

Noonan syndrome and RASopathies: Clinical features, diagnosis and management

Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. Clinical presentations are similar, featured with typical facial features, short stature, intellectual disability, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). The PTPN11 (40–50%), SOS1 (10–20%), RAF1 (3–17%), and RIT1 (5–9%) mutations are common in NS patients. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.

Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome / 소아과

PURPOSE: To analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations. METHODS: Twenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy. RESULTS: The mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group. CONCLUSION: The 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.

Case Series Outcomes of Cochlear Implantation in Children with Noonan Syndrome / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Hearing loss is a common complication associated with Noonan syndrome (NS), and the level of hearing loss for NS patients with sensorineural loss ranged from normal to severe. Additional insights into the outcome of cochlear implantation (CI)in children with NS with or without comorbidities are needed. SUBJECTS AND METHOD: In this study, five patients with NS, four with a mutation in PTPN11 and one who tested negative in mutation screening, diagnosed with the clinical scoring systemand underwent CI at ages ranging from 16 to 50 months were retrospectively reviewed. Patientswere evaluated for auditory perception (Categories of Auditory Performance), speech production (Korean Version of the Ling's Stage), and language ability (Receptive and Expressive Vocabulary Test). RESULTS: In five of the children with NS, CI was performed without any complications. Threepatients who received CI before 30 months of age showed outstanding outcomes. One patientwho received CI at 50 months showed limited benefit. One patient who was diagnosed with developmental delay and cochlear nerve hypoplasia underwent CI at 28 months with poor outcome. DISCUSSION: Our report suggests that although the benefit may be influenced by comorbidities associated with NS or delay in hearing rehabilitation, profound hearing loss in patientswith NS may be restored to normal levels in terms of auditory/speech perception and vocabulary/language development. The variable hearing outcomes also underscore the need for earlyscreening and detection of profound hearing loss, and regular follow-up for hearing evaluationin patients with NS.

A 'Full House' Glomerulopathy in a Patient with Multiple Lentigines Syndrome: A Case Report / Glomerulopatía 'full house' en un paciente con síndrome de lentigos múltiples: un reporte de caso

ABSTRACT Multiple lentigines syndrome (MLS) is an autosomal dominant disease which is usually diagnosed clinically by the presence of characteristic features. The molecular genetic testing is an adjuvant diagnostic tool to identify the mutation of particular genes such as PTPN11 genes, RAF1, BRAF or MAP2K1 genes. This syndrome was formerly known as LEOPARD syndrome or Noonan syndrome with multiple lentigines. 'LEOPARD syndrome ' is an acronym of characteristic features (Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, and Deafness). There was no previous case report about any glomerulonephropathy in association with MLS. We present a case of a patient with MLS with recurrent nephrotic syndrome who was found to have histologic evidence of 'full house ' glomerulopathy.

RESUMEN El síndrome de lentigos múltiples (SLM) es una enfermedad autosómica dominante que de modo general se diagnostica clínicamente por la presencia de rasgos característicos. La prueba genética molecular es una herramienta de diagnóstico auxiliar utilizada para identificar la mutación de genes específicos tales como los genes PTPN11, RAF1, BRAF, o los genes MAP2K1. Este síndrome se conocía anteriormente como síndrome del leopardo o síndrome de Noonan con múltiples lentigos. El síndrome toma su nombre del acrónimo en inglés LEOPARD, que describe sus rasgos característicos (L lentigos; E conducción electrocardiográfica de las anormalidades; O hipertelorismo ocular; P estenosis pulmonar; A anormalidades de los genitales; R retardo del crecimiento; y D deafness, 'sordera ' en inglés), y que fuera introducido por Gorlin et al en 1969. No existía ningún reporte de caso anterior sobre glomerulonefropatía asociada con SLM. Presentamos el caso de un paciente con SLM con síndrome nefrótico recurrente en el que se halló evidencia histológica de glomerulopatía 'full house'.

Oral Features in a Child with Noonan Syndrome : A Case Report / 대한소아치과학회지

Noonan syndrome is characterized by distinctive facial features, short stature, and congenital heart disease. It is a congenital genetic disorder with a prevalence of between 1/1,000 and 1/2,500 in both genders.An 11-year-old boy with Noonan syndrome visited the hospital with an ectopically positioned tooth. A pulmonary stenosis was diagnosed and his growth and development were delayed. In many cases of this diseases there is obvious hemostasis, which he was not experiencing. His facial appearance showed characteristic features of Noonan syndrome. The patient showed a dental class II relationship, labioversion of the upper anterior teeth, and a shallow overbite. Radiographic examination revealed that the upper right canine was ectopically positioned, which led to root resorption of the upper right lateral incisor. A lateral cephalometric radiograph revealed a craniofacial pattern that was within normal limits. Surgical opening and button attachment on the impacted upper right canine were performed and traction was applied on the impacted tooth using a removable appliance.This patient was mildly affected by Noonan syndrome and showed some dental problems. However, few studies have reported the oral characteristics of Noonan syndrome despite its high incidence. Thus, this case report describes the oral features and management of Noonan syndrome.

Four cases of PTPN11 associated RASopathies:Analysis of the correlation between gene mutation and clinical phenotype / 中华内分泌代谢杂志

PTPN11 is the most common mutation gene of RAS disease, which is located in the upstream of RAS/MAPK pathway and participates in signal transduction. Because the molecular mechanism of RAS's disease involves the same pathway, it may present a certain commonality in clinic, but the different genotypes with PTPN11 mutation may also express different phenotypes. Therefore, it is not easy to identify and diagnose this disease early in clinic. The present article aims to analyze the correlation between the clinical phenotype and genotype of 4 patients with RAS disease.

Growth hormone therapy in patients with Noonan syndrome

Noonan syndrome (NS) is an autosomal dominant disorder that involves multiple organ systems, with short stature as the most common presentation (>70%). Possible mechanisms of short stature in NS include growth hormone (GH) deficiency, neurosecretory dysfunction, and GH resistance. Accordingly, GH therapy has been carried out for NS patients over the last three decades, and multiple studies have reported acceleration of growth velocity (GV) and increase of height standard deviation score (SDS) in both prepubertal and pubertal NS patients upon GH therapy. One year of GH therapy resulted in almost doubling of GV compared with baseline; afterwards, the increase in GV gradually decreased in the following years, showing that the effect of GH therapy wanes over time. After four years of GH therapy, ~70% of NS patients reached normal height considering their age and sex. Early initiation, long duration of GH therapy, and higher height SDS at the onset of puberty were associated with improved final height, whereas gender, dosage of GH, and the clinical severity did not show significant association with final height. Studies have reported no significant adverse events of GH therapy regarding progression of hypertrophic cardiomyopathy, alteration of metabolism, and tumor development. Therefore, GH therapy is effective for improving height and GV of NS patients; nevertheless, concerns on possible malignancy remains, which necessitates continuous monitoring of NS patients receiving GH therapy.

Gene mutation and clinical phenotype analysis of patients with Noonan syndrome and hypertrophic cardiomyopathy / 中华儿科杂志

Objective@#To analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy.@*Method@#Determined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database.@*Result@#Three mutant genes (PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3) in five cases all had been reported to be related to hypertrophic cardiomyopathy. The reported hypertrophic cardiomyopathy relevant genes MYPN, MYH6 and MYBP3 had also been found in case 1 and 2. Patients with same gene mutation had different clinical manifestations. Both case 4 and 5 had RAF1 mutation (c.770C>T). However, case 4 had special face, low IQ, mild pulmonary artery stenosis, and only mild ventricular hypertrophy.@*Conclusion@#Noonan syndrome is a genetic heterogeneity disease. Our study identified specific gene mutations that could result in Noonan syndrome with hypertrophic cardiomyopathy through molecular biology methods. The results emphasize the importance of gene detection in the management of Noonan syndrome.

Noonan syndrome caused by mutation of SHOC2 gene: a case report / 临床儿科杂志

Objective To investigate the clinical phenotype and molecular diagnosis of Noonan syndrome (NS) caused by mutations in SHOC2 gene. Methods The clinical data and gene testing results of one child with NS were analyzed retrospectively. Results This is an 8-month-old infant. Since birth, the boy had feeding and sleeping difficulties, irritability, and growth retardation. The boy had large head circumference, sparse, thin and yellow hair, broad and prominent forehead, flat nose, slightly wide eye distance, and slightly bilateral eye fissure outward tilt, no eyelid ptosis. Echocardiography showed patent foramen ovale,ventricular septum and left ventricular hypertrophy.A novel mutation(De novo)was found in the SHOC2 gene, heterozygous missense mutation c.4A>G, p.Ser2Gly His parents were normal genotypes. According to the clinical characteristics, relevant literature was reviewed. The clinical manifestation of sleep difficulty has not been reported in the NS patients with SHOC2 mutation.Conclusions This is the first domestic reported NS case with SHOC2 mutation.The phenotype is consistent with the foreign reports.Sleep difficulty may be a new phenotype of NS with SHOC2 mutation.