Subject(s)
Humans , Male , Child , Noonan Syndrome , LEOPARD Syndrome , Hypertelorism , Pulmonary Valve Stenosis , Hearing Loss, SensorineuralSubject(s)
Humans , Male , Child , Noonan Syndrome , LEOPARD Syndrome , Hypertelorism , Pulmonary Valve Stenosis , Hearing Loss, SensorineuralABSTRACT
INTRODUÇÃO: A Síndrome de Leopard, considerada uma fenocópia da cardiomiopatia hipertrófica (CMH) é uma rasopatia, caracterizada por alterações de crescimento, lentiginose, alterações oculares, genitais e cardíacas. Devido à sua raridade, há poucasinformações na literatura sobre a história natural da doença. Este caso descreve a evolução de 18 anos de um paciente com esta síndrome. RELATO DO CASO: masculino, 19 anos, iniciou acompanhamento com 1 ano e 3 meses de idade. Assintomático, possuíamanchas hipercrômicas na pele,sobretudo face, dorso emembrossuperiores. O ecocardiograma evidenciava já no segundo ano de vida, hipertrofia biventricular, com espessura septal e de parede posterior de 10/9 mm, gradiente de via de saída do ventrículo esquerdo (VSVE) de 107mmHg e de 50mmHg na via de saída do ventrículo direito (VSVD). Havia também movimento sistólico anterior do folheto mitral e função contrátil preservada. Do ponto de vista neurológico, foi identificado atraso no desenvolvimento neuropsicomotor. Aos 4 anos, a massa ventricular esquerda era de 149g, septo de 15mm e parede posterior de 11mm, com gradiente de 101mmHg em VSVE, fração de ejeção de ventrículo esquerdo (FEVE) de 74%. O painel genético identificou mutação no gene PTPN11, compatível com síndrome de Leopard. Hoje, aos 19 anos, apesar de manter-se oligossintomático, apresenta sinais de disfunção ventricular, com FEVE 47%, strain longitudinal de 6, fractional area change (FAC) 30%, septo de 30mm, parede posterior 19mm, massa ventricular de 487g. O gradiente na VSVE é de 82mmHg e na VSVD de 103mmHg. A ressonância magnética cardíaca atual evidencia realce tardio subendo/mesocárdico, com massa de fibrose estimada em 10g (3% do total). Há dilatação biventricular, com FEVE estimado pela ressonância de 37%. DISCUSSÃO: Em comparação com o fenótipo habitual da CMH, pacientes portadores de síndrome de Leopard apresentam sintomas mais precocemente na infância e podem manter progressão da hipertrofia ao longo de vários anos, diferentemente da CMH, que habitualmente atinge um platô em sua evolução. Não é bem estabelecido qual o risco de morte súbita associado à esta síndrome, nem quais critérios utilizar na indicação de CDI. Há relatos de melhora dos sintomas após realização de miectomia, porém ainda não temos registro se há resposta com uso de inibidores de miosina ATPase. CONCLUSÃO: A síndrome de Leopard, diferente da CMH, tem evolução desfavorável, com aumento progresso da hipertrofia ventricular esquerda ao longo dos anos e disfunção ventricular precoce.
Subject(s)
Humans , Male , Adult , LEOPARD SyndromeSubject(s)
LEOPARD Syndrome , Female , Humans , LEOPARD Syndrome/complications , LEOPARD Syndrome/diagnosis , LEOPARD Syndrome/genetics , Fetus , Nervous SystemSubject(s)
Cardiomyopathy, Hypertrophic , LEOPARD Syndrome , Noonan Syndrome , Humans , LEOPARD Syndrome/complications , LEOPARD Syndrome/diagnosis , LEOPARD Syndrome/genetics , Noonan Syndrome/complications , Noonan Syndrome/diagnosis , Noonan Syndrome/genetics , Mutation , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Phenotype , Genotype , Protein Tyrosine Phosphatase, Non-Receptor Type 11/geneticsABSTRACT
BACKGROUND: We aimed to examine clinical features and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z-score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z-score (absolute regression); (3) a reduction ≥15% of the MLVWT z-score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2-12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%-100%) 1 year after presentation and 80.9% (95% CI, 70.1%-90.7%) at 5 years. Patients with MLVWT z-score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6-7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.
Subject(s)
Cardiomyopathy, Hypertrophic , LEOPARD Syndrome , Noonan Syndrome , Child , Adult , Humans , Infant , Child, Preschool , LEOPARD Syndrome/diagnosis , LEOPARD Syndrome/genetics , Retrospective Studies , Ventricular Remodeling , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Noonan Syndrome/diagnosis , Noonan Syndrome/geneticsABSTRACT
INTRODUCTION: Noonan syndrome and related conditions (RASopathies) are known to be associated with abnormalities in many organ systems. It is our impression that few otolaryngologists are familiar with the manifestations of these syndromes and we therefore reviewed our hospital's patient cohort to identify the prevalence of ear, nose and throat disorders in these children. METHODS: We cross-referenced various hospital department databases (otolaryngology, audiology, cardiology, haematology and genetics) to try to identify as many children with Noonan and other RASopathies as possible. We then performed a retrospective review of electronic patient records. RESULTS: We identified 67 children with Noonan, Costello, LEOPARD and other RASopathy syndromes. Around half have been seen in otolaryngology and audiology clinics. Otitis media with effusion requiring ventilation tubes occurred in 4% of children. 10% have suffered recurrent acute otitis media. 9% have a sensorineural hearing loss. 7% have undergone adenotonsillectomy for obstructive sleep apnoea. Airway anomalies and head and neck malformations occur but are rare. DISCUSSION: Children with Noonan and other RASopathies present commonly to otolaryngology and audiology clinics. The prevalence of sensorineural hearing loss is high and audiological screening is likely to be worthwhile. Surgeons should be aware that complications of surgery are common and can be very severe, especially in those with cardiac anomalies.
Subject(s)
Hearing Loss, Sudden , Noonan Syndrome , Nose Diseases , Pharyngeal Diseases , Humans , Male , Female , Child , Noonan Syndrome/diagnosis , Pharyngeal Diseases/epidemiology , Hearing Loss, Sudden/epidemiology , Costello Syndrome , Nose Diseases/epidemiology , Sinusitis , Tonsillitis , LEOPARD SyndromeABSTRACT
PURPOSE: To report a case of Noonan syndrome with multiple lentigines with unusual ocular features. METHODS: The authors describe a case of a 7-year-old girl with Noonan syndrome with multiple lentigines and anomalous optic disks. RESULTS: A 7-year-old girl with genetically proven Noonan syndrome with multiple lentigines ( PTPN11 gene mutation) and anomalous optic disks was referred for treatment of persistent macular detachment after 1 year of conservative follow-up. The right eye demonstrated an optic disk coloboma with the best-corrected visual acuity of 20/32, the left eye demonstrated an optic disk pit with serous macular detachment (best-corrected visual acuity 20/50-20/80). Optical coherence tomography demonstrated a neurosensory detachment. Twenty-five gauge pars plana vitrectomy was performed with posterior hyaloid detachment, drainage over disk pit area, and SF6 20% gas tamponade. Surgery resulted in subretinal fluid reduction and improvement of the visual acuity to 20/32. CONCLUSION: A case of Noonan syndrome with multiple lentigines with optic disk coloboma in the right eye and optic disk pit with related maculopathy in the left eye. To the best of the authors' knowledge, this is the first reported case describing the association of Noonan syndrome with multiple lentigines and congenital optic disk anomalies. Optic disk pit maculopathy was managed surgically because of its longstanding nature with the deteriorating visual acuity.
Subject(s)
Coloboma , Eye Abnormalities , LEOPARD Syndrome , Macular Degeneration , Optic Disk , Pigmentation Disorders , Retinal Detachment , Retinal Diseases , Female , Humans , Child , Optic Disk/abnormalities , Coloboma/complications , Coloboma/diagnosis , Coloboma/surgery , Vitrectomy/methods , LEOPARD Syndrome/complications , LEOPARD Syndrome/surgery , Retinal Diseases/complications , Retinal Detachment/surgery , Eye Abnormalities/complications , Eye Abnormalities/diagnosis , Eye Abnormalities/surgery , Macular Degeneration/complications , Tomography, Optical Coherence , Pigmentation Disorders/complicationsABSTRACT
Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. This family of genetic disorders constitute one of the largest groups of developmental disorders with variable penetrance and severity, associated with distinctive congenital disabilities, including facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was first clinically described decades ago, and several genes have since been identified, providing a molecular foundation to understand their physiopathology and identify targets for therapeutic strategies. These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. This manuscript comprehensively reviews the most frequently mutated genes responsible for NS and NSML, covering their role in the current knowledge of cellular signalling pathways, and focuses on the pathophysiological outcomes on mitochondria and energy metabolism.
Subject(s)
LEOPARD Syndrome , Noonan Syndrome , Energy Metabolism/genetics , Germ-Line Mutation , Humans , LEOPARD Syndrome/genetics , Mitochondria/genetics , Mitochondria/pathology , Noonan Syndrome/genetics , Noonan Syndrome/pathology , ras Proteins/geneticsABSTRACT
This study aimed to assess the nature of peripheral nervous system (PNS) involvement in three patients with Noonan syndrome (NS) or NS with multiple lentigines (NSML) as a related RASopathy, presenting primary with intractable neuropathic pain. We studied three unrelated adult patients with severe neuropathic pain and muscle weakness of the limbs. Nerve conduction studies and needle electromyography (EMG) were performed and PNS involvement was assessed by nerve ultrasound imaging, complemented with spinal magnetic resonance imaging (MRI) for the evaluation of proximal nerve segments. Targeted whole-exome sequencing analysis was performed when the diagnosis of NS was suspected. Two patients showed a PTPN11-related dominant and one a LZTR1-related recessive NS or NSML phenotype. The nature of PNS involvement was documented using nerve ultrasound and MRI, showing generalized or multifocal thickening of nerve roots, plexuses and peripheral nerves in all three patients. Nerve imaging using ultrasound and MRI aids in further detailing the nature of neuropathic pain and nerve hypertrophy in patients with NS. This study underlines the relevance of nerve ultrasound in neuropathies and pain syndromes. A NS diagnosis should not be overlooked in longstanding, unexplained neuropathic pain syndromes, with or without muscular weakness. Nerve ultrasound studies can help raise the suspicion for this relatively prevalent inherited multisystem disorder, which is still rather unknown among neurologists, particularly when other potential syndromic features are inconspicuous.
Subject(s)
LEOPARD Syndrome , Neuralgia , Noonan Syndrome , Humans , LEOPARD Syndrome/genetics , Mutation , Neuralgia/diagnostic imaging , Neuralgia/genetics , Noonan Syndrome/diagnostic imaging , Noonan Syndrome/genetics , Phenotype , Transcription Factors/genetics , UltrasonographySubject(s)
Cochlear Implantation/methods , LEOPARD Syndrome/surgery , Child , Child, Preschool , Female , Humans , Infant , MaleABSTRACT
PURPOSE: Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11Y279C mutation. This study is performed to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a low-dose of dasatinib in NSML mice and to determine its effectiveness in ameliorating the development of HCM. METHODS: Dasatinib was administered intraperitoneally into NSML mice with doses ranging from 0.05 to 0.5 mg/kg. PK parameters of dasatinib in NSML mice were determined. PD parameters were obtained for biochemical analyses from heart tissue. Dasatinib-treated NSML mice (0.1 mg/kg) were subjected to echocardiography and assessment of markers of HCM by qRT-PCR. Transcriptome analysis was performed from the heart tissue of low-dose dasatinib-treated mice. RESULTS: Low-dose dasatinib exhibited PK properties that were linear across doses in NSML mice. Dasatinib treatment of between 0.05 and 0.5 mg/kg in NSML mice yielded an exposure-dependent inhibition of c-Src and PZR tyrosyl phosphorylation and inhibited AKT phosphorylation. We found that doses as low as 0.1 mg/kg of dasatinib prevented HCM in NSML mice. Transcriptome analysis identified differentially expressed HCM-associated genes in the heart of NSML mice that were reverted to wild type levels by low-dose dasatinib administration. CONCLUSION: These data demonstrate that low-dose dasatinib exhibits desirable therapeutic PK properties that is sufficient for effective target engagement to ameliorate HCM progression in NSML mice. These data demonstrate that low-dose dasatinib treatment may be an effective therapy against HCM in NSML patients.
Subject(s)
Cardiomyopathy, Hypertrophic , LEOPARD Syndrome , Animals , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/genetics , Dasatinib/pharmacology , Dasatinib/therapeutic use , Disease Models, Animal , LEOPARD Syndrome/drug therapy , LEOPARD Syndrome/genetics , LEOPARD Syndrome/metabolism , Mice , MutationABSTRACT
LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis.Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.
Subject(s)
LEOPARD Syndrome , Skin Neoplasms , Humans , LEOPARD Syndrome/genetics , Mutation , Phenotype , SkinABSTRACT
BACKGROUND: Noonan Syndrome with Multiple Lentigines (NSML) and Noonan Syndrome (NS) can be difficult to differentiate clinically in early childhood. This study aims to describe characteristics of the ventricular septum that may differentiate NSML from NS. We hypothesize that the shape of the ventricular septum determined by echocardiography correlates with genotype and may distinguish patients with NSML from those with NS. METHODS: We analyzed data from 17 NSML and 67 NS patients. Forty normal and 30 sarcomeric hypertrophic cardiomyopathy (HCM) patients were included as controls. Septal morphology was qualitatively evaluated, and septal angle was measured quantitatively at end diastole. We recorded the presence of a ventricular septal bulge (VSB) and reviewed genetic testing results for each patient. RESULTS: The most important findings were a sigmoid septum (71%) and VSB (71%) in NSML. NSML septal angle was decreased compared to the normal and sarcomeric HCM control groups, respectively (149 ± 13 vs. 177 ± 3, p < 0.001; 149 ± 13 vs. 172 ± 7, p < 0.001). NS septal angle was similar to the controls (176 ± 6 vs. 177 ± 3, p > 0.5; 176 ± 6 vs. 172 ± 7, p > 0.5). NSML-linked pathogenic variants were associated with sigmoid septum and VSB. CONCLUSIONS: These findings provide novel phenotypic evidence to clinicians that may offer incremental diagnostic value in counseling families in ambiguous NSML/NS cases. IMPACT: Characteristics of the ventricular septum are linked to specific gene variants that cause NSML and NS. Sigmoid septum and VSB are associated with NSML. This novel echocardiographic association may help clinicians distinguish NSML from NS in ambiguous cases. Early distinction between the two may be important, as syndrome-specific therapies may become available in the near future. This study may encourage further research into genotype-phenotype associations in other forms of HCM.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Echocardiography , LEOPARD Syndrome/genetics , Mutation , Noonan Syndrome/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Ventricular Septum/diagnostic imaging , Adolescent , Adult , Cardiomyopathy, Hypertrophic/etiology , Child , Child, Preschool , Diagnosis, Differential , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Infant , LEOPARD Syndrome/complications , LEOPARD Syndrome/diagnosis , Male , Noonan Syndrome/complications , Noonan Syndrome/diagnosis , Phenotype , Predictive Value of Tests , Retrospective Studies , Young AdultABSTRACT
The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.
Subject(s)
Genetic Variation , LEOPARD Syndrome/genetics , Noonan Syndrome/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Alleles , Amino Acid Substitution , Genetic Association Studies , Heterozygote , Humans , Male , Middle Aged , Models, Molecular , Mutation , Mutation, Missense , Pedigree , Protein Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistryABSTRACT
SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene in human. Clinically, SHP2 has been identified as a causal factor of several diseases, such as Noonan syndrome, LEOPARD syndrome as well as myeloid malignancies. Interestingly, both loss-of-function and gain-of-function mutations occur in the PTPN11 gene. Analyses by biochemical and cell biological means as well as probing with small molecule compounds have demonstrated that SHP2 has both phosphatase-dependent and independent functions. In comparison with its phosphatase activity, the non-phosphatase-like function of SHP2 has not been well introduced or summarized. This review mainly focuses on the phosphatase-independent functions and its regulation by small molecule compounds as well as their use for disease therapy.