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LEOPARD Syndrome

Noonan Syndrome with Multiple Lentigines


Presentation

  • The authors present a 31-year-old man with a Chiari type I malformation (CM-1) occurring in conjunction with LEOPARD syndrome. He presented with severe dysphagia requiring placement of a percutaneous endoscopic gastrostomy (PEG) tube.[ncbi.nlm.nih.gov]
  • Case presentation We report two cases of LEOPARD syndrome with hypertrophic cardiomyopathy in a 10-year-old girl and an 18-year-old boy. In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present.[ncbi.nlm.nih.gov]
  • This is a case report of a classical presentation of the Leopard syndrome from the Indian subcontinent.[ncbi.nlm.nih.gov]
  • We present herein a patient with LEOPARD syndrome and distinctive features. It was noteworthy that our patient presented with the concern of generalized lentiginosis and subsequent evaluation revealed that the patient had LEOPARD syndrome.[ncbi.nlm.nih.gov]
  • LS shares many features with Noonan syndrome (NS), in which lentigines and deafness are usually not present.[ncbi.nlm.nih.gov]
Short Stature
  • CONCLUSIONS: LEOPARD syndrome patients display distinctive features apart from multiple lentigines, such as a higher prevalence of hypertrophic cardiomyopathy and lower prevalence of short stature.[ncbi.nlm.nih.gov]
  • The male patient had progressively increasing generalised multiple lentiginosis, ocular hypertelorism, pulmonary stenosis, short stature, cryptorchidism, and pectus excavatum.[ncbi.nlm.nih.gov]
  • She had short stature, hypertelorism, neurofibroma, café au lait spots and multiple lentigines. She had features of severe pulmonary hypertension and differential clubbing and cyanosis.[ncbi.nlm.nih.gov]
  • Noonan syndrome with multiple lentigines should be suspected in patients who demonstrate one or more of the following cardinal features: Lentigines Cardiac abnormalities Short stature Pectus deformity Facial dysmorphia.[dermnetnz.org]
  • The diagnosis may be on clinical basis as the diagnostic clues of LS are: multiple lentigines and cafè-au-lait-spots, short stature, distinctive face, congenital heart disease, conduction abnormalities, abnormal genitalia, and sensorineural deafness.[ncbi.nlm.nih.gov]
Hemoptysis
  • A sixteen year old girl presented with history of hemoptysis of one week duration. She had history of dyspnea on exertion and frequent respiratory infections in childhood.[ncbi.nlm.nih.gov]
Failure to Thrive
  • […] syndrome Relevant diseases: Noonan syndrome Noonan syndrome plus other features Cardio-facio-cutaneous syndrome LEOPARD syndrome Costello syndrome Legius syndrome Inclusion criteria At least 2 of the suggestive clinical features: Early feeding difficulty/ failure[eastgenomics.org.uk]
  • She presented failure to thrive and psychomotor retardation, and was diagnosed with biventricular obstructive hypertrophic cardiomyopathy for which she had received high-dose beta-blocker therapy.[degruyter.com]
  • Congenital heart defects Skin abnormalities including rough skin and keratosis pilaris Failure to thrive Hypotonia Growth delays Three different genes have been found to be associated with CFC syndrome (BRAF, MEK1, MEK2), so genetic testing may be able[care.com]
  • At the age of 4 years, failure to thrive was reported ( Figure 1b ). At that time, she underwent cardiac catheterisation and pulmonary valve angioplasty and developed ML and multiple café-au-lait spots.[nature.com]
Regurgitation
  • Echocardiography revealed mild mitral regurgitation (MR), hypokinetic posterior inter-ventricular septum with left ventricular ejection fraction of 50% and diagnosed as ischemic heart disease.[ijpd.in]
  • In addition, there was a patent foramen ovale and minimal aortic and mitral regurgitation, the latter a result of a prolapse of the anterior leaflet of the mitral valve.[ajronline.org]
  • Schneider, Pulmonary Valve Stenosis and Regurgitation, Valvular Heart Disease, 10.1007/978-1-59745-411-7_12, (265-279), (2009).[doi.org]
Dysphagia
  • He presented with severe dysphagia requiring placement of a percutaneous endoscopic gastrostomy (PEG) tube. Evaluation included magnetic resonance imaging (MRI) of the brain and cervical spine that revealed CM-1 with an extensive cervical syrinx.[ncbi.nlm.nih.gov]
Macroglossia
  • In addition to the cardinal signs of the syndrome this patient presented some abnormalities which have not been previously described such as macroglossia, multiple dental anomalies, basilar impression and platybasia, megacolon, hypertrophy of clitoris[ncbi.nlm.nih.gov]
  • We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment.[ncbi.nlm.nih.gov]
  • The patient had a severe anterior open bite (no contact of the upper and lower front teeth) due to macroglossia ( Figure 2 ).[scielo.br]
Hearing Impairment
  • We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment.[ncbi.nlm.nih.gov]
  • Case 4 had moderate hearing impairment. Point mutation of the PTPN11 gene was found in all patients. LS has typical skin manifestations. All patients should undergo a comprehensive examination, especially echocardiography and electrocardiography.[ncbi.nlm.nih.gov]
  • If individuals with NSML demonstrate hearing impairment, hearing aids may be beneficial.[rarediseases.org]
  • impairment 0008625 30%-79% of people have these symptoms Atrioventricular canal defect 0006695 Cryptorchidism Undescended testes Undescended testis [ more ] 0000028 Decreased fertility Abnormal fertility 0000144 Low-set, posteriorly rotated ears 0000368[rarediseases.info.nih.gov]
Winged Scapula
  • Some individuals with NSML may exhibit additional skeletal abnormalities such as unusually prominent shoulder blades (winged scapula), abnormal sideways curvature of the spine (scoliosis), and/or the development of abnormal front-to-back spinal curvature[rarediseases.org]
Cafe-Au-Lait Spots
  • cafe au lait spots of neurofibromatosis.[ncbi.nlm.nih.gov]
  • […] first year of life demonstrates that the diagnosis of LS in the first months of age can be clinically suspected in patients presenting with three main features, that is, characteristic facial features (100%), hypertrophic cardiomyopathy (HCM) (87%), and cafe-au-lait[ncbi.nlm.nih.gov]
  • In addition, LEOPARD syndrome is confused with Neurofibromatosis Type 1 due to the presence of cafe-au-lait spots. CFC Syndrome CFC (craniofaciocutaneous) Syndrome is a condition that affects multiple parts of the body.[care.com]
  • The child had right hemiparesis, pectus carinatum, right-sided cryptorchidism with poorly developed scrotum, and multiple pigmented macules along with multiple cafe-au-lait spots.[jpgmonline.com]
Aggressive Behavior
  • Findings included aggressive behavior and impairment of social interaction, communication, and range of interests.[ncbi.nlm.nih.gov]
Hypertelorism
  • Abstract Lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retarded growth, and deafness syndrome (multiple lentigines syndrome) is most often characterized by multiple lentigines and[ncbi.nlm.nih.gov]
  • We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment.[ncbi.nlm.nih.gov]
  • In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present.[ncbi.nlm.nih.gov]
  • LEOPARD syndrome (LS) is an autosomal dominant syndrome characterized by multiple lentigines and café-au-lait spots, electrocardiographic-conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormalities of the[ncbi.nlm.nih.gov]
  • Facial dysmorphism includes ocular hypertelorism, palpebral ptosis and low-set ears. Stature is usually below the 25th centile.[ncbi.nlm.nih.gov]
Short Neck
  • neck Decreased length of neck 0000470 Short stature Decreased body height Small stature [ more ] 0004322 Strabismus Cross-eyed Squint Squint eyes [ more ] 0000486 Subvalvular aortic stenosis Narrowing of blood vessel below aortic heart valve 0001682[rarediseases.info.nih.gov]
  • Ocular hypertelorism, down-slanting palpebral fissures, ptosis, blue–green irides, short nose with a wide base and depressed nasal bridge, low-set and posteriorly angulated ears with thick helices, micrognathia, short neck with excessive nuchal skin and[nature.com]
  • Other features shared between the two conditions include short stature, intellectual disability, lax joints, and head/neck features such as a highly arched palate, a short neck, a large forehead, and low-set ears.[forgottendiseases.org]
  • Note the short neck with pterigium colli, teletelia, pectus excavatum and diffuse lentiginosis on the trunk. Cardiovascular system Electrocardiographic anomalies and progressive conduction anomalies are the most common heart defects [ 4, 6 – 8 ].[ojrd.com]
  • Note the short neck with pterigium colli, teletelia, pectus excavatum and diffuse lentiginosis on the trunk. Cardiovascular system Electrocardiographic anomalies and progressive conduction anomalies are the most common heart defects [ 4 , 6 - 8 ].[ncbi.nlm.nih.gov]
Gerstmann Syndrome
  • This is the first report of an association between the Leopard and Gerstmann syndromes and one of the few to demonstrate a computed tomographic abnormality in the latter.[ncbi.nlm.nih.gov]

Workup

  • A small number of patients with LEOPARD syndrome had an extensive cardiac workup using invasive and noninvasive techniques.[ajronline.org]

Treatment

  • Treatment response to intravenous immunoglobulins was excellent. In patients with LEOPARD syndrome and acute neuropathies, treatment with intravenous immunoglobulins should be considered.[ncbi.nlm.nih.gov]
  • The cardiac defects in LS/ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR.[ncbi.nlm.nih.gov]
  • If necessary, isolated lentigines can be removed through the use of chemical peels, cryotherapy, laser treatments or surgical excision. For some patients, treatment with topical retinoids and hydroquinone cream may be helpful.[dermnetnz.org]
  • Standard Therapies Treatment The treatment of NSML is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists.[rarediseases.org]
  • The patient then underwent treatment with an implantable pacer-cardioverter-defibrillator device. Further evaluation revealed several well-established features of the disorder.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis appears to be related to the type of structural, myocardial, and arrhythmogenic cardiac disease, especially hypertrophic cardiomyopathy (HCM).[ncbi.nlm.nih.gov]
  • Cardiac involvement may have a significant impact on the prognosis, however, appearance of severe abnormalities such as hypertrophic cardiomyopathy usually precedes the occurrence of multiple lentigines and may be asymptomatic.[ncbi.nlm.nih.gov]
  • Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death.[ncbi.nlm.nih.gov]
  • In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up.[ncbi.nlm.nih.gov]
  • With the only exception of ventricular hypertrophy, adults with LS do not require special medical care and long-term prognosis is favourable.[ncbi.nlm.nih.gov]

Etiology

  • In this case report we describe these anomalies and discuss the relationship between them and the proposed etiology of the disease.[ncbi.nlm.nih.gov]
  • Our results suggest that visual and visuoperceptual abilities are commonly impaired in patients with Noonan and LEOPARD syndrome and they are probably related to a multifactorial etiology.[ncbi.nlm.nih.gov]
  • Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM.[ncbi.nlm.nih.gov]
  • Etiology and Pathophysiology In most individuals, NSML and Noonan syndrome (NS) are allelic disorders resulting from different missense mutations. 90% of these mutations are in the PTPN11 gene.[unboundmedicine.com]

Epidemiology

  • There is no epidemiologic data available regarding how many individuals suffer from the syndrome worldwide; however, there are approximately 200 cases described in medical literature.[en.wikipedia.org]
  • Frequency No epidemiologic data are available.[emedicine.medscape.com]
  • No epidemiologic data are available on the real incidence of LEOPARD syndrome; however, this seems to be a rare disease, being often underdiagnosed, as many of its features are mild.[degruyter.com]
  • Epidemiology Penetrance is high but difficult to quantify due to ascertainment bias and variable expressivity. Often, the diagnosis is made in an adult only after the diagnosis of a more severely affected child.[unboundmedicine.com]
Sex distribution
Age distribution

Pathophysiology

  • Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations. Copyright 2014, American Society for Microbiology. All Rights Reserved.[ncbi.nlm.nih.gov]
  • Etiology and Pathophysiology In most individuals, NSML and Noonan syndrome (NS) are allelic disorders resulting from different missense mutations. 90% of these mutations are in the PTPN11 gene.[unboundmedicine.com]
  • LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines, is a rare autosomal dominant disorder most often caused by missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP2. [1] Pathophysiology The term[emedicine.medscape.com]
  • Etiology and Pathophysiology LEOPARD syndrome and a related disorder, Noonan syndrome (NS), are allelic disorders resulting from different missense mutations. 90% of these mutations are in the PTPN11 gene.[5minuteconsult.com]

Prevention

  • He had recurrent upper extremity aneurysms requiring multiple operations and finally PTFE reinforced venous grafts to prevent further aneurysmal degeneration. He has multiple other peripheral aneurysms, thus far asymptomatic.[ncbi.nlm.nih.gov]
  • We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest.[ncbi.nlm.nih.gov]
  • This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy.[ncbi.nlm.nih.gov]
  • We found that the GAB1/phosphoinositide 3-kinase (PI3K) complex was more abundant in fibroblasts from LS than control subjects and that both AKT and GSK-3beta hyperphosphorylation were prevented by reducing GAB1 expression or by overexpressing a GAB1[ncbi.nlm.nih.gov]
  • 1 Department of Pedodontics and Preventive Dentistry, Krishnadevaraya College of Dental Sciences and Hospital, Bangalore, Karnataka, India 2 Department of Pedodontics and Preventive Dentistry, A.E.C.S Maaruti College of Dental Science and Research Centre[jisppd.com]

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