[LEOPARD syndrome].
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Abnormalities, Multiple↗
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Noonan syndrome with café-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus.
Noonan syndrome, multiple lentigines syndrome (LEOPARD syndrome), Watson syndrome and neurofibromatosis type 1 share certain clinical manifestations. We present a linkage analysis using microsatellite markers located in the neurofibromatosis type 1 region at 17q11 in a family with Noonan syndrome and café-au-lait spots and in another family with multiple lentigines syndrome. No linkage of the disease to the neurofibromatosis type 1 locus was found in the families investigated. On the basis of our results, we suggest that neither familial multiple lentigines syndrome nor Noonan syndrome is caused by a defect in the neurofibromatosis type 1 gene.
Cafe-au-Lait Spots↗
Noonan syndrome and its related disorders.
The diagnosis of Noonan syndrome still rests on its clinical features. There are several syndromes to consider in the diagnosis of Noonan syndrome. These include cardio-facial-cutaneous syndrome, LEOPARD syndrome, neurofibromatosis-Noonan syndrome and Costello syndrome. The facial appearance and part of the clinical features of these syndromes are very similar to Noonan syndrome. Molecular research likely will elucidate whether these syndromes are variations of Noonan syndrome or etiologically different disorders.
Abnormalities, Multiple↗
Giant melanosomes in the dysplastic nevus syndrome. Electron microscopic observations.
Multiple pigmented lesions including benign lentigines, typical nevi, and dysplastic nevi from 3 patients with the dysplastic nevus syndrome contained giant melanosomes (GM). Ultrastructurally the GM were composed of microvesicles, but lacked limiting membrane and filamentous internal structure. As such, they resembled the GM found in 4 other patients with dysplastic nevus syndrome, leopard syndrome and ocular albinism, but differed from those found in the café-au-lait spots of neurofibromatosis, nevus spilus, vitiliginous achromia, and certain animals.
Humans↗
Factitial dermatitis as the presenting sign of multiple lentigines syndrome. Therapeutic effect of autodermabrasion.
Factitial dermatitis was the presenting sign of the multiple lentigines syndrome (leopard syndrome) in a young woman. Six years of an unremitting succession of erosive lesions was medically interpreted as a continuous, nonverbal appeal for help in avoiding an undesirable job. Manifestations of her multiple lentigines syndrome included generalized lentigines, mild mental retardation, diabetes mellitus, transitory ECG abnormalities, a cardiac murmur, ocular hypertension, eye muscle paresis, webbed toes, and skeletal deformities of the hands and chest. Through the years, the repetitive sequence of factitial, erosive, nonscarring lesions eradicated her lentigines, leaving the relatively inaccessible back as the only site of residual multiple lentigines.
Abnormalities, Multiple↗
The Leopard (multiple lentigines) syndrome revisited.
The Leopard syndrome, an acronym, consists of the following features: L-lentigines (multiple), E-electrocardiographic abnormalities, O-ocular hypertelorism, P-pulmonary stenosis, A-abnormalities of genitalia, R-retardation of growth and D-deafness (sensorineural). In addition to the lentigines a few large dark café-noir spots may be scattered over the trunk. Electrocardiographic abnormalities include the S1, S2, S3 pattern and frequently there is pulmonary valvular dysplasia characterized by a pulmonary systolic ejection murmur but no ejection click. Some patients have had subaortic or subpulmonic defects. Others have had atrial septal defect. Hypospadias, cryptorchidism or absence of one ovary has been found. The syndrome is inherited as an autosomal dominant trait.
Adolescent↗
PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.
Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.
Adolescent↗
High incidence of malformation syndromes in a series of 1,073 children with cancer.
Constitutional molecular defects are known to play a role in oncogenesis, as shown by the increased incidence of embryonic cancers in children with Beckwith-Wiedemann syndrome (BWS) or of leukemia in children with Down syndrome. To establish the incidence and spectrum of malformation syndromes associated with childhood cancer we performed a clinical morphological examination on a series of 1,073 children with cancer. We diagnosed a syndrome in 42 patients (3.9%) and suspected the presence of a syndrome in another 35 patients (3.3%), for a total of 7.2%. This incidence of patients with a proven or suspected syndrome is high, and points to a possible association. We describe new syndrome-tumor associations in several entities: cleidocranial dysostosis (Wilms tumor), Bardet-Biedl syndrome (BBS) (acute lymphoblastic leukemia), Kabuki syndrome (neuroblastoma), LEOPARD syndrome (neuroblastoma), Poland anomaly (osteosarcoma; Hodgkin disease), and blepharophimosis epicanthus inversus syndrome (Burkitt lymphoma). Twenty of the 42 syndrome diagnoses were not recognized in the patients prior to this study, indicating that these diagnoses are commonly missed. We propose that all children with a malignancy should be examined by a clinical geneticist or a pediatrician skilled in clinical morphology to determine if the patients have a malformation syndrome.
Abnormalities, Multiple↗
[Progressive cardiomyopathic lentiginosis].
We report on a 30-year-old man with progressive cardiomyopathic lentiginosis. This syndrome is first described by Polani and Moynahan 1972. They distinguish between the earlier described multiple lentigines syndrome, the LEOPARD syndrome (L-entiginosis, E-lectrocardiographic conduction defects, O-cular hypertelorism, P-ulmonary stenosis, A-bnormalities of genitalia, R-etardation of growth, D-eafness) and the progressive cardiomyopathic syndrome. The progressive cardiomyopathic syndrome is characterised by multiple symmetrical lentigines, hypertrophic obstructive cardiomyopathy and retardation of growth. All characteristics were present in our patient with only mild right ventricular hypertrophic cardiomyopathy.
Adult↗
Noonan syndrome and related disorders: genetics and pathogenesis.
Noonan syndrome is a pleiomorphic autosomal dominant disorder with short stature, facial dysmorphia, webbed neck, and heart defects. In the past decade, progress has been made in elucidating the pathogenesis of this disorder using a positional cloning approach. Noonan syndrome is now known to be a genetically heterogeneous disorder with nearly one half of cases caused by gain-of-function mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2. Similar germ line mutations cause two related genetic disorders, Noonan-like disorder with multiple giant cell lesion syndrome and LEOPARD syndrome, and somatic PTPN11 mutations can underlie certain pediatric hematopoietic malignancies, including juvenile myelomonocytic, acute lymphoblastic, and acute myelogenous leukemias. A mouse model of PTPN11-related Noonan syndrome was recently generated, providing a reagent for studying disease pathogenesis in greater depth as well as experimenting with novel therapeutic strategies.
Animals↗
[Congenital sensorineural deafness and associated syndromes].
The etiology of perceptive deafness, especially the congenital variety, requires investigation. The presence of a variety of signs associated with deafness constitutes an "associated syndrome" and helps to define a possible genetic origin. These syndromes only represent a small percentage of overall causes of deafness in children, since at most they account for only 10% of cases. Certain syndromes are encountered more often or are well known, others are extremely rare or have only been described recently. The authors report six of these very rare syndromes discovered among their patients: a KID syndrome, a Leopard syndrome, a Norrie syndrome, a Jervell and Lange Nielsen syndrome, a recently described entity called CEE with deafness and an External Neuro-Cochleo-Pancreatic syndrome which would not appear to have been previously described.
Abnormalities, Multiple↗
Comprehensive non-invasive pre-surgical magnetic resonance imaging in a patient with LEOPARD's syndrome cardiomyopathy.
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Cardiomyopathies↗
A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene.
Signs of neurofibromatosis type 1 (NF1) and Noonan syndrome (NS), two distinct autosomal dominant disorders, occur together in patients reported as Watson syndrome (WS), neurofibromatosis-Noonan syndrome (NFNS), partial LEOPARD syndrome, NS with features of NF1, and NF1 with Noonan-like features. The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades. Only recently, there is increasing evidence for WS and NFNS being allelic to NF1 in the majority of patients. In this study we describe seven novel patients from five unrelated families with variable phenotypes of the NF1-NS spectrum which were systematically analyzed for mutations in the disease-causing genes NF1 for NF1 and PTPN11 for NS. Heterozygous mutations or deletions of NF1 were identified in all patients, while no PTPN11 mutation was found. The NF1 mutation segregated with the phenotype in both familial cases. These results support the hypothesis that variable phenotypes of the NF1-NS spectrum represent variants of NF1 in the majority of cases. Constitutive deregulation of the Ras pathway either through activating mutations of PTPN11 or through haploinsufficiency of neurofibromin, which acts as a Ras-inactivating GTP-ase, is probably the common pathogenetic mechanism explaining the phenotypic overlap of NS and NF1.
Adult↗
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.
Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
Adult↗
The occurrence of supernumerary teeth with isolated, nonfamilial leopard (multiple lentigines) syndrome: report of case.
A case of leopard syndrome with abnormal dental findings of supernumerary teeth is described. The risks involved with providing dental care to patients with this syndrome is also discussed.
Abnormalities, Multiple↗
Cutaneous manifestations of cardiac diseases.
Many general signs familiar to physicians can be found on the skin in cardiac patients. These include (a) cyanosis, central and peripheral, (b) erythremia, flushing and erythema, (c) digital clubbing and (d) alteration in texture. Specific cardiac conditions often have useful diagnostic cutaneous clues. Of these the association of coronary heart disease, hyperlipidemia and xanthomas is the most important. Rare syndromes such as the "leopard syndrome" often have distinctive skin signs. Multisystemic disorders may affect the heart and skin simultaneously or in sequence. They include collagen vascular diseases, amyloidosis, sarcoidosis and relapsing polychondritis. Finally iatrogenic disease arising from treatment of cardiac or cutaneous disease may induce changes in one or the other organ. The heart and the skin have much in common. These manifestations help elucidate the cause, evaluate the diagnosis, and follow the treatment and progress of these diseases.
Heart Diseases↗
Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.
Noonan syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2's activation-inactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.
Animals↗
[Isolated intimal stenosis of the renal artery and curable arterial hypertension in Recklinghausen's disease. Association of hypoplastic stenosis of the aortic and pulmonary trunks and sigmoid aortic regurgitation].
The case of a patient with Von Recklinghausen's disease with multiple localisations, cardiac, aortic, pulmonary and renal artery is reported. Neurofibromatosis was confirmed by the presence of a "royal" tumour on the left elbow and of many "café au lait" spots of over 15 mm diameter. There was no craniofacial dysmorphism or intellectual impairment. The karyotype was normal. The cardiovascular lesions comprised: - stenosis of the left renal artery resulting in renovascular hypertension. This was due to pure intimal hyperplasia; - supravalvular aortic stenosis with hypoplasia of the ascending aorta. There was no craniofacial dysmorphism or intellectual impairment. The karyotype was normal. The cardiovascular lesions comprised: - stenosis of the left renal artery resulting in renovascular hypertension. This was due to pure intimal hyperplasia; - supravalvular aortic stenosis with hypoplasia of the ascending aorta. There was no craniofacial dysmorphism or intellectual impairment. The karyotype was normal. The cardiovascular lesions comprised: - stenosis of the left renal artery resulting in renovascular hypertension. This was due to pure intimal hyperplasia; - supravalvular aortic stenosis with hypoplasia of the ascending aorta, severe aortic regurgitation with dilatation of the aortic ring without rheumatic valvular thickening; - supra valvular pulmonary stenosis which was atypical in site, extension and in the absence of post stenotic dilatation. The pressure gradient was mild (22 mm Hg). There was a striking similarity between the pulmonary and aortic lesions. This new syndrome may be classified amongst the genetic cardiocutaneous syndromes such as the Gorlin or "leopard" syndrome, Watson's syndrome and Noonan's syndrome. Unusual features are the absence of craniofacial abnormalities, normal intelligence, and the left-sided dominance aggravated by hypertension due to curable intimal stenosis of the renal artery.
Adolescent↗