A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome

Du‐Thanh, Aurélie; Cavé, Hélène; Bessis, Didier; Puso, Carine; Guilhou, Jean‐Jacques; Dereure, O.

doi:10.1001/archderm.143.9.1210

Cited by 9 publications

(7 citation statements)

References 13 publications

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“…SHP2 functions as a cytoplasmic signalling transducer downstream of multiple receptors for growth factors, cytokines and hormones, with a particular role through the RAS-mitogen activated protein kinase (MAPK) pathway [ 20 , 21 ]. To the best of our knowledge, 11 different missense PTPN11 mutations, in exon 7, 12 and 13 (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Gly), have been reported so far, two of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases [[ 9 , 10 , 22 - 29 ], personal data]. Germinal mutations in the PTPN11 gene are also responsible for about 40–50% of Noonan (NS) and Noonan-like/Multiple Giant Cell lesions syndrome cases [ 30 , 31 ].…”

Section: Aetiologymentioning

confidence: 99%

Leopard syndrome

Sárközy

Digilio

Dallapiccola

2008

Orphanet J Rare Dis

256

198

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LEOPARD syndrome (LS, OMIM 151100) is a rare multiple congenital anomalies condition, mainly characterized by skin, facial and cardiac anomalies. LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. About 200 patients have been reported worldwide but the real incidence of LS has not been assessed. Facial dysmorphism includes ocular hypertelorism, palpebral ptosis and low-set ears. Stature is usually below the 25th centile. Cardiac defects, in particular hypertrophic cardiomyopathy mostly involving the left ventricle, and ECG anomalies are common. The lentigines may be congenital, although more frequently manifest by the age of 4-5 years and increase throughout puberty. Additional common features are café-au-lait spots (CLS), chest anomalies, cryptorchidism, delayed puberty, hypotonia, mild developmental delay, sensorineural deafness and learning difficulties. In about 85% of the cases, a heterozygous missense mutation is detected in exons 7, 12 or 13 of the PTPN11 gene. Recently, missense mutations in the RAF1 gene have been found in two out of six PTPN11-negative LS patients. Mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. LS is largely overlapping Noonan syndrome and, during childhood, Neurofibromatosis type 1-Noonan syndrome. Diagnostic clues of LS are multiple lentigines and CLS, hypertrophic cardiomyopathy and deafness. Mutation-based differential diagnosis in patients with borderline clinical manifestations is warranted. LS is an autosomal dominant condition, with full penetrance and variable expressivity. If one parent is affected, a 50% recurrence risk is appropriate. LS should be suspected in foetuses with severe cardiac hypertrophy and prenatal DNA test may be performed. Clinical management should address growth and motor development and congenital anomalies, in particular cardiac defects that should be monitored annually. Hypertrophic cardiomyopathy needs careful risk assessment and prophylaxis against sudden death in patients at risk. Hearing should be evaluated annually until adulthood. With the only exception of ventricular hypertrophy, adults with LS do not require special medical care and long-term prognosis is favourable.

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Section: Aetiologymentioning

confidence: 99%

Leopard syndrome

Sárközy

Digilio

Dallapiccola

2008

Orphanet J Rare Dis

256

198

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“…The mutation NM_002834.5(PTPN11):c.1493G>T (NP_002825.3:p.Arg498Leu) has been described in 4 previous patients [Sarkozy et al, 2004;Du-Thanh et al, 2007;Hung et al, 2007;Limongelli et al, 2008]. Their phenotypes are summarized in Table 2.…”

Section: Intracerebral Hemorrhage In Noonan Syndrome With Multiple Lementioning

confidence: 93%

“…Although the patient reported by Hung et al [2007] carried the same mutation as our patient, this individual was diagnosed phenotypically as NS. The reports published by Sarkozy et al [2004] and Du-Thanh et al [2007] describe patients with NSML presenting this mutation. Facial dysmorphisms were present in all patients, while other symptoms occurred only in some cases, highlighting the presence of ICH as a unique finding of our report.…”

Section: Intracerebral Hemorrhage In Noonan Syndrome With Multiple Lementioning

confidence: 99%

Noonan Syndrome with Multiple Lentigines and PTPN11 Mutation: A Case with Intracerebral Hemorrhage

2021

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Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant disorder with an unknown prevalence. Characteristics of this disease include cutaneous, neurologic, and cardiologic abnormalities. In this case report, we present a 12-year-old girl who was admitted to the emergency department for acute-onset left weakness, unsteady gait, nausea, and vomiting. Her physical exam notably showed left side upper motor neuron signs and dysmetria. CT scan revealed an acute hemorrhage of the right thalamus. Physical exam exhibited several craniofacial dysmorphisms and lentigines. The genetic test revealed a heterozygous missense mutation in the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene and a variant of unknown significance of the MYH11 gene. To the best of our knowledge, this is the first case of a patient with NSML presenting an intracerebral hemorrhage.

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“…Only reported cases with well-documented relevant information about the gender, variant type of the PTPN11 gene, and/or the detailed phenotypes of the transmitting parent and the affected child were included. After a literature search related to NS/NSML with PTPN11 p.Arg498Trp [12,13,[15][16][17][18][19], 39 parent-child matched pairs with information about each gender, the p.Arg498Trp of the PTPN11 gene, and/or the NS/NSML's clinical phenotypes were included in this study.…”

Section: Literature Review Of Ptpn11 Parg498trpmentioning

confidence: 99%

Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review

Han,

Park

2024

Genes

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Background: Noonan syndrome (NS)/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case. Methods: In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of PTPN11 were searched from 2000 to 2022. Results: We present a case of a proband with a PTPN11 variant (c.1492C > T/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the PTPN11 p.Arg498Trp variant, cardiac abnormalities (6/11), facial dysmorphism (7/11), skin pigmentation (4/11), growth problems (4/11), and sensorineural hearing loss (2/11) have been observed. NS/NSML patients with the PTPN11 p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated PTPN11. Conclusions: Paternally inherited NS/NSML caused by a PTPN11 p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene–gene interactions, gene–environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype.

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A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome

Cited by 9 publications

References 13 publications

Leopard syndrome

Leopard syndrome

Noonan Syndrome with Multiple Lentigines and <b><i>PTPN11</i></b> Mutation: A Case with Intracerebral Hemorrhage

Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review

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