A 3‐bp deletion mutation of <i>PTPN11</i> in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia

Yoshida, Rie; Miyata, Masafumi; Nagai, Toshiro; Yamazaki, Toshio; Ogata, Tsutomu

doi:10.1002/ajmg.a.30029

Cited by 33 publications

(19 citation statements)

References 17 publications

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“…Consistent with these results, all previous children with NS/MPD carrying a mutated PTPN11 gene have been documented to be sporadic cases. 3,14 These findings suggest that NS/MPD is associated with mutations that might be associated with decreased fertility or have more severe consequences on fetal survival. This is consistent with the observation that mutations associated with NS/MPD have only rarely been identified in patients with familial NS cases, and that mutants detected in families transmitting NS are unlikely to be associated with NS/MPD.…”

Section: Resultsmentioning

confidence: 95%

“…9 Infants with NS are predisposed to developing a myeloproliferative disorder (NS/MPD), which may regress without treatment or follow an aggressive clinical course similar to JMML. [10][11][12][13][14] By contrast, cases of JMML that arise in patients without NS have a poor prognosis without hematopoietic stem cell transplantation. [15][16][17][18] Recent studies show that children with JMML have improved outcomes when they are treated aggressively early in the course of disease.…”

Section: Introductionmentioning

confidence: 99%

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The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Kratz

Niemeyer

Castleberry

et al. 2005

Blood

237

196

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Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n ‫؍‬ 69) or NS/MPD (n ‫؍‬ 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n ‫؍‬ 107); (2) patients with NS/MPD (n ‫؍‬ 19); and (3) patients with NS (n ‫؍‬ 243). Glu76 was the most commonly affected residue in JMML (n ‫؍‬ 45), with the Glu76Lys alteration (n ‫؍‬ 29) being most frequent. Eight of 19 patients with NS/ MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 IntroductionThe PTPN11 proto-oncogene encodes Src-homology tyrosine phosphatase 2 (SHP-2), a protein tyrosine phosphatase with a role in signal transduction and hematopoiesis. 1,2 Somatic PTPN11 mutations exist in 35% of juvenile myelomonocytic leukemia (JMML) specimens and are less frequent in other leukemias. 3-6 SHP-2 relays signals from activated growth factor receptors to Ras. PTPN11, KRAS2, NRAS, and NF1 mutations are found in mutually exclusive subsets of patients with JMML. 3,4 These data support the hypothesis that hyperactive Ras signaling plays a central role in JMML.Germ-line PTPN11 mutations cause approximately 50% of cases of Noonan syndrome (NS), 7,8 a congenital disorder characterized by facial anomalies, short stature, and heart defects. 9 Whereas NS is frequently inherited as an autosomal dominant condition, almost half of the constitutional PTPN11 mutations found in NS arise sporadically. Germ-line PTPN11 mutations are also found in patients with multiple lentigene syndrome (LS), a rare developmental disorder clinically related to NS. 9 Infants with NS are predisposed to developing a myeloproliferative disorder (NS/MPD), which may regress without treatment or follow an aggressive clinical course similar to JMML. 10-14 By contrast, cases of JMML that arise in patients without NS have a poor prognosis without hematopoietic stem cell transplantation. [15][16][17][18] Recent studies show that children with JMML have improved outcomes when they are treated aggressively early in the course of disease. 18 Therefore, differentiating JMML from NS/MPD and identifying patients with NS/MPD who will require aggressive treatment are important clinical questions. We identify PTPN11 mutations in 77 newly reported patients with JMML and NS/MPD, and compare the mutational spectrum in JMML, NS/MPD, and NS/LS to determine if genotype-phenotype correlations exist that may help guide diagnosis and clinical management. Study designTissue samples (bone marrow, peripheral blood, and, rarely, buccal swab and skin fibroblasts) from patients with JMML and NS/MPD were collected under Institutional...

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Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Kratz

Niemeyer

Castleberry

et al. 2005

Blood

237

196

View full text Add to dashboard Cite

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“…For NS itself, PTPN11 mutations account for roughly 50% of cases [Musante et al, 2002;Tartaglia et al, 2002;Zenker et al, 2004]; nearly all mutations are of the missense type, although a 3-bp deletion has been observed [Yoshida et al, 2004]. PTPN11 missense mutations are also responsible for a large proportion of the patients with LEOPARD syndrome, which is allelic to NS [Digilio et al, 2002].…”

Section: Discussionmentioning

confidence: 98%

Neurofibromatosis-Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient

et al. 2005

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Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial anomalies, webbed neck, sternal deformity, heart defects, and, in males, cryptorchidism. PTPN11 encodes SHP2, an important component of several signal transduction pathways that acts as a positive regulator of RAS-mitogen activated protein kinase signaling. Neurofibromatosis type 1 (NF1) is another autosomal dominant disorder characterized by hamartomas in multiple organs. The NF1 gene encodes a GAP-related protein, which acts as a negative regulator of the Ras-mediated signal transduction pathway. Clinical overlap between both syndromes, neurofibromatosis-Noonan syndrome (NFNS) is well known. We studied a female patient with typical findings of NFNS and found two mutations: a novel PTPN11 transversion, 1909A --> G, resulting in Gln510Arg, and an NF1 transversion, 2531A --> G, resulting in Leu844Arg. She inherited the PTPN11 mutation from her father and had a de novo NF1 mutation. This is the first report of molecular concurrence of both disorders in the same patient.

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“…Notably, the cases of Doisaki et al had a mild and self-limiting clinical course. Yoshida et al also reported that a patient with Noonan syndrome developed JMML with a self-limiting course [7]. By contrast, our patient had an aggressive clinical course that was typical for isolated JMML with PTPN11 mutation.…”

Section: Discussionmentioning

confidence: 72%

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation

et al. 2015

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After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.

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A 3‐bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia

Cited by 33 publications

References 17 publications

The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Neurofibromatosis-Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation

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