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...

Gray Platelet Syndrome (GPS) is an autosomal recessive bleeding disorder with large platelets that lack α-granules. We found that mutations of NBEAL2 (neurobeachin-like 2), encoding a BEACH/ARM/WD40 domain protein, cause GPS. We demonstrated that human megakaryocytes and platelets express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.

Leukocyte adhesion deficiency-1/variant (LAD1v) syndrome presents early in life and manifests by infections without pus formation in the presence of a leukocytosis combined with a Glanzmann-type bleeding disorder, resulting from a hematopoietic defect in integrin activation. In 7 consanguineous families, we previously established that this defect was not the result of defective Rap1 activation, as proposed by other investigators. In search of the genetic defect, we carried out homozygosity mapping in 3 of these patients, and a 13-Mb region on chromosome 11 was identified. All 7 LAD1v families share the same haplotype, in which 3 disease-associated sequence variants were identified: a putative splice site mutation in CALDAGGEF1 (encoding an exchange factor for Rap1), an intronic 1.

Gray platelet syndrome (GPS) is an in-

Summary:Neurological complications may occur in BMT recipients (11-59%), frequently contributing to morbidity or mortality. They are the main causes of death in 10-15%. Lifethreatening neurological complications were seen in 11 out of 113 (9.7%) children who underwent BMT from HLAmatched family (n ¼ 7) or mismatched donors (n ¼ 4) at our institution. Diagnoses of patients with neurological complications were acute myeloblastic leukemia (AML) (five), thalassemia major (two), Fanconi anemia (two), Omenn syndrome (one) and leukodystrophy (one), and the neurological events were seen between days þ 13 and þ 85 after transplantation. Minor symptoms including reversible, nonrepetitive seizures were excluded. Cyclosporine A toxicity was diagnosed in six children. The rest of the complications were brain abscess/meningoencephalitis (two), severe hypomagnesemia (one), busulfan toxicity (one), sustained hypertension (three), and intracranial hemorrhage (three). Six patients with neurological complications suffered from 4grade II graft-versus-host disease (GvHD), and all were high risk for transplantrelated complications. In this study, risk status of the underlying disease, mismatched transplantation, a diagnosis of AML (advanced stage), older age and 4grade II GvHD were important adverse factors for the development of severe life-threatening neurological complications. Bone Marrow Transplantation (2005) 35, 71-76.