A number sign (#) is used with this entry because of evidence that Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) is caused by heterozygous mutation in the CBL gene (165360) on chromosome 11q23.

For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).

Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) is a developmental disorder resembling Noonan syndrome (NS1; 163950) and is characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity. Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as seen in patients with Noonan syndrome (summary by Martinelli et al., 2010 and Niemeyer et al., 2010).

Martinelli et al. (2010) reported 4 unrelated probands, including 1 who met the diagnostic criteria for NS and 3 who had a phenotype reminiscent of Noonan syndrome, but without fulfilling the complete diagnostic criteria. Clinical features were highly variable, but generally included dysmorphic facial features, short neck, developmental delay, hyperextensible joints, and thorax abnormalities with widely spaced nipples. The facial features consisted of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Three had cardiac defects, such as enlarged left atrium with dysrhythmias, bicuspid aortic valve with stenosis, and mitral valve insufficiency. None of the patients developed a hematologic malignancy.

Perez et al. (2010) reported 3 unrelated female patients who developed juvenile myelomonocytic leukemia at ages 26 months, 13 months, and 12 months, respectively. Each also had additional features suggestive of an underlying developmental disorder reminiscent of Noonan syndrome. One female child had failure to thrive with poor sucking and postnatal growth retardation and delayed psychomotor development. Dysmorphic facial features included broad forehead, hypertelorism, epicanthic folds, deeply grooved philtrum, thick lips, mild retrognathism, thick, posteriorly rotated ears with overfolded helices, short neck, thin hair and low posterior hairline. She had a single cafe-au-lait spot on the abdomen. She was hyperactive, with short attention span and poor verbal skills. The second child was Tunisian and showed postnatal failure to thrive. She also had microcephaly, triangular facies, high cranial vault, bilateral epicanthic folds, thick lips, prominent philtrum, posteriorly rotated helices, and somewhat sparse hair. Brain imaging showed nonspecific hyperintense signals in the periventricular white matter, but psychomotor development was normal. The third child had a broad forehead, arched eyebrows, hypertelorism, palpebral ptosis, short upturned nose, flat malar areas, deeply grooved philtrum, posteriorly rotated ears with thick helices and large lobules. Other features included pectus excavatum, hypermobile finger joints, redundant skinfolds, and 3 cafe-au-lait spots. She had mildly delayed development but was in the first grade. All 3 received successful cord blood allograft treatment for JMML.

Niemeyer et al. (2010) reported 21 children with JMML who had homozygous CBL mutations in leukemic cells. Sixteen of 21 patients had been previously reported by Loh et al. (2009). Normal tissue from 17 of 21 children was found to harbor a heterozygous germline mutation (see, e.g., 165360.0005-165360.0009), and normal tissue from 4 children was not available for analysis. A large percentage of these children showed dysmorphic facial features, developmental delay, cryptorchidism, and impaired growth, consistent with a Noonan syndrome-like disorder. The leukemia improved spontaneously in 5 of 6 children who did not undergo transplantation, even though the homozygous CBL mutation persisted in peripheral blood. In addition, 4 of these patients developed clinical signs consistent with vascular pathology, including optic atrophy, hypertension and an acquired cardiomyopathy; 1 had Takayasu arteritis. Niemeyer et al. (2010) postulated that the CBL mutation contributed to dysregulated lymphocyte signaling and vasculitis.

Bulow et al. (2015) reported 3 unrelated patients with genetically confirmed NSLL who presented with symptoms prenatally. One patient showed fetal pleural effusions at 21 weeks' gestation, necessitating thoracocentesis at gestational week 27. After birth at 31+5 weeks, the patient was diagnosed with chylothorax, which resolved at age 9 months. On fetal ultrasound, the second child showed hydrothorax, ascites (fetal hydrops), and hepatosplenomegaly, and the third child showed fetal hydrops and pleural effusions; both of these pregnancies were complicated by polyhydramnios. All patients had additional classic features of the disorder, including dysmorphic facial features, cardiac malformations, and delayed development. Only 1 of the patients developed JMML. Bulow et al. (2015) noted that the abnormalities of the lymphatic system observed in these patients was consistent with alteration of the RAS (see, e.g., 190020) signaling pathway.

Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia is an autosomal dominant disorder (Martinelli et al., 2010; Perez et al., 2010).

Martinelli et al. (2010) identified 4 different heterozygous mutations in the CBL gene (165360.0001-165360.0004) in 4 unrelated probands with a Noonan syndrome-like disorder. Two of the mutations were de novo, and 2 were inherited from an affected father. In vitro functional expression studies showed that the mutations all caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS (190020).

In 3 unrelated patients with a Noonan syndrome-like disorder with juvenile myelomonocytic leukemia, Perez et al. (2010) identified a heterozygous germline mutation in the CBL gene (Y371H; 165360.0005). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that heterozygous mutation in the CBL gene is associated with predisposition for the development of JMML. Perez et al. (2010) suggested the moniker 'CBL syndrome.'

Loh et al. (2009) reported 3 patients who presented with JMML who had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (601511) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. They did not find CBL mutations in JMML patients with known PTPN11 (176876)/RAS mutation, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene.