Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia

CBL syndrome presents with a variable multisystem phenotype. Affected individuals typically show distinctive craniofacial features including broad forehead, hypertelorism, and dysmorphic ears; postnatal growth restriction; and, in male individuals, cryptorchidism. Neurological involvement is prominent, with developmental delay and learning difficulties reported in most affected individuals; intellectual outcomes range from normal cognition to moderate impairment. Café au lait macules and juvenile xanthogranulomata occur in a subset, overlapping with the cutaneous findings of neurofibromatosis type 1. A defining clinical feature is predisposition to juvenile myelomonocytic leukaemia, which typically presents before three years of age and, in this genetic context, often follows a self-limiting course with spontaneous resolution and a less aggressive clinical course than other juvenile myelomonocytic leukaemia subtypes. Congenital heart defects are observed less frequently than in classic . Phenotypic expression is highly variable; some affected individuals fulfil classic Noonan-syndrome diagnostic criteria, while others show only subtle features.

Due to insufficient data, no reliable statement on prevalence can currently be made.

CBL syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Once the familial pathogenic variant has been identified, prenatal molecular testing is possible.

Diagnosis is established by molecular genetic testing identifying a germline pathogenic variant in CBL. No established clinical diagnostic criteria, biochemical marker, or imaging finding is specific to the condition; clinical suspicion is raised by the combination of variable Noonan-spectrum features and, where present, juvenile myelomonocytic leukaemia.

Main differential diagnoses include:

• (classic): higher prevalence of congenital heart disease without specific juvenile myelomonocytic leukaemia predisposition; PTPN11, SOS1, and others
• : coarser facies, ectodermal features, more severe intellectual disability; BRAF, KRAS, MAP2K1, MAP2K2
• : coarse facies, loose skin, papillomata, predisposition to rhabdomyosarcoma rather than juvenile myelomonocytic leukaemia; HRAS

• Establishing the diagnosis: confirming the molecular cause allows accurate diagnosis, prognostic counselling, and informed reproductive planning.
• Specific and individualised surveillance: identification of the pathogenic variant enables targeted, gene-tailored surveillance and management decisions, which are determined by the treating physicians.
• Family member testing: once the familial pathogenic variant has been identified, predictive testing of at-risk relatives can clarify their variant status and guide their own care and reproductive choices.

• Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al. Noonan syndrome. 2001 Nov 15 [updated 2025 Dec 4]. In: GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301303.
• Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794-800. PMID: .
• Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87(2):250-257. PMID: .
• Perrino MR, Das A, Scollon SR, Mitchell SG, Greer MC, Yohe ME, et al. Update on pediatric cancer surveillance recommendations for patients with neurofibromatosis type 1, Noonan syndrome, CBL syndrome, Costello syndrome, and related RASopathies. Clin Cancer Res. 2024;30(21):4834-4843. PMID: .