Pigmentary Findings in Neurofibromatosis Type 1–like Syndrome (Legius Syndrome): Title and subTitle BreakPotential Diagnostic Dilemmas

The study by Messiaen and colleagues¹ in this issue of JAMA provides a significant advance in understanding the clinical presentation and genetic spectrum of individuals with SPRED1 mutations that alter sprouty-related EVH1 domain–containing protein 1 function. It is clearly a vanguard report for understanding neurofibromatosis type 1 (NF1)–like syndrome, recently designated Legius syndrome.² Legius syndrome is deemed a more appropriate term to avoid confusion in counseling families regarding anticipatory guidance. The term NF1-like syndrome implies overlap with myriad medical complications associated with NF1, which this report demonstrates is not the case. The few reports of individuals with loss-of-function SPRED1 mutations have shown that the primary phenotype of Legius syndrome is café au lait macules, sometimes associated with axillary freckling, inguinal freckling, or both.^{3 - 5} Messiaen et al¹ provide supportive information on the phenotype of Legius syndrome with an increased number of individuals, document the lack of a specific genotype-phenotype correlation, and clarify the clinical overlap with NF1.

Based on current knowledge, the clinical practice guidelines for an individual with Legius syndrome should primarily be focused on developmental delays, learning disabilities, and attention-deficit/hyperactivity disorder, but future studies will be needed to assess the appropriate clinical management regimen. For example, Messiaen et al¹ described some individuals with abnormal angiogenesis, leading to the question of whether individuals with mutations in SPRED1 are at risk of vascular malformations, cardiovascular defects, and hypertension as observed in NF1. Isolated cases of malignancies have also been reported in Legius syndrome,^{1 ,4 ,6} and the potential for malignant predisposition must be considered given the role of the RAS–mitogen-activated protein kinase (MAPK) signal transduction pathway in cellular growth and differentiation. Pasmant et al⁶ theorized that individuals with Legius syndrome are predisposed to leukemia in childhood. However, the relatively large number of individuals reported by Messiaen et al¹ suggests that tumorigenesis is not associated with Legius syndrome, as no systematic occurrence of a malignant tumor type was observed. Still, approximately 100 individuals have been reported to date, even fewer with a detailed phenotype, and it will be important to further characterize the phenotypic spectrum of Legius syndrome, especially to identify potential rare manifestations.

Messiaen et al¹ provide important insights into a clinical description of this syndrome and a better understanding of the phenotypic variability of disorders of the RAS-MAPK pathway. Specifically, 35 of 42 patients had more than 5 café au lait spots, of which almost half also had freckling of the axillae, inguinal area, or both. These data raise the question of sole reliance on pigmentary manifestations to establish the diagnosis of NF1, especially in younger individuals. As the authors¹ point out, “ . . . a correct diagnosis has important implications . . . ” and they advocate molecular genetic testing to distinguish Legius syndrome from NF1. Their findings also challenge the specificity of the National Institutes of Health consensus diagnostic criteria for NF1.⁷

Neurofibromatosis type 1 is a common autosomal dominant condition due to mutations in the NF1 gene, and like SPRED1, its protein product, neurofibromin, interacts directly with RAS. Clinical diagnostic criteria were developed several decades ago and since that time have been the mainstay for the diagnosis of NF1.^{7 - 8} The diagnostic criteria⁷ state that the clinical diagnosis of NF1 is made if 2 or more of the following are found: (1) 6 or more café au lait macules larger than 5 mm in diameter in prepubertal individuals and larger than 15 mm in greatest diameter in postpubertal individuals; (2) 2 or more neurofibromas of any type or 1 plexiform neurofibroma; (3) freckling in the axillary or inguinal regions; (4) optic glioma; (5) 2 or more Lisch nodules (iris hamartomas); (6) a distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis; and (7) a first-degree relative (parent, sibling, or offspring) with NF1 by the above criteria. These NF1 clinical diagnostic criteria have been used for many years, but more than one-third of individuals with Legius syndrome also fulfill these clinical diagnostic criteria, decreasing the utility of applying these criteria.

The pigmentary findings of Legius syndrome and NF1 are the only overlapping physical manifestations in regard to the NF1 clinical diagnostic criteria. Café au lait macules are typically the first manifestation of NF1, with inguinal freckling or axillary freckling as the next most common manifestation. Accordingly, diagnosis is tenuous when patients have these 2 pigmentary features without other age-related manifestations of NF1. The findings reported by Messiaen et al,¹ along with the other published cases, bring this diagnostic dilemma into clear focus. Although freckling in the axillary region or inguinal region is a distinctive diagnostic feature of NF1, it is an extension of the pigmentary findings of café au lait macules and is not an independent feature that carries as much diagnostic weight as neurofibromas, optic pathway tumors, or distinctive osseous lesions. Crowe⁹ reported that axillary freckling occurs only when there is other evidence of hyperpigmentation.

Despite the NF1 diagnostic criteria having been applied for decades, the criteria are not without flaws requiring adjustments. For instance, the examples of the criterion for the distinctive osseous lesions may not be accurate.¹⁰ The authors of the original diagnostic criteria noted that other disorders of pigmentation can be confused with NF1 and stated, “Some patients, particularly children, have insufficient findings to meet NF-1 and NF-2 criteria. . . . Molecular genetics may permit a diagnosis of NF-1 or NF-2 in these patients. This may require modification of current NF-1 or NF-2 diagnostic criteria. Patients who do not fit into the NF-1 or NF-2 group by clinical or genetic criteria may, in the future, constitute the basis for establishing additional types of NF.”⁷ This emphasizes anticipation of future modification of the criteria.

As noted by Messiaen et al,¹ the unique but similar pigmentary features of NF1 and Legius syndrome present a diagnostic dilemma in younger sporadic individuals who do not have other NF1 manifestations or family history. One approach to integrate this new information into the established diagnostic criteria is to consider combining the 2 criteria for the unique pigmentary findings of NF1 (multiple café au lait macules and axillary or inguinal freckling) into a single criterion. This modification of the diagnostic criteria would prevent premature diagnosis of NF1 based on pigmentary findings alone and would increase the clinical utility of molecular testing for SPRED1 and NF1 mutations.

In addition to SPRED1 mutations causing a pigmentary pattern similar to NF1, there are likely other genetic causes for similar presentations. For example, Nyström et al¹¹ described a family with café au lait macules, inherited in an autosomal dominant pattern, without genetic segregation with either NF1 or SPRED1. In addition, some older individuals who lack neurofibromas and Lisch nodules may still have NF1 mutations as has been described by Upadhyaya et al¹² in a cohort of individuals with a 3-bp in-frame deletion (c.2970_2972 delAAT) in NF1. The use of mutation analysis of NF1 and SPRED1 can clarify diagnostic uncertainty but must be weighed in conjunction with age and the potential effects of mutation analysis on clinical management and family dynamics.

The study by Messiaen et al¹ provides important information about Legius syndrome and enables clinicians to use good clinical judgment in situations where it is now realized that there is phenotypic overlap for distinct disorders. As new genes resulting in phenotypes similar to NF1 and Legius syndrome are discovered, clinicians must adapt diagnostic approaches and clinical management protocols to meet the needs of patients affected with these disorders.