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Patients carrying Arg1809 substitution with no choroidal abnormalities: a further proof of a “Quasi-Incomplete” NF1 phenotype

European Journal of Human Genetics volume 31, pages 136–137 (2023)Cite this article

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Neurofibromatosis type 1 (NF1; MIM 162200) is a genodermatosis due to heterozygous mutations in NF1 (MIM 613113) that explains why it is also classified among RASopathies. The diagnosis is based on recently revised criteria that include minimal clinical and genetic criteria for diagnosing and differentiating NF1 and Legius syndrome (LGSS; MIM 611431) [1]. These include typical café-au-lait macules (CALMs, at least six and with an age specific diameter), skinfold freckles, Lisch nodules (LNs) and choroidal abnormalities (CAs), neurofibromas, skeletal dysplasia and optic glioma. One further criterion is represented by the detection of a pathogenetic heterozygous variant in NF1 [1]. The cited typical NF1 features tend to appear in an age dependent manner making clinical diagnosis uncertain in those young cases who lack pathognomonic features such as tumors or LNs. In youngers, CALMs and freckling can be the solely manifestation of the NF1 yet they, alone, are not anymore specific for NF1 [1]. In pediatric age, differential diagnosis between NF1 and LGSS becomes fundamental considering that, among RASopaties, LGSS is the one that mostly overlaps to NF1. It is due to heterozygous pathogenetic variants in SPRED1, and lead to a very mild phenotype with pigmentary features of NF1 [1]. In terms of prevalence LGSS occurs in about 1/46,000–1/75,000 live births, accounting for about 4% of patients followed at a neurofibromatosis clinic, whereas NF1 occurs in about 1/2000–1/3000. LGSS typically lack all tumoral NF1 features, and LNs [1]. In the least decades, only few genotype–phenotype correlations in NF1 have been reported [1]. Among these, aminoacidic substitutions of Arg1809 are related to a milder NF1 phenotype [2,3,4]. In 2015, Rojnueangnit et al. described the phenotypical features of the largest reported cohort of patients carrying Arg1809 substitutions [4]. The authors highlighted how fewer patients had LNs compared to other NF1 patients (6/51 in individuals ≥9 years and 10/91 in all ages) [4]. Merging data from their population with those from already published an even lower proportion of patients with LNs came out 10/119 (8.4%). Indeed, none of the previous authors did find LNs in their Arg1809 patients. One of the patients presenting LNs and reported by Rojnueangnit et al. was a 22-year-old woman with a segmental form of NF1, in whom two different somatic variants [c.5425C>T (p.Arg1809Cys) and an in‐frame deletion of 228 residues c.(63_205)_(888_958)del (p.Arg69_Lys296del)] were detected in melanocytes cultured [4]. Rojnueangnit et al. did not detect any clear-cut cutaneous, dermal and/nor subdermal neurofibromas in their personal series in line with previous reports. Noonan syndrome features, including short stature, macrocephaly, and thoracic anomalies are frequently present [4]. Thus, patients with Arg1809 substitutions typically present CALMs and freckling, tend not to show typical NF1-related tumors (e.g., optic gliomas, plexiform NF) while congenital heart defects are not typically observed [4]. In the studied cohort of 7000 NF1 patients, the Arg1809 substitution occurred with a frequency of 1.23% [4].

LNs occur in more than 95% of NF1 adults and in fewer than half of those younger than 5 years of age [5]. In patients with typical CALMs, without NF1-related tumors, and lacking iris LNs, Arg1809 substitution in NF1 or mutations in SPRED1 should be suspected.

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Acknowledgements

We are grateful to the patients and their families.

Funding

No financial assistance was received.

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Author notes

  1. These authors contributed equally: Claudia Santoro, Rosa Boccia.

Authors and Affiliations

  1. Child and Adolescent Neuropsychiatry Clinic, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Via Pansini 5, 80131, Naples, Italy

    Claudia Santoro

  2. Department of Women’s and Children’s Health, and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Via De Crecchio 4, 80138, Naples, Italy

    Claudia Santoro & Silverio Perrotta

  3. Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, 80132, Napoli, Italy

    Rosa Boccia, Claudio Iovino & Francesca Simonelli

  4. Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138, Naples, Italy

    Giulio Piluso

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  1. Claudia Santoro
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Contributions

CS conceived, wrote and revised the manuscript; GP and SP enrolled patients, wrote and revised the manuscript; FS, CI and RB conceived the work and performed ophthalmological examination, wrote and revised the manuscript.

Corresponding authors

Correspondence to Claudia Santoro or Rosa Boccia.

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The authors declare no competing interests.

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Ethical approval was not required, because ophthalmological assessment is clinically routinely performed in patient s with NF1. Written informed consent for publication was obtained by all patients and/or their parents.

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Santoro, C., Boccia, R., Iovino, C. et al. Patients carrying Arg1809 substitution with no choroidal abnormalities: a further proof of a “Quasi-Incomplete” NF1 phenotype. Eur J Hum Genet 31, 136–137 (2023). https://doi.org/10.1038/s41431-022-01236-1

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