B. Petrák 1; D. Zemková 2; P. Seeman 1; P. Tesner 3; R. Kremlíková Pourová 3
Klinika dětské neurologie, 2. LF UK a FN Motol, Praha
1; Pediatrická klinika 2. LF UK a FN Motol, antropologická ambulance, Praha
2; Ústav biologie a lékařské genetiky, 2. LF UK a FN Motol, Praha
Cesk Slov Neurol N 2021; 84/117(2): 211-213
Letter to Editor
Legius syndrome (LGSS, MIM 611431) is a rare autosomal dominant (AD) hereditary neurocutaneous disease, due to pathogenic variants in the SPRED1 gene (15q14), affecting the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway and with skin spots called café-au-lait macules (CALM) and sometimes axillary and/or inquinal freckling (numerous small brown spots similar to freckles). LGSS was described in 2007 as an NF1-like syndrome by differentiation from patients diagnosed with von Recklinghausen type I neurofibromatosis (neurofibromatosis type 1, NF1, MIM 162200) . The estimated prevalence of LGSS in the population is 1 : 46,000–1 : 75,000 [2,3]. In addition to cutaneous findings, LGSS is described as a phenotype with macrocephaly, facial dysmorphia, short stature, skin lipomas, specific learning disabilities (SLD), and Attention Deficit Hyperactivity Disorder (ADHD) [1,2]. The definition of patients with LGSS against the clinical picture of NF1 is diagnostically important in that they do not have gliomas, neurofibromas, Lisch nodules (iris hamartomas) or bone dysplasia (Tab. 1a). Molecular genetic detection of a pathogenic heterozygous mutation of the SPRED1 gene is necessary for a clear determination of LGSS [1–4].
Tab. 1a. Diagnostic symptoms LGSS .
Suspicion of a diagnosis of LGSS can be expressed in individuals who have:
Dysplastic pigmentation of white coffee spots (café-au-lait macula, CALM), simultaneously with/without the finding of intertriginous freckling (numerous small round brown spots similar to freckles, in predilection places - in the axillae and groin).
Simultaneously with the absence of other diagnostic symptoms of NF1 – no neurofibromas or plexiform neurofibromas were found, no optical glioma, Lisch nodules or bone dysplasias (sphenoid bone wing dysplasia, thinning of the cortical part of long bones with/without pseudoarthrosis).
To diagnose LGSS, at least two of the following criteria must be found:
1. White coffee spots on the skin (café-au-lait macula, CALM) in numbers of 5 or more. Multiple axillary or inquinal freckling may be present. No other NF1 diagnostic criteria were found.
2. Mutations in the SPRED1 gene in a heterozygous state at molecular genetic testing.
3. One of the proband's parents has a diagnosed LGSS according to the above dg. criteria.
Another possible component of the LGSS clinical picture:
b) Small stature
c) Specific learning disabilities (SLD)
d) Behavioural disorders and developmental disorders (concentration disorders and / or hyperactivity – ADD syndrome, ADHD syndrome)
e) Multiple lipomas
f) Chest deformities
g) Stigmatization of facies - corresponds to the finding in Noonan syndrome.
NF1 is a multisystemic, AD hereditary neurocutaneous disease which affects skin, central and peripheral nervous system, eyes, bones, and vascular walls. The cause of the disease is a mutation in the tumour suppressor gene NF1 (17q11.2) and a disorder in the production of neurofibromin - a negative regulator of the Ras complex . The clinical diagnosis of NF1 is defined by seven diagnostic criteria (Tab. 1b), including CALM and skin freckling . In addition to diagnostic criteria, NF1 also has further broad spectrum of clinical manifestations . Both LGSS and NF1 are currently classified as RASopathies, a group of diseases caused by disorders of the Ras/MAPK signalling pathway . The oncological risk is significantly lower in LGSS than in NF1 [1,2].
Molecular genetic testing of the SPRED1 gene has been available in the Czech Republic since 2011 . The aim of the present case report is to improve the differential diagnosis in patients with multiple skin CALMs.
ab. 1b. Diagnostic criteria NF1 .
White coffee spots on the skin (café-au-lait macula, CALM) in the quantity of six or more - until puberty of one dimension at least ≥ 5 mm; after puberty of one dimension at least ≥ 15 mm.
Multiple axillary and/or inquinal freckling (numerous small brown spots similar to freckles, in predilection places - in the axillae and groin).
Two or more neurofibromas or one or more plexiform neurofibromas.
Glioma of the optic pathway.
Typical bone lesions (dysplasia of the wing of the sphenoid bone, thinning of the cortical part of the long bones with/without pseudoarthrosis).
Two or more Lisch nodules (iris hamartomas) on both sides.
A first-degree relative (parent, sibling or offspring) with a proven diagnosis of NF1 according to the above criteria.
Two sisters, now sixteen years old (identical twins) were monitored by a paediatrician for a positive perinatal history (gemini, delivered by an acute caesarean section for preeclampsia of the mother at 36 weeks of gestation) and low birth weight (twin A with a birth weight of 2,240 g, length 44 cm, twin B with birth weight 2,140 g, length 44 cm). Postpartum adaptation was good for both. Both had adequate psychomotor development with independent walking from 1 year of age and adequate speech development. Due to the cutaneous finding of CALM (Fig. 1a) and suspicion of NF1, at the age of 2 and half years the girls were sent for examination to the paediatric neurological outpatient clinic of the Motol University Hospital, where they are still being monitored. The girls' mother and maternal grandmother also have a CALM skin finding. The neurological findings in both girls were permanently without focal changes, without dysmorphic features of the face (except for deeper-set eyes), with small stature, with a slight pectus excavatum and genua vara. No neurofibromas, Lisch nodules or bone dysplasias were found in the sisters, no glioma of the visual pathway or other pathology on the MRI of the brain. Due to their short stature, both are monitored by an anthropologist and an endocrinologist, and their sexual characteristics are fully expressed. Due to their genua vara they are in orthopaedic care, so far with a conservative procedure. Both girls have excellent school results, without learning disabilities.
Twin A had two CALMs on its skin from neonatal age with progression of their number to the end of infancy and with indicated freckling from the age of 5. At 16, she has 10 CALMs on her trunk and limbs and only the indicated freckling in the groin. At anthropological examination at 14 years and 10 months of age, she already had a final height of 150.3 cm (–2.3 SD), weight 51.5 kg (–0.4 SD), BMI 22.8 (1.1 SD), and a relatively large head circumference of 55.1 cm (0.3 SD). The lower limbs of 66.8 cm length (–2.6 SD) were shortened against the trunk (ratio of sitting height to length of lower limbs 2.4 SD), with the genua vara and pedes plani to planovalgi more to the right, foot length 22.6 cm (–0.9 SD). The value of growth hormone (insulin-like growth factor 1, IGF1) was within the norm (449 µg/L), with IGF1 0.24 SD. Due to the familial prevalence of small stature (mother's height 166 cm, father 165 cm) the endocrinologist did not indicate growth hormone therapy.
Twin B had one CALM on her skin from neonatal age, with the progression of their number until the end of infancy and with indicated freckling from the age of 5. At 16, the patient has six CALMs, and mild groin freckling – more pronounced than in her sister. At anthropological examination at 14 years and 10 months of age, she already had the final height of 150.3 cm (–2.3SD), weight 50 kg (–0.6 SD), BMI 22.1 (0.9 SD), head circumference 54.8 cm (0.1 SD). The lower limbs of 66.3 cm length (–2.7 SD) were shortened against the trunk (2.7SD), with genua vara and pedes plani on the right, the length of the foot was 22.4 cm (–1 SD). The IGF1 value was normal (419 µg/L), with IGF1 at 0.01SD. The endocrinologist did not indicate growth hormone therapy.
As only cutaneous symptoms of NF1 were found in both sisters (clearly expressed by CALM and only indicated freckling), no examination of the NF1 gene was performed, but examination of the SPRED1 gene was indicated directly, where a previously not described variant c.1093C>T (p.Gln365Ter) in exon 7 was found in a heterozygous state, which predicts the formation of a premature stop codon and a truncated protein and is most likely pathogenic and thus the cause of LGSS in both sisters. This mutation was subsequently also proved in their mother and maternal grandmother (Fig. 1b). Molecular genetic testing using a set of polymorphic STR markers confirmed that they were identical, i.e., monozygotic twins.
LGSS represents an important differential diagnosis for individuals with multiple CALMs or with CALM and freckling, and thus with the appearance of "mild development” of NF1 - without neurofibromas, gliomas and other tumour processes [1,2]. Of the common diagnostic symptoms with NF1, only CALM was clearly expressed in our patients, freckling was only indicated. From the other clinical signs common to NF1 and LGSS, there was only short stature (–2.3SD), which was not associated with low IGF1 levels (as may be the case with NF1) , but with shortening of the lower limbs against the trunk. We did not observe facial stigmatization, macrocephaly or SLD, described in other patients with LGSS [1,2,5,9], in our patients.
Although the patients are identical twins, their phenotype differs slightly - by the number of CALMs, the expression of freckling, the severity of the genua vara and also the length of the lower limbs.
We have not found a case of LGSS in monozygotic twins in the literature, and this is also why we consider our case report to be important. LGSS must be considered in patients with multiple CALMs without further manifestations of NF1 or in patients with a diagnosis of NF1, as determined by the finding of CALM and freckling without evidence of a causal mutation in the NF1 gene [2,10]. Currently, it is possible to use the examination of a panel of genes related to the Ras/MAPK signalling pathway to diagnose both NF1 and LGSS .
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
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