Synonym(s)

NF1-like syndrome
Neurofibromatosis 1-like syndrome

Prevalence

Unknown

Inheritance

Autosomal dominant

Age of onset

Childhood
Infancy

Neonatal
Legius syndrome, also known as NF1-like syndrome, is a rare, genetic, skin pigmentation disorder characterized by
multiple caf-au-lait macules with or without axillary or inguinal freckling.
The prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence
may be higher than expected due to misdiagnosis of cases as NF1. The incidence of NF1 is reported to be 1/3,000,
and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying
Legius syndrome(SPRED1).
The clinical presentation of Legius syndrome is very similar to that of neurofibromatosis type 1 (NF1, see this
term). Patients typically present with multiple caf-au-lait spots sometimes associated with intertriginous freckling,
but lack Lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations.
The number of caf-au-lait macules tends to increase with age during childhood. Other less common
manifestations include short stature, macrocephaly, Noonan-like facies, pectus excavatum/carinatum, lipomas,
hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (ADHD), and
developmental delay.
Legius syndrome is caused by heterozygous inactivating mutations in the SPRED1 gene (15q14), involved in
regulation of the RAS-MAPK signal transduction pathway. Nearly 100 different mutations in this gene have been
identified. The proportion of cases related to de novo mutations is not yet known. No genotype-phenotype
correlations have been found.
About 50% of patients with Legius syndrome fulfill the diagnostic criteria for NF1 but have a far milder phenotype
compared to NF1 patients. Diagnosis is difficult to make solely on the basis of the clinical features given overlap
with other disorders characterized by multiple caf au lait spots. The presence of characteristic clinical signs in
parents of affected individuals is supportive of diagnosis. However, molecular genetic testing is required to confirm
the diagnosis and testing is available on a clinical basis.
Legius syndrome is differentiated from NF1 on the basis of absent non-pigmentary clinical manifestations of this
disorder (Lisch nodules, neurofibromas, optic glioma, bone abnormalities). Correct diagnosis of Legius syndrome
patients is essential because of the differences in prognosis and long-term monitoring compared to NF1. Other
disorders to consider include Noonan syndrome, Noonan syndrome with lentigines (LEOPARD syndrome), and
McCune-Albright syndrome (see these terms).
Prenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.
Legius syndrome follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to
affected families.
Drug therapy should be considered for the behavioral manifestations of the disorder (ADHD). Physical, speech, and
occupational therapy is recommended for developmental delay and educational support for learning difficulties.
The prognosis for patients with Legius syndrome is very good based on current knowledge of disease
manifestations and complications.

Synonym(s)

Del(17)(q11)
Monosomy 17q11
NF1 microdeletion syndrome
Neurofibromatosis type 1 microdeletion syndrome

Prevalence

Unknown

Inheritance

Age of onset
17q11 microdeletion syndrome is a rare severe form of Neurofibromatosis type 1 (NF1; see this term)
characterized by mild facial dysmorphism, developmental delay, intellectual disability, increased risk of
malignancies and a large number of neurofibromas.
The prevalence of 17q11 microdeletion syndrome is not known. About 5% of NF1 cases are reported to have
deletions of the entire NF1 gene. More than 170 affected patients have been reported to date.
Affected individuals often have unusual body habitus and facial dysmorphism including facial coarsening, prominent
forehead, ptosis, down-slanting palpebral fissures, hypertelorism, broad nose, broad nasal bridge, low set ears and,
micrognathia. Patients develop a large number of neurofibromas, often with early onset, including multiple
cutaneous neurofibromas, and less commonly plexiform neurofibromas. Other characteristic features include
attention deficit/hyperactivity disorder (AD/HD), delayed cognitive development and intellectual disability. Some
patients are reported to have microcephaly or macrocephaly, optic pathway glioma, iris coloboma (see these
terms), heart defects (mitral valve prolapse, aortic dilatation), large hands and feet, connective tissue dysplasia
(joint hyperflexibility, soft palm skin), muscular hypotonia, scoliosis, pectus excavatum, and bone cysts. A higher
risk of malignancy for NF1 and non-NF1 tumors is reported: malignant peripheral nerve sheath tumors (MPNST;
lifetime risk of 16-26%), retroperitoneal fibrosarcoma, and medulloblastoma with extensive nodularity (see these
terms).
Germline and mosaic microdeletions of the NF1 gene and its flanking regions caused by non-allelic homologous
recombination (NAHR) are reported in patients with this disorder. Most occur de novo.
Most cases are de novo and unaffected parents have a very low recurrence risk. Affected individuals have a 50%

risk of transmitting the microdeletion, and prenatal and preimplantation genetic diagnosis is possible.

Synonym(s)

NF1
Von Recklinghausen disease

Prevalence

1-5 / 10 000

Inheritance

Autosomal dominant

Age of onset

Infancy
Neonatal

Neurofibromatosis type 1 (NF1) is a clinically heterogeneous, neurocutaneous, genetic disorder characterized by

caf-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, and multiple neurofibromas.
Prevalence is reported to be 1/3,000 live births. NF1 is reported in many ethnic groups and affects males and
females equally.
The clinical features are highly variable, even within the same family. Multiple caf-au-lait macules are found in
almost all patients (some at birth and most before the first year). Intertriginous freckling develops starting at 5
years. Multiple cutaneous and subcutaneous neurofibromas develop in adults. In older patients, they keep
increasing in number and size. Cutaneous neurofibromas do not become malignant. Plexiform neurofibromas
(growing along the nerve and its branches) may cause disfigurement, pain, and functional problems and are
usually present at birth and may become malignant later in life. Ocular manifestations include optic pathway
gliomas and iris hamartomas (Lisch nodules). Optic pathway gliomas usually develop before age 6 years, and rarely
progress thereafter. Osteopenia, osteoporosis, bone overgrowth, short stature, macrocephaly, scoliosis, skeletal
dysplasia (sphenoid wing, vertebral), and pseudoarthrosis may be present. Other features include hypertension,
vasculopathy, intracranial tumors, malignant peripheral nerve sheath tumor (MPNST; see this term), and
occasionally seizures or hydrocephalus. Intellectual development is usually not severely affected but cognitive
deficits and learning difficulties are frequent (50%-75%). The overall cancer risk is higher than the general
population (lifetime risk of 10-12% for MPNST, mostly between 20-40 years; increased risk of breast cancer before
age 50). Three variant forms have been described: familial spinal neurofibromatosis, segmental neurofibromatosis,
and 17q11 microdeletion syndrome. Watson syndrome forms part of the NF1 spectrum. Neurofibromatosis-Noonan
syndrome is a variant of NF1 in 99% of cases (see these terms).
NF1 is caused by mutations in the tumor suppressor neurofibromin 1 NF1 gene (17q11.2) and rarely by 17q11
microdeletion (only 5%).
Formal diagnostic criteria have been established. 2 or more of the following are diagnostic: more than 5 caf-aulait macules, 2 or more neurofibromas or one plexiform neurofibroma, optic glioma, freckling, 2 or more Lisch
nodules, specific bone dysplasias, first-degree relative. MRI can determine the extent of plexiform neurofibromas.
Molecular genetic testing can be requested but is mostly not needed.
Legius syndrome (SPRED1 gene) is often clinically indistinguishable from NF1 and is seen in about 2% of people
fulfilling NF1 diagnostic criteria. There are however a small number of individuals with NF1 who also do not develop
other non-pigmentary manifestations, like Legius syndrome. Constitutional mismatch repair deficiency syndrome
(CMMR-D) should be considered. Other differential diagnoses include McCune-Albright syndrome, Noonan
syndrome with lentigines (LEOPARD syndrome) and Proteus syndromes. Most cases of Jaff-Campanacci syndrome
are cases of NF1 (see these terms).
Prenatal and preimplantation genetic testing for at-risk pregnancies is possible
The mode of inheritance is autosomal dominant. 1 in 2 cases is caused by de novo NF1 mutations. Penetrance is
100% but disease manifestations vary widely, complicating genetic counseling.
Specific cardiovascular, ocular, neurological and orthopedic manifestations should be treated by corresponding
specialists. Cutaneous or subcutaneous neurofibromas can be removed surgically. Plexiform neurofibromas are far
more difficult to treat.
Overall prognosis is good but significant morbidity is common. MPNST generally has a poor prognosis. Malignancy
and vascular disease are the most common causes of early demise.

Synonym(s)

NFNS
Neurofibromatosis type 1-Noonan syndrome

Prevalence

Unknown

Inheritance

Autosomal dominant

Age of onset

Infancy

Neonatal
Neurofibromatosis-Noonan syndrome is a complex disorder of neurofibromatosis type 1 (NF1) with clinical signs
characteristic for Noonan's syndrome, such as small stature, ptosis, hypoplastic middle part of the face, pterygium
colli, learning disability and hypotonia. The genetic anomaly causing the syndrome has not yet been clearly
established. It is believed to be the NF1gene.

NF-1 can be characterized by:

Multiple cafe-au-lait colored spots on skin

Tumors of varying sizes on or under the skin

Lisch nodules on the iris of the eyes

Freckling in the underarm or groin area

Possible learning disabilities

Possible bone deformities, including scoliosis

Possible optic glioma

Possible family history of NF

Symptoms sometimes present at birth

Gena NF1 a fost clonat la nivelul braului lung al regiunii centromerice a cromozomului 17 (17q11.2) i
caracterizat ca i protein Ras-GAP (GTPase-activating protein); produsul genei este neurofibromina,
un peptid care stimuleaz hidroliza intrinsec a guanozinei trifosfat i care acioneaz ca i supresor
tumoral (pierderea complet a neurofibrominei prin mutaii somatice se observ n forma tumoral a
NF1).
Deleiile largi ale acestei gene sunt frecvente i pot fi detectate prin FISH; aceti pacieni pot avea alte
semne adiionale i mai multe pete caf-au-lait comparativ cu ali pacieni cu NF1. Mutaiile liniei
germinale n una din alelele neurofibrominei poate cauza proliferarea tegumentului (pete caf-au-lait) sau
a celulelor Schwann (neurofibroame).

Semnele clinice eseniale pentru diagnostic sunt: neurofibroame multiple; pete caf-au-lait; noduli
Lisch.

Tabloul clinic: rareori debut de la natere; petele apar n 80% din cazuri la vrsta de 1 an iar pn la
vrsta de 4 ani apar la 100% din cazuri; diagnosticul este susinut de prezena a cel puin 6 sau mai multe
pete de cel puin 1,5 cm. diametru (la copil, 5 pete de cel puin 0,5 cm.); pistruii axilari (mai rar inghinali i
perineali) sunt deseori un semn cheie pentru diagnostic; ei apar, de regul, dup vrsta de 3 ani; tumorile
benigne se dezvolt din sistemul nervos periferic fiind constituite din matrix extracelular, celule Schwannlike, fibroblati, celule mastoidiene, celule endoteliale, celule perineurale; cel mai frecvent ele apar sub
forma unor neurofibroame cutanate mici care cresc apoi sub forma unor noduli pigmentai moi; uneori
neurofibroamele sunt de tip plexiform etalate de-a lungul unui traiect nervos; rareori, neurofibroamele sunt
mari i apar de la natere sau n prima copilrie; nodulii Lisch (hamartoamele pigmentate ale irisului) apar
dup 6 ani la 95% din cazuri i dup 20 ani la 100%.
Trsturi ocazionale: tumorile cerebrale (gliom, astrocitom, meningiom, neurofibrom) apar la 5-10% din
cazuri; macrocefalie, hidrocefalie, statur mic moderat; convulsii i anomalii EEG la 20%; deficitul
mintal cu disabiliti la nvtur, hiperactivitate, tulburri de vorbire (50%), cefalee; hipertensiune
arterial (feocromocitom, stenoza arterei renale); scolioz, ncurbare hipoplastic a membrelor inferioare
cu pseudoartroz la natere, leziuni osoase cu osteoscleroz localizat, fuziuni costale, spina bifida,
absena rotulei, dislocare de radius sau uln, hipertrofie local, deformarea pediculilor vertebrali, displazia
aripii sfenoidale; nevi cutanai, nevi verucoi, lipoame, angioame, neurofibroame renale, stomacale,
cardiace, linguale, sau la nivelul vezicii urinare; glaucom, ptoz palpebral, opacitate cornean, melanom
al irisului cu potenial malign;
Criterii de diagnostic pentru NF1 stabilite de NIH (National Institute of Health ):
Pentru diagnostic se cere prezena a dou din urmtoarele 7 semne:
1) minimum 6 pete caf-au-lait de cel puin 0,5 cm nainte de pubertate i 1,5 cm. dup pubertate;
2) pistrui axilari sau inghinali;
3) cel puin 2 neurofibroame cutanate sau unul plexiform;
4) cel puin 2 noduli Lisch;
5) o leziune scheletic specific;
6) un gliom optic;
7) un printe sau un frate afectat;
Diagnostic prenatal
n formele familiale, dup ce mutaia familiei a fost pus n eviden prin metode de biologie molecular,
studiul ADNfetal este posibil, teoretic, fie prin metoda indirect (analiza linkage), fie prin analiza mutaiei

genice. n familiile cu unul sau mai muli afectai, analiza linkage este util pentru identificarea purttorilor
genei NF1 anormale i stabilirea diagnosticului predictiv.

Molecular Genetics and Cell Biology

Molecular genetics provides unique opportunities for research in the neurofibromatoses.
The gene for NF-1 has just been mapped to a site on chromosome 17 using a number
of large kindreds. Recent evidence has localized NF-2 to chromosome 22 through
analysis of tumor DNA. The immediate issues that must be addressed for NF-1 and NF2 are the possibility of genetic heterogeneity among families and the identification of
useful DNA markers closely flanking the genes.
In the near future, it will be possible to accurately trace the NF-1 and NF-2 genes in
families by genetic linkage. A consequence of the identification of closely linked markers
will be the availability of prenatal diagnosis. Individuals with minimal expression can be
definitively diagnosed. Those individuals demonstrated not to carry the NF genes can
be removed from the at-risk category.
The isolation of the NF-1 and NF-2 genes can be accomplished by recombinant DNA
technology. Because many questions about the pathophysiology of the
neurofibromatoses can be addressed through knowledge of the structure of the relevant
genes, strong support of this line of investigation is recommended. Culture studies using
Schwann and other related cell types clearly will be important. Signals leading to
modulation of NF gene expression and to the variable phenotypes seen in vivo may be
revealed in this in vitroapproach.
The analysis of tumor DNA from NF-2 patients has already demonstrated the value of
direct studies of tumor material. The elucidation of the mechanistic basis of tumor
formation in the neurofibromatoses is likely to have significant implications for other
neoplastic disorders. Therefore, it is recommended that tumor tissue from NF patients
continue to be made accessible to investigators who are attempting to identify the basis
of abnormal growth control.
Appropriate animal models for NF-1 and NF-2 will be desirable for testing potential
therapies under in vivo conditions and for extending cell culture findings. Molecular
genetic techniques provide an avenue to the development of such animal models. The
development of such models is strongly recommended.