Table 3.

Genes of Interest in the Differential Diagnosis of Neurofibromatosis 1

Gene(s)DisorderMOIClinical Characteristics / Comment
AKT1 1 Proteus syndrome See footnote 1.Hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, & hyperostoses
BRAF
MAP2K1
PTPN11
RAF1 		Noonan syndrome with multiple lentigines (previously referred to as LEOPARD syndrome)ADMultiple lentigines, ocular hypertelorism, deafness, & congenital heart disease
BRAF
KRAS
LZTR1
MAP2K1
NRAS
PTPN11
RAF1
RIT1
SOS1 		Noonan syndrome (NS)AD
(AR) 2		Short stature, congenital heart defect, neck webbing, & characteristic facies. Persons w/NF1 may have NS-like facial features. Facial features of NS change w/age. Features found irrespective of age: low-set, posteriorly rotated ears w/fleshy helices, vivid blue or blue-green irides, hypertelorism, downslanted palpebral fissures, epicanthal folds, & ptosis.
GNAS 3Fibrous dysplasia/McCune-Albright syndrome (FD/MAS)See footnote 3.Large CALMs w/irregular margins & polyostotic fibrous dysplasia
KIT
SNAI2 		Piebald trait (OMIM 172800)ADAreas of cutaneous pigmentation & depigmentation w/hyperpigmented borders of the unpigmented areas, & white forelock
LZTR1
SMARCB1 		Schwannomatosis ADPredisposition to develop multiple schwannomas & (less often) meningiomas. Most common presenting feature: localized or diffuse pain or asymptomatic mass.
MLH1
MSH2
MSH6
PMS2 		Constitutional mismatch repair deficiency (CMMRD; see Lynch Syndrome.)ARRare childhood cancer predisposition syndrome. Affected persons often have colorectal cancer or cancer of the small intestine prior to 2nd decade of life. Cutaneous phenotype is remarkably similar to NF1. CMMRD is distinguishable from NF1 in that the parents are often consanguineous & 1 or both parents often have clinical findings &/or family history of Lynch syndrome due to heterozygous pathogenic variant at one of these loci. Typically, neither parent has clinical findings consistent w/NF1.
NF2 Neurofibromatosis 2 (NF2)ADBilateral vestibular schwannomas, schwannomas of other cranial & peripheral nerves, cutaneous schwannomas, meningiomas, & juvenile posterior subcapsular cataract
PDGFRB Infantile myofibromatosis (OMIM 228550)ADMultiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, & viscera
SPRED1 Legius syndrome ADMultiple CALMs w/o neurofibromas, other tumors, or Lisch nodules. Addl features of Legius: freckling, lipomas, macrocephaly, & learning disabilities / ADHD / DDs. ~8% of children w/≥6 CALMs & no other features of NF1 have Legius syndrome. 5

AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; CALMs = café au lait macules; DD = developmental delay; MOI = mode of inheritance; NS = Noonan syndrome

1.

A somatic mosaic AKT1 pathogenic variant has been identified in more than 90% of individuals meeting Proteus syndrome diagnostic criteria. There are no confirmed occurrences of vertical transmission or sib recurrence.

2.

NS is most often inherited in an AD manner. NS caused by pathogenic variants in LZTR1 can be inherited in either an AD or an AR manner.

3.

FD/MAS is the result of early embryonic postzygotic somatic activating mutation of GNAS. There are no verified instances of vertical transmission of FD/MAS.

5.

Clinically distinguishing Legius syndrome from NF1 may be impossible in a young child because neurofibromas and Lisch nodules do not usually arise until later in childhood or adolescence in those with NF1. Examination of the parents for signs of Legius syndrome or NF1 may distinguish the two conditions, but in simplex cases, reevaluation of the individual after adolescence or molecular testing may be necessary to establish the diagnosis [Legius et al 2021].

From: Neurofibromatosis 1

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