Table 2.

NFIX-Related Malan Syndrome: Frequency of Select Features

SystemFeature% of Persons w/Feature 1Comment
Facial Distinctive facial features100%
Growth Macrocephaly100%77% of adults maintain a head circumference >2 SD above mean.
Postnatal length/height >2 SD above mean56%Final adult height falls w/in 2 SD of mean in two thirds of affected persons.
Neurologic Developmental delay / intellectual disability100%May vary from moderate to severe
Hypotonia65%
Epilepsy / EEG anomalies10/16 (63%) 2Persons w/contiguous deletion incl NFIX & surrounding genes have higher risk of epilepsy compared to those w/intragenic NFIX pathogenic variant.
Autonomic signs4/16 (25%) 2Incl episodic ataxia w/dizziness & nausea &/or postural fainting
Neurobehavioral/psychiatric manifestations12/14 (86%) 2, 310/15 (67%) 2 showed hypersensitivity to noise. 3
Musculoskeletal Slender body habitus16/16 (100%) 2
Advanced bone age76%
Abnormal spine curvature12/16 (75%) 2
Pectus carinatum, excavatum, or mixed10/16 (63%) 2
Pes planus11/16 (69%) 2
Long hands & fingers10/16 (63%) 2
Long bone fractures5/16 (31%) 2
Eye Refractive errors75%
Strabismus10/16 (63%) 2
Esotropia9/16 (56%) 2
Nystagmus5/16 (31%) 2
Blue sclerae11/16 (69%) 2Mainly persisting after infancy
Cataract2/16 (13%) 2Mainly polar posterior cataract
Optic nerve hypoplasia25%
Cardiovascular Cardiovascular anomalies4%Low-grade mitral regurgitation is most common finding; 4 other CHD & aortic root dilatation are less common but require assessment & monitoring (see Management).
Mouth Malocclusion7/16 (44%) 2
Ogival (narrow) palate / dental crowding9/16 (56%) 2
Dental caries6/16 (38%) 2
Oral apraxia / hypersalivation31% (5/16) 2
Other Constipation50% (8/16) 2
Hepatomegaly25% (4/16) 2
Low BMI38% (6/16) 2
Cryptorchidism13% (2/16) 2
Hearing loss2%Of the 2 reported persons w/this finding, both had sensorineural hearing loss.

BMI = body mass index; CHD = congenital heart defects; SD = standard deviations

1.

Percentages refer to individuals with a pathogenic variant in NFIX. These frequencies may vary slightly in individuals who have a continuous gene deletion involving NFIX, although this is not significant except where noted [Priolo et al 2018]; see also Genotype-Phenotype Correlations.

2.

When a fraction is specified, the percentage refers to a specific cohort of affected individuals who underwent a deep phenotyping analysis by an experienced team [Macchiaiolo et al 2022].

3.
4.

Low-grade mitral valve regurgitation has been recorded in at least one third of individuals. However, this data should be considered a minor anomaly and not sufficient to classify MALNS as a condition predisposing to cardiovascular disease and/or heart anomalies.

From: NFIX-Related Malan Syndrome

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