Table 1 Main features of MALNS according to previous literature (Priolo et al., 2018) and its differential diagnosis

Generalized overgrowth and macrocephaly

Prenatal overgrowth: MALNS may result in large for gestational age (LGA) newborns with weight at birth > 2 SDS in 15% of cases

Post-natal overgrowth: it is observed in childhood and adolescence with a height > 2 SDS reported in 56% of cases. The final height falls within two SDS from the mean in two-thirds of individuals

Macrocephaly is a ubiquitous sign in generalized overgrowth syndromes. In MALNS it is observed in > 75% of individuals

Facial gestalt

Long and narrow face with a triangular shape, high and prominent forehead, short nose with anteverted nares, everted lower lip and small mouth and prognathia/prominent chin becoming more evident in adulthood. Blue sclerae are frequently observed. Other less frequent features include highly arched palate and dental crowding, sparse hair, loose and soft skin, and facial asymmetry

Peculiar neuropsychiatric behavior and intellectual disability

Both features are quite frequent/constant. Although few studies have been published [2, 11], intellectual disability seems to vary from moderate to severe. Anxiety and noise sensitivity are other neuropsychiatric features frequently reported. In some cases, self- or hetero-aggressive behavior is described. Autistic features have been observed in 31% of individuals [2]. These features impede adequate interaction between individuals and environment leading to challenging behavior [12]

Neurological features

Hypotonia is observed in 76% of cases. Seizures and electroencephalogram (EEG) anomalies are common and more frequently observed among individuals with NFIX microdeletions. Central nervous system anomalies characterized by wide ventricles, Corpus Callosum Hypoplasia, and Chiari malformation type 1 are more frequent than brain atrophy. Other neurological findings are different degrees of Optic Nerves Hypoplasia in 13 cases

Musculo-skeletal anomalies

Bone age is advanced in 80% of individuals. Scoliosis, hyper-kyphosis or hyper-lordosis, pectus excavatum/carinatum, slender habitus and long hands are extremely frequent

Ophthalmological features

Mainly represented by strabismus and refractive disorders such as myopia, hypermetropia and astigmatism, with an overall frequency of 76%. Other findings are nystagmus and strabismus

Cardiovascular diseases

Four individuals with aortic root dilatation and one with pulmonary artery dilatation have been reported [2, 13, 14]

Differential diagnosis

Sotos syndrome (MIM 117550), which is caused by heterozygous mutation in NSD1 (MIM 606681) or by deletions within the 5q.35 region. Weaver syndrome (MIM 277590), which is caused by heterozygous mutation in EZH2 (MIM 601573). Other syndromes with marfanoid habitus and ID