FGFR2 gene encodes for the fibroblast growth factor receptor type 2, and belongs to the homonymous family comprising related, though individually distinct, tyrosine kinase receptors (including FGFR1, FGFR3, and FGFR4). FGFRs share a similar structure, comprehensive of 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain, and are able to bind 22 different ligands (FGF) (Azoury et al., 2017). The binding between FGF ligands and FGFRs triggers the dimerization and activation of the kinase domains and the phosphorylation of the receptor. This process activates a downstream signalling pathway involving phosphoinositide 3-kinase (PI3K)/Akt, protein kinase C (PKC), phospholipase C (PLC), and mitogen-activated protein kinase (MAPK) that regulate several biological processes, such as bone development, differentiation of mesenchymal and neuroectodermal cells, intracellular survival and proliferative cellular mechanisms (Azoury et al., 2017; Goyal et al., 2021).
FGFR2 is abundantly expressed in the cartilage of the cranial base, where it is implicated in osteoprogenitor proliferation, differentiation, and apoptosis (Azoury et al., 2017). Recent research highlighted that autosomal dominant FGFR2 mutations might result in constitutive activation of the receptor, which, in its turn, may determine an early differentiation of the osteoprogenitors, hence a premature suture fusion (Mangasarian et al., 1997; Robertson et al., 1998; Azoury et al., 2017). In light of the above, it is not surprising that most FGFR2 pathogenic variants (mainly missense ones) lead to syndromic craniosynostosis (i.e., Crouzon, Apert, Pfeiffer, Beare-Stevenson cutis gyrate, Jackson-Weiss, and Seathre-Chotzen-like syndromes) with a multisystemic involvement (Azoury et al., 2017).
However, FGFR2 is nearly ubiquitously expressed, being particularly present in the brain, the respiratory system, male and female tissues, and the skin (Fig. 1); therefore, mutations in this gene have been associated with other clinical phenotypes, such as Hypospadias and Lacrimo-auriculo-dento-digital syndrome (Azoury et al., 2017; Stenson et al., 2020).
Even though the evidence available today is still sparse and anecdotal, recent data from the literature unravelled a potential role of FGFR2 on neurodevelopment as well (Tammimies et al., 2015; Coci et al., 2017; Szczurkowska et al., 2018; Kweon et al., 2018; Gracia-Darder et al., 2022). In a study designed to better understand the correlation between phenotypic differences and genetic testing in ASD patients, Tammimies et al. (2015) reported a presumed loss-of-function mutation (c.A1295G) of FGFR2 in an autistic child with dolichocephaly and deep-set eyes, without features of craniosynostosis. Moreover, Gracia-Darder et al. (2023) lately provided new evidence on the topic. In fact, they reported the case of a subject affected by rounded and velvety epidermal nevus (RAVEN) associated with heterochromia of hair and ASD since the age of 18 months. A heterozygous variant (p.Cys382Arg) in FGFR2 was detected and the authors suggested a possible causative factor of this variant in the aetiology of their patient’s autism. In addition, Coci et al. (2017) reported three siblings affected by two distinct forms of severe neuropsychological impairments inclusive of autistic features, who turned out to carry two different unbalanced translocations t(10;22)(q26.13;q13.32) of genetic material between the long arms of chromosomes 10 and 22, deriving from a maternal balanced translocation. Interestingly, these two chromosomes harbour important genes implicated in central nervous system development and body growth, including the FGFR2 gene. Lastly, Kweon et al. (2018) carried out a genome-wide analysis on 135 ADHD subjects, revealing four quantitative trait loci comprising several promising candidates that could potentially be related to ADHD, inclusive of FGFR2. This is of interest if considered that our patient also received a co-diagnosis of ADHD (Table 1).
Table 1
Summary of the clinical features of the patient here described, and comparison with cases from the literature presenting a potential involvement in Autism Spectrum Disorder of the FGR2 gene.
Feature | Present patient | Tammimies et al., 2015 | Gracia-Darder et al., 2023 | Coci et al., 2017 (Patient 1) | Coci et al., 2017 (Patient 2) | Coci et al., 2017 (Patient 3) |
Age (years) | 12 | - | 2 | 13 | 11 | 9 |
Sex | Male | Male | Male | Female | Female | Male |
Genetic alteration | SNP | SNP | SNP | Unbalanced translocation: der(10) t(10;22)(q26.13; q13.32) | Unbalanced translocation: der(22) t(10;22)(q26.13;q13.32) | Unbalanced translocation: der(10) t(10;22)(q26.13; q13.32) |
Nucleotide change | c.412G > A | c.1295A > G | c.1147T > C | - | - | - |
Effect on protein | p.Asp138Asn | p.Asp432Gly, near splice site | p.Cys382Arg | - | - | - |
Inheritance | De novo | Paternal | De novo | Maternal balanced translocation t(10;22)(q26.13;q13.32) | Maternal balanced translocation t(10;22)(q26.13;q13.32) | Maternal balanced translocation t(10;22)(q26.13;q13.32) |
Main clinical picture | Severe ASD | ASD | RAVEN | Complex phenotype affecting neurological and skeletal systems, ASD | Intellectual disability | Complex phenotype affecting neurological and skeletal systems |
Other associated clinical features | ADHD | Left temporal lobe septated intraparenchymal cyst | Autistic traits | Epilepsy | Autistic traits | Autistic traits, Epilepsy |
Dysmorphic features | Plagiocephaly, macrocephaly, macrosomia, arched palate, syndactyly of the 2nd and 3rd toe-fingers bilaterally, flat feet, generalized hypotonia, and ligament laxity. | Dolichocephaly, deep-set eyes | Hair heterocromia | Microcephaly, broad and prominent forehead, flat midface, narrow tip nose, hypotelorism, and strabismus convergens | Macrocephaly | Dolichocephaly, narrow tip nose, hypotelorism, and strabismus convergens) |
Legend
ASD: Autism Spectrum Disorder; ADHD: Attention Deficit Hyperactivity Disorder; FGFR2: fibroblast growth factor receptor 2; RAVEN: rounded and velvety epidermal nevus
The above data, although not definitive, point out the potential involvement of FGFR2 in the etiology of neurodevelopmental disorders, such as autism and ADHD.
Szczurkowska et al. (2018) have already proposed such a role for FGFR2: they demonstrated that the mutual regulation of FGFR2 and the cell adhesion molecule NEGR1 is apparently implicated in the genesis of impaired core behaviours related to autism spectrum disorder in mice. In particular, the downregulation of either one of these two genes leads to a defective NEGR1-FGFR2 complex (which in its turn would converge on the Extracellular signal-regulated kinases/Akt downstream signalling pathway), eventually affecting neuronal migration and the spine density during mouse cortical development, being therefore responsible for the autistic symptoms. Earlier, Vaccarino et al. (2009) had already suggested that FGF, a family of genes regulating cortical size and connectivity, may determine increased brain volume, minicolumn pathology and excessive network excitability. The developmental alterations induced by mutations in these genes may be responsible for sensory hyper-reactivity, often found in autism.
Finally, it is worth recalling our patient’s main clinical features, partially overlapping with those present in certain FGFR2-related syndromes, such as high-arched palate (as in Pfeiffer syndrome, #MIM 101600), syndactyly of the 2nd and 3rd toes (Jackson-Weiss syndrome #MIM 123150 and Sathre-Chotzen syndrome, #MIM 101400), plagiocephaly (Sathre-Chotzen syndrome, #MIM 101400), developmental delay and intellectual disability (Beare-Stevenson cutis gyrate syndrome, #MIM 123790, Crouzon syndrome, #MIM123500, and Pfeiffer syndrome #MIM 101400), within a predominant condition of autism spectrum disorder.
All these data not only corroborate the already proposed pathogenicity of FGFR2 in neurodevelopmental disorders, including autism and ADHD but also specifically support its etiological role in our patient’s case. Given the recent breakthrough of next-generation sequencing techniques, such as WES, we reckon that the analysis of FGFR2 should be included, and its variants should be taken in mind when a neurodevelopmental disorder, especially in association with craniosynostosis and body overgrowth, are evident. Further evidence is needed to reveal the specific role of certain FGFR2 variants in determining distinct phenotypes to finally delineate a more precise genotype-phenotype correlation within this rare and intriguing group of disorders.