While hypochondroplasia (HCH) is primarily understood as a skeletal dysplasia, a substantial and growing body of literature — spanning case reports, cohort imaging studies, and murine developmental biology — points to a distinct neurodevelopmental dimension of the condition rooted in the same FGFR3 signaling pathway responsible for the skeletal phenotype. For clinicians managing HCH patients, particularly those presenting with seizures, learning difficulties, macrocephaly, or developmental delay, this literature is increasingly relevant to diagnostic and counseling discussions.

FGFR3 is postulated to play a role in brain development, mainly in hippocampal development, and FGFR3 mutations are known to interfere with brain development in mouse embryos (Romeo et al., 2014). FGFR3 is expressed in the brain during embryogenesis (Peters et al., 1993; Walshe & Mason, 2000), and in mice its expression is high during development in the rhinal and piriform cortices — structures corresponding to the anterior parahippocampal gyrus in humans — as well as in the hippocampus, amygdala, and striatum (Linnankivi et al., 2012).

Fgfr3 knockout mice show a measurable reduction in cerebral cortex and hippocampal volume (Moldrich et al., 2011), while gain-of-function Fgfr3 mutant mice show the opposite effect: increased neuroprogenitor proliferation, increased cortical thickness, and selective expansion of the temporo-occipital cortex, with preliminary evidence of hippocampal dysplasia and reduced CA3/dentate gyrus volume (Thomson et al., 2007; Thomson et al., 2009; Inglis-Broadgate et al., 2005). A related gain-of-function model (Fgfr3ᵏ⁶⁵⁰ᴱ, overexpressed specifically in postmitotic glutamatergic neurons) produced disrupted radial glial mitosis, abnormal inside-out cortical migration, and hippocampal patterning defects, even though the brain enlargement itself paralleled human thanatophoric dysplasia (Zhang et al., 2020).

This body of work offers a plausible mechanistic substrate for the structural brain findings increasingly documented in HCH patients carrying the common N540K variant.

A chronological line of case reports has built the clinical picture, each adding detail to a converging phenotype:

• Grosso et al. (2003) were the first to describe bilateral medial temporal lobe dysgenesis in a patient with HCH (and, separately, a patient with the allelic Muenke syndrome), noting inadequate gray-white matter differentiation, defective gyri, and an abnormally shaped hippocampus on MRI, in patients who were otherwise cognitively normal.

• Kannu et al. (2005) described two further HCH patients with the same finding, explicitly proposing that FGFR3 mutations might cause cerebral malformations in HCH as they do in thanatophoric dysplasia.

• Kannu & Aftimos (2007) added a third case, reinforcing that FGFR3 is expressed in the brain during development and plays a role in hippocampal formation.

• Romeo et al. (2014) reported a patient with bilateral anterior hippocampal infolding and focal cortical rim dysplasia at the gray-white matter junction, identified using higher-resolution (2mm) MRI sequencing than prior reports — proposing the constellation of FGFR3 mutation, medial temporal lobe dysgenesis, and focal epilepsy may represent a distinct, under-recognized syndrome.

• Peters et al. (2018) (Boston Children’s Hospital) reported a further case with bilateral temporal lobe dysplasia, redundant sulci, and a rotated hippocampus, framing the imaging findings as a direct window into the cerebral pathogenesis of FGFR3-related disorders.

• Bernardo et al. (2021), reporting three additional cases of focal epilepsy and temporal lobe malformation in FGFR3-mutant children, explicitly revisited the question of causality — concluding the pattern likely reflects a genuine, non-coincidental association rather than incidental co-occurrence.

Beyond individual case reports, larger systematic cohort studies have confirmed this is a reproducible — not anecdotal — finding:

• A Finnish cohort of 13 FGFR3 N540K-positive HCH patients found that all 8 who underwent brain MRI had bilateral temporal lobe dysgenesis: abnormally shaped temporal horns, aberrant hippocampal configuration, and poorly formed, abnormally oriented parahippocampal gyri. Six of 13 patients had a seizure history, and severe neurodevelopmental problems (global delay or intellectual disability) were present in 42% (Linnankivi et al., 2012).

• A Toronto cohort of 9 children with HCH found hippocampal dysplasia and hypoplastic dentate gyrus in all 7 who underwent MRI, alongside near-universal temporal lobe enlargement, abnormal triangular temporal horns, and oversulcation extending into the medial occipital lobes. The authors explicitly linked this to murine data showing FGFR3-driven progenitor overproliferation in the temporo-occipital cortex (Philpott et al., 2013).

• A more recent single-case report identified posterior periventricular white matter hyperintensities not previously described in the HCH neuroimaging literature, suggesting the full radiological spectrum associated with this pathway may still be incompletely characterized (Mimura et al., 2021).

• A related study in achondroplasia (the more severe allelic FGFR3 disorder) found temporal lobe malformations as well, suggesting the brain phenotype may exist along the same severity spectrum as the skeletal one, rather than being unique to HCH (Soni et al., 2020).

Not all findings are uniform, and the literature reflects genuine open questions rather than settled consensus:

• A Danish cohort study of 20 HCH patients found epilepsy in only 2, and structural temporal lobe dysgenesis was not assessed at all — illustrating how unevenly this research has translated into standardized clinical neuroimaging practice across centers (Doherty et al., 2017).

• Several of the case-reported patients with confirmed temporal lobe/hippocampal dysgenesis were cognitively and developmentally normal (Grosso et al., 2003; Romeo et al., 2014), indicating the structural finding does not reliably predict neurocognitive outcome.

• Ascertainment bias is a consistent limitation: imaging in most cohorts was performed only on clinical indication (seizures, macrocephaly), so the true population prevalence of this phenotype in neurologically asymptomatic HCH patients remains unknown (Linnankivi et al., 2012).

Despite open questions, several authors have proposed that temporal lobe/hippocampal dysgenesis is intrinsic to the N540K mutation given its consistency across unrelated, geographically distinct cohorts (Linnankivi et al., 2012; Philpott et al., 2013). Recommendations arising from this literature include a low threshold for neuroimaging in HCH patients with seizures, disproportionate macrocephaly, or developmental concerns (Linnankivi et al., 2012), and closer neurodevelopmental follow-up generally, even in the absence of overt symptoms.

The precise mechanism by which gain-of-function FGFR3 variants disrupt hippocampal and parahippocampal morphogenesis — and why this occurs with apparent specificity to the N540K substitution relative to other FGFR3-related skeletal dysplasias — remains undefined. Murine models implicate altered progenitor proliferation, premature cortical gyrification, and reduced expression of the cortical hem marker Wnt2b, which may secondarily affect the adjacent hippocampal primordium (Thomson et al., 2009). Whether these mechanisms translate directly to the human phenotype, and how they relate to the highly variable neurocognitive outcomes seen clinically — from normal development to global delay — has not been established.

This represents a meaningful, still-open gap in the literature. Larger, prospective, genotype-stratified studies correlating specific FGFR3 variants with structural neuroimaging and longitudinal neurodevelopmental outcomes are needed to clarify the true prevalence, clinical significance, and underlying biology of this association.

1. Grosso S, Farnetani MA, Berardi R, et al. Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia. Am J Med Genet A. 2003;120A:88-91.

2. Kannu P, Hayes IM, Mandelstam S, Donnan L, Savarirayan R. Medial temporal lobe dysgenesis in hypochondroplasia. Am J Med Genet A. 2005;138:389-391.

3. Kannu P, Aftimos S. FGFR3 mutations and medial temporal lobe dysgenesis. J Child Neurol. 2007;22:211-213.

4. Linnankivi T, Mäkitie O, Valanne L, Toiviainen-Salo S. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012;158A:3119-3125.

5. Philpott CM, Widjaja E, Raybaud C, Branson HM, Kannu P, Blaser S. Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation. Pediatr Radiol. 2013;43:1190-1195.

6. Romeo A, Lodi M, Viri M, Parente E, Baldi M, Righini A, Milani D. Does the co-occurrence of FGFR3 gene mutation in hypochondroplasia, medial temporal lobe dysgenesis, and focal epilepsy suggest a syndrome? Pediatr Neurol. 2014;50:427-430.

7. Doherty MA, Hertel NT, Hove HB, Haagerup A. Neurological symptoms, evaluation and treatment in Danish patients with achondroplasia and hypochondroplasia. J Rare Dis Res Treat. 2017;2(4):25-32.

8. Okazaki T, Saito Y, Ueda R, et al. Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis. Brain Dev. 2017;39:67-71.

9. Peters JM, et al. Hypochondroplasia and epilepsy: temporal lobe dysgenesis in FGFR3 mutations. J Int Child Neurol Assoc. 2018.

10. Mimura PMP, Castro JTS, Jarry VM, França Júnior MC, Reis F. New MRI findings in a patient with hypochondroplasia caused by the FGFR3 N540K variant. Arq Neuropsiquiatr. 2021;79(7):656-657.

11. Bernardo P, Budetta M, Aliberti F, et al. Temporal lobe malformations, focal epilepsy, and FGFR3 mutations: a non-causal association? Neurol Sci. 2021;42:2063-2067.

12. Soni N, et al. Temporal lobe malformations in achondroplasia: expanding the brain imaging phenotype associated with FGFR3-related skeletal dysplasias. AJNR Am J Neuroradiol. 2020.

13. Peters K, Ornitz D, Werner S, Williams L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol. 1993;155:423-430.

14. Walshe J, Mason I. Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick embryo. Mech Dev. 2000;90:103-110.

15. Moldrich RX, Mezzera C, Holmes WM, et al. Fgfr3 regulates development of the caudal telencephalon. Dev Dyn. 2011;240:1586-1599.

16. Inglis-Broadgate SL, Thomson RE, Pellicano F, et al. FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development. Dev Biol. 2005;279:73-85.

17. Thomson RE, Pellicano F, Iwata T. Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen-activated protein kinase activation. J Neurochem. 2007;100:1565-1578.

18. Thomson RE, Kind PC, Graham NA, et al. Fgf receptor 3 activation promotes selective growth and expansion of occipitotemporal cortex. Neural Dev. 2009;4:4.

19. Zhang Y, et al. Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality. 2020.