Skeletal dysplasia

Gene: FGFR1

Green List (high evidence)

Comment on mode of inheritance: As only 1/4 biallelic FGFR1 cases presented with skeletal dysplasia (vertebral anomalies), the MOI should remain MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted for the Skeletal dysplasia panel.

Created: 27 Feb 2026, 1:19 p.m. | Last Modified: 27 Feb 2026, 1:19 p.m.

Panel Version: 8.33

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Presented with absent puberty, severe split hand/foot malformation (both hands and feet), cryptorchidism, absent septum pellucidum, hypoplastic anterior corpus callosum; no clefting reported. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in carrier family members.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing. P1 had alobar HPE, P2 - lobar.

PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).

Created: 27 Feb 2026, 1:18 p.m. | Last Modified: 27 Feb 2026, 1:18 p.m.

Panel Version: 8.33

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465

Publications

• 23154428
• 23812909
• 25394172

Green List (high evidence)

disorganized development of skeletal components gp of SD, craniosynostosis syndromes gp of SD, Limb hypoplasia-reduction defects gp of SD. Variants also associated with Encephalocraniocutaneous lipomatosis, (somatic mosaism) 613001;Hypogonadotropic hypogonadism 2 with or without anosmia 147950. Variants in disorders with SD are GOF missense variants. Pfeiffer & Jackson-Weiss: P252R only. LOF associated with a different disorder (147950). Do you report variants in this gene as part of your current diagnostic practice? YES - for CSS; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hartsfield syndrome 615465; Jackson-Weiss syndrome 123150; Osteoglophonic dysplasia 166250; Pfeiffer syndrome 101600; Trigonocephaly 1 190440

Mode of pathogenicity
Other - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FGFR1; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment when marking as ready: Associated with phenotype in G2P. Numerous variants reported in these phenotypes.

Created: 12 Jul 2016, 7:07 a.m.

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:04 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Encephalocraniocutaneous lipomatosis, somatic mosaism 613001; Hartsfield syndrome 615465; Hypogonadotropic hypogonadism 2 with or without anosmia 147950; Jackson-Weiss syndrome 123150; Osteoglophonic dysplasia 166250; Pfeiffer syndrome 101600; Trigonocephaly 1 190440

Variants in this GENE are reported as part of current diagnostic practice