Differences in sex development

Gene: FGFR1

Red List (low evidence)

Comment on list classification: There is only one individual reported in literature with a biallelic FGFR1 variant and a diagnosed difference in sex development (ambiguous genitalia - PMID: 27055092). Other reported cases are more aligned with diagnosis of Hypogonadotropic hypogonadism (FGFR1 is already Green on that panel). Hence, this gene can only be rated Red on Differences in sex development given the evidence available.

Created: 27 Mar 2026, 10:42 a.m. | Last Modified: 27 Mar 2026, 10:42 a.m.

Panel Version: 4.15

PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

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. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

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.

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 Mar 2026, 10:36 a.m. | Last Modified: 27 Mar 2026, 10:36 a.m.

Panel Version: 4.14

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

Publications

• 23154428
• 23812909
• 25394172
• 27055092
• 32853167
• 34589657
• 41108094

Green List (high evidence)

PMID:41108094 reports a 14 year old male patient with micropenis, hypoplasia of the testes and angulation of the penis and was found to have a likely pathogenic FGFR1 c.263_264del p.Val88Alafs*22.

PMID:34589657 reports a 7 year old male patient with history of bilateral cryptorchidism and was found to have a pathogenic FGFR1 c.1955A>C p.His652pro.

PMID: 32853167 reports a 16 year old male with micropenis and bilateral cryptorchidism and was found to have a FGFR1 c.1864C>T p.Arg622*

Additional male patient identified at WMGL with bilateral cryptorchidism and micropenis was found to have FGFR1 c.2008G>A p.Glu670Lys
Sources: Literature, Research

Created: 4 Feb 2026, 1:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypogonadotropic hypogonadism 2 with out without anosmia

Publications

• (PMID: 41108094
• 34589657
• 32853167)

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