Clefting

Gene: FGFR1

Green List (high evidence)

Comment of mode of inheritance: 2/4 biallelic FGFR1 cases reported in literature presented with clefting. Hence, the MOI should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, until more evidence emerges (watchlist_moi tag added).

Created: 27 Feb 2026, 1:25 p.m. | Last Modified: 27 Feb 2026, 1:25 p.m.

Panel Version: 6.20

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 median cleft lip and palate, while P2 showed no clefting.

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, 1:24 p.m. | Last Modified: 27 Feb 2026, 1:24 p.m.

Panel Version: 6.20

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

Comment on phenotypes: removed Pfeiffer syndrome, 101600- no cases for clefting

Created: 30 May 2017, 12:30 p.m.

Comment on publications: In Hartsfield syndrome, several patients with mutations in FGFR1 have clefts as a feature PMID:1342859, 14564207, 19504604. In Hypogonadotropic hypogonadism 2 with or without anosmia (also knowns as Kallmann syndrome 2) there are large numbers of patients with clefts as a feature PMID:12627230, 16606836, 25394172.

Created: 30 May 2017, 12:29 p.m.

Comment on publications: In Hartsfield syndrome, several patients with mutations in FGFR1 have clefts as a feature PMID:1342859, 14564207, 19504604

Created: 30 May 2017, 8:48 a.m.

Included only those associated disorders where clefting is reported as a feature (not included in this entry Encephalocraniocutaneous lipomatosis, Jackson-Weiss syndrome, Osteoglophonic dysplasia, Trigonocephaly 1)

Created: 30 May 2017, 8:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hartsfield syndrome, 615465; Hypogonadotropic hypogonadism 2 with or without anosmia, 147950; Pfeiffer syndrome, 101600