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Pituitary hormone deficiency v4.11 FGF8 Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS:
PMID: 29584859 Hong et al., 2018
Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes.
Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments).
Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency.

PMID: 21832120 McCabe et al., 2011
Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.

MONOALLELIC CASES:
PMID: 27363716 Dubourg et al., 2016
Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant.
- Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant.
- 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo)
- 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly.
- 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1).
No pituitary deficiency reported for these patients.

PMID: 21045958 Arauz et al., 2010
Study screened 360 probands with HPE for sequence variations in FGF8.
Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF.
The same variant was reported in an IHH patient in PMID: 18596921.

FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).; to: BIALLELIC CASE REPORTS:
PMID: 29584859 Hong et al., 2018
Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes.
Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments).
Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency.

PMID: 21832120 McCabe et al., 2011
Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.

PMID: 31748124 - IHH Proband 15, male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification.
PMID: 18596921 - Case 3 - IHH proband homozygous for FGF8 p.Phe40Leu variant. Additional FGFR1 mutations were also detected.

MONOALLELIC CASES:
PMID: 27363716 Dubourg et al., 2016
Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant.
- Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant.
- 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo)
- 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly.
- 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1).
No pituitary deficiency reported for these patients.

PMID: 21045958 Arauz et al., 2010
Study screened 360 probands with HPE for sequence variations in FGF8.
Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF.
The same variant was reported in an IHH patient in PMID: 18596921.

FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).
Pituitary hormone deficiency v4.11 FGF8 Ida Ertmanska changed review comment from: PMID: 29584859 Hong et al., 2018 - BIALLELIC
Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes.
Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments).
Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency.

PMID: 21832120 McCabe et al., 2011 - BIALLELIC
Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.; to: BIALLELIC CASE REPORTS:
PMID: 29584859 Hong et al., 2018
Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes.
Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments).
Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency.

PMID: 21832120 McCabe et al., 2011
Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.

MONOALLELIC CASES:
PMID: 27363716 Dubourg et al., 2016
Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant.
- Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant.
- 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo)
- 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly.
- 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1).
No pituitary deficiency reported for these patients.

PMID: 21045958 Arauz et al., 2010
Study screened 360 probands with HPE for sequence variations in FGF8.
Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF.
The same variant was reported in an IHH patient in PMID: 18596921.

FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).
Pituitary hormone deficiency v0.65 SHH Ivone Leong Tag watchlist tag was added to gene: SHH.
Pituitary hormone deficiency v0.65 SHH Ivone Leong Marked gene: SHH as ready
Pituitary hormone deficiency v0.65 SHH Ivone Leong Gene: shh has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.28 SHH Ivone Leong Classified gene: SHH as Amber List (moderate evidence)
Pituitary hormone deficiency v0.28 SHH Ivone Leong Added comment: Comment on list classification: Promoted from red to amber. SHH is confirmed to be associated with Holoprosencephaly 3 in OMIM but not in Gene2Phenotype. It is also a green gene in the Holoprosencephaly panel (Version 1.6). However, there is only one report where two unrelated Dutch patients with combned pituitary hormone deficiency had variants in SHH. One missense variant is predicted to be pathogenic and another variant in the 3' UTR region was shown to decrease SHH expression in in vitro tests.
Pituitary hormone deficiency v0.28 SHH Ivone Leong Gene: shh has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.27 SHH Ivone Leong Publications for gene: SHH were set to
Pituitary hormone deficiency v0.5 SHH Ivone Leong gene: SHH was added
gene: SHH was added to Pituitary hormone deficiency. Sources: UKGTN,Radboud University Medical Center
Mode of inheritance for gene: SHH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SHH were set to Microphthalmia with coloboma 5 (611638); Holoprosencephaly 3 (142945)