Table 1.
Human diseases associated with pituitary hypoplasia or deficiency.
| congenital, syndromic hypopituitarism | |||||
|---|---|---|---|---|---|
| disease | cases per million | inheritance | hypothalamic-hypophyseal phenotype | causative mutations/variants | (potential) HH signaling … |
| septo-optic dysplasia and its variants | 100 | AD, AR, multigenetic | GHD, ACTHD, TSHD, GnRHD, DI | ARNT2, BMP4, FGF8, FGFR1, HESX1, KAL1, OTX2, PAX6, PROKR2, SOX2 , SOX3, SHH , (GLI2) (71–73) | … inactivation due to SHH, (GLI2) germline mutations (74) |
| holoprosencephaly | 100 | X-linked recessive, AD, AR | GHD, ACTHD, TSHD, DI | CDON , DISP1 , DLL1, FGF8, FOXH1, GAS1 , GLI2 , NODAL, PTCH1 , SHH , SIX3, TGIF, TDGF1, ZIC2 (35, 75–84) | … inactivation due to CDON, DISP1, GAS1, GLI2, PTCH1, SHH germline mutations (35, 76–84) |
| GLI2 mutations | 42 - 63 | AD | GHD, ACTHD | GLI2 (85) | … inactivation due to GLI2 germline mutations (85) |
| hypopituitarism with cerebellar abnormalities | 2.7 - 6.4 | AD | GHD panhypopituitarism |
LHX4 (75) | … is required for LHX3/LHX4 pituitary embryonic precursors (7) |
| hypopituitarism with spine abnormalities | 1.5 - 5.4 | AR | GHD, ACTHD, TSHD, FSHD/LHD panhypopituitarism |
LHX3 (75) | |
| pituitary stalk interruption syndrome | (~1,000 cases) | AD, AR | GHD, ACTHD, TSHD, FSHD/LHD | CDON , GPR161 , HESX1, HHAT , LHX4, OTX2, PROKR2, PTCH1 , PTCH2 , SOX3 (86) | … inactivation due to CDON, GPR161, HHAT, PTCH1, PTCH2 germline mutations (86) |
| Pallister-Hall syndrome | (~100 cases) | AD | GHD panhypopituitarism |
GLI3 (87) | … inactivation due to GLI3 germline mutations (87) |
| isolated hormone deficiencies | |||||
| isolated GHD | 100 - 250 | sporadic or 3-30% familial | GHD | GH1, GHRHR, GLI2 , HESX1, LHX4, OTX2, SOX3 (75, 85) | … inactivation due to GLI2 germline mutation (85) |
| Kallmann syndrome | 20 - 100 | X-linked recessive AD, AR, oligogen | LHD, FSHD | CHD7, FGF8, FGFR1, KAL1, PROK2, PROKR2, SOX10, WDR11 (75) | … inactivation due to WDR11 germline mutations (88, 89) |
| CHARGE syndrome | 66 - 86 | AD | GHD, ACTHD, TSHD, FSHD/LHD | CHD7 (90) | … inactivation due to CHD7 mutations (91) |
| Wolfram Syndrome | est. 1.3 - 2 | AR | DI | WFS1 (92) (rarely CISD2) | … inactivation due to Wfs1 mutation (93) |
ACTHD, ACTH deficiency; AD, autosomal dominant; ADHD, ADH deficiency; AR, autosomal recessive; DI, diabetes insipidus; est., estimated; FSHD/LHD, FSH deficiency/LH deficiency; GHD, GH deficiency; GnRHD, GnRH deficiency; MSHD, MSH deficiency; OXTD, OXT deficiency; PRLD, PRL deficiency; TSHD, TSH deficiency.
Wiedemann-Steiner syndrome or PHACES (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies, and Eye anomalies Syndrome), which are also associated with pituitary hypoplasia or deficiency, are not listed. Genes associated with HH signaling are highlighted in bold.