Table 1.

Endocrine, Neuroradiological and extrapituitary manifestations of mutations in genes implicated in CCH in humans, and in the corresponding knockout mouse model

Gene with mutation	Inheritance	Hormone deficits	Additional features	MRI	Mouse model
TSHB	AR	TSH	−	E, N	−
TRHR	AR	TSH	−	N	Trhr1 −/−: N TSH, ⇓ T4, ⇓T3, ⇓PRL
Isolated TSH Deficiency or combined pituitary hormone deficiency
IGSF1	XL a	TSH±PRL, GH (transient)	Macroorchidism (males) Ovarian cysts (females)	N	Igsf1 Δ exon1 (male hemizygous):⇓TSH, ⇓T3, ⇓TRHR mRNA, normal pituitary PRL
Combined pituitary hormone deficiency
POU1F1	AR, AD	GH, TSH, PRL	−	APH	Pou1f1dw/dw (Snell dwarf): ⇓TSH, ⇓PRL, ⇓GH, Dwarfism
PROP1	AR	GH, TSH, LH, FSH, PRL, evolving ACTH deficiencies	−	APH (may be transient), N, E	Prop1 −/−: ⇓TSH, ⇓GH, ⇓LH, ⇓PRL, ⇓FSH, Pituitary hypoplasia, dwarfism, hypogonadism
Specific Syndrome
HESX1	AR, AD	Panhypopit GH and evolving TSH, ACTH, LH/FSH deficiency	Septo-optic dysplasia and its variants	APH, EPP, ACC, ONH	Hesx1 −/−: Anterior CNS defects, pituitary dysplasia, anopthalmia, defective olfactory development, bifurcations in Rathke's pouch.
LHX3	AR	GH, TSH, LH, FSH, PRL (ACTH)	Limited neck rotation, short cervical spine, sensorineural deafness	APH, N, E	Lhx3−/−: Absent TSH, GH, LH, PRL, pituitary hypoplasia, lethal
LHX4	AD	GH, TSH, ACTH, variable gonadotrophin deficiencies	Cerebellar abnormalities	APH, EPP	Lhx4 −/−:⇓TSH, ⇓GH, ⇓LH, ⇓PRL, ⇓POMC, pituitary hypoplasia, lethal
SOX3	XL	GH,TSH, ACTH, LH, FSH	Variable mental retardation	APH, EPP Persistent craniopharyn-geal canal	Sox3 null (homozygous /hemizygous): Variable phenotype. More severe with craniofacial abnormalities, midline CNS defects ⇓TSH, ⇓GH, ⇓LH, ⇓FSH
OTX2	AD	GH, TSH, ACTH, LH, FSH	Uni/Bilat. Anophthalmia Retinal dystrophy	N, APH, EPP	Otx2 −/−:Absent forebrain and midbrain, lethal

E, Enlarged; N, Normal; APH, Anterior pituitary hypoplasia; EPP, Ectopic posterior pituitary; ACC, Agenesis of corpus callosum; ONH Optic nerve hypoplasia; TSH thyroid-stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; ACTH, Adrenocorticotrophic hormone; Panhypopit.; Panhypopituitarism, AR, Autosomal recessive; AD, Autosomal Dominant; XL, X-linked, −/− homozygous null. References: Rabeler et al. (2004), Zeng et al. (2007). Sun et al. (2012), Camper et al. (1990). Nasonkin et al. (2004), Dattani et al. (1998), Sheng et al. (1996), Sheng et al. (1997), Rizzoti et al. (2004) and Acampora et al. (1995)

^aBut 1/3 females affected.