The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism

Figures & data

Figure 1 Cascade of signalling molecules and transcription factors in the developing pituitary.

Table I. Human mutations causing abnormal hypothalamo‐pituitary development and function.

Gene	Phenotype	Inheritance
Combined pituitary hormone deficiency (CPHD):
POU1F1	GH, TSH, prolactin deficiencies; usually severe; small or normal AP	R, D
PROP1	GH, TSH, LH, FSH, prolactin deficiencies; evolving ACTH deficiency; small, normal or enlarged AP	R
Specific syndrome:
HESX1	IGHD, CPHD, Septo‐optic dysplasia; APH, EPP, absent infundibulum, ACC	R, D
LHX3	CPHD (GH, TSH, LH, FSH, prolactin deficiencies), short neck, limited rotation; small, normal or enlarged AP, short cervical spine	R
LHX4	CPHD (GH, TSH, ACTH deficiencies); small AP, EPP, cerebellar abnormalities	D
SOX3	IGHD and mental retardation, panhypopituitarism; APH, infundibular hypoplasia, EPP	XL
SOX2	Hypogonadotropic hypogonadism; APH, bilateral anophthalmia/microphthalmia, abnormal corpus callosum, learning difficulties, oesophageal atresia, sensorineural hearing loss	de novo
TBX19	Neonatal ACTH deficiency	R

AP(H) = anterior pituitary (hypoplasia); EPP = ectopic posterior pituitary; ACC = agenesis of corpus callosum; ACTH = adrenocorticotropic hormone; FSH = follicle‐stimulating hormone; GH = growth hormone; IGHD = isolated growth hormone deficiency; LH = luteinizing hormone; TSH = thyroid stimulating hormone; R = recessive; D = dominant; XL = X‐linked.

Figure 2 A: Sagittal magnetic resonance imaging (MRI) scan of the head of a normal child. Note the well formed corpus callosum (CC) and the optic chiasm (OC) and the posterior pituitary (PP) which appears as a bright fossa within the sella turcica. B: Sagittal MRI scan of two siblings with a homozygous R160C mutation in HESX1. In the first sibling (i) the splenium of the corpus callosum is more hypoplastic than the rest of the structure and the posterior pituitary is partially descended as compared with sibling 2 (ii) who has a severely hypoplastic corpus callosum, ectopic posterior pituitary and lack of visible pituitary stalk (PS). C: Sequential MRI scanning of a patient with a 13‐bp deletion (del112‐124) in PROP1 reveals waxing and waning of a pituitary mass (denoted by arrow); (i) on presentation, (ii) 4 months after initial MRI, (iii) 12 months after initial MRI, (iv) 21 months after initial MRI. D: Coronal and sagittal MRI scans from one patient (panels (i) and (ii)) and sagittal scan from a second patient (iii) with SOX3 duplication showing anterior pituitary (AP) hypoplasia; partial hypoplasia of the infundibulum (I) in the first patient, which is absent in the second; and an ectopic/undescended posterior pituitary, more severe in patient 2. Note the cyst in the corpus callosum identified in patient 1. Figures A and B derived from Brickman et al. (22). Figures C and D derived from Turton et al. (39) and Woods et al. (108) respectively and reproduced with permission from Clinical Endocrinology (Blackwell Publishing) and the American Journal of Human Genetics (University of Chicago Press).

Table II. Reported mutations in the PROP1 gene.

Nucleotide change	Location	Type of mutation	Effect on protein	Reference
c.2T>C	Exon 1	missense (initiation codon)	No translation	48
c.109+1G>T	Intron 1	splice site	Aberrant splicing	54
c.112_124del13	Exon 2	frameshift	Truncation at nucleotide 480	50
c.149_150delAG	Exon 2	frameshift	Truncation at codon 109	58
c.150delA	Exon 2	frameshift	Truncation at nucleotide 480	65
c.157delA	Exon 2	frameshift	Truncation at codon 164	51
c.211C>T	Exon2 (HD)	missense	R71C	47
c.212G>A	Exon2 (HD)	missense	R71H	47
c.217C>T	Exon 2 (HD)	missense	R73C	37, 40
c.218G>A	Exon 2 (HD)	missense	R73H	43
c.247C>T	Exon 2 (HD)	nonsense	Q83X	42
c.263T>C	Exon 2 (HD)	missense	F88S	44
c.295C>T	Exon 2 (HD)	nonsense	R99X	43
c.296G>A	Exon 2 (HD)	missense	R99Q	46
c.296_297delGA c.301_302delAG	Exon 2 (HD)	frameshift	Truncation at codon 109	36
c.343‐2A>T	Intron 2	splice site	Aberrant splicing	40
c.349T>A	Exon 3 (HD)	missense	F117I	36
c.358C>T	Exon 3 (HD)	missense	R120C	36, 61
c.467insT	Exon 3	frameshift	Truncation at codon 191	52
c.582G>A	Exon 3	nonsense	W149X	59
c.629delC	Exon 3	frameshift	Altered trans‐activation domain at codon 210	53

Note: HD denotes mutation located within homeobox.

Table III. Mutations within the POU1F1 gene.

Mutation	Type of Mutation	Location	Inheritance	Reference
Q4X	nonsense	Exon 1	Recessive	136
P14L	missense	Exon 1	Dominant	131
P24L	missense	Exon 1	Dominant	79
F135C	missense	Exon 3	Recessive	137
R143Q	missense	Exon 3	Recessive	79
R143L	missense	Exon 3	Recessive	138
K145X	nonsense	Exon 3	Recessive	139
A158P	missense	Exon 4 (POU)	Recessive	140
Q167K	missense	Exon 4 (POU)	Dominant	141
R172Q	missense	Exon 4 (POU)	Recessive	92
R172X	nonsense	Exon 4 (POU)	Recessive	77
E174G	missense	Exon 4 (POU)	Recessive	142
W193R	missense	Exon 4 (POU)	Recessive	143
W193X	nonsense	Exon 4 (POU)	Recessive	144
L194Q	missense	Exon 4 (POU)	Recessive	138
K216E	missense	Exon 5	Dominant	145
E230K	missense	Exon 6 (HD)	Recessive	144
F233L	missense	Exon 6 (HD)	Recessive	132
P239S	missense	Exon 6 (HD)	Recessive	146
c.725_726delAA (reported as Q242R)	frameshift	Exon 6 (HD)	Recessive	147
c.747delA	frameshift	Exon 6 (HD)	Recessive	143
E250X	nonsense	Exon 6 (HD)	Recessive	148
c.778insA	frameshift	Exon 6 (HD)	Recessive	91
F262L	missense	Exon 6 (HD)	Recessive	147
R271W	missense	Exon 6 (HD)	Dominant	80
V272X	nonsense	Exon 6 (HD)	Recessive	149

Notes: POU denotes mutation within the POU specific domain; HD denotes mutation within the POU homeodomain.

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