PROP1
PROP1 (Prophet of POU1F1) encodes a 226- amino acid paired- like homeodomain transcription factor which activates POU1F1 expression and pituitary organogenesis. Currently, bi- allelic PROP1 mutations are the most frequently recognized genetic cause of CPHD worldwide. In general, short stature is the first symptom reported, prob ably due to combined GH and TSH deficiency. Growth failure usually develops within the first year of life (height – 1.5 ± 0.9 SDS at 1.5 years of age) and becomes more prominent later in childhood between the ages of 1.5 and 3 years (– 3.6 ± 1.3 SDS at 3 years of age), when parents search for medical assistance. At diagnosis, bone age is usually severely delayed (– 4.0 SDS; 2.5 y). Gonadotropins deficiency may be manifested as a lack of pubertal development or a failure to complete puberty. The hormonal deficiencies can emerge asynchronously over time, even among individuals carrying the same genotype. Some patients develop corticotrophin deficiency, so all patients with PROP1 pathogenic variants deserve lifetime clinical surveillance. Furthermore, as GH replacement can increase cortisol metabolism, it is necessary to be aware of the signs of an unveiled adrenal insufficiency. On neuroimaging the pituitary stalk is normal and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic, but may be normal or even enlarged, which may be mis diagnosed as a tumour. The pituitary can wax and wane in size before undergoing complete involution for reasons as yet undetermined.
PROP1 mutations lead to CPHD in an autosomal recessive inheritance pattern, therefore the prevalence of these mutations is higher in familial cases and in patients born to consanguineous parents. Different types of molecular defects have been described disrupting PROP1 function, varying from complete gene deletion to frame shift, small deletions and insertions, and point mutations including missense, nonsense, splicing variants, and mutations affecting the initiation codon.
POU1F1
POU class 1 homeobox 1 (formerly called PIT1) is a member of the POU family of transcription factors that regulate mammalian de velopment and is important for the development of GH, PRL, and TSH lineages. Usually GH and PRL deficiencies are detected at first presentation and severe short stature is the first complaint. TSH deficiency can be present from infancy and such patients may present with severe mental retardation, or it can emerge later in life. On MRI, the anterior pituitary can be small or normal and the posterior pituitary is eutopic. The first reports were about homozygous mutations but heterozygous mutations with dominant- negative effects have also been described, thus recessive and dominant inheritance modes are possible.
