PHENOTYPIC VARIABILITY IN FAMILIAL COMBINED PITUITARY-HORMONE DEFICIENCY CAUSED BY A PROP1 GENE MUTATION RESULTING IN THE SUBSTITUTION OF ARG-]CYS AT CODON-120 (R120C)

As pituitary function depends on the integrity of the hypothalamic-pit uitary axis, any defect in the development and organogenesis of this g land may account for a form of combined pituitary hormone deficiency ( CPHD). A mutation in a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (PROP1), has been ident ified as causing the Ames dwarf (df) mouse phenotype, and thereafter, different PROP1 gene alterations have been found in humans with CPHD. We report on the follow-up of two consanguineous families (n = 12), wi th five subjects affected with CPHD (three males and two females) caus ed by the same nucleotide C to T transition, resulting in the substitu tion of Arg--> Cys in PROP1 at codon 120. Importantly, there is a vari ability of phenotype, even among patients with the same mutation. The age at diagnosis was dependent on the severity of symptoms, ranging fr om 9 months to 8 yr. Although in one patient TSH deficiency was the fi rst symptom of the disorder, all patients became symptomatic by exhibi ting severe growth retardation and failure to thrive, which was mainly caused by GH deficiency (n = 4). The secretion of the pituitary-deriv ed hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, f ollowing a different pattern in each individual; therefore, the defici encies developed over a variable period of time. All of the subjects e ntered puberty spontaneously, and the two females also experienced men arche and periods before a replacement therapy was necessary.