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Phenotypic Variability in Familial Combined Pituitary Hormone Deficiency Caused by a PROP1 Gene Mutation Resulting in the Substitution of ArgCys at Codon 120 (R120C)¹

Division of Pediatric Endocrinology, University Children’s Hospital (C.F., J.D., K.R., A.E., U.M., P.E.M.), 3010 Bern, Switzerland; and Howard Hughes Medical Institute, University of California-San Diego (W.W.), La Jolla, California 92093-0648

Address all correspondence and requests for reprints to: Prof. Dr. Primus E. Mullis, Department of Pediatrics, Pediatric Endocrinology, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland 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 identified 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), with five subjects affected with CPHD (three males and two females) caused by the same nucleotide C to T transition, resulting in the substitution of ArgCys in PROP1 at codon 120. Importantly, there is a variability of phenotype, even among patients with the same mutation. The age at diagnosis was dependent on the severity of symptoms, ranging from 9 months to 8 yr. Although in one patient TSH deficiency was the first symptom of the disorder, all patients became symptomatic by exhibiting severe growth retardation and failure to thrive, which was mainly caused by GH deficiency (n = 4). The secretion of the pituitary-derived hormones (GH, PRL, TSH, LH, and FSH) declined gradually with age, following a different pattern in each individual; therefore, the deficiencies developed over a variable period of time. All of the subjects entered puberty spontaneously, and the two females also experienced menarche and periods before a replacement therapy was necessary.

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