A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty

Abstract

We report a 28-year-old-female who presented with primary amenorrhoea, absence of puberty, obesity and normal stature. The subject was clearly short as a child, with a height more than 2 SD below normal until the age of 15 years. The pubertal growth spurt failed to develop. She continued growing at a prepubertal rate until growth ceased at the age of 20 years, reaching her final adult height of 157 cm (SDS -0.86) without hormonal treatment. A combined pituitary hormone stimulation test of anterior pituitary function showed deficiencies of GH, LH and FSH, and low normal serum levels of TSH and PRL. Magnetic resonance imaging revealed a hypoplastic pituitary with markedly reduced pituitary height. In addition, a whole body dual energy X-ray absorptiometry scan showed high levels of body fat (54%). Combined pituitary hormone deficiencies with a hypoplastic pituitary suggested the diagnosis of a Prophet of Pit-1 (PROP1) gene mutation. Normal stature in this case, however, confounded this diagnosis. Sequencing of PROP1 revealed homozygosity for a single base-pair substitution (C to T), resulting in the replacement of an Arg by a Cys at codon 120 (R120C) in the third helix of the homeodomain of the Prop-1 protein. To our knowledge, this is the first report of a patient with a mutation in the PROP1 gene that attained normal height without hormonal treatment, indicating a new variability in the PROP1 phenotype, with important implications for the diagnosis of these patients. We suggest that this can be explained by (i) the presence of low levels of GH in the circulation during childhood and adolescence; (ii) the lack of circulating oestrogen delaying epiphyseal fusion, resulting in growth beyond the period of normal growth; and (iii) fusion of the epiphyseal plates, possibly as a result of circulating oestrogens originating from peripheral conversion of androgens by adipose tissue.

Fig. 1

Genealogical tree showing the affected patient [black, (homozygous) (5)] and nonaffected individuals [white (wild-type) and grey (heterozygous)]. Dotted symbols represent individuals not available for this study. Squares represent males and circles represent females. The broken line symbol represents a divorce.

Fig. 2

(a) Growth chart representing the height of the patient between the ages of 0 and 28 years, based on the data in Table 2 (closed circles). The curves for 97th, 50th and 3rd percentile for girls are shown for comparison (Kuczmarski et al., 2000). (b) Weight curve of the patient between the ages of 0 and 28 years, based on data obtained from school records, clinical, personal and family history. The curves for 97th, 90th 50th and 3rd percentile for girls are shown for comparison.

Fig. 3

Coronal (a) and sagittal (b) images obtained by magnetic resonance imaging showing the hypoplastic pituitary gland of the patient.