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.

Hypothalamic and pituitary development: novel insights into the aetiology

“…Most patients present with early-onset GH deficiency and growth retardation; however, normal growth in early childhood has been reported in a patient who attained a normal final height without GH replacement therapy (86). TSH deficiency is also highly variable and has been reported as the first presenting symptom in some cases, while others show delayed TSH deficiency which may not be present at birth (77,(87)(88)(89).…”

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

“…The PROP1 358C>T (R120C) missense mutation identified in family V has never been described in Brazilian families, and only a few families of European, Mexican-American, and Jewish-Moroccan origins have been reported before (7,17,(41)(42)(43). The two brothers, born from a consanguineous marriage, developed progressive CPHD but were only diagnosed in adulthood (at 29 and 37 years of age).…”

Growth without growth hormone (GH): A case report

“…However, the role of leptin as a regulatory signal of GH secretion remains to be identified 24 , especially in obese, GH deficient subjects following craniopharyngioma removal 25 since the correlation of leptin with obesity and body mass index is an otherwise adequately described phenomenon 24 . Additionally, growth without GH was also observed in a patient with deficiencies of GH, LH and FSH, and a hypoplastic pituitary due to a mutation in the PROP1 gene 26 .…”