The "Little People" of the Island of Krk - Revisited. Etiology of Hypopituitarism Revealed

Abstract

Hereditary dwarfism was first recognized in inhabitants of the island of Krk in the Adriatic in 1864. Since then 24 related dwarfs have been recorded. Their pedigrees and heights are presented. Ten of these patients live in the villages Bascanska Draga and Jurandvor. Six have been studied by the authors. Clinical examination revealed dwarfism, obesity, dry wrinkled skin, and lack of sexual development. Hormonal investigations showed the absence of growth hormone (GH) unresponsive to growth hormone releasing hormone (GHRH), absence of luteinizing hormone (LH) and follicle stimulating hormone (FSH) unresponsive to gonadotropin releasing hormone (GnRH), and absence of thyrotropin stimulating hormone (TSH) unresponsive to TRH. Basal serum prolactin (PRL) was low but secretion of ACTH was normal as evidenced by normal Cortisol levels. Hypopituitarism in this isolate was not associated with a shortened life span or an increased incidence of diabetes. PROP-1 is a pituitary specific transcription factor that is required for the embryologic development of the pituitary cell types that ultimately produce GH, PRL, TSH and FSH/LH postnatally. Examination of genomic DNA from two of the patients revealed homozygosity for a one bp deletion in codon 50 of exon 2 of PROP-1. This mutation introduces a frame shift and

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

“…Importantly, evidence presented by Krzisnik and coworkers (74) shows increased longevity in hypopituitary patients with mutations at the Prop-1 locus, the same gene that is mutated in the Ames dwarf. In sharp contrast, mice overexpressing G H live significantly shortened lives, exhibit increased indices of free radical processes (66), decreased antioxidative defenses (14,67), signs of accelerated aging including reduced replicative potential of cells in vitro (75), and signs of premature central nervous system aging including reduced catecholamine turnover, increased astrogliosis, and impaired learning and memory (19,76,77).…”

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

“…4,[8][9][10][12][13][14] Participants gave written informed consent in their native language for genetic testing. This study was approved by the Institutional Ethics Committee of University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, the Czech Republic.…”

“…4 DNA samples of two patients from Krk (one from Baščanska Draga and one from Jurandvor village) 26 were analyzed in the present study. Both patients displayed the same ancestral haplotype as the other patients with the c. Table 4).…”

Hormonal regulation of longevity in mammals

“…Individuals with mutations in the PROP-1 gene, the same gene mutated in the Ames dwarf, also display characteristics of hypopituitarism. These individuals did not receive hormone replacement and were shown to reach very advanced ages, exceeding the average life expectancy of the general population (Krzisnik et al, 1999). In addition, the employment history and educational performance of these human dwarfs indicated no significant cognitive issues.…”