Pygmy

Clinical Features

Efe Pygmies from the Ituri forest of northeast Zaire have the shortest mean adult stature of any population on earth, with a mean adult male height of 4 feet, 8 inches, and a mean adult female height of 4 feet, 5 inches (Diamond, 1991).

Biochemical Features

Rimoin et al. (1969) found that African Pygmies failed to respond to exogenous human growth hormone (GH; 139250) in the presence of normal serum levels of growth hormone and somatomedin, or insulin-like growth factor-1 (IGF1; 147440), suggesting a defect in end-organ responsiveness to one or both hormones.

Merimee et al. (1981) demonstrated isolated deficiency of IGF1 in Pygmies of the Central African Republic, and proposed a genetically determined basis of growth deficiency in this population. However, protein deficiency may also have been responsible for the low IGF1 levels (Underwood et al., 1982). In African Pygmies in Zaire, Merimee et al. (1987) found that prepubertal Pygmy children and controls did not differ in linear growth or in serum concentrations of IGF1 and IGF2 (147470). However, they found that adolescent Pygmy boys and girls had one-third the mean serum concentration of IGF1 of control adolescents who were similar in age and Tanner stage of development. IGF2 and testosterone levels were normal in all groups. Merimee et al. (1987) postulated that short stature in Pygmies was due to the absence of accelerated growth during puberty and that IGF1 was a principal factor responsible for normal pubertal growth.

In cultures of B lymphocytes derived from Pygmies, Merimee et al. (1989) found a significant decrease in IGF1 secretion when stimulated by GH compared to normal control cells (4.24 ng/ml compared to 12.3 ng/ml in controls), although the cultures had similar cell density.

In a longitudinal growth study comparing Efe Pygmy children and children of non-Pygmy rural African farmers of known age from birth to age 5 years, Bailey (1991) found that suppression of Pygmy growth occurs from birth, not solely at puberty. Bailey (1991) emphasized that previous studies of Pygmy growth were of individuals of estimated, not known, age.

In 5 of 7 Pygmies, Geffner et al. (1995) found a decrease in IGF1 levels compared to controls. In vitro studies on T cells isolated from the Pygmies showed no colony growth in response to IGF1 or to growth hormone compared to controls. There was no difference in growth response of the cells to insulin. By in vitro analysis of 6 cell lines from Pygmies, Hattori et al. (1996) determined that the Pygmy-derived cells showed markedly decreased cell surface expression of IGF1 receptors (IGF1R; 147370) compared to controls, although the affinity of IGF1 binding to the receptor was similar in the 2 cell lines. There was a substantially decreased level of IGF1 receptor mRNA (2 to 13% of control) in the Pygmy cells, with a normal mRNA half-life. Moreover, the IGF1 receptors in the Pygmy cells were not autophosphorylated and did not transmit an intracellular signal in response to physiologic levels of IGF1, indicating a functional defect. Hattori et al. (1996) concluded that the short stature of African Pygmies is related to IGF1 receptor insensitivity, and suggested that human stature in general may be genetically regulated via control of expression of the IGF1R gene.

Molecular Genetics

Bowcock and Sartorelli (1990) found no difference in the distribution of IGF1 RFLPs in Pygmies versus non-Pygmy black Africans. There was also no correlation of IGF1 genotype with height in the Pygmies. Suspecting an abnormality in the transcriptional regulation of the IGF1 gene in Pygmies, Bowcock and Sartorelli (1990) performed direct sequencing of a DNA region 330-bp upstream of the IGF1 initiation site; no mutations were identified in that region.

Hattori et al. (1996) detected no pathogenic mutations by sequence analysis of IGF1R cDNA from transformed T lymphocyte lines derived from Pygmies.

In 2 non-Pygmy patients with short stature and IGF1 resistance (see 270450) due to decreased number or function of cell surface IGF1 receptors, Abuzzahab et al. (2003) identified mutations in the IGF1R gene (147370.0001-147370.0003). Abuzzahab et al. (2003) noted that the finding of a reduction in the number of IGF1 receptors in Pygmies was based entirely on in vitro studies of transformed lymphocytes.

Animal Model

The mouse mutation called pygmy (pg), a recessive that maps to mouse chromosome 10, has only similarity of name to the human condition. In pg mice, Xiang et al. (1990) identified a mutation in the pg gene (HMGA2; 600698).