Kowarski Syndrome

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Retrieved

2019-09-22

Source

Omim

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Genes

POU1F1, RNPC3, GHRHR, GHRH, GHSR, KISS1R, KISS1, CSHL1, NR5A1, GH1, TG, TACR3, GNRH1, GNRHR, HESX1, SOX3, LHX4, GLI2, PROP1, OTX2, LHX3, IGF1, GHR, IGHD, IGFBP3, SLC20A1, BTK, PHEX, PAX6, FBXO8

POU1F1, RNPC3, GHRHR, GHRH, GHSR, KISS1R, KISS1, CSHL1, NR5A1, GH1, TG, TACR3, GNRH1, GNRHR, HESX1, SOX3, LHX4, GLI2, PROP1, OTX2, LHX3, IGF1, GHR, IGHD, IGFBP3, SLC20A1, BTK, PHEX, PAX6, FBXO8, GPR101, HGH1, FBRS, ALB, SDS, SOAT1, SHBG, BRD2, PRL, MMUT, POMC

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A number sign (#) is used with this entry because of evidence that Kowarski syndrome is caused by mutation in the growth hormone gene (GH1; 139250) on chromosome 17q. Mutation in the GH1 gene also causes several types of isolated growth hormone deficiency (IGHD); see 262400 for a summary.

Description

Kowarski syndrome, or short stature associated with bioinactive growth hormone, is characterized clinically by normal or slightly increased GH secretion, pathologically low IGF1 (147440) levels, and normal catch-up growth on GH replacement therapy (Besson et al., 2005).

Clinical Features

Kowarski et al. (1978) studied 2 unrelated 3-year-old boys with growth retardation and delayed bone ages, and with normal immunoreactive growth hormone after stimulation but low levels of somatomedin. Unlike the result in patients with Laron dwarfism (262500), exogenous human growth hormone induced normal levels of somatomedin and a significant increase in growth rate. The family data provided no clue to the genetics. The authors suggested that the phenotype may be caused by secretion of a biologically inactive but immunoreactive growth hormone molecule.

Valenta et al. (1985) described a similar case; furthermore, they confirmed a structural abnormality of the growth hormone molecule: 60 to 90% of circulating growth hormone was in the form of tetramers and dimers (normal, 14 to 39% in plasma) and the patients' growth hormone polymers were abnormally resistant to conversion into monomers by urea.

Chen (1988) suggested that a biologically ineffective mutant GH molecule may be the basis of 'pituitary dwarfism' in some cases.

Molecular Genetics

Takahashi et al. (1996) reported the case of a boy with short stature who was heterozygous for a mutation in the GH1 gene (139250.0008). In this child, growth hormone not only could not activate the GH receptor (GHR; 600946) but also inhibited the action of wildtype GH because of its greater affinity for GHR and GH-binding protein (GHBP; see 600946) that is derived from the extracellular domain of the GHR. Thus, a dominant-negative effect was observed.

In a girl with short stature, Takahashi et al. (1997) demonstrated a biologically inactive growth hormone resulting from a heterozygous mutation in the GH1 gene (139250.0013). At age 3 years, the girl's height was 3.6 standard deviations below the mean for age and sex. Bone age was delayed by 1.5 years. She had a prominent forehead and a hypoplastic nasal bridge with normal body proportions. She showed lack of growth hormone action despite high immunoassayable GH levels in serum and marked catch-up growth to exogenous GH administration. Results of other studies were compatible with the production of a bioinactive GH, which prevented dimerization of the growth hormone receptor, a crucial step in GH signal transduction.

Besson et al. (2005) described a Serbian patient with Kowarski syndrome who was homozygous for a mutation in the GH1 gene that disrupted the first disulfide bridge in growth hormone (139250.0021). The parents were each heterozygous for the mutation and were of normal stature.