Kowarski syndrome

Lore & Background

Allen Avinoam Kowarski and colleagues described the first two cases in 1978, proposing that the children's growth impairment was caused by a mutation in the growth hormone gene that altered the structure of their secreted growth hormone, reducing its biological activity while retaining its ability to bind antibodies used in the RIA-GH. This speculation was confirmed by Valenta et al. in 1985, who found that 60 to 90% of circulating growth hormone in a patient was in the form of tetramers and dimers, abnormally resistant to conversion into monomers by urea. Takahashi et al. reported a boy heterozygous for a GH1 mutation whose growth hormone not only could not activate the GH receptor but also inhibited wild-type GH due to greater affinity for GHR and GHBP, demonstrating a dominant-negative effect. Another case by Takahashi et al. involved a girl with a heterozygous mutation producing bioinactive GH that prevented dimerization of the growth hormone receptor. Besson et al. described a Serbian patient homozygous for a GH1 mutation disrupting the first disulfide bridge; the parents were heterozygous and of normal stature.

Reader's Guide

Kowarski syndrome is significant because it highlights a form of growth failure distinct from classic growth hormone deficiency, where immunoassayable GH levels are normal or high but the hormone is biologically inactive. This created a diagnostic dilemma, as the initial test involved a six-month trial of GH therapy, which was difficult to justify for a rare disorder. The standard growth hormone stimulation test was found unreliable by Zadik et al. (1990) and Carel et al. (1997), with the 24-hour integrated concentration of GH suggested as a better alternative. Bistrizer et al. proposed a diagnostic procedure using the ratio of growth hormone measured by radioreceptor assay (RRA-GH) to that by radioimmunoassay (RIA-GH); a significantly low ratio indicated Kowarski syndrome and predicted responsiveness to GH therapy. Advances in DNA analysis later confirmed that various mutations in the GH1 gene cause the syndrome. The syndrome's legacy includes improved understanding of GH structure-function relationships and the development of more specific diagnostic tests, though a reliable practical procedure remains needed.

Did You Know?

• Valenta et al. found that 60 to 90% of circulating growth hormone in one patient was in tetramer and dimer forms, versus 14% to 39% normally.
• Takahashi et al. reported a boy with a GH1 mutation whose growth hormone inhibited wild-type GH via a dominant-negative effect.
• Bistrizer et al. proposed a diagnostic test using the RRA-GH/RIA-GH ratio, which was significantly below normal in Kowarski syndrome patients.

The Original Description and Early Hypothesis

In 1978, a team led by Allen Avinoam Kowarski published the first clinical account of what would become known as Kowarski syndrome, describing two children who presented with a puzzling pattern of growth failure. Both patients showed height and bone age falling at least two standard deviations below the age-appropriate mean, yet their blood levels of growth hormone, measured by radioimmunoassay, were normal or even slightly elevated. At the same time, their serum IGF-1 (then called somatomedin) was low, and both children responded dramatically to recombinant growth hormone therapy with a marked acceleration in growth velocity. Kowarski and colleagues proposed that a mutation in the growth hormone gene had produced a structurally altered hormone molecule. This mutant form could still be recognized by the antibodies in the radioimmunoassay, explaining the falsely reassuring blood levels, but it had lost much of its biological potency. Crucially, the children's growth machinery remained fully capable of responding to properly structured, active growth hormone, a finding that pointed toward a defect in the hormone itself rather than in the body's ability to use it.

Molecular Confirmation and Genetic Diversity

The hypothesis Kowarski raised in 1978 was not proven for years. In 1985, Valenta and colleagues examined a single patient and found that 60 to 90 percent of the circulating growth hormone existed as tetramers and dimers, far above the normal range of 14 to 39 percent, and that these abnormal polymers resisted conversion to monomers even when exposed to urea. Takahashi and co-workers later reported two separate cases in the mid-1990s. In one boy, a heterozygous mutation in the GH1 gene produced a hormone that not only failed to activate the growth hormone receptor but also blocked the action of normal wild-type hormone, because the mutant molecule had a stronger affinity for both the receptor and the growth hormone-binding protein, creating a dominant-negative effect. In a young girl, the same kind of heterozygous mutation yielded a biologically inactive hormone that prevented the receptor from dimerizing, a critical step in signal transduction. Besson and colleagues in 2005 described a Serbian child who was homozygous for a GH1 mutation that disrupted the first disulfide bridge in the hormone; both parents carried one copy of the mutation and were of normal height.

The Diagnostic Dilemma and Evolving Tests

Confirming Kowarski syndrome has always been a practical headache. Because the condition is officially classified as an orphan disease, the earliest diagnostic approach—administering growth hormone for six months and observing whether the child grew faster—was difficult to justify for a rare disorder. The standard growth hormone stimulation test, which flags peak levels below a normal threshold as evidence of deficiency, proved unreliable for this purpose. Zadik and colleagues in 1990 argued for a 24-hour integrated concentration measurement instead, a suggestion supported by Albertsson Wikland in 1992 and by Carel in 1997, who confirmed the poor reliability of stimulation tests. A more targeted solution came from Bistrizer and team in 1987: they exploited the fact that functional growth hormone must bind a specific receptor on responsive cells. By measuring the ratio of radioreceptor-assay levels to radioimmunoassay levels, they showed that Kowarski syndrome patients had a significantly depressed ratio compared with normal subjects. A modified version of this ratio test, published in 1995, also predicted which growth-impaired children would respond to therapy, and DNA-based mutation screening for the GH1 gene on chromosome 17q22-q24 is now available as a confirmatory tool.

Clinical Picture and Therapeutic Response

Children with Kowarski syndrome present with a distinctive and sometimes confusing clinical portrait. Height and bone age sit at least two standard deviations below the age and sex mean, yet the child's body proportions are typically normal. In one well-documented girl, height was 3.6 standard deviations below the mean at age three, bone age was delayed by a year and a half, and she showed a prominent forehead with a hypoplastic nasal bridge—features that might suggest a skeletal dysplasia rather than a hormonal problem. Blood work compounds the confusion: radioimmunoassay returns normal or even slightly elevated growth hormone levels, while IGF-1 runs low, mimicking a pattern that does not fit classic growth hormone deficiency. The defining clinical feature, however, is the therapeutic response. When these children receive recombinant, structurally normal growth hormone, they exhibit a significant and marked acceleration in growth velocity, often described as catch-up growth. This robust response confirms that the defect lies in the hormone molecule the body produces, not in the downstream signaling pathways or the growth plates themselves, and it underscores that the condition is treatable once correctly identified.