IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations. In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers. In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.

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These two patients support the key role for IGF-I in intrauterine and postnatal growth. The different phenotypes of these and earlier described patients may be associated with variability in IGF-I signaling. The degree of intrauterine growth retardation may be partially determined by the presence or absence of maternal IGF-I resistance.

Summary:It is generally assumed that busulphan/cyclophoshamide (Bu/Cy)-based conditioning regimens for haematopoietic stem cell transplantation (SCT) do not affect growth. We evaluated growth and endocrine function after Bu/Cybased conditioning in 64 children without a history of irradiation. Mean height standard deviation scores remained stable, but unexplained disturbances of growth after SCT were found in 17/48 (35%) of the children without growth-limiting disorders (10/23 in patients treated for haematological malignancies). In 10 patients, growth hormone (GH) secretion status was evaluated, and insufficient GH secretion was diagnosed in four patients. Thyroid function was evaluable in 52 patients. Two developed antibody-mediated thyroid disorders and 10 (19%) compensated primary hypothyroidism. Gonadal function was evaluable in 21 patients and was normal in all seven patients treated with low-dose Bu (8 mg/kg), whereas seven of the 14 children receiving high-dose Bu (16-20 mg/kg) developed gonadal failure; the majority of these patients had not been exposed to gonadotoxic therapy prior to Bu/Cy. Of the 49 evaluable patients, 16 developed subclinical hyperparathyroidism. We conclude that, besides gonadal and thyroid dysfunction, impaired growth and hyperparathyroidism often occur after Bu/Cy conditioning for SCT and that growth impairment may be the result of insufficient GH secretion.

In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083–8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH–insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.