Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 715625007; ICD10CM: E34.322; ORPHA: 73273;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q26.3 | Insulin-like growth factor I, resistance to | 270450 | Autosomal dominant; Autosomal recessive | 3 | IGF1R | 147370 |
A number sign (#) is used with this entry because resistance to insulin-like growth factor I (IGF1RES) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the gene encoding the IGF1 receptor (IGF1R; 147370) on chromosome 15q26.
Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
Lanes et al. (1980) described a 10-year-old white boy with growth deficiency. Growth hormone (GH; 139250) stimulation tests yielded normal results. Somatomedin-C levels (IGF1; 147440), measured by three methods, were very high, suggesting end-organ insensitivity to somatomedin-C. An inhibitor of somatomedin and an increased protein binding in the plasma were both excluded. The authors concluded that the defect was at the IGF1 receptor or postreceptor level. Bierich et al. (1984) reported an infant who was small at birth and grew extremely slowly postnatally. At age 3 years, the girl's height was 65 cm, weight 5.6 kg, and bone age 21 months. Basal plasma GH and basal somatomedin-C were both increased, but somatomedin-C was not further increased by GH administration. Receptor studies with skin fibroblasts showed a 50% decrease of specific binding of somatomedin-C to the IGF1 receptor.
Momoi et al. (1992) reported a Japanese girl with intrauterine growth retardation (IUGR) and increased plasma IGF1. She also had malar hypoplasia, up-slanting palpebral fissures, blue sclerae, and thin, stiff hair. Psychomotor development was normal. IGF1 increased appropriately after GH administration and showed normal bioactivities and binding to cultured skin fibroblasts from the patient. Momoi et al. (1992) suggested a tissue-specific defect of IGF1 receptors.
Abuzzahab et al. (2003) reported a boy with IUGR and poor postnatal growth. He also showed microcephaly, mild facial dysmorphism, wide-set nipples, pectus excavatum, clinodactyly, delayed bone age, and mild motor development and speech delay. Serum IGF1 was elevated. The patient's mother and half sib were both small for gestational age at birth; as an adult, the mother had short stature, but was not dysmorphic. The authors also reported a girl with IUGR and persistent short stature with delayed bone age, mild motor delay, and psychiatric symptoms, including anxious affect, pressured speech, obsessive tendencies, and social phobias. At age 4.5 years, she had normal levels of serum IGF1.
Raile et al. (2006) provided follow-up on the mother and 2 sons reported by Abuzzahab et al. (2003). At age 8.5 years, the older brother's mild developmental delay persisted, and he had been placed in a special school. His 3-year-old half brother exhibited primary microcephaly, short stature, and delayed bone age. Both half sibs exhibited similar dysmorphic features, including a broad nasal bridge, broad and rounded nasal tip, long and smooth philtrum, thin upper lip, and an everted, fleshy lower lip. In addition, both had short broad fingers, short distal phalanges, and bilateral clinodactyly. The authors noted that the mother finished high school after 8 years without a regular exam, corresponding to the level of special school education.
Kawashima et al. (2005) described a Japanese mother and daughter who were heterozygous for a missense mutation in the IGF1R gene. The proband was a 6-year-old girl who had IUGR and showed growth failure at age 2 years. At age 6 years, her bone age was 3.9 years, and she was also diagnosed with mental retardation. Her 35-year-old mother was born with IUGR and showed short stature as an adult, but underwent normal puberty and was otherwise healthy. The proband's father and 2 brothers were not born with IUGR and were of normal stature, whereas her maternal grandmother and a maternal aunt were short.
Inagaki et al. (2007) reported a large 3-generation Russian family segregating autosomal dominant short stature. The proband was a 13.6-year-old girl who was born with IUGR and had delayed bone age and short stature. Examination showed a somewhat triangular face shape and small hands and feet. The proband's mother, maternal aunt and uncle, and maternal grandfather also exhibited severe short stature (-5 to -6.1 SD), whereas her father and younger brother had heights at -2.2 and -1.2 SD, respectively. Her affected 45-year-old maternal aunt had no obvious medical problems and had undergone normal puberty with menarche at age 13 years. The proband had an elevated basal IGF1 level and was unresponsive to treatment with recombinant human GH.
Fang et al. (2012) studied a brother and sister, born of consanguineous Lebanese parents, with IUGR, short stature, and mild developmental delay. The brother was microcephalic, and both sibs exhibited facial dysmorphism, including broad nasal bridge, synophrys, prominent epicanthi, low-set ears, thin upper lip, high-arched palate, and small opalescent teeth; the sister also showed left convergent strabismus, fifth-finger clinodactyly, and multiple cafe-au-lait spots. In addition, both sibs had elevated plasma IGF1 levels, and the brother underwent GH therapy with an increase in height velocity. At age 14 years, he began spontaneous puberty and showed normal pubertal progression. At age 14.5, he developed insulin-requiring diabetes mellitus (see 222100); the authors noted that his mother had insulin-requiring gestational diabetes and his maternal grandmother had adult-onset diabetes. At age 20.3 years, the brother had short stature (final height, -5.91 SD) and had finished secondary school with learning support. His younger sister was diagnosed with abdominal Burkitt lymphoma (see 113970) at 5 years of age; although she responded initially to chemotherapy, she succumbed to residual disease at age 5.7 years. Both parents and a brother were reported to be of normal stature (mother, -1.16 SD; father, -1.44 SD), and the parents had normal serum IGF1 levels.
Gannage-Yared et al. (2013) reported a 13.5-year-old girl, born of first-cousin Lebanese parents, who had severe IUGR and persistent short stature. Echocardiography showed patent foramen ovale, small perimembranous ventricular septal defect (VSD), 2 narrowed pulmonary branch arteries with increased Doppler gradient, and a continuation of the inferior vena cava to the azygos vein. At 4.5 years of age, she was thin and small, with reduced subcutaneous fat, triangular small face, deep-set eyes with upslanting palpebral fissures, slight convergent strabismus, arched eyebrows, low-set ears, high-arched palate, brittle and eroded teeth, microretrognathism, pterygium colli, clinodactyly, and sandal gap. Bone age was delayed by 6 months, and echocardiography showed closed foramen ovale with VSD still evident. Ophthalmologic examination was normal. Examination at age 13.5 years showed microcephaly, mild intellectual impairment, and a high-pitched voice, as well as axillary acanthosis nigricans and truncal obesity. Bone age was accelerated, corresponding to a chronologic age of 15 years. Her IGF1 level was very high, and although fasting glucose was normal, baseline insulin levels were high. Gannage-Yared et al. (2013) suggested that hyperinsulinism might have played a role in the proband's advanced bone age. No other members of her family were born with IUGR or showed postnatal growth retardation.
Prontera et al. (2015) described an Italian girl, born of consanguineous parents, who had severe IUGR and microcephaly. Echocardiography showed patent foramen ovale, small interatrial septal defect, and 2 narrowed pulmonary branch arteries. Brain MRI showed underrepresentation of cerebral gyri and hypoplastic corpus callosum. Laboratory evaluation showed elevated serum IGF1 levels, with normal GH, insulin, and glucose. Examination at 9 months of age revealed a markedly progeroid appearance with reduced subcutaneous fat and lipodystrophy, sparse scalp hair, prominent scalp veins, widely open sutures, and persistent fontanels, as well as dysmorphic features including triangular face with hypoplastic facial bones, deep-set eyes with upslanting palpebral fissures, low-set ears, micrognathia, microstomia, thin lips, and high-arched palate. Ocular examination showed strabismus and Rieger anomaly as well as intraocular abnormalities. She also had delayed eruption of dentition and delayed bone age. At 2 years of age, neuropsychiatric evaluation showed global developmental delay, with inability to walk alone, axial hypotonia and mild hypertonia in lower limbs, and poor language development. The proband's parents and grandmothers as well as multiple other relatives had short stature, and both grandmothers and several other short-statured relatives also had type 2 diabetes (see 125853). Prontera et al. (2015) considered the proband to have a form of SHORT syndrome (269880), with the additional features of elevated IGF1, central nervous system defects, developmental delay, and a pronounced progeroid appearance, which they designated 'SHORT syndrome type 2.' The authors also noted that distinguishing this phenotype from neonatal progeroid syndrome (264090) could be challenging, especially at birth.
IGF1 Resistance due to Increased Binding Protein
Among 9 patients with short stature, Heath-Monnig et al. (1987) identified 1 young girl with normal serum growth hormone responses to provocative stimuli and an elevated level of IGF1. Using the alpha-aminoisobutyric acid (AIB) uptake method of Kaplowitz et al. (1984), Heath-Monnig et al. (1987) found that fibroblasts from the girl were significantly less sensitive to IGF1 (ED50 of 10.7 ng/ml; normal mean, 3.2 ng/ml); fibroblasts from her mother and father showed an ED50 of 5.0 ng/ml and 4.3 ng/ml, respectively, both above the normal mean. Further in vitro studies showed normal numbers of cell surface binding sites and normal binding affinity. The authors concluded that the child had IGF1 resistance. Using an IGF1 variant with a reduced affinity to IGF1-binding proteins (IGFBP; see, e.g., 146730, 146731, 146732, 146733) and normal IGF1 receptor binding capacity, Tollefsen et al. (1991) found normal IGF1 biologic activity in fibroblasts from the patient reported by Heath-Monnig et al. (1987). In addition, there was a 10-fold increase in the amount of a 21-kD cell surface binding protein in the patient's fibroblasts. Tollefsen et al. (1991) concluded that the resistance to IGF1 action in this patient was caused by an abnormal production and/or cell association of IGF binding proteins which presumably interfered with the binding of IGF1 to its receptor.
Among 50 children with short stature and elevated serum IGF1, Abuzzahab et al. (2003) identified a boy with a heterozygous nonsense mutation in the IGF1R gene (147370.0003) that reduced the number of IGF1 receptors on fibroblasts. His mother and a half sib, who were both small for gestational age, carried the mutation.
In a group of 42 patients with unexplained IUGR and subsequent short stature, Abuzzahab et al. (2003) identified 1 girl who was compound heterozygous for 2 mutations in the IGF1R gene (147370.0001- 147370.0002). Fibroblasts cultured from the patient had normal numbers of cell surface IGF1 receptors but decreased IGF1 receptor function compared to control fibroblasts.
Kawashima et al. (2005) screened 24 Japanese patients with unexplained IUGR and short stature for mutations in the IGF1R gene and identified heterozygosity for a missense mutation (R709Q; 147370.0004) in a 6-year-old girl who was also diagnosed with mental retardation. The mutation was inherited from her 35-year-old mother, who had IUGR at birth and short stature as an adult, but was otherwise healthy.
In a 13.6-year-old Russian girl with IUGR, short stature, and an elevated IGF1 level, Inagaki et al. (2007) sequenced the IGF1R gene and identified heterozygosity for a missense mutation (R481Q; 147370.0005). A maternal aunt with short stature was also heterozygous for the R481Q variant; mutation status of the proband's parents was not reported.
In a Lebanese brother and sister with IUGR, short stature, microcephaly, dysmorphic facial features, mild developmental delay, and elevated IGF1 levels, Fang et al. (2012) sequenced the IGF1 and IGF1R genes and identified compound heterozygosity for missense mutations in the IGF1R gene (E121K, 147370.0006 and E234K, 147370.0007). Their unaffected consanguineous parents were each heterozygous for 1 of the mutations. The authors stated that the brother, who developed insulin-requiring diabetes at age 14.5 years, was the first reported case of diabetes mellitus associated with IGF1R mutations, although they noted that impaired glucose tolerance had previously been reported in patients with heterozygous IGF1R mutations (Walenkamp et al., 2006; Mohn et al., 2011).
In a 13.5-year-old girl, born of first-cousin Lebanese parents, who had severe IUGR, short stature, microcephaly, facial dysmorphism, reduced subcutaneous fat, mild developmental delay, and elevated IGF1 levels, Gannage-Yared et al. (2013) sequenced the IGF1 and IGF1R genes and identified homozygosity for a missense mutation in IGF1R (R10L; 147370.0008), for which her unaffected parents were heterozygous.
By exome sequencing in a 2-year-old Italian girl with severe IUGR, short stature, microcephaly, progeroid features, developmental delay, and elevated IGF1 levels, Prontera et al. (2015) identified homozygosity for a c.2201G-T transversion in the IGF1R gene (147370.0009), predicted to affect the splicing process. Her short-statured consanguineous parents were heterozygous for the mutation, as were both of her grandmothers, who had short stature and type 2 diabetes.
Exclusion Studies
IGF1 resistance due to a reduction in the number and function of cell surface IGF1 receptors has been proposed to explain the growth phenotype of African Pygmies (265850), but no mutations in the IGF1R gene have been identified in cultured transformed Pygmy lymphocyte lines (Hattori et al., 1996).
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Bierich, J. R., Moeller, H., Ranke, M. B., Rosenfeld, R. G. Pseudopituitary dwarfism due to resistance to somatomedin: a new syndrome. Europ. J. Pediat. 142: 186-188, 1984. [PubMed: 6088245] [Full Text: https://doi.org/10.1007/BF00442446]
Fang, P., Cho, Y. H., Derr, M. A., Rosenfeld, R. G., Hwa, V., Cowell, C. T. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J. Clin. Endocr. Metab. 97: E243-E247, 2012. Note: Electronic Article. [PubMed: 22130793] [Full Text: https://doi.org/10.1210/jc.2011-2142]
Gannage-Yared, M.-H., Klammt, J., Chouery, E., Corbani, S., Megarbane, H., Abou Ghoch, J., Choucair, N., Pfaffle, R., Megarbane, A. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Europ. J. Endocr. 168: K1-K7, 2013. Note: Electronic Article. [PubMed: 23045302] [Full Text: https://doi.org/10.1530/EJE-12-0701]
Hattori, Y., Vera, J. C., Rivas, C. I., Bersch, N., Bailey, R. C., Geffner, M. E., Golde, D. W. Decreased insulin-like growth factor I receptor expression and function in immortalized African Pygmy T cells. J. Clin. Endocr. Metab. 81: 2257-2263, 1996. [PubMed: 8964861] [Full Text: https://doi.org/10.1210/jcem.81.6.8964861]
Heath-Monnig, E., Wohltmann, H. J., Mills-Dunlap, B., Daughaday, W. H. Measurement of insulin-like growth factor I (IGF-I) responsiveness of fibroblasts of children with short stature: identification of a patient with IGF-I resistance. J. Clin. Endocr. Metab. 64: 501-507, 1987. [PubMed: 3818890] [Full Text: https://doi.org/10.1210/jcem-64-3-501]
Inagaki, K., Tiulpakov, A., Rubtsov, P., Sverdlova, P., Peterkova, V., Yakar, S., Terekhov, S., LeRoith, D. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J. Clin. Endocr. Metab. 92: 1542-1548, 2007. [PubMed: 17264177] [Full Text: https://doi.org/10.1210/jc.2006-2354]
Kaplowitz, P. B., D'Ercole, A. J., Underwood, L. E., Van Wyk, J. J. Stimulation by somatomedin-C of aminoisobutyric acid uptake in human fibroblasts: a possible test for cellular responsiveness to somatomedin. J. Clin. Endocr. Metab. 58: 176 only, 1984. [PubMed: 6358242] [Full Text: https://doi.org/10.1210/jcem-58-1-176]
Kawashima, Y., Kanzaki, S., Yang, F., Kinoshita, T., Hanaki, K., Nagaishi, J.-i., Ohtsuka, Y., Hisatome, I., Ninomoya, H., Nanba, E., Fukushima, T., Takahashi, S.-I. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J. Clin. Endocr. Metab. 90: 4679-4687, 2005. [PubMed: 15928254] [Full Text: https://doi.org/10.1210/jc.2004-1947]
Lanes, R., Plotnick, L. P., Spencer, M., Daughaday, W. H., Kowarski, A. A. Dwarfism associated with normal serum growth hormone and increased bioassayable, receptorassayable, and immunoassayable somatomedin. J. Clin. Endocr. Metab. 50: 485-488, 1980. [PubMed: 6987254] [Full Text: https://doi.org/10.1210/jcem-50-3-485]
Mohn, A., Marcovecchio, M. L., de Giorgis, T., Pfaeffle, R., Chiarelli, F., Kiess, W. An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree. Horm. Res. Paediat. 76: 136-143, 2011. [PubMed: 21811077] [Full Text: https://doi.org/10.1159/000324957]
Momoi, T., Yamanaka, C., Kobayashi, M., Haruta, T., Sasaki, H., Yorifuji, T., Kaji, M., Mikawa, H. Short stature with normal growth hormone and elevated IGF-I. Europ. J. Pediat. 151: 321-325, 1992. [PubMed: 1396882] [Full Text: https://doi.org/10.1007/BF02113248]
Prontera, P., Micale, L., Verrotti, A., Napolioni, V., Stangoni, G., Merla, G. A new homozygous IGF1R variant defines a clinically recognizable incomplete dominant form of SHORT syndrome. Hum. Mutat. 36: 1043-1047, 2015. [PubMed: 26252249] [Full Text: https://doi.org/10.1002/humu.22853]
Raile, K., Klammt, J., Schneider, A., Keller, A., Laue, S., Smith, R., Pfaffle, R., Kratzsch, J., Keller, E., Kiess, W. Clinical and functional characteristics of the human arg59ter insulin-like growth factor I receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R. J. Clin. Endocr. Metab. 91: 2264-2271, 2006. [PubMed: 16569742] [Full Text: https://doi.org/10.1210/jc.2005-2146]
Tollefsen, S. E., Heath-Monnig, E., Cascieri, M. A., Bayne, M. L., Daughaday, W. H. Endogenous insulin-like growth factor (IGF) binding proteins cause IGF-I resistance in cultured fibroblasts from a patient with short stature. J. Clin. Invest. 87: 1241-1250, 1991. [PubMed: 1707060] [Full Text: https://doi.org/10.1172/JCI115125]
Walenkamp, M. J. E., van der Kamp, H. J., Pereira, A. M., Kant, S. G., van Duyvenvoorde, H. A., Kruithof, M. F., Breuning, M. H., Romijn, J. A., Karperien, M., Wit, J. M. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J. Clin. Endocr. Metab. 91: 3062-3070, 2006. [PubMed: 16757531] [Full Text: https://doi.org/10.1210/jc.2005-1597]