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Severe IGF-1 deficiency (SPIGFD)
Severe insulin-like growth factor 1 (IGF-1) deficiency (SPIGFD) is a rare genetic condition characterized by impaired growth and short stature due to insufficient IGF-1 production
Prevalence
10-20/100,000
33,100 - 66,200
US Estimated
51,350 - 102,700
Europe Estimated
Age of Onset
ICD-10
E34.3
Inheritance
Autosomal dominant
Autosomal recessive
Mitochondrial/Multigenic
X-linked dominant
X-linked recessive
5 Facts you should know
FACT
SPIGFD is a rare endocrine disorder characterized by severe growth failure due to inadequate IGF-1 levels, despite normal or elevated growth hormone (GH)
FACT
SPIGFD results from specific defects in the GH-IGF-1 axis
FACT
SPIGFD leads to severe growth failure and other developmental challenges
FACT
Untreated SPIGFD has long-term health consequences
FACT
Early diagnosis and intervention are critical to optimize growth outcomes
Interest over time
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Primary Clinical Features
Severe Proportionate Growth Failure
- Height significantly below the third percentile from infancy
- Markedly reduced height velocity despite normal or elevated GH level
Delayed Bone Maturation
- Radiographic evidence of delayed skeletal age
- Reduced epiphyseal development
Distinctive Facial Features (in Severe Cases)
- Frontal bossing
- Midface hypoplasia
- Micrognathia
Metabolic and Endocrine Abnormalities
- Severely reduced serum IGF-1 despite normal or elevated GH levels
- Low IGFBP-3 levels (though variability exists)
- No response to exogenous GH therapy
Additional Clinical Manifestations
Neonatal or infantile hypoglycemia
due to impaired IGF-1–mediated glucose regulation
Thin muscle mass
despite adequate nutrition
Delayed dentition
and smaller jaw size
Sensorineural hearing loss
(reported in some cases)
Cognitive effects
(rare, but reported in cases with severe IGF-1 deficiency)
References:
Child Growth Foundation. Primary IGF-1 Deficiency. Child Growth Foundation. Available at: https://childgrowthfoundation.org/conditions/igf1-deficiency/. Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature, growth hormone deficiency, and primary insulin-like growth factor-I deficiency. J Clin Endocrinol Metab. 2008;93(11):4210-4217. doi:10.1210/jc.2008-1238.
Current treatments
The goal of treatment for familial Mediterranean fever (FMF) is to control symptoms because there is no cure for the condition.
Treatment of an acute episode may include:
Recombinant IGF-1 Therapy (Mecasermin)
The primary treatment for SPIGFD involves the administration of recombinant human IGF-1 (mecasermin). This therapy directly replaces deficient IGF-1 to promote growth and metabolic regulation. It requires careful monitoring for hypoglycemia, intracranial hypertension, and lipohypertrophy.
Hypoglycemia Management
Due to IGF-1’s insulin-like effects, hypoglycemia is a key concern. Strategies include dietary adjustments, meal-timed injections, and close glucose monitoring.
Adjunctive and Investigational Therapies
- GH Therapy: Typically ineffective due to GH receptor insensitivity but useful in differential diagnosis.
- IGF-1 and IGFBP-3 Combinations: Investigated to improve IGF-1 stability and bioavailability.
- Long-Acting IGF-1 Analogues: Being developed to enhance adherence and efficacy.
- Gene Therapy: A future potential approach targeting genetic causes of IGF-1 deficiency.
Long-Term Monitoring
Growth parameters, bone maturation, and metabolic markers should be regularly assessed. Surveillance for adverse effects, particularly hypoglycemia and intracranial hypertension, is essential.
Mecasermin therapy remains the standard of care, with emerging treatments focusing on optimizing IGF-1 delivery and stability.
References:
Chernausek SD. Managing the child with severe primary insulin-like growth factor-1 deficiency (IGFD). Growth Horm IGF Res. 2008;18(4):313-319. doi:10.1016/j.ghir.2008.02.003. Rogol AD, Clayton PE, Cuneo RC. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Horm Res Paediatr. 2013;80(3):193-202. doi:10.1159/000354336. Savage MO, Bang P. The variability of responses to growth hormone therapy in children with growth hormone deficiency and Turner syndrome. J Clin Endocrinol Metab. 2012;97(3):E503-E515. doi:10.1210/jc.2011-2757. Child Growth Foundation. Primary IGF-1 Deficiency. Available at: https://childgrowthfoundation.org/conditions/igf1-deficiency/. Accessed February 2025. UK IGF-1 User's Group. Recombinant IGF-1 Therapy in Children with Severe Primary IGF-1 Deficiency (SPIGFD): Guidelines. 2018. Available at: https://www.bsped.org.uk/media/1464/uk-igf1-users-group-guidelines-20181.pdf. Accessed February 2025.
Top clinical studies
| Title | Description | Phases | Status | Interventions | More Information |
|---|---|---|---|---|---|
| Somatropin (Norditropin) in Insulin-like Growth Factor (IGF) Deficient Children | This trial is conducted in the United States of America (USA). This is a 12 month study to determine if Norditropin is safe and effective in children with IGF deficiency. | PHASE3 | COMPLETED | DRUG: somatropin | Learn more |
| Metabolic Effects of GH and IGF-I in Growth Hormone Deficient(GHD) and Diabetes and Impaired Glucose Tolerance(IGT) | The aim of this study is to measure effects of the combined treatment with GH and IGF-I on glucose sensitivity and body composition in patients with GHD and IGT or diabetes. | PHASE3 | COMPLETED | DRUG: NutropinAq (GH) and Increlex (IGF-I)|DRUG: NutropinAq and placebo | Learn more |
| Recombinant Human Insulin-Like Growth Factor (rhIGF-1) Treatment of Short Stature Associated With IGF-1 Deficiency | This study is intended to assess the effects of once daily dosing of recombinant human insulin-like growth factor (rhIGF-1) in increasing height velocity. | PHASE2|PHASE3 | COMPLETED | DRUG: rhIGF-1 (mecasermin) for a period of 86 weeks | Learn more |
| Prepubertal Children With Growth Failure Associated With Primary Insulin-Like Growth Factor-1 (IGF-1) Deficiency | This study is intended to determine whether twice daily weight based dosing with recombinant human insulin-like growth factor (rhIGF-1) will safely and effectively increase the growth of prepubertal children with short stature associated with low IGF-1 levels but who produce sufficient growth hormone (GH). Subjects will be randomized to either an observation arm or to active treatment. | PHASE3 | COMPLETED | DRUG: rhIGF-1 (mecasermin, Tercica, Inc.) | Learn more |
| Replacement GH Therapy After Bariatric Surgery in Patients With Very Severe Obesity | Obesity and obesity-related diseases have reached epidemic proportions in Western countries (1-3). Laparoscopic-adjustable silicone gastric banding (LASGB) is a purely restrictive operation that determine effective weight loss without inducing malabsorption (4-6). However, also after LASGB body weight loss is almost invariably associated with Free Fat Mass (FFM) loss, and the relevance of the FFM contribution to total energy expenditure is well-known (7-8). Different endocrine axes are reported to affect FFM. We previously reported that low levels of DHEA-S, an adrenal steroid with controversial anti-adipogenic and anti-atherogenic effects, are increased after the massive and sustainable weight loss induced by LASGB in severely obese premenopausal women and correlated with the higher post-operative FFM (9-10). It is also well known that GH/IGF-I axis exerts relevant effects on FFM and that reduced GH levels might increase Fat Mass (FM) and reduce FFM (11,12). Morbidly obese patients have a reduced GH secretion, generally reversible after weight loss (13-14). In a recent study currently in press, we reported that a persistent deficiency in the GH/IGF-I axis in very obese females is associated to lower decrease in FM after LASGB. Low IGF-I plasma levels have also been reported to be independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients (15) and ultrasound- measured hepatic left lobe volume might represent a reliable tool for the evaluation of liver involvement in obesity (16). GH deficiency (GHD) in adult patients is associated with an increase in FM and a parallel decrease in FFM (17). The severity of GDH is correlated to cardiovascular risk, body composition abnormalities and bone loss, and decreased left ventricular ejection fraction (18-20). GH therapy has been demonstrated to be effective in normalizing body composition, with beneficial effects up to a 2-years follow-up period (21-24). GH therapy has also been reported to be effective in sparing FFM during weight loss in obese patients and metabolic syndrome (25,26). However, these studies have some limitations due to the duration of the treatment and the lack of a preliminary evaluation of the GH/IGF-I axis secretory status in obese patients before the GH therapy. At present there are no data on the evaluation of the GH/IGF-I status before and after bariatric surgery and the effectiveness of recombinant GH treatment in very severe obese patients. | PHASE3 | COMPLETED | DRUG: Recombinant GH Saizen (Merck-Serono) | Learn more |