AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1966 in Israel, Zvi Laron and colleagues reported a genetic form of dwarfism in 3 Yemenite Jewish siblings with clinical and biochemical features of growth hormone deficiency (GHD), but with "abnormally high concentrations of immunoreactive serum growth hormone." The underlying defect was thought to be an inborn error in growth hormone (GH) synthesis resulting in an immunologically detectable but metabolically inactive GH. Within 2 years, 19 additional Israeli patients of Asian Jewish ancestry were identified. Subsequent work led to the identification of more than 250 patients worldwide, with the vast majority of cases being traced to Semitic or Mediterranean origins. These patients were proven to have levels of circulating GH within the reference range but were demonstrated to be metabolically unresponsive to exogenous GH. Initially termed Laron-type dwarfism, this condition is currently known as Laron syndrome (LS), primary GH insensitivity (GHI), or primary GH resistance.

A consensus classification system has been developed to distinguish various forms of GHI. This is depicted below, adapted from Laron Z et al (1993).

Classification of growth hormone insensitivity

Primary GH insensitivity (eg, Laron syndrome, hereditary and/or congenital defects)

• Growth hormone receptor (GHR) defects (quantitative and qualitative)
• Abnormalities of GH signal transduction (postreceptor defects)
• Primary defects of insulinlike growth factor-1 (IGF-I) synthesis or secretion

Secondary GH insensitivity (acquired conditions; may be partial or transient)

• Circulating antibodies to GH that inhibit GH action
• Antibodies to the GHR
• Primary defects of IGF-I synthesis
• GHI caused by malnutrition
• GHI caused by liver disease
• Other conditions that cause GHI

Pathophysiology

LS is a familial disorder with an autosomal recessive form of inheritance. The underlying metabolic defect concerns a lack of responsiveness to GH. Patients with LS typically have low serum levels of IGF-I, despite serum levels of GH that are within the reference range or elevated. Exogenous GH does not accelerate their growth or stimulate serum levels of IGF-I or insulinlike growth factor binding protein-3 (IGFBP-3). Cellular unresponsiveness to GH was demonstrated in vitro by the failure of GH to stimulate erythroid progenitor cells from the peripheral blood of patients.

Direct evidence of a defect in the GHR came in 1984 when Laron and colleagues demonstrated that hepatic microsomes obtained by liver biopsy of 2 patients did not bind radiolabeled GH. With the advent of modern molecular biology, the human GHR has been cloned and characterized. This led to the observation that serum GH binding protein (GHBP) was structurally identical to the extracellular domain of the GHR. Subsequently, absence of circulating GHBP was demonstrated in patients with LS. The initial studies of the GHR gene in Israeli patients with LS showed that some, but not most, contained gene deletions.

To date, more than 33 mutations of the GHR have been discovered in approximately half of the 250 patients with LS that have been reported. Most of these comprise a wide variety of point mutations, of which the vast majority have been in the extracellular domain. Mutations resulting in defective GHR dimerization or abnormal GH-GHR signal transduction have also been reported. Other forms of GHI with similarly severe insulin-like growth factor (IGF) deficiency (eg, from defects in IGF synthesis or secretion or from defects in GH signal transduction) have clinical features similar to those of GHI secondary to GHR deficiency. Examples include IGF-I gene deletion and mutations of STAT5b that interfere with normal JAK-STAT signaling. Image 1 schematically depicts the normal GH-IGF axis and the GH-IGF axis showing the 4 potential defects capable of causing GHI.

Frequency

International

More than 250 cases have been reported worldwide.

Mortality/Morbidity

Impaired intellectual development appeared to be associated with LS based on the initial studies of the Israeli cohort. Of the 18 original patients identified, only 3 had average intelligence quotient (IQ) scores and 9 of them were intellectually disabled. This has not been observed largely in other populations. Follow-up studies of the Israeli cohort 25 years later revealed persistent cognitive deficits but greater variability, ranging from normal intelligence (including one patient with a PhD) to severe mental retardation. Other contributing factors could not be ruled out considering that the cognitive studies did not include family controls.

Race

Ethnic background is known for approximately 90% of the patients reported to have LS. A significant majority (65%) are of known Semitic origin. This group includes Arabs, Asian Jews, and a large genetic isolate of Ecuadorian conversos (Jewish individuals who converted to Christianity during the Spanish Inquisition). The Ecuadorian group and the Israeli Moroccan/Sephardic Jewish patients are believed to be derived from a common ancestor, likely in medieval Spain prior to the expulsion of Jews in 1492 during the inquisition. Many conversos escaped to the New World, settling in remote mountains in efforts to avoid the inquisitors who pursued them. Consanguinity and propagation of the mutation was in large part a product of such geographic isolation.

The largest genetic isolates have been those reported in Israel and Ecuador, whereas smaller ones have been reported in Turkey and in the Bahamas. Numerous patients of Indian, Pakistani, and Italian ethnicity have been reported. Roughly 90% of patients with LS can trace their origins to the Mediterranean area, the Middle East, or to the Indian Peninsula. While no obvious explanation exists for this geographic localization, consanguinity was or still is common in most of the above noted populations.

Sex

Sex predilection varies significantly in the reported populations. The male-to-female (M:F) ratio for the original 26 Israeli patients was 0.73:1. In Ecuador, the initial impression was that of a marked predominance among females, with an M:F ratio of 0.5:1, but this was not observed upon reanalysis. Outside of Israel and Ecuador, the M:F ratio is 1.5:1. No clear explanation for these differences currently exists, and most experts believe that no sex difference exists in the incidence of LS.

Age

LS is a congenital disorder.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The clinical features of LS are summarized below (see Summary of clinical features of LS).

• Clinically, patients with LS present in a manner virtually indistinguishable from those with severe GH deficiency.
• • Pregnancy is usually uncomplicated. Intrauterine growth and resulting birth size are usually normal.
  • Relative obesity, although not by weight, is actually present at birth with a relative excess of adipose tissue in the context of thin bones and diminished muscle mass.
  • Congenital malformations, craniofacial abnormalities, and other physical features may be noted at birth and are outlined below.
  • Gross motor developmental milestones are typically delayed because of underdeveloped musculature.
  • Hair and nail growth is sparse.
  • Onset of teething is delayed.
• Postnatal linear growth is severely abnormal, with rapid decline in standard deviation score (SDS) for length beginning after birth.
• • The pubertal growth spurt is absent.
  • Adult stature is severely affected. Employing US standards, adult stature ranges from -3.8 to -9 SDS in the world literature and from -5.3 to -12 in the Ecuadorian population.
  • Weight gain occurs in relative excess to linear growth, and patients with LS become increasingly obese.
• Small penile size is noted in childhood. Puberty is often delayed, more frequently in boys with LS than in girls with LS. Under the influence of sex steroids, full sexual development with normal penile size is reached in adulthood. Adult sexual function and reproductive capacity is normal. Women with LS require operative delivery.
• Metabolic abnormalities include fasting hypoglycemia, hypercholesterolemia, osteopenia, and decreased sweating. Approximately 50% of infants and children with LS manifest overt symptoms of hypoglycemia, including seizures. Additional individuals may demonstrate significant fasting hypoglycemia in the absence of symptomatology.

Physical

The constellation of physical findings closely resembles those of severe GH deficiency. They are highlighted below by system.

• Growth and body proportions
• • Birth weight and length likely are within reference ranges.
  • Linear growth velocity is strikingly abnormal.
  • Relative obesity is present, with increased weight-to-height ratio, which increases with age.
  • In the Israeli cohort, the upper segment–to–lower segment ratios were increased for sex and chronologic age, denoting short limbs for trunk size. This was not as apparent in the European and Ecuadorian cohorts within which segmental ratios were normal for bone age. Segmental ratios of adults with LS are childlike.
• Head, ears, eyes, nose, throat
• • Hair is quite sparse in infancy through early childhood.
  • Blue sclera may be noted, particularly in those of Mediterranean or Middle Eastern origin.
  • Facial bone growth is particularly retarded and fontanelle closure is delayed, but the overall growth of the skull is relatively normal. This leads to a disproportionate cephalofacial relation with frontal bossing, saddle nose, shallow orbits, and the setting sun sign of the eyes.
  • Tooth development is delayed, and teeth may often be defective.
  • The larynx is narrow, resulting in a very high-pitched voice.
• Genitourinary features
• • Genitalia and gonads are small from birth.
  • Pubertal development is delayed, but adult sexual maturation is eventually achieved.
  • Penile size is reduced during childhood but reaches normal adult size.
• Extremities and musculoskeletal features
• • Musculature is underdeveloped.
  • Walking and other gross motor milestones are delayed.
  • Hands and feet are small.
  • Limited elbow extensibility has been observed, although mostly in the Ecuadorian cohort only.
  • Hip dysplasia, notably avascular necrosis of the femoral head (Legg-Calve-Perthes disease) has been observed in up to 25% of patients (Ecuador).
• Skin: The skin is thin and has a fine texture with wrinkles, as in premature aging.
• Summary of clinical features of LS
• • Epidemiology
    • Consanguinity
    • Varying sex ratios (population dependent)
  • Growth
    • Normal birthweight, usually normal birth length
    • Severe postnatal growth failure
    • Bone age delay (may be advanced for height age)
    • Segmental ratios abnormal for age (Israel), normal for bone age (Europe, Ecuador), childlike in adulthood
  • Development
    • Gross motor delay (because of hypomuscularity)
    • Decreased intelligence in Israeli cohort, normal intelligence in others
  • Craniofacial characteristics
    • Sparse hair
    • Frontal bossing
    • Hypoplastic nasal bridge
    • Shallow orbits
    • Craniofacial disproportion because of decreased vertical dimension of face
    • Blue sclera
    • Delayed dental development
    • High-pitched voice
  • Musculoskeletal and body composition
    • Hip dysplasia - Avascular necrosis of the femoral head
    • Limited elbow extensibility
    • Underdeveloped musculature
    • Osteopenia
    • Thin prematurely aged skin
    • Obese - Markedly decreased ratio of lean body mass to fat mass
  • Sexual development
    • Micropenis in childhood, normal genital growth during adolescence
    • Delayed puberty
    • Normal sexual and reproductive function
  • Metabolic features
    • Hypoglycemia
    • Decreased sweating
    • Hypercholesterolemia

Causes

LS is an inherited disorder consisting of a genetic defect in the GHR transmitted in an autosomal recessive fashion. Consanguinity has been a major contributor to its development in described populations. The diversity of mutations in the GHR gene that cause LS is quite striking. The more than 33 mutations reported to date range from exon deletions to a variety of point mutations, including missense, nonsense, splice, and frameshift mutations. Considering that the underlying GHR mutation has been described in only half of the known cases of LS, additional mutations likely exist. Most defects are in the extracellular hormone-binding domain, resulting in absence of circulating GHBP. Reports have also been made of mutations affecting the transmembrane and cytoplasmic domains of the GHR.

An animal model has been developed in the form of a mouse in which the GHR gene has been disrupted. Similar to human LS, serum GHBP, IGF-I, and IGFBP-3 are severely reduced. The -/- Laron mice show marked postnatal growth retardation. In contrast to individuals with LS who have a tendency toward obesity, the -/- mice had significant reduction in weight gain. Also of note, the -/- Laron mice had significantly increased lifespan. The relevance of this is not yet understood and contradicts previous data suggesting an antiaging role for GH.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

LS must be differentiated primarily from severe GHD in which clinical phenotype can be indistinguishable. This is achieved mainly based on serum GH concentrations, which are within reference ranges or elevated in LS. Serum GHBP levels are typically depressed. Provocative testing of pituitary GH secretion usually reveals elevated basal GH and increased peak GH levels. IGF generation tests document failure to respond adequately to GH. LS must then be differentiated from other causes of GHI, which are listed above (see Classification of growth hormone insensitivity). Ultimately, the definitive diagnosis of LS is made with identification of an abnormality in the GHR gene.

WORKUP

Section 5 of 11  

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• Follow-up
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• Multimedia
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Lab Studies

• Please refer to Hyposomatotropism and Short Stature for the complete workup for growth failure.
• • Because LS mimics the phenotype of severe GHD, provocative GH testing may be indicated.
  • If GHI is suspected, appropriate laboratory studies include serum IGF-I, IGFBP-3, basal GH, and GHBP levels and an IGF/IGFBP-3 generation test. This test involves the assessment of serum IGF-I and IGFBP-3 levels following stimulation with GH.
  • Serum glucose determination is necessary to document possible hypoglycemia.
  • A fasting lipid panel may be used to identify potential hypercholesterolemia.

Imaging Studies

• A left hand and wrist radiograph can be used to assess bone age.
• Additional radiographs or dual photon and dual energy x-ray absorptiometry aid in the evaluation of potential osteopenia.
• A hip radiograph series is necessary to assess for Legg-Perthes disease (aseptic necrosis of the capital femoral epiphysis).
• An MRI of the pituitary may be required if GHD has not been ruled out.

TREATMENT

Section 6 of 11  

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• Follow-up
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Medical Care

• The only effective treatment currently available for patients with classic GHI is recombinant human IGF-I (rhIGF-I).
• For those with secondary forms of GHI, the underlying cause (eg, malnutrition, liver disease) should be identified and treated appropriately.
• Infants with LS may require more frequent feedings to avoid hypoglycemia.
• Periodic blood sugar monitoring is necessary for some patients with LS and for all patients with LS who are receiving rhIGF-I therapy.

Consultations

A pediatric orthopedic surgeon may be consulted, as indicated.

Diet

The dietary recommendations for LS are mainly to ensure adequate caloric intake to facilitate growth and avoid hypoglycemia.

Activity

Participation in contact sports may be contraindicated in some cases depending on the degree of osteopenia and fracture risk.

MEDICATION

Section 7 of 11  

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Human IGF-I was first synthesized using recombinant DNA technology in 1986. The subcutaneous form of rhIGF-I became available in the early 1990s. Since that time, multiple trials have been conducted investigating its use in children with LS.

Depicted in Image 3 are the initial growth velocity data from the first randomized, double-blind, placebo-controlled trial on the safety and efficacy of rhIGF-I, conducted in the Ecuadorian cohort by Guevara-Aguirre et al (1995). To date, results have been reported for 69 patients with GHI who have received rhIGF-I for at least 12 months. IGF-I has been demonstrated to markedly improve height velocity and normalize serum IGF-I levels. Significant improvement in height SDS ranging from a gain of 1.2-1.9 z scores has been observed. Serum IGFBP-3 levels did not rise with treatment.

Studies of adults have shown beneficial metabolic effects, including improvements in lean body mass. Overall, therapy has been well tolerated. Frequency of hypoglycemia has varied considerably depending on the study, ranging from a rate equivalent to placebo control to frequent and severe.

While results of treatment thus far have been promising, much more remains to be known about the long-term anabolic actions of IGF-I or about the optimal dosage of administration. IGF-I has been approved for use in patients with LS in Japan and in Israel. rh-IGF-I recently received approval from the US Food and Drug Administration (FDA) in 2005 for use in LS.

The newest therapy that will soon be available for use in LS patients is rhIGF-I/rhIGFBP-3 complex. Much less published data is available regarding its efficacy and safety profile.

Drug Category: Peptide growth factors

rhIGF-I is a member of the somatomedin polypeptide hormones. IGF-I mediates the anabolic and growth-promoting effects of GH. Endogenous IGF-I is required for normal growth and brain development.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Routinely monitor growth and development at 3-month intervals. If the patient is receiving rhIGF-I therapy, monitor for adverse effects and monitor IGF-I levels at least annually.

Transfer

• Monitor blood sugar to ensure euglycemia. The patient may require IV dextrose to achieve euglycemia.

Deterrence/Prevention

• Genetic counseling regarding mode of transmission, the possible contributions of consanguinity, and the risk of future offspring having LS is an important aspect of education and prevention.
• Prenatal genetic testing is not widely available commercially.

Complications

• Osteopenia increases patients' risk for fractures.

Prognosis

• Prognosis appears to be good, although information on longevity or expected life span is currently lacking.

Patient Education

• With IGF-I therapy, parents and patients are instructed to observe for and report adverse effects. Parents and patients are also instructed to recognize the signs and symptoms of hypoglycemia, how to treat hypoglycemia, and, when deemed appropriate, how to monitor blood sugar at home.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center and Teeth and Mouth Center. Also, see eMedicine's patient education articles Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Growth Failure in Children, Growth Hormone Deficiency FAQs, and Teething.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Close monitoring is mandatory to screen for possible adverse effects in patients on IGF-I therapy.

Special Concerns

• When appropriate, refer the patient to an early childhood intervention program to reduce the possible risk of permanent developmental delays.

MULTIMEDIA

Section 10 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Schematic depiction of the normal growth hormone–insulinlike growth factor (GH-IGF) axis and the GH-IGF axis showing the 4 potential defects capable of causing growth hormone insensitivity (GHI).
	View Full Size Image
Media type:  Image

Media file 2:  Short stature associated with Laron syndrome.
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Media type:  Photo

Media file 3:  Initial growth velocity data from the first randomized, double-blind, placebo-controlled trial on the safety and efficacy of recombinant human insulinlike growth factor-1 (rhIGF-I).
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Jul 10, 2006