History
The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor abnormalities differ from GHRD in not having hypoglycemia, because the counter-regulatory effects of GH are not impaired. IGF-I mutations differ from GHRD with severe mental retardation, sensorineural deafness, micrognathia, microcephaly, and intrauterine growth retardation. Heterozygous IGF-I receptor mutations have no or mild-to-moderate effect on brain development, but they do result in intrauterine growth retardation.
A single case report exists of a homozygous mutation resulting in severe prenatal and postnatal growth failure with malformations in a Lebanese child born of parents who were first cousins who were unaffected by their heterozygosity. [34]
Physical Examination
Clinical characteristics of GHRD and STAT5b mutation
The clinical features with GHRD and STAT5b mutation are not distinguishable from those of severe GH deficiency.
15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
ALS deficiency has modest, at most, effect on growth, without any other phenotypic features. [13, 14, 15, 16, 17, 18, 19] IGF-I mutations result in severe intrauterine and postnatal growth failure, deficient brain development in utero, and severe mental retardation, deafness, and micrognathia. [3, 4, 5, 6] Heterozygous IGF-1 receptor mutations result in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and normal to moderately retarded cognitive development. [7, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]
Clinical characteristics of GHRD
Growth characteristics include typically normal birth weight and birth length; growth failure from birth with growth velocity half of normal; height deviation that correlates with (low) serum levels of IGF-I and IGFBP-3; adult stature -4 to -12 standard deviations below normal mean; delayed bone age, but advanced for height age; and small hands and feet.
A 21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, his IGF-I level is 4 times hers, and his IGFBP3 level is twice hers.
Craniofacial characteristics include sparse hair before age 7; frontotemporal hairline recession all ages; prominent forehead (bossing); head size more normal than stature with impression of large head; "setting sun sign" (sclera visible above iris at rest) 25% in children younger than 10 years (which, together with the craniofacial disproportion, can lead to impression of hydrocephalus and unnecessary workup); hypoplastic nasal bridge, shallow orbits; decreased vertical dimension of face; blue scleras; prolonged retention of primary dentition with decay; normal permanent teeth that may be crowded; absent 3rd molars; sculpted chin; unilateral ptosis; and facial asymmetry (15%, only reported in GHRD).
Musculoskeletal/body composition features include: hypomuscularity with delay in walking; avascular necrosis of femoral head (in 25% of those with GHRD); high-pitched voices in all children, most adults; thin, prematurely aged skin; limited elbow extensibility after 5 years of age; children underweight to normal for height, most adults overweight for height; and marked decrease of ratio of lean mass to fat mass compared to normal at all ages.
Metabolic characteristics include hypoglycemia (fasting), increased cholesterol and LDL-C levels, and decreased sweating.
Sexual development characteristics include small penis in childhood with normal growth with adolescence, delayed puberty, and normal fertility.
Causes
More than 50 mutations in the GHR gene have been described in the approximately 250 known patients with GHRD. The report of the characterization of the GHR gene included the first description of a genetic defect of the GHR, a deletion of exons 3, 5, and 6. Recognition that the exon 3 deletion represented an alternatively spliced variant without functional significance resolved the dilemma of explaining deletion of nonconsecutive exons.
In contrast to the alternatively spliced variant lacking exon 3, the first mutation of this exon has been described in a typical GHR-deficient patient with heterozygosity for a nonsense mutation in exon 4, and family studies indicate that heterozygosity for the exon 3 mutant has no effect. In addition to the original exon 5, 6 deletion, another deletion of exon 5 has been described, along with numerous nonsense mutations, missense mutations, frame shift mutations, splice mutations, and a unique intronic mutation resulting in insertion of a pseudo-exon. A number of other mutations have been described that are either polymorphisms or have not occurred in the homozygous or compound heterozygous state. [24]
The point mutations that result in severe GH insensitivity when present in the homozygous state or as a compound heterozygote are all associated with the typical phenotype of severe GHD. All but a few of the defects result in absent or extremely low levels of GH binding protein (GHBP). Noteworthy is the D152H missense mutation that affects the dimerization site, thus permitting the production of the extracellular domain in normal quantities but failure of dimerization at the cell surface, which is necessary for signal transduction and IGF-I production. Two defects that are close to (G223G) or within (R274T) the transmembrane domain result in extremely high levels of GHBP. These defects interfere with the normal splicing of exon 8, which encodes the transmembrane domain, with the mature GHR transcript being translated into a truncated protein that retains GH binding activity but cannot be anchored to the cell surface. [35]
The intronic mutation present in the heterozygous state in a mother and daughter with relatively mild growth failure (both with standard deviation score [SDS] for height -3.6), and resulting in a dominant negative effect on GHR formation, is not associated with other phenotypic features of GH deficiency. This splice mutation preceding exon 9 results in an extensively attenuated, virtually absent intracellular domain. [36]
Japanese siblings and their mother have a similar heterozygous point mutation of the donor splice site in intron 9, also resulting in mild growth failure compared to GHRD but with definite, although mild, phenotypic features of GHD. [37] GHBP levels in the Caucasian patients were at the upper limit of normal with a radiolabeled GH binding assay and in Japanese patients the levels were twice the upper limit of normal using a ligand immunofunction assay. These heterozygous GHR mutants transfected into permanent cell lines have demonstrated increased affinity for GH compared to the wild-type full-length GHR, with markedly increased production of GHBP. When cotransfected with full-length GHR, a dominant negative effect results from overexpression of the mutant GHR and inhibition of GH-induced tyrosine phosphorylation and transcription activation. Naturally occurring truncated isoforms have also shown this dominant negative effect in vitro.
A novel intronic point mutation was discovered in a highly consanguineous family with 2 pairs of affected cousins with GHBP-positive GH insensitivity and severe short stature, but without the facial features of severe GHD or GHRD. This mutation resulted in a 108-bp insertion of a pseudo-exon between exons 6 and 7, predicting an in-frame, 36-residue amino acid sequence in a region critically involved in receptor dimerization. [38]
Homozygous mutations described in the patients with STAT5b dysfunction have been associated with consanguinity. [11] By 2010 16 discrete mutations of the ALS gene had been reported in 21 individuals from 16 families, all resulting in absence of ALS and very low levels of IGF-I and IGFBP3 in the circulation, but modest, at worst, effects on growth. [13, 14, 15, 16, 17, 18, 1] Seven discrete heterozygous mutations of the IGF-I receptor have been described, resulting in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and mental retardation (from none to moderate). [6, 17, 18, 19, 20, 21] Thus far, only 4 mutations previously noted for the IGF1 gene have been described. [3, 4, 5, 6]
Complications
Cardiovascular risk may be increased in GHRD, similar to that seen with GH deficiency in adults, and associated with increased total and LDL cholesterol levels.
While pregnancy is uncomplicated in GHRD, delivery requires cesarean delivery.
Infants, toddlers, and preschool children with GHRD appear to be at greater risk of death from prevalent infections than unaffected siblings.
Obesity, particularly in females, becomes a serious problem with aging but has not been associated with insulin resistance, diabetes, or increased cancer risk, as is seen in unaffected populations and unaffected relatives. [33]
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Diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets beginning with the GH-releasing hormone receptor (GHRHR), indicated in bold and italicized.
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A 50-year-old woman with GHRD (right) and her 75-year-old mother, indicating premature aging appearance. Photos were taken at the same distance, emphasizing the small size of the subject and relative foreshortening of the facies.
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A 10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
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15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
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A 21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, his IGF-I level is 4 times hers, and his IGFBP3 level is twice hers.
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Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Dr Frank Diamond) and the seated chief.
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Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
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Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
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Four subjects with growth hormone (GH) receptor deficiency due to the E180 splice mutation on the GH receptor gene. From left to right, the first woman, age 22 years, was treated from age 4 years, when she had a height standard deviation score (SDS) of -8, to age 14 years with insulinlike growth factor-1 at a dose of 80 µg/kg body weight bid; adult height is -4.3 SDS and body fat percent is 39.8. The other 3 women were treated for 3 years with 120 µg/kg bid and are aged 30, 23, and 27 years with body fat content of 49.3%, 49%, and 54.6% and with heights of 120.7 cm, 120.8 cm, and 118.5 cm, respectively. Females with GH insufficiency who had comparable baseline characteristics and were treated with 120 µg/kg twice daily to adult height in the US trial only reached 112 cm, 121.2 cm, and 120.8 cm. These observations suggest no greater statural attainment with prolonged high-dose therapy than with short-term, high-dose treatment, consistent with the observation of disproportionate advancement of osseous maturation by the higher dose. Courtesy of The Journal of Clinical Endocrinology and Metabolism (Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab 98: 839–845, 2013).
Tables
Condition |
Growth failure |
GH |
GH binding protein |
IGF-I |
IGFBP3 |
Genetic |
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GHRD - Recessive forms |
Severe |
Elevated |
Absent-low* |
Very low |
Very low |
GHRD - Dominant negative forms |
Mild-moderate |
Elevated |
Increased |
Very low |
Low-normal |
STAT5b mutation |
Severe |
Elevated |
Normal |
Very low |
Very low |
ALS mutation |
None-moderate |
Normal |
Normal |
Very low |
Very low |
IGF-I gene mutation |
Severe |
Elevated |
Normal |
Absent-high** |
Low-normal |
IGF-I receptor mutation |
Mild-moderate |
Normal-elevated |
Normal |
Normal-elevated |
Normal-elevated |
Acquired |
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GH inhibiting antibodies |
Severe |
Absent |
Normal |
Very low |
Low |
Malnutrition |
None-mild |
Elevated |
Decreased |
Variable |
Variable |
Diabetes mellitus |
None-mild |
Elevated |
Decreased |
Decreased |
Increased |
Renal disease |
Mild-severe |
Normal |
Decreased |
Normal |
Increased |
Hepatic disease |
Mild-severe |
Elevated |
Normal-increased |
Decreased |
Normal |
*Increased in mutations of or near the transmembrane domain of the GH receptor**Absent with partial IGF1 gene deletion; very high with abnormal IGF-I |
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