Skeletal dysplasia

Gene: GHR

Green List (high evidence)

RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - female with height 109.9 cm (−3.89 SD) at 8yrs 8 mo; low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side; WES
P2 - Spanish boy with height of 88.8 cm (−3.1 SD) at 3.8yrs; serum IGF-I was low normal; parents height: father -1.8SD and mother −2.46 SD) - variant inherited from the mother; targeted Sanger seq of GHR
P3 - 12yo female with short stature: 119.6 cm, −4.30 SD; high basal GH and low IGF-1 noted; father, mother, and grandfather all of very short stature (-3.6 to -4.3 SD). Variant in GHR inherited from the mother; targeted Sanger seq of GHR
P4 - Pakistani proband; height of 85.4 cm (−4.17 SD) at 4 yrs old; low IGF-I of 16 ng/mL (normal, 54 to 178); carried de novo GHR c.899dupC mutation and p.R229H missense variant inherited from the mother

PMID: 21900382 Derr et al., 2011 - FUNCTIONAL EVIDENCE for pathogenicity of GHR c.899dupC - mutant protein is expressed as normal, but found to be completely unresponsive to GH (no STAT5B phosphorylation); STAT5B activity was also significantly reduced when mutant protein was co-expressed with WT - confirmed dominant effect

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).

Created: 8 Jun 2026, 4:23 p.m. | Last Modified: 8 Jun 2026, 4:23 p.m.

Panel Version: 9.13

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271

Publications

• 21900382
• 33912130
• 34453441
• 36943306
• 37474955

Green List (high evidence)

Not listed in SD nosology paper - growth disorder. Many cases; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Laron dwarfism, 262500; Growth hormone insensitivity; increased responsiveness to growth hormone 604271

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: GHR; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 12:49 p.m.