Researchers have identified a wide spectrum of growth disorders—including several not previously considered part of the growth hormone insensitivity (GHI) spectrum—presenting analogously with short stature and normal GH production, according to a study published in The Journal of Clinical Endocrinology & Metabolism. “The clinical and genetic etiology of GHI is expanding,” the study authors write.Although the underlying disease mechanisms are diverse, these overlapping disorders may be considered part of an extended GHI spectrum.”

Based on the combination of short stature, normal GH secretion, and insulin-like growth factor (IGF)-I deficiency as a basis for genetic investigation being reported in previous publications, the researchers undertook genetic characterization of 149 patients with short stature (height standard deviation score [SDS] ≤ –2.0) referred with suspected GHI and features that overlapped with known GH-IGF-I axis defects. From 2008 to 2020, they conducted genetic analysis of this cohort by utilizing a combination of candidate gene sequencing (CGS), whole exome sequencing (WES), array comparative genomic hybridization (aCGH), and a targeted whole genome short stature gene panel.


Incidence of Consanguinity High in Patient Cohort

“We identified genetic diagnoses in 80 subjects (54%), with 45 of them (56%) having known GH-IGF-I axis defects,” the study authors stated. The remaining 35 (44%) had diagnoses of 3M syndrome (OBSL1, CUL7, and CCDC8), Noonan syndrome (PTPN11, SOS1, and SOS2), Silver-Russell syndrome (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations and disorders not previously associated with GHI (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, MACS syndrome, and Bloom syndrome).

“This study confirms our previous findings in a smaller series of 107 patients that a genetic diagnosis is more likely to be identified in patients from consanguineous families, and in patients presenting with a lower height SDS and ICF-I SDS value,” the authors write. “The incidence of consanguinity is high in our patient cohort (34%), which significantly increases the likelihood of detecting recessive disorders.”

The researchers concur that detailed clinical and genetic assessment may identify a diagnosis and inform clinicians. “We anticipate this strategy will evolve to whole genome sequencing in all patients, once costs and bioinformatic tools are equivalent,” the study team notes. “Many overlapping disorders have significant comorbidities and a definitive genetic diagnosis allowed screening tests to be initiated. A diagnosis also informs prognosis, clinical management, and countenances genetic counseling. Advancing molecular knowledge of the GHI continuum has added likely benefits of facilitating targeted clinical therapies and preventing inappropriate use of recombinant human growth hormone (rhGH) in premalignant conditions.”