Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes

Abstract

Context: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding.

Objective: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects.

Methods: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel.

Results: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome).

Conclusion: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.

Keywords: Growth hormone insensitivity (GHI); genetic; overlapping disorders; short stature.

Figure 1.

Flowchart showing the genetic analyses undertaken and the diagnostic outcomes of the GHI subjects (n = 149). Genes for candidate gene sequencing (CGS) were chosen depending on the clinical and biochemical features of the patients. Next generation sequencing included: Whole exome sequencing (WES), short stature genomic panel, and array comparative genomic hybridization (aCGH). Diagnoses were made in a total of 80/149 (54%) subjects, leaving 69/149 (46%) undiagnosed. Our center identified a genetic defect in 75 (50%) subjects (94% of those diagnosed) and a further 5 diagnoses were made at the local referring institution (‘other modality’). These included 2 patients with molecular defects consistent with Silver–Russell syndrome (SRS; 11p15LOM and mUPD7, respectively) and 3 patients with autoimmune lymphoproliferative syndrome (ALPS), Lysinuric protein intolerance and microcephalic osteodysplastic primordial dwarfism type II (MOPD type II), respectively. These diagnoses were suspected by the referring clinician or clinical geneticist and confirmed by genotyping.

Figure 2.

The range of genetic diagnoses and the diagnostic modality in the patients with suspected growth hormone insensitivity. (A) The range of diagnostic modalities that secured the genetic diagnoses in 80/149 (54%) diagnosed subjects. CGS, Candidate gene sequencing; WES, Whole exome sequencing; Panel, short stature genomic panel; aCGH, array comparative genomic hybridization; OM, other modality. (B) Range of genetic diagnoses. Group 1: known GH–IGF-I axis genetic variants (n = 45; GHR n = 40, IGFALS n = 4, and IGFIR n = 1); group 2: overlapping disorders comprising 3M syndrome genetic variants (n = 10; OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1); Noonan syndrome (NS) genetic variants (n = 4; PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1); Silver–Russell syndrome (SRS) (n = 2; loss of methylation on chromosome 11p15, uniparental disomy for chromosome 7); CNV, Class 3-5 copy number variations (n = 10, Class 4 1q21 deletion n = 2, Class 5 12q14 deletion n = 1, Class 3 5q12 deletion n = 1, Class4 Xq26 duplication n = 1, duplication of chromosome 10 n = 1, Class 3 7q21, and Class 4 7q31 deletion n = 1), Class 3 7q21 duplication and Xp22 duplication n = 1, Class 3 7q36 duplication n = 1, Class 3 3p22 deletion and 15q13 duplication n = 1), and additional overlapping disorders (n = 9; 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). GH–IGF-I, growth hormone-insulin-like growth factor-I; NS, Noonan syndrome; SRS, Silver Russell syndrome; CNV, copy number variant.

Figure 3.

Comparison of height SDS, IGF-I SDS, and consanguinity between patient groups with and without a genetic diagnosis. (A) Height SDS was significantly lower in the diagnosed group (n = 78) than in the undiagnosed group (n = 68) (mean height SDS –4.9 vs –3.4, respectively), P < .0001. (B) IGF-I SDS was significantly lower in the diagnosed group (n = 71) than in the undiagnosed group (n = 58) (mean IGF-I SDS –2.5 vs –1.9, respectively), P = .0384. (C) Consanguinity rates were significantly higher in the diagnosed group (n = 80) than in the undiagnosed group (n = 69) (53% vs 13%, P < .0001). *P ≤ .05, ****P ≤ .0001.

Figure 4.

Comparison of birth weight SDS, height SDS, and consanguinity between patients with known genetic diagnoses in the GH–IGF-I axis and overlapping disorders. (A) Birthweight SDS was significantly lower in the overlapping disorders group (n = 31) than in the known GH–IGF-I axis defect group (n = 40) (mean BW SDS –2.2 vs –0.8, respectively), P = .0027. (B) Height SDS was significantly lower in the known GH–IGF-I axis defect group (n = 44) than in the overlapping short stature disorders group (n = 34) (mean height SDS –5.3 vs –4.4, respectively), P = .0174. (C) Consanguinity rates were significantly higher in the GH–IGF-I axis group (n = 45) than in the overlapping disorders group (n = 35) (64% vs 37%, P = .0236). *P ≤ .05, **P ≤ .01.