Efficacy of long-acting growth hormone in Axenfeld-Rieger syndrome with a novel 3.824 Mb 4q25 deletion: a Case Report and systematic literature review

BackgroundAxenfeld-Rieger syndrome (ARS) is a multisystem disorder primarily caused by PITX2 mutations. While eye and dental anomalies are classic, the role of PITX2 as a dosage-sensitive regulator of the human growth axis remains clinically under-recognized. We aim to elucidate the link between large-scale 4q25 microdeletions and severe growth hormone deficiency (GHD).MethodsA 5.4-year-old boy with ocular segment dysgenesis and short stature underwent family-based whole-exome sequencing (WES). Standardized growth hormone (GH) stimulation tests and longitudinal growth dynamics analysis based on 44 precise clinical data points collected from birth to age 7.45 years were performed. A systematic literature review of 10 ARS cases with growth failure was conducted to propose a pathogenic model.ResultsWES identified a novel de novo 3.824Mb heterozygous deletion at 4q25 (arr[GRCh38] 4q25(108,929,697–112,753,289)×1), encompassing critical genes including CFI, EGF, PITX2, PANCR, and LARP7. Our systematic review revealed a dosage-sensitive correlation between the microdeletion scale at the 4q25 region and the severity of growth axis impairment. The patient exhibited complete GHD (peak GH: 4.22 ng/mL) and a 1.5-year bone age delay. Following 20 months of PEG-rhGH therapy, the patient achieved a significant catch-up growth with a cumulative height gain of 16.5 cm, with his height standard deviation score (Ht-SDS) improving from −2.0 SD to within the normal range. Our mechanistic model suggests that PITX2 haploinsufficiency disrupts the POU1F1 (Pit-1) transcriptional cascade, leading to pituitary hypoplasia.ConclusionThis study reports the one of the most extensive longitudinal follow-up of successful PEG-rhGH therapy in ARS to date. We propose that large 4q25 deletions represent a high-risk genotype for GHD. Mandatory growth monitoring and early endocrine screening are recommended for ARS patients with chromosomal deletions in this region to optimize developmental outcomes.