Growth retardation, alopecia, pseudoanodontia and optic atrophy (GAPO) syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the ANTXR1 gene. While significant progress has been made in understanding its molecular basis, no systematic description of the clinical phenotype is available.We conducted a comprehensive review of 105 cases reported in the available literature since the first description of GAPO syndrome in 1947. We summarise here the current understanding of the clinical phenotype and the genetic basis of the condition.Our findings point out the multisystemic nature of GAPO syndrome, primarily featuring skeletal, dermatological and ophthalmological manifestations. The condition is caused by the biallelic loss-of-function of ANTXR1 Histological findings throughout the reported cases underscore the critical role of excessive extracellular matrix deposition in the pathogenesis of GAPO syndrome. The evidence gathered suggests ANTXR1 as an important regulator of extracellular matrix homeostasis.This study highlights the clinical and molecular spectrum of GAPO syndrome. Early recognition, multidisciplinary care and genetic counselling are essential for improving patient outcomes. Future studies should focus on targeted therapies addressing extracellular matrix dysregulation.

GAPO syndrome (#230740) is a rare autosomal recessive disorder characterized by growth retardation, alopecia, pseudoanodontia, and optic malformations, hence the acronym GAPO. The presence of both dentitions in the ridge leads to abnormally thick alveolar ridges, which are thought to hinder full denture fabrication and placement. This article aims to report the success of full dentures in two cases with GAPO syndrome with no surgical intervention, and we include observations from the follow-ups. Patients diagnosed with GAPO syndrome and confirmed by molecular testing were recruited from the outpatient clinic for oral rehabilitation. The study included 3 patients, 1 male (patient 1) and 2 females (patients 2 and 3). Patient 3 failed to appear for the delivery session of her denture. The dentures of patients 1 and 2 had very good retention at the delivery sessions, and it was further enhanced during the follow-ups. The undercuts present due to the ridge ballooning in GAPO patients were retentive to classical dentures. The unexpected normal muscular tone aided the retention as well. GAPO patients are compliant and motivated to be dentally rehabilitated.

Primary failure of tooth eruption (PFE) is a rare genetic disorder characterized by the failure of teeth to erupt in the absence of obvious physical obstructions, often resulting in a progressive open bite that is resistant to orthodontic treatment. While PFE can be caused by genetic or systemic factors (such as cysts, tumors, and endocrine imbalances), the non-syndromic causes are primarily genetic, with an autosomal dominant inheritance pattern with variable expressivity. Several genes have been closely associated with the non-syndromic PFE form. The PTH1R (parathyroid hormone 1 receptor) is the most commonly PFE-associated gene. Additional genes associated with minor frequency are Transmembrane protein 119 (TMEM119), which reduces the glycolytic efficiency of bone cells, limiting their mineralization capacity and causing bone fragility; Periostin (POSTN), which regulates the extracellular matrix and the bone's response to mechanical stress; and Lysine (K)-specific methyltransferase 2C (KMT2C), which establishes histone methylation near the Wnt Family Member 5A (WNT5A) gene involved in dental development (odontogenesis). Syndromic forms of PFE are typically associated with complex multisystem disorders, where dental eruption failure is one of the clinical features of the spectrum. These syndromes are often linked to genetic variants that affect ectodermal development, craniofacial patterning, and skeletal growth, leading to abnormal tooth development and eruption patterns. Notable syndromes include GAPO syndrome, ectodermal dysplasia, and cleidocranial dysplasia, each contributing to PFE through distinct molecular mechanisms, such as disruptions in dental structure development, cranial abnormalities, or systemic developmental delays. The main aim of this review is to provide a comprehensive overview of the genetic basis underlying both syndromic and non-syndromic forms of PFE to facilitate precision diagnosis, foster the development of personalized therapeutic strategies, and offer new insights into managing this complex dental anomaly.

GAPO syndrome is an exceptionally-rare autosomal recessive disorder characterized by growth retardation, alopecia, pseudoanodontia, and optic abnormalities, with fewer than 60 cases reported globally. We present the first documented case in Syria, highlighting novel otolaryngological and radiological findings that expand the clinical spectrum of this syndrome. A 27-year-old male presented with chronic right-sided otalgia, unilateral conductive hearing loss, and persistent sinonasal symptoms. Examination revealed hallmark features of GAPO syndrome, including craniofacial anomalies, external auditory canal stenosis, and pseudoanodontia. Computed tomography demonstrated total aplasia of the paranasal sinuses and mastoid air cells-findings not previously reported in GAPO syndrome. Audiological evaluation revealed moderate conductive hearing loss attributed to external auditory canal stenosis and eustachian tube dysfunction, contrasting with the predominantly-sensorineural hearing loss reported in earlier cases. Additionally, unique ophthalmic findings, including peripheral congenital cataracts and a myelinated retinal nerve fiber layer, were observed. This case underscores the importance of comprehensive evaluations, including advanced imaging and audiological assessments, in identifying subtle or atypical manifestations of GAPO syndrome. It also highlights challenges in airway management due to craniofacial anomalies. The findings emphasize the necessity for a multidisciplinary approach to optimize care and improve outcomes in patients with GAPO. Further research is needed to clarify genotype-phenotype correlations and refine diagnostic criteria.

GAPO syndrome is usually diagnosed clinically owing to its characteristic features of growth retardation, alopecia, pseudoanodontia, and ophthalmic anomalies. Pseudoanodontia describes the failure of eruption of the two sets of teeth in these patients. Thus, the abnormal dental phenotype is the emergence of a set or part of a set of dentitions. This study reports the physical, oro-dental, and molecular findings of two new sibs with GAPO syndrome and provides a description of the dental phenotype of one of the patients reported before. The patients were subjected to full medical history taking and three generations-pedigree construction. They were phenotyped according to the elements of morphology: Standard terminology series. After parental consents were acquired, molecular analysis was carried out for the two sibs (Patient 1 & 2). These included a new gene variant associated with erupted teeth in GAPO syndrome and new clinical features. A new classification for the terminologies of eruption disturbances was suggested. The study asserts the importance of oro-dental examination and follow-ups as dental updates may occur in these cases.