Overview
Campomelic dysplasia (CD) is a rare congenital disorder typically caused by pathogenic variants in SOX9. Classic features include skeletal anomalies, a bowed long bones phenotype (campomelia), and a spectrum of midline defects. In some cases, dysplasia occurs without the typical bowing (acampomelic CD), illustrating the diverse genetic mechanisms that disrupt SOX9 regulation. Recent reports highlight that deletions upstream of SOX9 can dysregulate its expression, leading to CD even when the coding sequence itself is intact. In this context, we discuss a notable case of a 46,XY individual presenting as female with acampomelic Campomelic Dysplasia and absent minipuberty, attributed to an upstream SOX9 deletion.
Genetic Basis: Upstream Regulatory Deletions
SOX9 sits in a gene-rich region with distant regulatory elements that control its expression during development. Deletions or rearrangements upstream of SOX9 can remove enhancers or insulator regions, resulting in haploinsufficiency or misexpression. Such anomalies can produce the hallmark features of CD without direct coding mutations. Importantly, in 46,XY individuals, dysregulated SOX9 expression can bias gonadal development, resulting in discordant phenotypes where genotypic sex (46,XY) does not align with phenotypic sex (genitalia that appear female). This case underscores how upstream deletions can contribute to atypical sexual differentiation and eschew expectations based solely on SOX9 coding sequence exams.
Clinical Presentation: Absent Minipuberty and Gonadal Implications
Absent minipuberty—characterized by a lack of early postnatal activation of the hypothalamic-pituitary-gonadal axis—can be an important clinical clue in patients with CD and related disorders. In the described 46,XY girl, the absence of minipuberty reflects disrupted gonadal maturation, aligning with a broader sex development disturbance driven by SOX9 regulatory disruption. Clinicians should remain vigilant for delayed or absent pubertal milestones in infancy and early childhood, as these signs can reflect underlying genetic etiologies beyond typical XY gonadal development.
Gonadal and Midline Findings
SD (sex development) anomalies in CD due to upstream SOX9 disruptions often involve the gonads, uterus, or undifferentiated genitalia, with midline anomalies (e.g., olfactory system defects) reported in some cases. A key takeaway from related literature is the potential for olfactory agenesis or bulb anomalies to serve as supportive diagnostic indicators for acampomelic CD, further guiding targeted genetic testing in ambiguous cases.
Diagnostic Approach and Genetic Counseling
The diagnostic workup for suspected upstream SOX9-related CD should integrate detailed clinical phenotyping with comprehensive genomic analyses. Techniques include array comparative genomic hybridization (array CGH) and whole-genome sequencing with precise breakpoint mapping to identify noncoding regulatory deletions. It’s essential to interpret findings in a multidisciplinary framework, considering skeletal, facial, gonadal, and midline features, as well as brain and olfactory system involvement.
Genetic counseling for families is critical given the potential for germline mosaicism and variable expressivity. When an upstream regulatory deletion is confirmed, cascade testing for carrier relatives and future family planning discussions regarding recurrence risk should be initiated. Early identification of absent minipuberty or gonadal dysgenesis can inform surveillance for endocrine issues and guide endocrinology-led management strategies.
Clinical Implications and Future Directions
Understanding that upstream regulatory deletions can drive acampomelic CD expands diagnostic horizons beyond coding mutations. This insight emphasizes the need for high-resolution genetic testing in patients with discordant sex development and atypical skeletal features. Moreover, recognizing absent minipuberty as a potential sign can accelerate early interventions, including endocrinological assessments and supportive therapies that improve growth and development trajectories. As sequencing technologies evolve, more cases will clarify the prevalence and phenotypic range of upstream SOX9 disruptions, enabling refined genotype-phenotype correlations and tailored patient care.
Related case insights, including olfactory bulb agenesis as a diagnostic indicator for acampomelic CD, reinforce the value of a holistic, organ-system approach to this rare dysplasia. Clinicians should maintain a high index of suspicion for SOX9 regulatory anomalies in 46,XY individuals with female presentations and absent minipuberty, and pursue comprehensive genetic testing to confirm upstream deletions.
