Overview
Acampomelic campomelic dysplasia (ACD) is a subtler form of campomelic dysplasia characterized by skeletal anomalies without the classical bowed long bones. It results from haploinsufficiency or regulatory disruptions of the SOX9 gene, a pivotal regulator of chondrogenesis and sex development. In some cases, upstream deletions affecting the regulatory landscape of SOX9 lead to atypical phenotypes, including 46,XY individuals presenting as phenotypic females or with discordant gonadal sex. Here we discuss the pathogenic mechanism, clinical implications, and diagnostic considerations for upstream SOX9 deletions associated with ACD and absent minipuberty.
Genetic Basis: SOX9 and its Regulation
SOX9 is essential for cartilage formation and testis determination. While the coding region mutations can underlie classic campomelic dysplasia, non-coding regulatory elements upstream of SOX9 control its expression during development. Deletions or disruptions in this regulatory domain can reduce SOX9 dosage in specific tissues or developmental windows, producing the campomelic phenotype without skeletal bowing, or altering gonadal differentiation. An upstream regulatory deletion can therefore cause acampomelic forms and contribute to sex development disorders, including 46,XY gonadal dysgenesis with female external phenotype.
Clinical Presentation: 46,XY Female and Absent Minipuberty
In patients with upstream SOX9 deletions, the clinical spectrum often includes:
- ACD-like skeletal findings without overt tibial bowing
- Discrepancies between chromosomal sex and gonadal/phenotypic sex, frequently resulting in 46,XY individuals with female or ambiguous external genitalia
- Absent minipuberty, a phase in infancy characterized by transient activation of the hypothalamic-pituitary-gonadal axis, which is crucial for initiating normal genital development and gonadal maturation
- Potential implications for fertility and puberty timing later in life
Absent minipuberty signals a disruption of early gonadal axis activity, often indicating underlying dysgenesis or regulatory disruptions of sex-determining genes such as SOX9.
Diagnostic Approach
The diagnostic workup integrates clinical findings, imaging, and comprehensive genetic testing:
- Clinical assessment: skeletal survey forCampomelic features, measurement of growth parameters, and detailed genital examination.
- Radiology: targeted X-rays to assess for subtle bowing or other skeletal anomalies associated with AC D.
- Genetic testing: chromosomal analysis to confirm 46,XY status; microarray or comparative genomic hybridization to detect copy-number changes; and targeted sequencing with deletion/duplication analysis of the SOX9 regulatory region upstream of the gene.
- Functional studies: when available, hormonal profiling during infancy to evaluate the activity of the hypothalamic-pituitary-gonadal axis and to document absent or blunted minipuberty.
Identification of an upstream SOX9 deletion has important implications for prognosis and management, distinguishing AC D from other skeletal dysplasias and guiding family counseling.
Implications for Management and Counseling
Management is multidisciplinary, focusing on skeletal care, endocrine evaluation, and psychosocial support:
- Orthopedic monitoring for skeletal instability and potential deformities; physical therapy to optimize mobility
- Endocrine assessment for gonadal function, with consideration of early life hormonal status and long-term fertility planning
- Gender identity support and counseling, particularly in cases with 46,XY karyotype presenting as female phenotype
- Regular follow-up to monitor growth, development, and potential complications associated with regulatory disruptions of SOX9
Genetic counseling should emphasize the non-recurrent nature of many upstream regulatory deletions but also cover recurrence risk, depending on whether the deletion is de novo or inherited from a parent carrying a balanced rearrangement.
Clinical Significance and Take-Home Messages
Upstream deletions affecting SOX9 regulation illustrate how non-coding genetic regions can profoundly influence development and phenotypic presentation. In acampomelic campomelic dysplasia, absence of minipuberty can be a meaningful early clue to disrupted sex development and gonadal function, reinforcing the need for early hormonal and endocrine evaluation. Clinicians should consider regulatory region deletions of SOX9 in patients with ACD features who show discordance between chromosomal and phenotypic sex, and pursue comprehensive molecular testing accordingly.
References and Further Reading
Key case reports and reviews highlight the role of SOX9 regulatory elements in campomelic dysplasia and related disorders, including instances of olfactory bulb agenesis and other diagnostic indicators that refine the spectrum of AC D.
