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Campomelic Dysplasia with Sex Reversal Harboring a Novel Frameshift Mutation

Campomelic dysplasia (CD) is a rare genetic disease characterized by skeletal dyspla­ sia that also affects several other organ systems. CD is caused by a SOX9 mutation. We here report a case of CD with a 46, XY karyotype and female external genitalia. This child was born with a weight of 3.12 kg after 37 weeks of gestation. She exhibited a number of characteristic features including a small thoracic cage, bowing of both fe­ murs, clubbed feet, hypoplastic scapula, 11 pairs of ribs, a bell­shaped narrow thorax, micrognathia, macroglossia, a cleft palate, a flattened nasal bridge, and low set ears. She experienced additional distress because of the presence of a tracheal ring and because she had tracheomalacia. CD was diagnosed through nucleotide sequence analysis. A frameshift mutation, c.235delC (p.Gln79Argfs*31), was identified in the SOX9 gene that has not previously been reported.


INTRODUCTION
Campomelic dysplasia (CD) is a rare genetic disease that belongs to a group of lethal skeletal dysplasias. It is inherited as an autosomal dominant disorder. The term cam pomelia is derived from the Greek word campo (or campto), meaning bent limb 1) and is characterized by bowing of the long bones. Campomelia also affects the development of the skeleton, reproductive system, and other organ systems. This disorder is often life threatening in new borns because it causes respiratory distress. Another characteristic of this disorder is that most patients manifest maletofemale sex reversal. Further, some patients with the male karyotype (XY) have female or ambiguous genitalia 2) caused by a mutation in SOX9, a member of the SOX (SRYrelated HMG box) gene family. We here describe such a case involving a frameshift mutation in SOX9 that has not previously been reported.  We obtained informed consent from the parents to screen for genetic mutations and we isolated peripheral blood genomic DNA for this purpose. Nucleotide sequence analysis revealed a heterozygous c.235delC deletion mutation in exon 1 of the SOX9 gene, which we identified as a previously unreported p.Gln79Argfs*31 frameshift mutation ( Figure 2).
Ventilator weaning in this patient failed due to respiratory distress. A tracheal ring and mild tracheomalacia were detected by bronchoscopy. A tracheostomy was performed at 24 days of age. A subsequent video fluoroscopic swallowing study indi cated severe dysphagia, which resulted in nasogastric tube feeding.
There was one seizure event during the hospitalization period.
There were no specific findings from brain magnetic resonance imaging or electroencephalography. Anticonvulsant medications were eventually discontinued since the symptoms had abated.
She was discharged 83 days after birth with a home ventilator.
The patient was again hospitalized due to pneumonia at 10 It binds to the chondrocytespecific enhancer of the COL2A1 gene, which encodes type II collagen, the main cartilage matrix protein, and thereby activates it in these cells. SOX9 is also a tran scription factor that regulates the differentiation of cartilage cells.
Low levels of SOX9 lead to a decrease in COL2A1 expression and thereby cause skeletal abnormalities 7,8) .
In addition to chondrogenesis, the SOX9 gene plays a role

Conflicts of interest
No potential conflict of interest relevant to this article was reported. To date, two cases of CD have been genetically confirmed in Korea 11,12) ; however, the p.Gln79Argfs*31 frameshift deletion mutation in our current study has never been reported. This  14,15) . De novo translocations or inversions with breakpoints upstream of SOX9 are more likely to lead to the removal of one or more cisregulatory elements 15) . According to Mansour et al. 14) , the father of the patient also has the same SOX9 mutation, but his mutation was clinically silent. These findings were associated with better survival or diagnosis at an older age.

Author contributions
In conclusion, we here report a novel frameshift mutation in the SOX9 gene of a female with a 46, XY karyotype who was born with CD and maletofemale sex reversal. CD is a very rare and often fatal genetic disorder; however, the early diagnosis and

Ethical statement
The Institutional Review Board (IRB) approval for the study was received in June 2020. Retrospective data collection was