INTRODUCTION

A158V Missense Mutation in an Infant withAcampomelic Campomelic Dysplasia without

Sex ReversalMarvi Montano MD, PGY-2; Ferdinand Shamiyeh MD, PGY-1; Diba Farah MD, PGY-2; Angela Flores MD

Texas Tech University Health Sciences Center-Paul L Foster School of Medicine, El Paso, TX

SPINE MRI

CASE SUMMARY

CLINICAL FINDINGS

CONCLUSION

REFERENCES

2013 Texas Pediatric Society Electronic Poster Contest

Campomelic dysplasia (CD) presents as a rare constellation of findings associated with defective development of the skeletal and reproductive systems, and is seen in approximately 1 in 40,000-200,000 births. The majority of cases are due to mutations of the SOX9 gene on chromosome 17q24. Our case exhibits an atypical form of the classic manifestations; but is unique in that a new mutation has been discovered.

This case report aims to describe the clinical features of campomelic dysplasia and acampomelic dysplasia, identify the associated morbidities as well as discuss the only gene associated with this condition.

Figure 1. Multiple congenital anomalies including low-set ears, short neck, micrognathia, spade hands, tibial dimple and clubfeet.

PERTINENT PHYSICAL FINDINGS ON ADMISSION

Dysmorphic features• Microsomia• Flat nasal bridge• Low-set ears• Right nasal narrowing• Cleft palate• Long philtrum

• Respiratory distress• Small chest• Spade hands• Micropenis• Dislocated hips• Tibial cleft• Clubfeet

SKELETAL SURVEY

Figure 2. CXR showing thin ribs, bell-shaped chest, scoliosis, abnormal curvature to clavicles, hypoplastic ribs

Figure 4. Humerii with absent curvature

Figure 3. Spine radiograph showing hypoplastic and unstable C3-C5, hypoplastic scapulae

Figure 5. Dislocated hips and femurs with absent curvature

Figure 6. Normal tibia and bilateral club feet

CAMPOMELIC DYSPLASIA (CD) is a rare autosomal dominant syndrome caused by mutations in the SRY related gene SOX9, mapped to 17q24.3.1,2 SOX9 gene has an important regulatory function and is expressed in fetal chondrogenic and testicular tissues.1 It is characterized by both skeletal and extra skeletal features such as sex reversal of a 46, XY individual.2 Acampomelic campomelic dysplasia (ACD) is a variant and milder form of CD characterized by the absence of long bone curvature. Our patient had most of the clinical and radiologic features described for CD but without the bowing of the long bones. He had no evidence of sex reversal as his genotype and phenotype were both 46, XY.

DIAGNOSISThe diagnosis of CD and ACD is usually based on clinical and radiographic findings. Molecular genetic testing of SOX9, the only gene known to be associated with CD, is available in clinical laboratories and detects mutations or chromosome rearrangements in approximately 95% of affected individuals.

SEQUENCE ANALYSIS RESULTIn this patient, sequence analysis revealed a mutation heterozygous for A158V missense mutation. Individuals with ACD have higher probability of having missense mutation but there are no reports to suggest if this is a disease-causing mutation or a benign variant. Interestingly, Preiss et al reported a different amino acid substitution at the same codon A158T in association with CD. A158T mutation resulted in amino acid substitution Alanine with Threonine. The authors postulated that this mutation can lead to disruption of bone and testes formation.4 In our patient the amino acid substitution (Ala to Val) caused by the missense mutation occurred in a highly conserved region that may result in alteration of protein structure or function. Genetic testing of the parents will provide insight into role of the missense mutation in this patient. The mutation is likely pathogenic if it occurred de novo or segregates with the disorder in the family. However, if A158V missense mutation is inherited from a clinically unaffected parent, then it is likely a benign variant. Genetic testing was offered to the parents but they declined.

MANAGEMENT Care is best managed by a multidisciplinary team that includes plastic, orthopedic and neurosurgical teams. Gonads should be removed because of an increased risk of gonadoblastoma in undermusculinized 46, XY patients. Hearing aids may be required by patients with hearing loss or impairment.5

PROGNOSISMajority of the infants with CD die in the first year of life. Few survive beyond this period and the longest survivor reported was 20 years old.

COUNSELING. Majority of patients with CD have de novo mutation. However, parents should be counseled of the risk of occurrence in subsequent pregnancies due to germline mosaicism.5,6

Figure 7. Spine MRI showing severe aplasia of C1 segment, Hypoplasia of C3, C4, & C5 segments, Contusion C3, Severe C3-C4 hypoplasia

Figure 8. Brain MRI showing right intraventricular hemorrhage, Posterior fossa subdural hemorrhage

DISCUSSION

1. Wagner T, Jutta W, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutation in and around the SRY-related gene SOX9. Cell 1994; 79: 1111-1120.

2. Lynch SA, Gaunt ML, Minford AMB. Campomelic dysplasia: evidence of autosomal dominant inheritance. J Med Genet 1993; 30:683 - 6.

3. Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet 1995; 32:415–20.

4. Preiss S, Argentaro A, Clayton A, et al. Compound effects of point mutations causing campomelic dysplasia/Autosomal Sex Reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. J Biological Chem 2001; 276: 27864-27872.

5. Unger S, Scherer G, Superti-Furga A. Campomelic dysplasia. GeneReviews 2008.6. Mansour S, Offiah AC, McDowall S, et al.The phenotype of survivors of campomelic

dysplasia. J Med Genet 2002;39:597-602.

Our patient is a 40-week old male born to a 28 year-old G2P1Hispanic woman who had most of her prenatal care in Juarez, Mexico. Pregnancy was uneventful. The patient was delivered by NSVD with birth weight of 3291 grams and APGAR scores of 2 and 7 at 1 and 5 minutes respectively. He was intubated shortly after birth for poor respiratory effort. He had multiple congenital anomalies on physical examination. Microsomia, flat nasal bridge, low set ears, cleft palate, micrognathia, spade hands, small chest, abnormal spine curvature, bilateral clubfeet with tibial cleft and micropenis were noted (Figure 1). Skeletal survey revealed a bell-shaped chest, abnormal hooked curvature on clavicles, hypoplastic scapulae, scoliosis, hypoplastic C3-C5 vertebrae, scoliosis, dislocated hip but normal long bones (Figures 2 to 6). Spine MRI confirmed the abnormal cervical spine (Figure 7). Abdominal US did not show female reproductive structures. His phenotype and genotype were consistent with 46, XY. Sequence analysis of the SOX9 gene reported an A158V missense mutation resulting in the replacement of alanine codon (GCG) with a valine codon (GTG) that has not been previously reported.

• CD and ACD are rare conditions that can be diagnosed clinically however, mutations in the SOX9 gene has been implicated in these conditions

• Genetic sequencing of SOX9 should be done for individuals suspected to have this condition and genetic counseling should be offered to the family