Journal of Perinatology (2012) 32,75–77 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp IMAGING CASE REPORT Acampomelic campomelic dysplasia in genetic male without sex reversal

TE Herman and MJ Siegel Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA

Journal of Perinatology (2012) 32, 75–77; doi:10.1038/jp.2011.92 anteriorly bowed femora, short fibulae, lateral clavicular hooks, 11 pairs or ribs and club feet. Other features include hypertelorism, flat nasal bridge, low-set ears, tracheomalacia and complete Case presentation sex reversal in two thirds of affected genetic males.2–4 There is A 790-g infant was born by spontaneous vaginal delivery at a very high perinatal mortality in patients with CD who have 28-weeks gestation to a G 3, P 0,0,2,0 20-year-old mother. severe respiratory distress and CD is even considered to be a lethal 2,5 The pregnancy had been complicated by maternal diabetes mellitus skeletal dysplasia. However, there are patients who survived and bipolar disorder. In the delivery room, the infant was beyond infancy. The development of gonadoblastoma has been 6 hypotonic and required positive pressure respiration. Several reported in longer-time survivors with complete sex reversal. attempts at intubation were unsuccessful because of significant Most patients with CD have mutations in the SOX9 gene, micrognathia. However, after successful intubation Apgars chromosome 17q 24.3-q25.1. The sex-determining region of improved; the Apgars were 8, 6, 7 and 9 at 1, 5, 10 and 15 min. chromosome Y or SRY gene is the determinant of testicular The neonate had a cleft palate, normal male genitalia and development. Any transcription factor that has more than 60% 7 mild hypotonia. Based on the micrognathia and cleft palate, a similarity to the DNA-binding motif of SRY is called a SOX gene. diagnosis of Pierre Robin sequence was made and a tracheostomy tube was placed on the third day of life. A skeletal survey (Figures 1–4) was obtained.

Denouement and discussion The radiographic findings of micrognathia, hypoplastic scapulae, lateral clavicular hooks, absent thoracic pedicles, bilateral anterior radial head dislocations and small vertical ilia are those of autosomal dominant campomelic dysplasia (CD).1,2 CD was originally described in 1971 by Marouteaux. He chose that name believing that the bowed, short femora and tibiae that occurred in his initially reported patients were an obligatory, integral feature of the syndrome. However, bowed bones are a variable feature of the syndrome.3,4 The somewhat paradoxical name of acampomelic CD has been given to patients similar to the one described here.3 Typical radiographic features of CD are microcephaly, micrognathia, cleft palate (Pierre Robin sequence), hypoplastic scapulae, non-mineralized thoracic pedicles, small vertical ilia, cervical kyphosis, vertebral anomalies, especially vertebral hypoplasia with resultant kyphoscoliosis, radial head dislocation, anteriorly bowed short tibiae with overlying soft-tissue dimpling, Figure 1 Frontal supine chest radiograph. Endotracheal tube ending at the carina and nasogastric tube are in place. There is diffuse granularity due to Correspondence: Dr TE Herman, Mallinckrodt Institute of Radiology, Washington University underlying hyaline membrane disease. Also there are bilateral lateral clavicular School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA. hooks (curved white arrows). The scapulae are very hypoplastic bilaterally (solid E-mail: [email protected] black arrows). The pedicles of vertebral bodies T5 to T8 are not ossified. The T4 Received 7 April 2011; revised 26 April 2011; accepted 25 May 2011 and T9 pedicles are present (solid white arrows). There are twelve ribs. Acampomelic CD in genetic male TE Herman and MJ Siegel 76

Figure 4 Lateral right elbow radiograph. The radial head (R) projects anteriorly to the distal humeral metaphysis (DHM) and not adjacent to the unossified capitellum. The proximal ulna is shallow. These findings are those of anterior congenital radial head dislocation. Figure 2 Lateral cervical spine radiograph. The endotracheal tube and nasogastric tube are again seen. The vertebral bodies are hypoplastic. There is straightening of the cervical lordosis, but not cervical kyphosis. SOX9 is a transcription factor which has a role in the production of type 2 collagen and in the production of anti-Mullerian hormone or Mullerian-inhibiting factor in male Sertoli cells.4,5 Abnormal development of the type 2 collagen may account for the skeletal dysplasia, and the role in Mullerian-inhibiting factor production, which may account for the 75% incidence of complete sex reversal in XY patients with CD.4–7 Interestingly, no SOX 9 mutations were identified in this patient. However, it is known that regulation of the SOX9 gene is complex and mutations distant to this gene may lead to CD.8 The differential diagnosis of acampoemlic CD consists of Cumming syndrome, which has a very similar skeletal dysplasia; other causes of Pierre Robin sequence, often the most striking clinical finding in acampomelic CD; and other diseases with congenital bowing of the long bones such as osteogenesis imperfecta, thanatophoric dysplasia, Stuve Wiedemann syndrome, Schwartz Jampel syndrome (type 2), kyphomelic dysplasia and Weismann Netter Stuhl syndrome.9 Cumming syndrome is an autosomal recessive condition, unlike the dominantly inherited CD, with bowed long bones, defect ossification of the vertebral bodies and small scapulaeFalmost identical in appearance to CD. However, these patients also have polycystic kidneys, cystic hygromas and polysplenia syndrome.10,11 The latter defects usually allow differentiation of these two conditions. Pierre Robin sequence may be isolated, (isolated Pierre Robin sequence may in fact be due to SOX9 dysregulation12) or associated with other syndromes such as Stickler syndrome, Treacher Collin Figure 3 AP left shoulder radiograph. The lateral clavicular hook and syndrome, velocardiofacial syndrome and cerebrocostmandibular hypoplastic scapula (black arrow) are well seen. syndrome.12 However, none of these conditions have the skeletal

Journal of Perinatology Acampomelic CD in genetic male TE Herman and MJ Siegel 77 dysplasia associated with CD. CD can be differentiated from 6 Hong JR, Barber M, Scott CI, Guttenberg M, Wolfson PJ. 3 year old phenotypic female other causes of congenital long bones bowing by its characteristic with campomelic dysplasia with bilateral gonadoblastoma. J Pedatr Surg 1995; 12: skeletal dysplasia. 1735–1737. 7 Foster JW, Dominguez Weglich MA, Guioli S, Kwos C, Weller PA, Stevanovic M et al. Campomelic dysplasia and autosomal sex reversal caused by mutations Conflict of interest in SRY related gene. Nature 1994; 372: 525–530. 8 Smyk M, Obersztyn E, Nowakowska B, Bocian E, Cheugn SW, Mazurczak T et al. The authors declare no conflict of interest. Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father. Am J Med Genetics 2007; 143A: 866–870. References 9 Farra C, Piguet C, Guillaume C, D’Ercole C, Phillip N. Congenital bowing of long bones; prenatal ultrasound findings and diagnostic dilemnas. Fetal Diag Ther 2002; 1 Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of 17: 236–239. campomelic dysplasia. J Med Genet 1995; 32: 415–420. 10 Watiker V, Lachman RS, Wilcox WR, Barroso I, Schafer AJ, Scherer G. Differentiating 2 Mansour S, Offiah AC, McDowall S, Sim P, Tolmie J, Hall C. Phenotype of survivors of campomelic dysplasia from Cumming syndrome. Am J Med Genet 2005; 135A: campomelic dysplasia. J Med Genet 2002; 39: 597–602. 100–112. 3 Savarirayan R, Banker A. Acampomelic campomelic dysplasia with denovo 5q;17q 11 Ming JE, McDonald McGkinn DM, Markowitz RI, Ruchelli E, Zackai EH. Heterotaxia in reciprocal translocation and severe phenotype. J Med Genet 1998; 35: 597–599. a fetus with campomeli, cervical lymphocele, polysplenia, and multicystic dysplastic 4 Kim HY, Yoon CH, Kim GH, Yoo HW, Lee BS, Kim KS et al. A case of campomelic kidneys: expanding the phenotype of Cumming syndrome. Am J Med Genet 1997; dysplasia without sex reversal. J Korean Med Sci 2011; 26: 143–145. 73: 419–424. 5 Jakubiczka S, Bettecken T, Koch G, Tuysuz B, Wollnik B, Wieacker P. Campomelic 12 Gordon CT, Tan TY, Benko S, FitzPatrick D, Lyonnet S, Farlie P. Long range dysplasia without sex reversal in a Turkis patient due to mutation Ala119Val within the regulation at the SOX( locus in development and disease. J Med Genet 2009; 46: Sox 9 gene. Clin Dysmorphol 2001; 10: 197–201. 649–656.

Journal of Perinatology