Costovertebral dysplasia in a patient with partial trisomy 22

Experimental and Molecular Pathology 80 (2006) 197 – 200 www.elsevier.com/locate/yexmp

Costovertebral dysplasia in a patient with partial trisomy 22 Vijay Tonk a,c,*, Golder Wilson a, Robert Schutt b, Justin Mock a, Herman Wyandt a,c,d, Hon Fong L. Mark c,d, Masamichi Ito c,e a b

Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Department of Orthopedics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA c Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USA d Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA e Department of Pediatrics, Boston University School of Medicine, Boston, MA 02118, USA Received 12 August 2005 Availabke online 2 November 2005

Abstract A newborn female presented with costovertebral dysplasia (CVD), subtle facial anomalies, and neonatal respiratory distress. Her karyotype demonstrated a small supernumerary NOR-positive marker that was subsequently identified as del(22)(q11.2). This extra structurally abnormal chromosome was found by DNA microsatellite marker analyses to be derived from a paternal chromosome 22. The child has had severe growth and developmental delay along with pulmonary insufficiency and hypoxia but is presently stable at age 20 months. Findings in our patient correlate with similar observations in children with small markers derived from D/G and D/D translocations reported before banding technology was available. These reports and recent mapping results suggest that a pericentric gene family, distributed on one or more acrocentric chromosomes, may have played a role in the development of the human axial skeleton. Data from additional studies will be needed to confirm or refute this hypothesis. D 2005 Elsevier Inc. All rights reserved. Keywords: Costovertebral dysplasia; CVD; D/D translocation; D/G translocation; Human axial skeleton; Partial trisomy 22; Pericentric gene family; Small supernumerary marker; Spondylocostal dysostosis; Spondylothoracic dysostosis

Introduction

Clinical report

ostovertebral dysplasia (CVD) is a rare, severe, and often lethal malformation that occurs in isolated form and as a component of syndromes like those of Jeune (Yang et al., 1987) or Jarcho – Levin (Karnes et al., 1991). We describe an infant with a supernumerary marker of chromosome 22 origin who has CVD and subtle facial changes that are quite different from other patients with partial or full trisomy 22. However, there are similarities with two previous instances of CVD associated with D/G (Turpin et al., 1959) or D/D (de Grouchy and Mlynarski, 1963) translocations that were published prior to the advent of banding technology.

KN is a female infant first evaluated in the neonatal nursery because of respiratory distress and a small chest. After an uncomplicated gestation, she was born at term at 2600 g (3rd percentile) to a 28-year-old mother of German origin and a 27year-old father of Mexican origin. Both parents are part of a Mennonite community living in Texas. The family history was essentially benign with no consanguinity. The delivery was normal with APGAR scores of 6 and 9, but she developed severe hypoxia and tachypnea that required NICU care for 10 days. Despite constant oxygen therapy by nasal cannula and increased-calorie formula, she exhibited severe growth failure. At age 22 months, her length was 47 cm, weight 3300 g, and head circumference 36 cm (all less than 3rd percentile for her age). Her facial appearance (Fig. 1A) demonstrated bi-temporal hollowing, upslanting palpebral fissures, broad nasal root, shallow nasal bridge, and anteverted nares. Other abnormalities included short neck, broad chest with severe pectus excavatum (Fig. 1B), contractures of fingers 2 – 4, dimples over the

* Corresponding author. Clinical Cytogenetics and Medical Genetics, Texas Tech University Health Sciences Center School of Medicine, 3601 4th Street. MS9406, Lubbock, TX 79430, USA. Fax: +1 806 743 1122. E-mail address: [email protected] (V. Tonk). 0014-4800/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2005.08.011

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Fig. 1. (A) Facies of the patient showing prominent forehead, long philtrum, down-turned corners of the mouth, and ptosis. (B) Chest of the patient showing pectus excavatum and hypoplasia. (C) Chest radiograph showing crab-like dysplasia of ribs with abnormal segmentation. (D) Lateral chest film showing rib anomalies and lordotic posture.

extremities, and hypotonia with muscle wasting. She exhibited rapid, shallow respiratory excursions with subcostal retractions and opisthotonic posturing with a fixed lordosis. She fixed and followed with no focal neurologic defects. Her chest radiograph (Fig. 1) showed severe CVD with crab-like appearance of the ribs and shortening of the vertebrae (Figs. 1C, D). Ophthalmology examination revealed bilateral macular hypoplasia and symmetric, small corneas. An echocardiogram revealed cor triatriatum with a left atrial membrane that did not obstruct blood flow and allowed bidirectional atrial shunting. On follow-up at 102 months of age, her length was 52.6 cm, weight 3800 g, and OFC 39.75 cm (all below the 3rd percentile with no gains after age 2 months). She has been in therapy programs for motor delays and is thought to have mild cognitive delay. She remains oxygen-dependent, has had one hospitalization for pneumonia, and is managed with agreement for non-intubation. Materials and methods A routine chromosome analysis was obtained from a 72-h PHA-stimulated peripheral blood lymphocyte culture using standard methods (Verma and Babu, 1995). Trypsin-G-banding was performed by the method of Seabright (1971) and silver staining by the method of Bloom and Goodpasture (1976). Identification of the origin of the marker was achieved by fluorescent in situ hybridization (FISH) using centromere enumeration probes for chromosomes 14/22 (D14Z1/D22Z1) and chromosome 15 (D15Z1) as well as whole chromosome painting probes (wcp14 and wcp22) according to the manufacturer’s instructions (Vysis, Downers Grove, IL). DNA was extracted from peripheral blood from the patient and her parents using an automated DNA extractor. Five to twenty nanograms of DNA was

amplified by PCR using six sets of primers targeted at various DNA microsatellite markers on chromosome 14 and chromosome 22 in the presence of 32P-dCTP, followed by polyacrylamide gel electrophoresis (PAGE). Results were visualized by autoradiography.

Results The karyotype showed a small supernumerary marker chromosome (Fig. 2A) that stained positive with silver. This extra structurally abnormal chromosome exhibited positive fluorescence with the centromeric probe D14Z1/D22Z1, giving a smaller signal than those on the normal 14 and 22 pericentromeric regions. The marker was negative with probe D15Z1. There was a small signal in the centromeric region with the painting probes wcp14 and wcp22 (equivalent to that with probe D14Z1/D22Z1)1, but no signal on any other part of the marker chromosome—thus suggesting that few if any unique sequences are present. The DNA studies (Fig. 2C) revealed biparental inheritance for one microsatellite marker (D14S550) derived from chromosome 14 and two microsatellite markers (D22S283 and D22S691) derived from chromosome 22. Three markers (D14S256, D14S420, and D22S685) were uninformative. D22S283 derived from the chromosome 22p region demonstrated polymorphisms 4, 2, and 1 in the patient, 4 and 2 in the

1 Vysis whole chromosome painting (wcp) probes include centromeric sequences so that chromosome painting by wcp14 and wcp22 probably yielded the same results as FISH using D14Z1/D22Z1.

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Fig. 2. (A) G-banded karyotype of the patient (arrow points to marker). (B) FISH analysis with probe D14Z1/D22Z1 (arrow points to marker). (C) Polyacrylamide gels showing maternal (mat), proband (prob), and paternal (pat) contributions for six different microsatellite markers (three for chromosome 14 and three for chromosome 22). Polymorphisms for each marker are numerically identified by size.

father, and 3 and 1 in the mother. The results indicate that the patient has an extra copy of a marker in the 22p region that is derived from her father. Discussion Costovertebral dysplasia (CVD), also known as spondylocostal or spondylothoracic dysostosis, involves variable changes of the chest and ribs that likely derive from primary malformation of the thoracic spine. CVD can occur alone with autosomal dominant inheritance (MIM #122600) (Rimoin et al., 1968) and with few accompanying features in the autosomal recessive Jarcho – Levin syndrome (MIM #277300) (Karnes et al., 1991). Other conditions with CVD include the Jeune syndrome of asphyxiating thoracic dystrophy with other skeletal, biliary, and cardiac anomalies (MIM #208500) (Yang et al., 1987), thoracopelvic dysostosis or Barnes syndrome with

laryngeal changes (MIM #187770) (Burn et al., 1986), spondylocostal dystostosis with anal atresia and urogenital anomalies (MIM #271520) (Casamassima et al., 1981), thoracomelic dysplasia with pelvic and radial anomalies (MIM #273740) (Rivera et al., 1988), cerebrofaciothoracic dysplasia with anomalies of the septum pellucidum and cerebral ventricles (MIM #213980) (Guion-Almeida et al., 1996), and the thoracic dysplasia – hydrocephalus syndrome with hydrocephalus and short limbs (MIM #273730) (Winter et al., 1987). Our patient has CVD with cor triatriatum and subtle facial changes, a pattern different from the intrauterine growth retardation, cardiac, urogenital, and other skeletal defects seen with partial trisomy 22 syndromes (de Beaufort et al., 2000; Tinkle et al., 2003). Genomic imprinting was also eliminated as a mechanism for anomalies in our patient by demonstrating biparental inheritance of chromosomes 14 and 22. Full and partial trisomy 22 can be associated with diaphragmatic hernia

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and heart defects, anomalies that are also associated with CVD (Burn et al., 1986; Casamassima et al., 1981; Rivera et al., 1988; Guion-Almeida et al., 1996; Winter et al., 1987). Although microsatellite results show probable derivation of our marker from a paternal chromosome 22, the more limited and specific phenotype in our patient suggests that pericentromeric sequences from chromosomes 14 and 22 or ubiquitous to acrocentric pericentromeric regions may be present and include regulatory factors that influence a gene that is critical for the development of the axial skeleton. The trisomy of pericentromeric 22 material in our patient, along with known homology of pericentromeric regions of chromosomes 14 and 22 (Bailey et al., 2002), suggests that the D/D or D/G chromosome translocations observed previously (Turpin et al., 1959; de Grouchy and Mlynarski, 1963) were 14/14 and 14/22 translocations or involved similar homologous sequences. Chromosome 22 contains several duplicated segments, among them a 400 kb pericentromeric region that is homologous to that on chromosome 14 (Bailey et al., 2002). Although euchromatic sequences are infrequent in these pericentromeric regions, several novel genes have been created by these duplicated/rearranged segments, some sufficiently recent that they are transcribed in humans and gorillas but not in orangutans (Bailey et al., 2002). It is possible that more than one acrocentric chromosome may have pericentromeric genes that regulate costovertebral development. It is of interest to note that a locus for Jeune syndrome was recently mapped to chromosome 15q13 (Morgan et al., 2003). Our patient and the aforementioned translocations found by others raise the intriguing question whether pericentromeric duplications, deficiencies, or even balanced rearrangements of certain pericentromeric sequences of acrocentric chromosomes have a role in CVD and possibly represent one of several causes of CVD, which occurs in many syndromes. Additional case studies will be needed to confirm or refute the hypothesis of an association of CVD with our cytogenetic and molecular findings. Acknowledgments The authors express gratitude to the patient’s family for their support during this investigation. Our thanks also go to Chyrel Chumbley, Genetics Coordinator, Texas Tech University Health Sciences Center, Lubbock, TX. We also thank the laboratory staff of the Cytogenetic Laboratories and the laboratory staff of the Molecular Diagnostics Laboratory at the Center for Human Genetics, Boston University School of Medicine, as well as staff of Clinical Cytogenetics and Medical Genetics, Texas Tech University Health Sciences Center for their contributions to this study.

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