Multiple joint dislocations An additional skeletal finding in LowryтАУWood syndrome.код для вставкиСкачать
CLINICAL REPORT Multiple Joint Dislocations: An Additional Skeletal Finding in Lowry–Wood Syndrome? Cinzia Magnani,1* Salvatore Antonio Tedesco,2 Sara Dallaglio,1 Marcello Sommi,1 Ermanno Bacchini,3 Annalisa Vetro,4 Orsetta Zuffardi,4,5 and Giulio Bevilacqua1 1 Department of Pediatrics, University Hospital, Parma, Italy Department of Ophthalmology, University Hospital, Parma, Italy 2 3 Department of Radiology, University Hospital, Parma, Italy 4 Department of Medical Genetics, Pavia University, Pavia, Italy IRCCS Foundation, San Matteo Hospital, Pavia, Italy 5 Received 23 July 2007; Accepted 7 January 2009 We report on the case of a 17-year-old boy with clinical features compatible with Lowry–Wood syndrome: microcephaly, short stature, multiple epiphyseal dysplasia, tapetoretinal degeneration, and mental retardation. Bilateral restricted elbow extension, knock knees and hip dislocation were also present. Radiographs showed evidence of radial dislocation due to the absence of the radial heads, lateral dislocation of both patellae, multiple epiphyseal dysplasia that was more severe at the proximal femoral epiphyses, and dislocation of both hips with severe hip dysplasia. The patient developed a behavioral disorder at age 15. Conventional karyotyping was normal (46,XY). Molecular karyotyping, performed through array-based competitive genomic hybridization, showed copy number variants that were probably benign. We suggest that multiple joint dislocations, including the patellae, may be a sign of Lowry–Wood syndrome. How to Cite this Article: Magnani C, Tedesco SA, Dallaglio S, Sommi M, Bacchini E, Vetro A, Zuffardi O, Bevilacqua G. 2009. Multiple joint dislocations: An additional skeletal finding in Lowry–Wood syndrome? Am J Med Genet Part A 149A:737–741. mental retardation, and multiple joint dislocations that included elbows (due to bilateral absence of the radial heads), hips, knees, and patellae, resulting in impaired walking. Ó 2009 Wiley-Liss, Inc. CLINICAL REPORT Key words: Lowry–Wood syndrome; microcephaly; multiple The patient, the only child of an unrelated healthy couple, was delivered at the 35th week of gestation by cesarean because of intrauterine growth retardation. At birth the baby weighed 1,480 g, was 39 cm long and had a head circumference of 27 cm. All growth parameters, including head circumference, were below the 3rd centile. Sparse hair was also present all over his body at birth. During the first month of life, the head circumference progressively departed from the 3rd centile. At week 38 from conception, the distal femoral epiphyses were still absent. No other abnormalities were found on skeletal survey and on abdominal, cardiac and cerebral ultrasound. Prenatal infections (rubella, cytomegalovirus, toxoplasmosis) were excluded. epiphyseal dysplasia; multiple joint dislocations INTRODUCTION A combination of epiphyseal dysplasia and microcephaly characterizes Lowry–Wood syndrome (OMIM#226960), a rare condition in which mental retardation, congenital nystagmus and retinitis pigmentosa may also be present in various degrees [Hankenson et al., 1989; Brunetti-Pierri et al., 2003]. Restricted elbow extension, hip dislocation, and knock knees with walking impairment have been reported in patients with this condition [Lowry et al., 1989; Hankenson et al., 1989; Yamamoto et al., 1995]. However, to date, less than 10 patients with Lowry–Wood syndrome have been described in the literature. Any new case description may help to further elucidate the clinical features of this condition. We report on the case of a patient with multiple epiphyseal dysplasia, tapetoretinal degeneration, small head associated with Ó 2009 Wiley-Liss, Inc. *Correspondence to: Cinzia Magnani, Department of Pediatrics, University Hospital, Via Gramsci, 14-43100 Parma, Italy. E-mail: firstname.lastname@example.org Published online 13 March 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.32773 737 738 AMERICAN JOURNAL OF MEDICAL GENETICS PART A FIG. 1. A: Elbow radiograph, age 4. Agenesis or severe hypoplasia of the radial heads and radial dislocation can be noted. B: Hand radiograph, age 17 years, 5 months. Bone age corresponds to age 14. The apparent shortness of the 5th right metacarpal bone is due to a recent traumatic fracture. At 18 months, the patient had problems making his first steps, with frequent falls due to severely knocked knees (genu valgum). Since age 2, he has been wearing leg braces to walk. At age 4, a knee radiograph confirmed evidence of knock knees and severe hypoplasia of the distal femoral and proximal tibial epiphyses as well as laterally dislocated small patellae. Pelvic radiograph revealed the presence of hypoplastic and fragmented proximal femoral epiphyses. At age 5, an elbow radiograph was performed because of restricted movements of both elbows and wrists. The radiograph showed agenesis of the radial heads with bilateral radial dislocation (Fig. 1A). Radiological signs progressively deteriorated over the following years. Skeletal surveys performed when the boy was 9 and 11, respectively, revealed severe hip dysplasia with dislocation of both femoral heads, flattened and fragmented proximal femoral epiphyses, partial knee joint dislocation, prominent medial femoral condyles, and hypoplasia of the lateral femoral condyles (Fig. 2A,B). A spine radiograph did not reveal any abnormalities (Fig. 3). The boy’s picture is shown in Figure 4. After four surgical procedures to correct knock knees and patella dislocation, the patient was seen again at age 17. He weighed 45 kg FIG. 2. A: Pelvis radiograph, age 9. The epiphyses are markedly flattened and fragmented, the femoral necks are short and broad. B: Knee radiograph, age 9. Knock knees (genu valgum), hypoplasia of the distal femoral and proximal tibial epiphyses, and laterally dislocated small patellae can be noted. FIG. 3. Anteroposterior/lateral spine radiograph, age 9. Platyspondyly is absent. (<3rd centile), was 145 cm tall (<3rd centile), and had a head circumference of 48 cm (<3rd centile). Figure 5 shows height and head circumference growth over the years [Tanner and Whitehouse, 1976]. Arm span was 126 cm, but this measurement could not be performed accurately because of restricted elbow extension. Sitting height was 78 cm (<1 standard deviation), forearm length was 23 cm (5th–10th centile), and hand length was 16.5 cm (<3rd centile) according to Hall et al. . The boy had a small head, upslanting palpebral fissures, thick lips, and crowded and twisted teeth. The hair was thin. Elbow extension and forearm supination were incomplete. Bone age determined according to Greulich and Pyle  was delayed (14 years at 17 years, 4 months). The apparent shortness of the 5th metacarpal bone of the right hand was due to a recent traumatic fracture (Fig. 1B). Both knees retained excessive mobility in the frontal plane, the patellae were hypermobile, and the hips showed restricted abduction due to retraction of both long adductors. A procedure of adductor tenotomy was planned. Reportedly, the patient had trouble seeing in the dark. The ophthalmological examination showed astigmatism requiring lens correction. Due to the patient’s aversion to light during standard fundus examination, imaging was performed using the Heidelberg Retina Angiograph (HRA) system. The acquired infrared images allowed fundus description. The fundus of both eyes presented none of the ‘‘typical’’ pigmentary changes that are usually associated with retinitis pigmentosa, but there were significant signs of diffuse tapetoretinal degeneration, such as attenuation of retinal MAGNANI ET AL. 739 vessels, a pale optic disk, and mild chorioretinal atrophy [Popovic et al., 2005]. The periphery of the fundus was essentially normal. Full-field flash electroretinography (ERG), performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard using HK-loop electrodes and an Espion system (Diagnosys UK, Cambridge, UK), revealed reduced amplitude responses (‘‘a’’ and ‘‘b’’ waves) for scotopic (rod, rod-cone and oscillatory potentials) and photopic conditions (50 cone, 32-Hz flicker), with no differences and/or asymmetry between the right and the left eye [Marmor et al., 2004]. During the examination the patient showed significant photophobia. ERG responses confirmed a reduced photoreceptor and internal retinal function. The patient was mentally retarded and entitled to special school education. At age 15, he displayed aggressive behavior and was admitted to an educational community. Laboratory tests (immunoglobulins, thyroid hormones, serum calcium, phosphate, alkaline phosphatase) were in the normal range. Results from metabolic screening tests and chromosome analysis (46,XY) were also normal. METHODS DNA was extracted from the patient’s peripheral blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Molecular karyotyping was performed through array-based competitive genomic hybridization (array-CGH) using the Human Genome CGH Microarray Kit 244A (Agilent, Santa Clara, CA) according to the manufacturer’s protocol. This platform is a 60mer oligonucleotide-based microarray that allows genome-wide survey and molecular profiling of genomic aberrations with an average resolution of about 20 kb. The array was analyzed through an Agilent scanner using Agilent’s Features Extraction software (v9.1). A graphical overview was obtained using Agilent’s CGH Analytics Software (v3.4.27) based on the Build 35 genome assembly of May 2004 (hg 17). RESULTS The analysis revealed six small deletions/duplications ranging from 43 to 250 kb, which were all reported in the Database of Genomic Variants (http://projects.tcag.ca/variation/, Build 36 genome assembly) as common variants in a control population. The complete list of these copy number variants (CNV) is reported in Table I. DISCUSSION FIG. 4. The patient at age 12 years, 8 months. As can be noted, the head is small and elbow extension is limited. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] In our patient, the presence of microcephaly, tapetoretinal degeneration and multiple epiphyseal dysplasia suggested a diagnosis of Lowry–Wood syndrome, a rare condition first described by Lowry in two brothers who shared several clinical signs with this patient, especially on the skeletal level [Lowry and Wood, 1975; Lowry et al., 1989]. In the two brothers, the authors reported restricted elbow extension and restricted forearm supination, with the younger brother also showing radiological evidence of bilateral dislocated radial heads. Similar clinical findings due to posterior radial head dislocation associated with radial hypoplasia were described in 740 AMERICAN JOURNAL OF MEDICAL GENETICS PART A FIG. 5. Linear growth and head circumferences from age 1 to 17. another patient affected by Lowry–Wood syndrome [Hankenson et al., 1989]. Our patient had restricted elbow extension associated with agenesis or severe hypoplasia of the radial heads, resulting in abnormal joint relation and, consequently, in a functional defect of the elbow joint. The knee joint was also involved in one of Lowry’s patients, who had knock knees defined as progressive by the authors and treated surgically [Lowry et al., 1989]. The symptoms seem to be similar to those seen in our patient, who had unstable knock knees and lateral patella dislocation and had to undergo repeated surgery in order to walk. Significant knee involvement was also reported by other authors [Yamamoto et al., 1995]. Yamamoto’s patient was defined as knock-kneed by the authors; he often fell when he started to walk and wore leg braces for walking. Knock knees and the use of leg braces were also reported in one of Hankenson’s patients [Hankenson et al., 1989]. Our patient had lateral patella dislocation bilaterally, a feature that has never been reported before in Lowry–Wood syndrome. Patella dislocation has been occasionally described in multiple epiphyseal dysplasia and in knock knees; in this particular case, it might be part of a more general joint dysplasia [Makitie et al., 2003]. The hip joint was also involved in our patient, who had severe hip dysplasia with limited hip function, particularly abduction. Hip dislocation and subluxation have been reported by other authors in patients that underwent surgical procedures [Lowry et al., 1989; Hankenson et al., 1989]. A late and dysplastic development of the epiphyses may cause abnormal joint relations and susceptibility to joint dislocations in Lowry–Wood syndrome. Our patient also had eye symptoms, which were characterized by tapetoretinal degeneration with attenuation of retinal vessels and chorioretinal atrophy. This feature, detected for the first time when the boy was 13, is likely to be a late symptom arising during adolescence, as also happened in the case of the two brothers first described in the literature [Lowry et al., 1989]. Finally, over the years our patient showed behavioral worsening. He became very aggressive and eventually had to be admitted to an TABLE I. CNVs and Relative Genomic Position Found in the Proband Type of rearrangement Gain Loss Loss Gain Loss Gain a Cytoband 3q26.1 8p11.22 16q22.1 17q21.31 22q11.23 22q11.23 The position includes the first and the last abnormal oligomer. Size (kb) 100 150 43 45 43 250 Position (referred to build 36)a chr3:163,997,255–164,101,776 chr8:39,356,595–39,511,632 chr16:68,710,277–68,754,234 chr17:41,521,544–41,566,540 chr22:22,681,995–22,725,305 chr22:23,984,069–24,233,484 MAGNANI ET AL. educational community. This symptom has never been reported before and it could be an occasional finding in a patient with microcephaly and mental retardation. Array-CGH analysis, never before carried out in patients with Lowry–Wood, showed CNVs that were probably benign. ArrayCGH results indicate that imbalances exceeding 20 kb are not responsible for the patient’s phenotype and suggest a single gene disorder. Nevin et al.  already advanced the hypothesis of autosomal recessive inheritance. More recently, mutations of the hypothetical LWS gene or contiguous gene disruption have been suggested as a possible cause of the disorder [Brunetti-Pierri et al., 2003]. There are a number of other conditions that have features similar to our patient’s symptoms. In particular, we considered differential diagnosis with Taybi–Linder and genitopatellar syndromes. Taybi–Linder syndrome is also characterized by microcephaly, short stature, multiple joint dislocations, and neonatal sparse hair; however, the high mortality rate, early enlarged metaphyses and platyspondyly reported in this condition were not present in our patient [Sigaudy et al., 1998]. As to genitopatellar syndrome, dislocated or abnormal patellae, dislocated hips, contractures involving the knees and the elbows in addition to microcephaly have all been described in this condition, but the absence of genital and renal abnormalities made such diagnosis less likely [Armstrong and Clarke, 2002]. We assume that our patient may suffer from Lowry–Wood syndrome and that severe hypoplasia/agenesis of the radial heads and multiple joint dislocations (of elbows, hips, and knees including the patellae) might be additional signs of this syndrome. 741 Brunetti-Pierri N, De Brasi D, Ikegawa S, Camera G, Andria G, Sebastio G. 2003. A new patient with Lowry-Wood syndrome with mild phenotype. 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