close

Вход

Забыли?

вход по аккаунту

?

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: cmagnani@unipr.it
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. [1989]. 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 [1984] 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. [1986] 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.
Am J Med Genet 118A:68–70.
Greulich WW, Pyle SI. 1984. Radiographic atlas of skeletal development of
the hand and wrist. Stanford California: Stanford University Press.
Hall JG, Froster-Iskenius UG, Allanson JE. 1989. Handbook of normal
physical measurements. New York: Oxford University Press.
Hankenson LG, Ozonoff MB, Cassidy SB. 1989. Epiphyseal dysplasia with
coxa vara, microcephaly, and normal intelligence in sibs: Expanded
spectrum of Lowry-Wood syndrome? Am J Med Genet 33:336–340.
Lowry RB, Wood BJ. 1975. Syndrome of epiphyseal dysplasia, short stature,
microcephaly and nystagmus. Clin Genet 8:269–274.
Lowry RB, Wood BJ, Cox TA, Hayden MR. 1989. Epiphyseal dysplasia,
microcephaly, nystagmus, and retinitis pigmentosa. Am J Med Genet
33:341–345.
Makitie O, Savarirayan R, Bonafe L, Robertson S, Susic M, Superti-Furga A,
Cole WG. 2003. Autosomal recessive multiple epiphyseal dysplasia with
homozygosity for C653S in the DTDST gene: Double-layer patella as a
reliable sign. Am J Med Genet Part A 122A:187–192.
Marmor MF, Holder GR, Seeliger MW, Yamamoto S. 2004. Standard for
clinical electroretinography. Doc Ophthalmol 108:107–111.
Nevin NC, Thomas PS, Hutchinson J. 1986. Syndrome of short stature,
microcephaly, mental retardation, and multiple epiphyseal dysplasia—
Lowry-Wood Syndrome. Am J Med Genet 24:33–39.
Popovic P, Jarc-Vidmar M, Hawlina M. 2005. Abnormal fundus autofluorescence in relation to retinal function in patients with retinitis
pigmentosa. Graefes Arch Clin Exp Ophthalmol Oct 243:1018–1027.
Sigaudy S, Toutain A, Moncla A, Fredouille C, Bourliere B, Ayme S, Philip
N. 1998. Microcephalic osteodysplastic primordial dwarfism TaybiLinder type: Report of four cases and review of the literature. Am J Med
Genet 80:16–24.
REFERENCES
Tanner JM, Whitehouse RH. 1976. Clinical longitudinal standards for
height, weight, height velocity. Arch Dis Child 51:170–179.
Armstrong L, Clarke JTR. 2002. Report of a new case of ‘‘genitopatellar’’
syndrome which challenges the importance of absent patellae as a definite
feature. J Med Genet 39:933–934.
Yamamoto T, Tohyama J, Koeda T, Maegaki Y, Takahashi Y. 1995. Multiple
epiphyseal dysplasia with small head, congenital nystagmus, hypoplasia
of corpus callosum, and leokonychia totalis: A variant of Lowry-Wood
syndrome ? Am J Med Genet 56:6–9.
Документ
Категория
Без категории
Просмотров
1
Размер файла
603 Кб
Теги
skeletal, syndrome, dislocation, joint, additional, multiple, findings, lowryтауwood
1/--страниц
Пожаловаться на содержимое документа