cone-rod dystrophy, growth hormone deficiency and spondyloepiphyseal dysplasia: report of a new case...
Post on 06-Jun-2016
Embed Size (px)
Cone-Rod Dystrophy, Growth Hormone Deficiencyand Spondyloepiphyseal Dysplasia:Report of a New Case Without NephronophtisisBertrand Isidor,1 Martine Le Merrer,2 Emmanuelle Ramos,3 Sabine Baron,3 and Albert David1*1Clinical Genetic Department, Nantes University Hospital, Nantes, France2Clinical Genetic Department, Necker Hospital, Paris, France3Pediatric Endocrinology Department, Nantes University Hospital, Nantes, France
Received 20 October 2007; Accepted 6 March 2008
TO THE EDITOR:
The association of retinitis pigmentosa (RP) and skeletal dysplasia
is rare and has been reported in few syndromes. Here, we describe a
new patient presenting an unusual combination of retinitis
pigmentosa (RP), postnatal short stature secondary to growth
hormone deficiency and spondyloepiphyseal dysplasia. The com-
bination of retinitis pigmentosa, hypopituitarism, nephronophti-
sis, and skeletal dysplasia has been reported previously and named
RHYNSsyndrome(OMIM602152).Ourpatient doesnot showany
renal involvement and skeletal findings are different.
The proposita is the second child of healthy nonconsanguineous
parents. Pregnancy was complicated by late hydramnios. APGAR
scores were reported as 6 and 8 at 1 and 5 min, respectively. Birth
weight was 2,420 g (3 SD), length 47 cm (1.5 SD), and OFC 34cm (1 SD). He required a 2 weeks hospitalization in a neonatalintensive care unit for hypotonia with poor feeding. Exams per-
formed at this time including transfontanellar echography and
lumbar punction, were normal. Optical Fundus examination
showed a pale retina. Control examination at 1 month was said
to be normal.
At 5 years 3 months, he was evaluated for short stature. The
height was 97.5 cm (3 SD) with normal OFC 50.5 cm (0.5 SD).Physical examination showed facial telangiectasy on the forehead
and eyelids, bilateral cryptorchidism, facial and truncal obesity and
short fingers and toes. Cryptorchidism required surgical interven-
tion at age of 9 years old.
Radiological examination at age 5 years 6 months old showed
abnormal development of the epiphyses. Proximal femoral epiph-
yses were flattened, irregular, and fragmented (Fig. 1). Mature
radiographs at age 14 years old showed that the shape of the femoral
head was flattened and ovoid; femoral necks were also abnormally
irregular, short and thick (Fig. 2). The epiphyseal development of
the distal femur, radius and ulna was consistently abnormal with
small and abnormally shaped secondary ossification centers
(Fig. 3). Carpal bone development was delayed. However, the
carpal bones together with the epiphyses of all metacarpals and
phalanges were relatively normal in size, shape, and contour
(Fig. 4). Vertebral bodies tended to have initially normal shape,
although slight vertebral anomalies as discretely ovoid vertebral
bodies could initially be observed. Spine abnormalities worsened
with time as vertebral bodies at age 10 showed slightly reduced
height, with irregular oval shape and anterior swelling (Fig. 5).
At age 6 years, an endocrine evaluation was also performed.
Growth hormone (GH) response to glucagon and Kerlone was
severely impaired (maximum peak 5.9 ng/ml) with low IGF1
plasma concentration: 38 ng/ml (N: 70885 ng/ml). Cortisol, LH,FSH,TSH,T4 and testosterone plasma concentrationswere normal
for prebubertal age. Biological exams (electrolytes, calcium, phos-
phorus, lactates, pyruvate, ammonium, blood gas, hepatic liver
enzymes), cardiac and abdominal echographies were normal.
Cerebral MRI showed a normal pituitary tract and hypophysis.
Karyotype was also normal: 46,XY. Replacement treatment with
biosynthetic hGH was started at the age of 10 years 9 months with
doses starting from 4.5 U/kg/week.
The patient began to complain of hemeralopia and photophobia
at 6 years of age. Ophthalmologic examination showed a decreased
visual acuity of 6/10 OD and OS. Ophtalmoscopy showed a pale
papillae and irregularly pigmentedmaculae, withmild constriction
Dr. Albert David, Service de Genetique Medicale, Centre HospitalierUniversitaire de Nantes, 7, quai Moncousu, 44093 Nantes Cedex, France.
Published online 13 May 2008 in Wiley InterScience
How to Cite this Article:Isidor B, Le Merrer M, Ramos E, Baron S,
David A. 2009. Cone-rod dystrophy, growth
hormone deficiency and spondyloepiphyseal
dysplasia: Report of a new case without
Am J Med Genet Part A 149A:788792.
2008 Wiley-Liss, Inc. 788
of the retinal vasculature. Goldman visual fields showed impaired
peripheral vision with annular peripheric scotome of 1530.In both eyes, electrophysiologic retinal testing (ERG) was almost
extinguished; rod responsesweremore than 95%reduced, and cone
response was 95% reduced. Control examination at 11 years of age
showed moderate astigmatic refractive error 1.5(1.25) 50OD and 1.25(0.75) 130 OS and a decreased visual acuity of3.2/10 OD and OS. ERG was completely extinguished in both eyes
and color vision assessment was also markedly abnormal.
In themost recent follow up, aged 17 years 3months, he was still
under GH therapy and his height was 164 cm (1.5 SD). He was
doing well in school. Neurological examination was normal, with-
out focal signs or cerebellar dysfunction. The last renal checkup at
age 18 years old was normal, showing normal renal sonography,
normal renal function (creatinine clearance 118.0 ml/min), andno proteinuria (
RHYNS (retinitis pigmentosa, hypopituitarism, nephronophti-
sis and skeletal dysplasia) syndrome also shares some common
features with those observed in our patient. This syndromewas first
described by Bianchi et al.  who described a boy with ptosis,
joint laxity, hypogenitalism, a retarded bone age and curved radii. A
case resembling the one reported by Bianchi et al.  with
nephronophtisis was reported by Di Rocco et al.  who
proposed the term of RHYNS syndrome. Radiographs showed
retardation of bone age, widespread osteopenia, epiphyseal hypo-
plasia, hypoplastic iliac boneswith irregular acetabularmargins and
thin tubular bones. Hedera andGorski  reported two further
cases with possible RHYNS syndrome but without renal involve-
ment. Description of the skeletal radiographic features of patients
reported with RHYNS syndrome are different from this patient for
whom no sign of renal involvement has ever been identified.
Another autosomal recessive syndrome with spondylometaphy-
seal dysplasia (SMD) and concomitant cone-rod dystrophy (CRD)
has been described by Walters et al. . Distinguishing SMD-
CRDfromother formsof SMDwere the absence of corner fractures,
vertebral bodies that were ovoid and distinctively abnormal, sever-
ity that was far less than in the Sedaghatian form of SMD (OMIM
250220), and absence of enchondromatous changes. Radiological
findings in our report consistedof epiphyseal dysplasiawith normal
metaphysis, vertebral bodies with normal size. The vertebral bodies
show platyspondyly, ovoid and flattening in the report of Walters
and colleagues. Furthermore, no growth hormone deficiency has
been observed in any of the eight cases described by Walters et al.
Other relevant conditions include the following:
In 2004, Megarbane et al. reported a girl with severe pre- and post-natal short stature, enlarged thorax, retinitis pigmentosa, pla-
tyspondyly, rhizomelic shortening of the long bones, bilateral
subluxation of the hips and advanced maturation of the epiph-
yses. The length was very severely impaired (3rd centile)compared to this report and no growth hormone deficiency
In 2006, Megarbane et al. described another patient, a girl and hercousin, presenting with postnatal short stature, retinitis pig-
mentosa, rhizomelic shortening of the long bones, short and
slightly bowed humeri with prominent deltoid tuberosities,
short and wide ribs and clavicles, severe dorso-lumbar scoliosis,
biconcave vertebral bodies of the thoraco-lumbar spine, and
narrowed lumbar canal. In addition, the girl showed amelo-
genesis imperfecta, and the radiographs showed short distal
ulnae, sloping epiphyses of the radii, short femoral necks, and
FIG. 4. Left hand radiography at age of 14 years 8 months showing
slight shortening of the metacarpals. The bone age was between
12 and 121/2 years old according to the male standard of Greulich
and Pyle. Note absent cone shaped epiphysis.
FIG. 5. Spine Radiography at age 10years. The vertebral bodies have
irregular oval shape and anterior swelling.
790 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
slightly flat uncovered femoral heads. Growth hormone defi-
ciency was not reported. In our report, there is no scoliosis, and
epiphyseal radiographics abnormalities are much different.
Another syndrome with retinal pigmentory dystrophy and
skeletal dysplasia is MainzerSaldino syndrome [Mainzer et al.,1970]. Patients reported with this syndrome also present renal
dysplasia and cerebellar ataxia which were absent in our case
[Mainzer et al., 1970; Giedion, 1979]. Furthermore, characteristic
skeletal features are