cone-rod dystrophy, growth hormone deficiency and spondyloepiphyseal dysplasia: report of a new case...

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    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


    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

    *Correspondence to:

    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


    DOI 10.1002/ajmg.a.32343

    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. [1988] 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. [1988] with

    nephronophtisis was reported by Di Rocco et al. [1997] 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 [2001] 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. [2004]. 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

    was observed.

    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.


  • 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


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