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

of 5/5
RESEARCH LETTER Cone-Rod Dystrophy, Growth Hormone Deficiency and Spondyloepiphyseal Dysplasia: Report of a New Case Without Nephronophtisis Bertrand Isidor, 1 Martine Le Merrer, 2 Emmanuelle Ramos, 3 Sabine Baron, 3 and Albert David 1 * 1 Clinical Genetic Department, Nantes University Hospital, Nantes, France 2 Clinical Genetic Department, Necker Hospital, Paris, France 3 Pediatric 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 RHYNS syndrome (OMIM 602152). Our patient does not show any 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 34 cm (1 SD). He required a 2 weeks’ hospitalization in a neonatal intensive 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 (þ0.5 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 concentrations were 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 pigmented maculae, with mild constriction *Correspondence to: Dr. Albert David, Service de Genetique Medicale, Centre Hospitalier Universitaire de Nantes, 7, quai Moncousu, 44093 Nantes Cedex, France. E-mail: [email protected] Published online 13 May 2008 in Wiley InterScience (www.interscience.wiley.com) 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 nephronophtisis. Am J Med Genet Part A 149A:788792. Ó 2008 Wiley-Liss, Inc. 788

Post on 06-Jun-2016

241 views

Category:

Documents

0 download

Embed Size (px)

TRANSCRIPT

  • RESEARCH LETTER

    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

    *Correspondence to:

    Dr. Albert David, Service de Genetique Medicale, Centre HospitalierUniversitaire de Nantes, 7, quai Moncousu, 44093 Nantes Cedex, France.

    E-mail: [email protected]

    Published online 13 May 2008 in Wiley InterScience

    (www.interscience.wiley.com)

    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

    nephronophtisis.

    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.

    [2004].

    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.

    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 cone-shaped epiphyses in the distal andmiddle

    phalanges were also absent (Fig. 4).

    The associationof retinal degeneration andbonedysplasiamight

    be attributed to dysfunctional primary cilia. The cilium is an

    evolutionarily conserved subcellular organelle, present at the sur-

    face of many eukaryotic cells in vertebrates, including kidney and

    endothelial cells, myocardial cells, odontoblasts, retinal photore-

    ceptor cells and cortex and hypothalamus. Defects in themolecular

    components of cilia are associated with a variety of human dis-

    orders, including cystic kidney disease, retinitis pigmentosa like

    Bardet-Biedl syndrome and Jeune asphyxiating thoracic dystrophy

    [Badano et al., 2006; Beales et al., 2007]. The pleiotropic distribu-

    tion of the ciliummight therefore explain the association of retinal

    dystrophy, hypophysis degeneration, and the bone dysplasia ob-

    served in this syndrome.

    In conclusion, we report on a boy with cone-rod dystrophy,

    growth hormone deficiency and spondyloepiphyseal dysplasia.

    This could be a new syndrome but as renal involvement can appear

    with age and has not always been reported with RHYNS syndrome,

    this syndrome cannot be definitively ruled out.

    REFERENCES

    Badano JL, Mitsuma N, Beales PL, Katsanis N. 2006. The ciliopathies: Anemerging class of human genetic disorders. Annu Rev Genom HumGenet 7:125148.

    Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, PearsonCG,KaiM,Hartley J, JohnsonC, IrvingM,ElciogluN,WineyM,TadaM,Scambler PJ. 2007. IFT80, which encodes a conserved intraflagellartransport protein, is mutated in Jeune asphyxiating thoracic dystrophy.Nat Genet 39:727729.

    Bianchi C, Barera G, Picciotti M, Barbiano di Belgioioso G, Bellini F. 1988.Juvenile nephronophthisis associated with new skeletal abnormalities,tapetoretinal degeneration and liver fibrosis. Helv Paediat Acta 43:449455.

    Di RoccoM, Picco P, Arslanian A, RestagnoG, Perfumo F, BuoncompagniA, GattornoM, Borrone C. 1997. Retinitis pigmentosa, hypopituitarism,nephronophthisis, and mild skeletal dysplasia (RHYNS): A new syn-drome? Am J Med Genet 73:14.

    GiedionA. 1979. Phalangeal cone shaped epiphysis of the hands (PhCSEH)and chronic renal disease: The conorenal syndromes. Pediat Radiol8:3238.

    Hedera P, Gorski JL. 2001. Retinitis pigmentosa, growth hormone defi-ciency, and acromelic skeletal dysplasia in two brothers: Possible familialRHYNS syndrome. Am J Med Genet 101:142145.

    LowryRB,WoodBJ. 1975. Syndromeof epiphyseal dysplasia, short stature,microcephaly and nystagmus. Clin Genet 8:269274.

    TABLE I. Clinical Comparison Between Our Patients and Other Syndromes With Retinitis Pigmentosa and Skeletal Dysplasia

    RHYNS

    Walters

    et al.

    [2004]

    Megarbane

    et al.

    [2004]

    Megarbane

    et al.

    [2006]

    MainzerSaldino

    syndrome

    LowryWood

    syndrome

    Present

    case

    Short stature , Rhizomelia Brachydactyly Nystagmus Retinitis pigmentosa Ptosis or enophtalmia Scoliosis Bowing of bones Metaphyseal abnormalities Epiphyseal abnormalities , (cone-shaped

    epiphysis)

    Bone age Retarded Normal Advanced Normal ? Retarded Retarded

    Abnormal vertebral bodies Renal failure or nephronophtisis / Growth hormone deficiency Mental retardation Deafness , Ptosis , Cerebellar ataxia Transmission AR? X-linked? AR AR? AR AR? AR Sporadic

    present; absent; , inconstant.

    ISIDOR ET AL. 791

  • Lowry RB, Wood BJ, Cox TA, Hayden MR. 1989. Epiphyseal dysplasia,microcephaly, nystagmus, and retinitis pigmentosa. Am J Med Genet33:341345.

    Mainzer F, Saldino RM, Ozonoff MB,Minagi H. 1970. Familial nephropa-thy associated with retinitis pigmentosa, cerebellar ataxia and skeletalabnormalities. Am J Med Genet 49:556562.

    Megarbane A, Melick N, Daou L. 2004. A newly recognized skeletaldysplasia with rhizomelic limbs and retinitis pigmentosa. Am J MedGenet Part A 130A:176180.

    Megarbane A, Ghanem I, Waked N, Dagher F. 2006. A newly recognizedautosomal recessive syndrome with short stature and oculo-skeletalinvolvement. Am J Med Genet Part A 140A:14911496.

    Nevin NC, Thomas PS, Hutchinson J. 1986. Syndrome of shortstature, microcephaly, mental retardation, and multiple epiphysealdysplasiaLowryWood syndrome. Am J Med Genet 24:3339.

    Walters BA, RaffML, Hoeve JV, Tesser R, Langer LO, France TD, Glass IA,Pauli RM. 2004. Spondylometaphyseal dysplasia with cone-rod dystro-phy. Am J Med Genet Part A 129A:265276.

    792 AMERICAN JOURNAL OF MEDICAL GENETICS PART A