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 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: 70–885 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 G�en�etique M�edicale, Centre Hospitalier

Universitaire de Nantes, 7, quai Moncousu, 44093 Nantes Cedex, France.

E-mail: albert.david@chu-nantes.fr

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:788–792.

� 2008 Wiley-Liss, Inc. 788

of the retinal vasculature. Goldman visual fields showed impaired

peripheral vision with annular peripheric scotome of 15–30�.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)� 50�

OD and �1.25(�0.75)� 130� OS and a decreased visual acuity of

3.2/10 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 clearance¼ 118.0 ml/min), and

no proteinuria (<0.20 g/l).

The patient reported herein has a severe rod-cone retinal dys-

trophy, spondyloepiphyseal dysplasia, and growth hormone defi-

ciency. Intellectual development is normal despite mild motor

delay and no renal involvement has been observed.

A few syndromes have been reported with the association of

skeletal dysplasia and retinal dystrophy (Table I). In most of these

syndromes RP is associated with metaphyseal dysplasia. To our

knowledge, there is only one other syndrome, the Lowry–Wood

syndrome (LWS) [Lowry and Wood, 1975; Lowry et al., 1989]

having the association of epiphyseal dysplasia and RP. These

authors describe two brothers with epiphyseal dysplasia, micro-

cephaly, nystagmus andRP. Spine radiographieswere in the normal

range. Skeletal radiographies showed bowing of long bones and

epiphyseal anomalies with flat femoral condyles and tibial articular

surfaces. Both alsohad learningdifficulties.A further observationof

a brother and a sister was reported by Nevin et al. [1986]. They

concluded that LWS is likely an autosomal recessive inheritance. In

ourpatientnonystagmuswasobserved, nomicrocephaly (OFCwas

slightly elevated [OFC¼ 59.5cm (þ2.3 SD)] at 16 years old) was

present, intelligence was normal, and radiographic abnormalities

were different (Table I).

FIG. 1. Pelvis radiographic findings at age 5 years 6 months. The

proximal femoral epiphyses are flattened, irregular and

fragmented.

FIG. 2. Pelvis radiographic findings aged 14 years 8 months. The

proximal femoral epiphyses are flattened with broad and short

femoral necks.

FIG. 3. Knee epiphyses are small and irregular in contour.

ISIDOR ET AL. 789

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, M�egarban�e 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, M�egarban�e et al. described another patient, a girl and her

cousin, 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 Mainzer–Saldino 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 7:125–148.

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 39:727–729.

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 43:449–455.

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 73:1–4.

GiedionA. 1979. Phalangeal cone shaped epiphysis of the hands (PhCSEH)and chronic renal disease: The conorenal syndromes. Pediat Radiol8:32–38.

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 101:142–145.

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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]

Mainzer–Saldino

syndrome

Lowry–Wood

syndrome

Present

case

Short stature þ þþþ þþþ þþþ þ,� þ þRhizomelia þ þþ þþ þ � þ þBrachydactyly þ þ � � � � þNystagmus � þ þ þ � þ �Retinitis pigmentosa þ þ þ þ þ þ þPtosis or enophtalmia þ � � � � � �Scoliosis � þ � þþ � � �Bowing of bones � þþ � þ � þ �Metaphyseal abnormalities � þþþ þ þ þ � �Epiphyseal abnormalities þ þ,� þ þ þ (cone-shaped

epiphysis)

þþ þþ

Bone age Retarded Normal Advanced Normal ? Retarded Retarded

Abnormal vertebral bodies � þþ þ þ � � þRenal failure or nephronophtisis þ/� � � � þ � �Growth hormone deficiency þ � � � � � þMental retardation � � � � þ �Deafness þ,� � � � � � �Ptosis þ,� � � � � � �Cerebellar ataxia � � � � þ � �Transmission AR? X-linked? AR AR? AR AR? AR Sporadic

þ¼ present; �¼ absent; þ,�¼ inconstant.

ISIDOR ET AL. 791

Lowry RB, Wood BJ, Cox TA, Hayden MR. 1989. Epiphyseal dysplasia,microcephaly, nystagmus, and retinitis pigmentosa. Am J Med Genet33:341–345.

Mainzer F, Saldino RM, Ozonoff MB,Minagi H. 1970. Familial nephropa-thy associated with retinitis pigmentosa, cerebellar ataxia and skeletalabnormalities. Am J Med Genet 49:556–562.

Megarbane A, Melick N, Daou L. 2004. A newly recognized skeletaldysplasia with rhizomelic limbs and retinitis pigmentosa. Am J MedGenet Part A 130A:176–180.

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:1491–1496.

Nevin NC, Thomas PS, Hutchinson J. 1986. Syndrome of shortstature, microcephaly, mental retardation, and multiple epiphysealdysplasia—Lowry–Wood syndrome. Am J Med Genet 24:33–39.

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:265–276.

792 AMERICAN JOURNAL OF MEDICAL GENETICS PART A