Journal of Medical Genetics 1988, 25, 73-78

Norrie disease resulting from a gene deletion: clinicalfeatures and DNA studiesDIAN DONNAI, R C MOUNTFORD, AND A P READFrom the Department of Medical Genetics, St Mary's Hospital, Manchester M13 OJH.

SUMMARY We describe a family in which two boys with Norrie disease have a deletion of theDXS7 locus. The deletion does not extend as far distally as the OTC or DXS84 loci. A full clinicaldescription of the patients is given to help establish the range of manifestations of Norrie disease.There is no evidence of any other X linked disease in our patients.

Norrie disease (NDP, McKusick No 31060) wasoriginally described as X linked blindness.' It ischaracterised by early vascular proliferation(pseudoglioma) in both retinas, atrophic irides,corneal clouding, and cataracts, progressing toshrinkage of the globes (phthisis bulbi). The eyefindings are well described,25 but extraocularabnormalities are less commonly illustrated. Diag-nosis is usually made on ophthalmological criteria,but we believe that in many cases the disorder isrecognisable on general clinical examination.

Carriers have no visual or auditory signs and untilrecently counselling was based on pedigree analysisalone. A suggestion of linkage between the NDPlocus and the glucose 6 phosphate dehydrogenaselocus has not been substantiated. However, in 1985Gal et at reported close linkage between NDP andthe polymorphic X chromosomal locus DXS7 de-fined by the probe L1U28, which lies within or closeto band Xpll.3. This linkage has been confirmed.78In one of the seven families studied by Gal et al7there was a deletion of the DXS7 locus in anaffected boy and several female relatives. A secondNDP family with a deletion was reported by de laChapelle et al,9 who used the deletion for carrierdetection and prenatal diagnosis.We describe a family where two affected boys

have a deletion of the DXS7 locus, which we believeis only the third such family reported. In addition todescribing the DNA findings, we present detailedclinical descriptions and review published cases. Wehope this will help to establish the range of clinicalmanifestations of the NDP gene.

Case reportsV. 1 (FIG 1)V.1 was the first child born to healthy non-consan-Received for publication 25 June 1987Accepted for publication 17 July 1987

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guineous parents after a normal pregnancy. Deli-'-very was normal and his birth weight was 2-6 kg atterm. His mother noted that his eyes looked cloudyon the eighth day of life. After ophthalmic evalua-tion a diagnosis of primary hyperplastic vitreous wassuggested and his left eye was enucleated at 14months because of shrinkage, pain, and the possi-bility of a tumour. Developmental delay was ap-parent from six months but investigations at thattime did not identify the cause. He was referred tothe genetic clinic at two years nine months and forthe first time the family history of blind distant malerelatives was obtained (fig 1). On examination heweighed 8-1 kg (<3rd centile), length 80 cm (<3rdcentile), and OFC 44 cm (<3rd centile). There was aprosthetic left eye and the right eye was shrunkenwith cataract and corneal clouding. His nasal bridgewas narrow and his ears prominent with unfoldedhelices (fig 2). Reflexes were abnormally brisk in hisarms and legs and his tone was increased. He couldnot sit, crawl, or chew but could hold a cup.

HI2,1 2 _ .1456 789-11123

IV1 Pdge 3 4 5

vb41 2 3 4

FIG I Pedigree offamily.

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FIG 2 V.1 at two years nine months. Note sunken right eyewith cataract, prosthetic left eye, narrow nasal bridge, andprominent ears.

Auditory brain stem electric response test suggestedthat his hearing was normal, and an EEG showed nofocal abnormalities.

Histological examination of the left eye hadshown anterior synechiae, ectropion uveae, a catar-actous dislocated lens, and total retinal detachmentwith proliferation of the pigment epithelium forminga pseudo tumour. There was also mild lymphocyticinfiltration and the appearances were thought to besuggestive of intrauterine infection. However, aftera clinical diagnosis ofNDP was proposed, supportedby a possible family history, the microscopicalchanges were reviewed and considered compatiblewith this diagnosis.

His progress has been poor. His right eye wasenucleated because of pain at eight years. Twoseizures occurred but a repeat EEG was normal. Atnine years he can sit unsupported but has a posturalscoliosis, he feeds himself with a feeder cup andspoon, and he has learnt a little sign language. Heshows pleasure at the sound of his mother's voiceand at her touch. He constantly grinds his teeth,thrusts his jaw, chews his fist, and scratches his skin.He is very thin with poor muscle bulk and coldextremities. His facial features are fine and his earslarge and prominent. Length is 102 cm (<3rdcentile) and OFC 46-6 cm (<3rd centile) (figs 3 and4). His testes are undescended.

v. 2 AND v. 3The normal four year old brother and two and a halfyear old sister of the proband have no visual,auditory, or developmental problems.

v.4He was born at 38 weeks' gestation after a normal

FIG 3 V. 1 at nine years. Note narrow nasal bridge,flattened malar region, and thin upper lip.

FIG 4 V.1 at nine years. Notepoor muscle bulk.

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Norrie disease resultingfrom a gene deletion: clinicalfeatures and DNA studies

pregnancy; birth weight was 2*98 kg, OFC 35 cm.His physical resemblance to V.1 was noted by hismother and she suspected eye problems within twoweeks of birth. Examination under anaesthetic atone month showed that the right anterior chamberwas totally flat with increased vascularisation; theleft pupil was dilated and unresponsive with a denseretrolental membrane. At that time intraocularpressures were normal and neither eye was small.He made extremely slow progress and by ninemonths could make a range of sounds and hold anobject placed in his hand. He was floppy and hadpoor head control but did appear to respond tohandling by his parents.When examined at 17 months his weight was only

5*92 kg (<3rd centile) and he was severely wasted(fig 5). He was facially similar to V.1 and dissimilarto V.2 and V.3. His nose was narrow, his malar areaflat, and his ears large. The left eye was enophthal-mic and there were bilateral cataracts (fig 6). He wasmicrocephalic (OFC 42*5 cm, <3rd centile) and hislength was 71 cm (<3rd centile). Audiologicalexamination showed dull tympanic membranes andthere was low compliance and low middle earpressure on impedence audiometry. He was admit-ted to hospital for nutritional assessment and

FIG 5 V.4 at 17 months. Note severe wasting and largeears.

FIG 6 V.4 at 17months. Note sunken eyes, narrow nasalbridge, and thin upper lip.

treatment and his weight did increase a little.Periods of decreased awareness and a series ofgeneralised myoclonic jerks were noted but an EEGwas normal. His testes are undescended.

ii.3, ii.7, iii.6, iii.7, AND III.13These males were all known to II.2 who reportedthat they were blind, had sunken eyes, and diedbetween infancy and adolescence. Developmentalretardation was a feature. We were unable tocontact this branch of the family or the medical staffinvolved with them.

Results of investigations

DNA extraction from peripheral blood leucocytes,restriction enzyme digestion, Southern blotting,hybridisation, and autoradiography were performedas described.10 Probes were labelled by hexanuc-leotide primed synthesis.11 DNA probes L1-28 and754 define the loci DXS7 and DXS84 respectively;OTC is an ornithine transcarbamylase cDNA. Theaffected boys showed a deletion with probe L1-28(fig 7), but not with OTC or 754.The hexose monophosphate shunt pathway in

peripheral blood leucocytes was examined bymeasuring the increase in NBT reduction afterstimulation with phorbol myristate acetate, and the

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1113 114 1V5 IV3 III 1 lvi IV2 V1

quip lip lIPmok V-P 41411..-k

0ZOO

V3 V2 VL l V4'-NM ..__

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dbFIG 7 Autoradiograph of TaqI digested DNA offamily members hybridised to radiolabelled probe L1-28. DNA fromV.1 and V.4 does not hybridise with this probe. All other samples show a single 12 kb band.

increase in the level of enhanced chemolumines-cence after stimulation with Zymozan. Results were

normal. This excludes any defect similar to chronicgranulomatous disease.Urine amino acid chromatography showed nor-

mal results. Serum creatine kinase levels were withinthe normal ranges for the affected boys and theirmother. The platelet count on V.4 was normal,and neither boy had any skin manifestations ofWiskott-Aldrich syndrome. No chromosomalabnormality was visible in cultured lymphocytesfrom the affected boys and their mother. Electro-retinography and fundal examination of the motherdid not show any evidence of the carrier state for Xlinked retinitis pigmentosa.

Discussion

Boys with X chromosome deletions sometimes havephenotypes which combine features of several Xlinked diseases. 12 The discovery of deletions in somebut not all NDP patients makes it desirable todistinguish those who may have chromosomal dele-tions spanning several loci from those with typical

NDP. Any additional features seen in patients withdeletions would then point to genes located on the Xchromosome near to the NDP locus. Thus, it isimportant to know what features constitute theusual phenotype of Norrie disease. Most reports arein ophthalmological publications and concentrate onthe eye findings. There are few full clinical descrip-tions.

Mental retardation of a moderate or severedegree is present in two-thirds of cases,2 and furtherregression is sometimes reported. There are reportsof odd manneristic behaviour patterns, not neces-sarily those associated with other blind subjects, andpsychotic behaviour is described in some affectedmales surviving to adult life. Self mutilation wasreported by Warburg2 in one patient and was notedin our patient V.1. Seizures or abnormal EEGs orboth have been frequently reported.

Microcephaly was present in the six patients ofMoreira-Filho and Neustein,s in the patient of Gal etal,13 and in our two patients. OFCs are notmentioned in most reports even where there wassevere mental retardation, but there was an abnor-

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mal pneumoencephalogram indicating cerebralatrophy in two of Warburg's patients, and brainexamination at necropsy of another of her patientsshowed abnormalities of the cerebral cortex andmesencephalon.

Birth weights in reported cases were generallynormal. In both our patients very poor muscle bulkwas a feature, in spite of dietary treatment. This wasalso a feature in other reports; Hansen3 reportedlower limb atrophy in his patients at 33 months andWarburg2 mentioned weight loss in the proband ofher family A.

Moreira-Filho and Neusteins thought their familyatypical because of hypogonadism manifested bycryptorchidism and low serum testosterone, butcryptorchidism was a feature in our patients, andwas coupled with delayed puberty in the patient ofGal et al.'3

Descriptions of physical appearance are generallynot given in published reports; we have been able toidentify only one published photograph of the wholeface of an affected male.2 He has a narrow nasalbridge, the appearance of hypotelorism accentuatedby the shrunken globes, flattened malar regions, anda thin upper lip. His ears are large and prominent. Alateral view of an affected male is shown byMoreira-Filho and Neustein,5 showing micro-cephaly, large ears, and sunken eyes. Photographsof part of the faces of other affected males2 4 alsoshow narrow nasal bridges. Our patients had finefeatures with narrow nasal bridges, hypotelorism,flattened malar regions, thin upper lips, and largeears. They look similar to one another and to thecase of Warburg,2 but totally dissimilar to theirnormal sibs.There is no evidence that our patients had any X

linked disease in addition to Norrie disease. Specifi-cally, they did not have Duchenne muscular dys-trophy, chronic granulomatous disease, Wiskott-Aldrich syndrome, or any detectable abnormality ofamino acid metabolism. Gal et al13 suggest thatseveral features of their patient (severe mentalretardation, growth disturbances, disorders of sex-ual development and maturation, and a clinicalhistory suggestive of an immune defect) have neverbeen reported in typical NDP, and thus suggest thatother disease loci are deleted. This implies thatthose reported patients who do show some of thesefeatures do so because of a deletion. It is not yetclear what proportion of NDP families have adeletion of DXS7. The published reports69 13 wouldsuggest three out of 16, but non-deleted males infamilies uninformative for linkage are not likely tobe reported. Perhaps 10% of NDP families may bedeleted for DXS7; deletion of the NDP locus itselfmay of course be more frequent. Thus, it remains to

be determined how much of the clinical variability isdue to some families having deletions. However,even within families the phenotype can be veryvariable; in Warburg's study2 males with mentalretardation and failure to thrive had affected rela-tives without these features.

Before appropriate DNA studies can be perfor-med, a clinical diagnosis must be made. Our firstpatient was incorrectly diagnosed as having adisorder with little or no genetic component. Thetypical eye findings are well described in almost allreports, but we suggest that the gestalt of Norriedisease may also help in diagnosis. The differentialdiagnosis includes retrolental fibroplasia of prema-ture babies subjected to oxygen therapy, intrauter-ine infections especially toxoplasmosis, retinoblas-toma, primary hyperplastic vitreous, and perhapsLowe's syndrome.

In our family the affected boys are deleted at theDXS7 locus but the deletion does not extend distallyas far as the OTC or DXS84 loci. The obligatecarriers 11I.4 and IV.2 must be hemizygous forDXS7; the females at risk IV.5 and V.3, might behemizygous or homozygous. We cannot measuregene dosage on Southern blots reliably enough fordiagnostic use; in addition the husband of eachobligate carrier has the same DXS7 type as his wife,which rules out the possibility of seeing aberrantsegregation of DXS7 types (apparent non-mater-nity) in daughters who have inherited the deletion.Thus, we are unable to assess the carrier status ofIV.5 and V.3 using L1.28.Family members are informative for RFLPs at the

OTC and DXS84 loci. IV.5 has the opposite OTCallele, and V.3 the opposite DXS84 allele, to thedeleted X in the affected boys. This suggests thatneither girl carries the deletion. Unfortunately,recombination makes this prediction unreliable. Thepeak lod scores for Li 28 versus OTC and DXS84are at 0=0.15 and 0.20 respectively.'4 The asym-metry of the lod score curve means that the averageerror rate is rather greater than these recombinationfractions (J H Edwards, 1987, personal communica-tion), even assuming the NDP locus does not liesignificantly proximal to DXS7. Therefore, IV.5 andV.4 have an appreciable risk of carrying thedeletion, and they will be offered fetal sexing andL128 studies in any pregnancies.

Immunological studies on the affected boys werecarried out by Dr Richard Pumphrey. Probes L1l28and 754 were a kind gift from Professor PeterPearson, and the OTC probe from Dr Kay Davies.RCM is supported by a Special Medical Develop-ment grant from the UK Department of Health andSocial Security.

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References

Norrie G. Causes of blindness in children. Acta Ophthalmol(Kbh) 1927;5:357-86.

2 Warburg M. Norrie's disease, a congenital progressive oculo-acoustico-cerebral degeneration. Acta Ophthalmol [Suppli(Kbh) 1966;89:1-147.

3 Hansen AC. Norrie's disease. Am J Ophthalmol 1968; 66:328-32.

4 Townes PL, Roca PD. Norrie's disease (hereditary oculo-acoustico-cerebral degeneration). Am J Ophthalmol 1973;76:797-803.Moreira-Filho CA, Neustein I. A presumptive new variant ofNorrie's disease. J Med Genet 1979;16:125-8.

6 Gal A, Stolzenberger C, Wienker TF, et al. Norrie's disease:close linkage with genetic markers from the proximal short arm

of the X chromosome. Clin Genet 1985;27:282-3.7 Gal A, Bleeker-Wagemakers L, Wienker TF, Warburg M,Ropers HH. Localisation of the gene for Norrie disease by link-age to the DXS7 locus. HGM8. Cytogenet Cell Genet 1985;40:633.Kivlin JD, Sanborn GE, Wright E, Cannon L, Carey J. Furtherlinkage data on Norrie disease. Am J Med Genet 1987;26:733-6.

9 De la Chapelle A, Sankila EM, Lindlof M, Aula P, Norio R.Norrie disease caused by a gene deletion allowing carrier detec-tion and prenatal diagnosis. Clin Genet 1985;28:317-20.

1' Maniatis T, Fritsch EF, Sambrook J. Molecular cloning: a lab-oratory manual. Cold Spring Harbor, NY: Cold Spring HarbourLaboratory, 1982.Feinberg AP, Vogelstein B. A technique for radiolabellingDNA restriction endonuclease fragments to high specific acti-vity. Anal Biochem 1983;132:6-13.

12 Francke U, Ochs HD, de Martinville B, et al. Minor Xp2lchromosome deletion in a male associated with expression ofDuchenne muscular dystrophy, chronic granulomatous disease,retinitis pigmentosa and McLeod syndrome. Am J Hum Genet1985;37:250-67.

'3 Gal A, Wieringa B, Smeets DFCM, Bleeker-Wagemakers L,Ropers HH. Submicroscopic deletion of the X chromosomeexplains a complex genetic syndrome dominated by Norrie dis-ease. Cytogenet Cell Genet 1986;42:219-24.

14 Goodfellow PN, Davies KE, Ropers HH. Report of the commit-tee on the X and Y chromosomes. HGM8. Cytogenet Cell Genet1985 ;40:296-352.

Correspondence and requests for reprints to Dr DDonnai, Department of Medical Genetics, StMary's Hospital, Hathersage Road, ManchesterM13 OJH.

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