J7Med Genet 1998;35:759-762

Spastic paraplegia, optic atrophy, microcephalywith normal intelligence, and XY sex reversal: anew autosomal recessive syndrome?

Ahmad S Teebi, Steven Miller, Harry Ostrer, Patrice Eydoux, Celine Colomb-Brockmann,K Oudjhane, G Watters

AbstractTwo female sibs of first cousin Iranianparents were found to have the syndromeof spastic paraplegia, optic atrophy withpoor vision, microcephaly, and normalcognitive development. Karyotype analy-sis showed a normal female constitution inone and a male constitution (46,XY) in theother. The XY female showed normalfemale external genitalia, normal uterusand tubes, and streak gonads. SRY genesequencing was normal. We conclude thatthe present family probably represents anew autosomal recessive trait of pleio-tropic effects including XY sex reversaland adds further evidence for the hetero-geneity ofspastic paraplegia syndromes asweli as sex reversal syndromes.(JMed Genet 1998;35:759-762)

Division ofMedicalGenetics A-608, TheMontreal Children'sHospital and McGillUniversity, 2300Tupper Street,Montreal, Quebec,Canada H3H 1P3A S TeebiP Eydoux

Division ofNeurology,The MontrealChildren's Hospitaland McGill University,Montreal, Quebec,CanadaS MillerG Watters

Human GeneticsProgram, Departmentof Pediatrics, New YorkUniversity MedicalCenter, New York,USAH OstrerC Colomb-Brockmann

Department ofMedical Imaging, TheMontreal Children'sHospital and McGillUniversity, Montreal,Quebec, CanadaK Oudjhane

Correspondence to:Dr Teebi.

Received 23 October 1997Revised version accepted forpublication4 February 1998

Keywords: spastic paraplegia; optic atrophy; micro-cephaly; sex reversal

Hereditary spastic paraplegia (HSP) is aheterogeneous group of spinocerebellar degen-eration disorders that are classified as non-syndromic, "pure", and syndromic. The non-syndromic form is usually autosomal dominant(MIM 182600'); however, autosomal recessiveand X linked recessive forms exist.2 3 The syn-dromic forms have been variably associatedwith ataxia, optic atrophy, extrapyramidalabnormalities, muscular dystrophy, and mentalretardation. Less common associations includeichthyosis, vitiligo, premature greying of hair,retinal dystrophy, and brachydactyly, amongothers.4'-l0 Syndromic HSP is often consideredto be autosomal recessive and appears to bemore frequent in Middle Eastern populations.

Sex reversal syndromes also constitute a het-erogeneous group and include syndromes withand without involvement of the SRY gene,which is implicated in male differentiation.'1-13We report two sisters of consanguineous

parents with infantile onset spastic paraplegia,optic atrophy, microcephaly with normal cog-nitive development, and XY sex reversal in one.

Case reportsPATIENT 1This patient was one of female twins; the otherwas stillborn with no obvious anomalies. Thepregnancy was otherwise uneventful and deliv-ery was normal at term in Iran. Birth weightwas 2750 g and birth length was 50 cm. Therewere no neonatal problems. At the age of 6

months the parents noticed that she had aproblem with tone and posture. Though shecould roll over at 6 months of age, she wasunable to support herself sitting. On evaluationat the age of 1 year she was found to have anormal CT scan of the brain and wasdiagnosed as having spastic diplegia. She couldcommunicate well and cognitive skills ap-peared normal.On examination at 4 years 4 months ofage she

appeared an alert and pleasant child with anoccipitofrontal circumference (OFC) of44.5 cm(<5th centile) and a length of 87 cm (<5th cen-tile) (fig 1). She was unable to get into a sittingor standing position independently, but was ableto crawl. She was not dysmorphic and the skinshowed a small hypopigmented area on the rightthigh and an extensive Mongolian spot on herback. She spoke with some dysarthria in Frenchand her native language. There was plagi-ocephaly with flattening of the left part of theocciput and prominence of the left ear. Ocularmovements were full and she followed light buthad markedly reduced vision. Hearing was nor-

Figure 1 Patient 1: note the spastic posture. (Photographsreproduced with permission.)

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Figure 2 Patient 1: axial T, MR image of the orbits showing optic nerve atrophy.

Figure 3 Patient 1: sagittal sonogram of the pelvis showing an infantile uterus (+ - +).

mal. There was no drooling. Stretch reflexeswere brisk in the upper limbs and markedly briskwith clonus in the lower limbs. The extensorplantar responses were present bilaterally. Tonein all four extremities was increased. She hadadductor spasm with scissoring and extensorthrusts ofthe lower extremities as she was placedin the standing position. There was difficultywith use ofthe upper limbs with grasp deficiencybilaterally. There was mild dystonic posturing ofthe hand when trying to reach for objects.An MRI scan showed only a possible reduc-

tion in the size of the optic nerves bilaterally(fig 2). Ophthalmological examination alsoshowed small optic nerves suggestive of opticatrophy with no pigmentary retinopathy andnormal maculae. Electroretinogram (ERG)and visual evoked responses (VER) suggestednormal retinal function and an optic nerve

conduction defect. Skeletal survey showedbilateral coxa valga and no brachydactyly or

cone shaped epiphyses. The karyotype was

46,XY. Pelvic ultrasound showed an infantileuterus and virtually no gonads were identified(fig 3). At 5 years of age she underwentdiagnostic laparoscopy, which showed a nor-

mal uterus, and laparotomy with excision ofstreak gonads. Histopathological examination

of specimens from both sides showed noevidence ofnormal ovarian or testicular tissues.Some nodular microscopic calcifications werenoted. Hormonal profile before surgeryshowed that LH was <1.5 U/l (normal 0-2),FSH 23.5 U/l (normal 0-5), testosterone 0.5mmol/l (normal 0-2), and dihydrotestosterone0.75 mmol/l (normal 2.2-10.3). Electromyo-graphy and motor and sensory nerve conduc-tion studies were normal. Somatosensoryevoked responses were suggestive of an abnor-mality rostral to the dorsal column nuclei, mostlikely in the thalamocortical projections bilater-ally. Auditory brainstem evoked responsesshowed normal brainstem conduction. Electro-encephalogram showed focal epileptiform ac-tivity over the right occipital region as well aspoor development of background for age, sug-gesting a moderately diffuse disturbance ofcerebral activity. Urine organic acids wereunremarkable with absence of 3-methyl-glutaconic acid.

PATIENT 2

This patient was born normally after 37 weeksof an unremarkable pregnancy. Birth weightwas 2650 g and birth length was 48 cm. Therewere no neonatal complications. Like hersister, she was noted to have problems withtone and posture at 6 months of age. On evalu-ation in Iran she was found to have a normalCT scan of the brain at 1 year of age and wasdiagnosed with spastic diplegia. She couldcommunicate well with only slightly delayedlanguage milestones. Cognitive skills wereotherwise normal.On examination at 2 years 6 months of age,

her OFC was 43 cm (<5th centile) and herheight was 80 cm (<5th centile) (fig 4). She wasalert and responsive. She had soft, cup shapedears and her skin showed five small cafe au laitspots with no axillary or inguinal freckling.Ocular movements were full and she hadnormal facial movement with no drooling.Stretch reflexes were brisk in the upper limbsand brisker in the lower limbs with some clonusat the ankles. Tone was increased in all fourextremities, particularly in the legs. She couldnot sit or stand independently. She had adduc-tor spasm with scissoring and standing on tip-toes when placed upright.An MRI scan, like her sister, showed only a

possible reduction in the size of the opticnerves bilaterally, but her vision was lessaffected. Ophthalmological examination alsoshowed small optic nerves suggestive of opticatrophy. Flash visual evoked responses sug-gested normal retinal function and an opticnerve conduction defect. Skeletal surveyshowed bilateral coxa valga. Karyotype analysiswas normal. Pelvic ultrasound showed aprepubertal uterus and normal ovaries. Elec-tromyography and motor and sensory nerveconduction studies were normal. Somatosen-sory evoked responses were suggestive of anabnormality rostral to the dorsal columnnuclei, most likely in the thalamocorticalprojections bilaterally. Auditory brainstemevoked responses were normal. Electroen-cephalogram showed an abnormal pattern of

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New spastic paraplegia syndrome

Figure 4 Patient 2: note the spastic posture.

reactivity of uncertain significance. Urinaryorganic acids were unremarkable with absenceof 3-methylglutaconic acid.At 4 years of age, OFC was 44.4 cm (<5th

centile) and height was 85 cm (<5th centile).There were no cranial nerve abnormalities.Plantar responses were extensor bilaterally. Shereached for objects awkwardly but better thanher sister. Apart from short stature, the generalmedical examination was unremarkable.

FAMILY HISTORYThe probands were the second and third ofthree daughters of phenotypically normalIranian parents who are first cousins. Their firstpregnancy was a normal female. Neurologicalexamination of the parents and their first childwas unremarkable. There is no family historyof neuromuscular disease, poor vision, femaleinfertility, or other defects.

CYTOGENETIC AND MOLECULAR CYTOGENETICINVESTIGATIONS

G banded chromosomes in peripheral blood ofpatient 1 showed a 46,XY constitution. This wasconfirmed by high resolution G banding andfluorescence in situ hybridisation (FISH) probesspecific for the X and Y centromeres(ONCOR). FISH probes from Xp2l were alsoused, which showed no duplication in thissegment. Her sister's (patient 2) G bandedchromosomes showed a 46,XX normal femaleconstitution. The parents' chromosomes were

normal.

SRY STUDIES

Genomic DNA was extracted from the bloodof the two patients, their parents, and their

normal sister. PCR was conducted withprimers that amplify the SRY open readingframe, plus about 90 bp upstream of startcodon and 70 bp downstream of stop codon.The PCR results were as expected from thekaryotypic data. Only patient 1 and her fatheramplified the SRY region. Patient l's SRYPCR product was subsequently cloned intovector pCRII and sequenced. The sequenceshowed no difference from the SRY publishedsequence. The results suggest that the patient'sgonadal dysgenesis cannot be accounted for bya mutation in SRY.

DiscussionSyndromic or complicated HSP is a relativelycommon group which includes individually rare,clinically and genetically diverse disorders thathave in common spasticity affecting predomi-nantly the lower extremities. Optic atrophy is afrequently encountered association'4 17 with ad-ditional peripheral neuropathy'8 or ataxia, as inBehr's syndrome.'9 20 Patients with this disorderhave excessive excretion of 3-methylglutaconicacid and 3-methylglutaric acid in their urine.20Mental retardation (MR) is also a commonfinding in many HSP syndromes59 17 21 23 withadditional cutaneous pigmentation disorder,24transverse limb defects,25 26 or retinal dystro-phy.27 Other individual syndromes include HSPwith MR, retinitis pigmentosa,28 and deafness,29HSP with peripheral neuropathy and painlessfoot ulcers,30 HSP with disordered pigmenta-tion, peripheral neuropathy, and normalintelligence3' and with ataxia,32 HSP withvitiligo, premature hair greying, peculiar facies,and normal intelligence,33 HSP with congenitalicthyosis,34 the syndrome of HSP, brachydactyly,cone shaped epiphyses, and normal intelligenceor Fitzsimmons syndrome,35 36 and others.'53740A significant overlap exists between some

HSP syndromes, such that two or more of theso called new syndromes represent a singleentity. The majority of these syndromes areautosomal recessive, many of which have beendescribed in Arab families or Jews originatingfrom Arab countries who often have highfrequencies of consanguineous mar-riages.2024-26 30 However, in a few syn-dromes the inheritance is probably X linkedrecessive. 14 15 23 41 42

However, the development of sex reversal inXY females may be the result of interferencewith testicular differentiation. This process iscontrolled mainly by the testicular determiningfactor (TDF) locus on distal Yp, which is thesex determining region Y (SRY), in addition toother genes located on the X chromosome andautosomes.'3 43 Mutations in SRY, however,only account for about 20% of cases of XYgonadal dysgenesis.'2 44 There is also evidenceof an Xp region that can suppress testiculardevelopment in the presence of normalSRY. '3 Many cases have been documentedand the sex reversal associated with thepresumptive locus appears to be the result ofduplication and not disruption.45 46 This locuswas assigned to a region on distal Xp2 1adjacent to the adrenal hypoplasia congenitacritical region and has been termed "DSS"

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(dosage sensitive sex reversal).47 There is clearevidence now for an important locus involvedin testicular development from studying cam-pomelic dysplasia patients with chromosomalrearrangements involving 1 7q24-25 or withoutchromosomal rearrangements but with muta-tions ofthe SOX9 gene.4849 Other loci have alsobeen implicated."350 51

The constellation of spastic paraplegia, opticatrophy, dysarthria, and microcephaly with nor-mal intelligence in two phenotypically femalepatients, with XY gonadal dysgenesis in one, isunlikely to be fortuitous. It may represent, how-ever, a previously unrecognised syndrome, eitherin the category of syndromic HSP or XY sexreversal syndromes.The presence of parentalconsanguinity and the involvement of sibs ofboth genotypes is suggestive of an autosomalrecessive trait with pleiotropic effects includingXY sex reversal. This indicates that more loci areinvolved in testicular differentiation. We concurwith Ferguson-Smith and Goodfellow" thatfuture identification and cloning of genes thatregulate SRY, and are regulated by SRY, will befacilitated by careful clinical analysis of sexreversed patients likethis.

We thank Susan Laurie for her secretarial assistance and AnaarSajoo for her assistance in organising the investigations.

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