Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the...

� 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1285–1296 (2006)

Blepharophimosis-Mental Retardation (BMR)Syndromes: A Proposed Clinical Classification ofthe So-Called Ohdo Syndrome, and Delineation

of Two New BMR Syndromes, OneX-Linked and One Autosomal Recessive

Alain Verloes,1,3* Dominique Bremond-Gignac,2,3 Bertrand Isidor,4

Albert David,4 Clarisse Baumann,1 Marie-Anne Leroy,5 Rene Stevens,6

Yves Gillerot,7 Delphine Heron,8 Benedicte Heron,9 Brigitte Benzacken,10

Didier Lacombe,11 Han Brunner,12 and Pierre Bitoun13

1Clinical Genetics Unit, APHP Robert Debre University Hospital, Paris, France2Ophthalmology Departments, APHP Robert Debre University Hospital, Paris, France

3INSERM U676, APHP Robert Debre University Hospital, Paris, France4Genetic Unit, Nantes University Hospital, Nantes, France

5Verlaine, Belgium6Pediatric Department, Clinique St. Joseph-Esperance, Liege, Belgium

7Institut de Pathologie et de Genetique, Loverval, Belgium8Clinical Genetic Unit, Pitie-Salpetriere University Hospital, Paris, France

9Neuropediatrics, APHP Jean Verdier Hospital, Bondy, France10Embryo-Cytogenetic and Reproductive Biology, Bondy, France

11Medical Genetics Department, Pellegrin University Hospital, Bordeaux, France12Medical Genetics Departments, University Hospital Jean Verdier, Bondy, France

13Department of Human Genetics, University Hospital, Nijmegen, The Netherlands

Received 19 June 2005; Accepted 15 March 2006

We report on 11 patients from 8 families with ablepharophimosis and mental retardation syndrome(BMRS) phenotype. Using current nosology, five sporadicpatients have Ohdo syndrome, associated with congenitalhypothyroidism in two of them (thus also compatible witha diagnosis of Young-Simpson syndrome). In two affectedsibs with milder phenotype, compensated hypothyroidismwas demonstrated. In another family, an affected boy wasborn to the unaffected sister of a previously reportedpatient. Finally, in the last sibship, two affected boys inaddition had severe microcephaly and neurologicalanomalies. A definitive clinical and etiologic classificationof BMRS is lacking, but closer phenotypic analysisshould lead to a more useful appraisal of the BMRSphenotype. We suggest discontinuing the systematic use ofthe term ‘‘Ohdo syndrome’’ when referring to patientswith BMRS. We propose a classification of BMRS intofive groups: (1) del(3p) syndrome, (possibly overlooked inolder reports); (2) BMRS, Ohdo type, limited to the

original patients of Ohdo; (3) BMRS SBBYS (Say-Barber/Biesecker/Young-Simpson) type, with distinctive dys-morphic features and inconstant anomalies including heartdefect, optic atrophy, deafness, hypoplastic teeth, cleftpalate, joint limitations, and hypothyroidism. BMRStype SBBYS is probably an etiologically heterogeneousphenotype, as AD and apparently AR forms exist; (4)BMRS, MKB (Maat–Kievit–Brunner) type, with coarse,triangular face, which is probably sex-linked; (5) BMRS V(Verloes) type, a probable new type with severe micro-cephaly, hypsarrhythmia, adducted thumbs, cleft palate,and abnormal genitalia, which is likely autosomal reces-sive. Types MKB and V are newly described here.� 2006 Wiley-Liss, Inc.

Key words: blepharophimosis; Ohdo syndrome; Young–Simpson syndrome; nosology; hypothyroidism

*Correspondence to: Alain Verloes, Clinical Genetics Unit, HopitalRobert Debre, 48 Boulevard Serurier, 75019 Paris.E-mail: [email protected]

DOI 10.1002/ajmg.a.31270

How to cite this article: Verloes A, Bremond-Gignac D, Isidor B, David A, Baumann C, Leroy M-A, Stevens R,Gillerot Y, Heron D, Heron B, Benzacken B, Lacombe D, Brunner H, Bitoun P. 2006. Blepharophimosis-mental

retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, anddelineation of two new BMR syndromes, one X-linked and one autosomal recessive. Am J Med Genet

Part A 140A:1285–1296.

INTRODUCTION

Blepharophimosis is an abnormal shortening ofthe horizontal width of the palpebral fissures (withsecondary ptosis) that gives a characteristic facialappearance and often requires the affected patient tohave an abnormal backward tilt of the head. Mostcommonly, severe blepharophimosis is associatedwith epicanthus inversus, an abnormal aspect ofthe inner angle of the lower lid that covers thelacrimal puncta. This combined anomaly constitutesthe blepharophimosis-epicanthus inversus-ptosis(BPES) syndrome.

Ohdo et al. [1986] delineated a syndrome ofblepharophimosis, ptosis, hypoplastic teeth, heartdefect, and mental handicap, to which his name iscurrently attached. During the following years,other cases of ‘‘Ohdo syndrome’’ were reported,with large clinical variability beyond the presence ofthe palpebral anomaly. Most cases were sporadic.We report on five sporadic cases, an uncle-nephewpair and two sets of sibs with features similar to thosedescribed by Ohdo, review the previous reportsof blepharophimosis-mental retardation syndrome(BMRS), and suggest a clinical classification in fivesubgroups, including two newly delineated entities.

CLINICAL REPORTS

Family 1

Patient 1 (Fig. 1). This girl was the second offive children, born at term to unrelated healthyparents. Family historywas not relevant. Birthweight(BW) was: 3,410 g (median), length (BL) 48 cm(�1 SD), occipitofrontal circumference (OFC)35 cm (�0.2 SD). Pregnancy was marked bypremature contractions for which the mother wastreated with bed rest for 7 weeks. Clinical examina-tion at birth showed a round face, narrow, slightlydownslanted palpebral fissures, flat nose with alarge, bulbous tip, posteriorly rotated ears, preauri-cular pits, cleft palate, and laryngomalacia. Brainultrasound scan and MRI showed hypoplasia of thecorpus callosum. The kidneys and heart wereultrasonographically normal. Swallowing difficultieswere prominent, and feeding was only possible bynasogastric tube feeding. This problem, combinedwith intolerance to cows milk protein and gastro-esophageal reflux lead to Nissen fundoplicationby coelioscopy, followed by gastrostomy at age9 months. ENT investigations did not reveal anatomic

anomalies of the upper airways, and there were nosigns of cranial nerve dysfunction. There waspsychomotor delay. Hypotonia was prominent dur-ing the first months but resolved progressively. Shewalked at age of 19 months. At the last examination,at 4 years, she was 100 cm tall (þ0.3 SD); sheweighted 16 kg (þ0.4 SD) and had an OFC of 50 cm(þ0.2 SD). Teeth erupted normally and were small.Blepharophimosis with mild ptosis was moremarked than in the neonatal period. Her cheekswere sagging andhermouthwasnarrow. Fundiwerenormal. Expressive speech was absent, but she waslearning using Makaton, an aided communicationsystem associating simplified sign language, gesture,and graphic aid (see http://www.makaton.org/).Hearing was normal. Drooling was still present,and oral feeding was limited to small amounts offluids. Figure 1 illustrates the progression of herdysmorphic features.

High-resolution karyotype (650 bands)—with spe-cial interest to chromosome 3—22q11 FISH andsubtelomeric FISH screen were normal. Thyroidfunction was normal.

A diagnosis of severe Ohdo syndrome wasproposed for this child, who had in this contextunusual ENT anomalies.

Family 2

Patient 2 (Fig. 2). This girl was the first childborn at term to unrelated healthy parents (Fig. 2). BWwas 2,550 g (�1.3 SD), BL 47 cm (�1.6 SD), and OFC33 cm (�1.3 SD) at term. She walked at age 2 years.Speech was delayed and the patient required specialschooling. She was seen for the first time at age19 years. She worked in a sheltered workshop. Shewas 158 cm tall (�1 SD), weighted 71 kg (þ2.9 SD),and had an OFC of 55 cm (median). She had roundface, blepharophimosis with bilateral, asymmetricptosis (despite surgical repair), and large, flat nosewith large, flat and bulbous tip and depressed root,hypoplastic alae nasi, and full cheeks. Her teeth werenot remarkable. She had bilateral cubiti valgi, genuavara, limitation in pronosupination of the forearmsand dorsiflexion of the ankles. Despite normalpubertal stages (menses at age 11.5 years) she hadno breast development. LHRH provocation test andcirculating gonadotrophin and steroid levels werenormal. Truncal obesity was present, with associatedhyperphagia.

High-resolution karyotype (550 bands), CGH, sub-telomeric screen, and thyroid tests were normal.

1286 VERLOES ET AL.

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

A diagnosis of mild Ohdo syndrome was proposedbased on overall facial appearance and absence ofchromosomal anomalies.

Family 3

Patient 3 (Fig. 3). This boy was the first childof a 27-year-old mother and a 34-year-old father(Fig. 3). BW was 3,050 g (�0.25 SD), length was52 cm (þ1 SD), and OFC was 34 cm (�1 SD). He wasseverely hypotonic from birth. Initial examinationrevealed blepharophimosis with ptosis, microsto-mia, small ears, preauricular pits and dysplasticpinnae, atrial septal defect, clinodactyly and over-riding third toes, cryptorchidism, micropenis, andinguinal hernias. A stridor due to laryngomalaciaresolved spontaneously. At the last examination, atage 23 months, he was 86 cm tall (�2 SD), weighed

10.1 kg (�2.7 SD), and had an OFC of 46.5 cm(�2.9 SD). His facial appearance was still dominatedby blepharophimosis, sagging cheeks, and micro-stomia with apparently small teeth. He was stillhypotonic with poor muscle bulk, but had anotherwise normal neurological examination. Hewas able to stand up and but walked only withassistance. He had feeding problems and a severedrooling, but was fed orally. Speech was limited tofive words.

Chromosomal analysis showed a paternally inher-ited, apparently balanced 46,XY,t(13;22)(q10;q10)translocation. Metabolic screening was normal. CGHand subtelomeric FISH screening yielded normalresults. Thyroid function tests were unremarkable.

FIG. 2. Patient 2 at age 17 years, note blepharophimosis (operated),pear-shaped nose and large cheeks.

FIG. 3. Patient 3, note severe hypotonia of the facial muscles.

FIG. 1. Patient 1: (a, b) Facial aspect soon after birth: note bulbous tip of thenose; (c, d) evolution of facial Gestalt between 1 and 2½ years: noteblepharophimosis with apparent hypertelorism, and full cheeks (e) small,regularly placed teeth.

BLEPHAROPHIMOSIS-MENTAL RETARDATION SYNDROMES 1287


A diagnosis of Ohdo syndrome was proposedbased on facial Gestalt and absence of chromosomalgain or loss (although a cryptic rearrangementbetween father and son could not be excluded).

Family 4

Patient 4 (Fig. 4). This girl, born at 37 weeks ofgestation, after IVF for primary maternal infertility,was the first child of a nonconsanguineous 33-year-old mother and 34-year-old father (Fig. 4). BW was2,550 g (�1.5 DS), BL 50.5 cm (þ1.5 DS), and OFC32.5 cm (�0.5 DS). CVS, performed because of ahygroma colli (4.6 mm) was normal 46, XX. At35 weeks, ultrasonographic follow-up revealedpolyhydramnios and femoral length below the thirdcentile. At birth, the girl required mechanicalventilation for 1 day. Facial dysmorphic features atbirth included blepharophimosis, a depressed nasalbridge, flattened nasal tip, small, low set, posteriorlyrotated ears, preauricular pits, micrognathia, nuchalskinfolds, and a posterior cleft of the hard and softpalates. Fingers were apparently long, thin andhypermobile, thumbs were long, the left hallux wasduplicated, and the right foot showed posturalmalposition with fibular deviation of the toes.The right knee was unstable with absent orhypoplastic patellae. ShehadASD, ostiumsecundumtype, perimembranous VSD, right-sided aortic arch

and a PDA that persisted beyond the neonatal periodand was surgically corrected. X-rays confirmedbifidity of the proximal phalanx of the hallux andduplication of the distal one. Delayed skeletalmaturation was compatible with hypothyroidism.Free T4 was 5.5 pg/ml (normal 8.5–18) and TSHwas 260 IU/ml (normal values: 0.20–4 IU). Cervicalultrasonography failed to locate the thyroidgland. Neurological examination showed axial andperipheral hypotonia. EEG showed a slow wavepattern and temporal spikes. Hypoplastic corpuscallosum was found on brain MRI. Fundi werenormal. At last follow-up at age 7 months, she was62 cm tall (�2 SD), weighted 5,300 g (�2.5 SD), andhad an OFC of 40.5 cm (�2 SD). She had axialhypotonia and psychomotor delay. The right patellawas still undetectable. High-resolution karyotype(600 bands) and FISH for 22q11, 3pter, and 3qterwere normal.

A diagnosis of severe Ohdo syndrome was initiallyproposed but switched to Young–Simpson syn-drome after discovery of the hypothyroidism.

Family 5

Patient 5 (Fig. 5). This girl is the first child ofnonconsanguineous French parents, both aged 32 atbirth of the proband (Fig. 5). Their medical historieswere unremarkable. Pregnancy was not compli-cated. She was born by caesarean for breechpresentation at 39 weeks of gestation. BW was:2,280 g (1.9 SD), BL was 46 cm (�2.1 SD), and OFCwas 33.5 cm (�0.8 SD). Hip dysplasia was treated bybracing. At clinical examination in the neonatalperiod, the following anomalies were recorded:blepharophimosis, bulbousnose, prominent cheeks,microretrognathia, median posterior palate cleft,dysplastic pinnae, and apparently short fingers andtoes. She had peripheral hypertonia and truncalhypotonia. Karyotype and subtelomeric screeningby FISH were normal. Congenital hypothyroidismwas detected by neonatal screening and the patient

FIG. 4. Patient 4 after birth: (a, b) note blepharophimosis with apparenthypertelorism, bulbous tip of the nose; (c) camptodactyly; (d) fibular deviationof the right toes; (e) duplication of the left hallux.

FIG. 5. Patient 5 in infancy. Note blepharophimosis, bulbous tip of the noseand microstomia.

1288 VERLOES ET AL.


was treated with oral thyroxin replacement. Scinti-graphy disclosed absence of thyroid fixation. At thelast follow-up, at age 10 months, she weighted 6,420g (�2.25 SDS), was 66.5 cm long (�2 SD), and had anOFC of 43.7 cm (�1 SD). Development was mildlydelayed.

A diagnosis of Young–Simpson syndrome wasproposed, although the facial appearance was lesstypical (lesser blepharophimosis and non-character-istic nose shape).

Family 6

Patient 6. This male child was born to a22- year-old G1P1 mother at 41 weeks. BW was3,240 g (�0.7 SD), BL 50.5 cm (þ0.3 SD), and OFC36 cm (þ0.7 SD). Pregnancy was marked bymaternal hypertension. Hypotonia and ill-specifiedfacial dysmorphism were noted at birth, andprompted several examinations. Cardiac ultrasono-graphy showed an ASD. Skeletal survey, cranial andabdominal ultrasound scans, and EEG were normal.Hypotonia persisted during the first months. Devel-opment was delayed. She sat at 9 months; stood at18 months, and walked at 24 months. She had onlyfour words by 3.5 years.

When initially examined in the genetic clinic atthe age of 3.5 years, facial dysmorphic featuresincluded epicanthic folds, blepharophimosis, ptosis,apparently small ears, microdontia, and a gapingopen mouth attitude. Ophthalmologic examinationshowed normal fundi and anterior segments, alter-nating strabismus and horizontal nystagmus causedby left-sided fixation. Brain CT and MRI imagingshowed discrete hyperintense areas of white matteraround the ventricular midline suggestive of delayedmyelin maturation, and non-specific ventricularenlargement, all interpreted as sequelae of perinatalasphyxia. Audiometry revealed mild conductivedeafness (�40 dB) secondary to Eustachian tubedysfunction.

Splenomegaly was noted in infancy. Screening forlysosomal storage disease on lymphocyte, serum,and fibroblasts was negative. There was no evidencefor spleno-portal hypertension, viral infection orNiemann-Pick type 1 disease. The enlarged spleenresolved spontaneously by the age of 4–5 yearswithout explanation. He developed absence typeseizures that required valproate treatment. Right-undescended testis was surgically corrected. At age 8years, bone maturation was rated at a 9-year level. Atthe age of 10 years and 8/12, he was 142.5 cm tall(þ1.3 SD), weighed 38.5 kg (þ1.9 SD), and had anOFC of 55.5 cm (þ1.1 SD). His ASD remained welltolerated. He used sign language to communicatewhereas expressive speech remained a challenge.

Despite normal neonatal thyroid screen, a thyroidscreen at the age of 9 years showed repeatedlyelevated TSH: 5.13 mIU/ml (normal 0.25–3.10 mIU/

ml) with normal T3: (4.4 ng/L—normal 3–7 ng/L)and free T4 levels: (13 ng/L—normal 12–22 ng/L)with negative anti-microsomal and anti-thyroglobu-lin antibodies. Hormonal thyroxin replacementtherapy was recently initiated.Patient 7 (Fig. 6). Patient 6’s younger brother

was born after an uneventful pregnancy andneonatal course (Fig. 6). BW was 3,050 g (�0.5SD), BL 48 cm (�0.8 SD), and OFC 36 cm (þ1.5 SD).Apgar score was 10/10. He had the same dysmorph-ism and followed a similar developmental course ashis brother. He had no speech at the age of 3 years.Right-undescended testis required surgical correc-tion. Cardiac ultrasonography revealed PDA thatresolved spontaneously. He also had an enlargedspleen. Cranial CT scan was normal. At last examina-tion at age 8 years, he had a weight of 25 kg (0.1 SD),height of 128 cm (þ0.5 SD), and OFC of 54.5 cm(þ1.4 SD). He was moderately mentally retarded,with very low verbal skills. His speech was almostabsent. Enuresis and occasional encopresis wereproblems. He had a seizure disorder treated withvalproate and primidone. His skin showed telan-giectasias on the cheeks. Thyroid screen at age7 years showed mildly elevated TSH (3.93 mU/ml—normal 0.25–3.10 mU/ml) with normal T3 (5.75) ng/L—normal 3–7 ng/L), and free T4 levels (16.4ng/L—normal 12–22 ng/L) with negative anti-microsomaland anti-thyroglobulin antibodies, and normal thyr-oid-binding globulin (430 nmol/L normal: 150–450nmol/L). Hormonal treatment was recommended.

High-resolution karyotype (600bands), FISH studyfor the 22q11 deletion, subtelomeric FISH screen,serum pyruvate, lactate and ammonia level, serumamino acids, urinary SAICAR (50-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide) and 7-hydroxycholesterol, as well as urinary organic acidchromatography were normal. Molecular study forfragile X was negative.

Parents were unrelated and without signs ofblepharophimosis, ptosis, cardiac, or genital anoma-lies. The father had a mild speech defect with a lisp

FIG. 6. Patient 6. a, b: Note blepharophimosis with epicanthus, small mouth,full cheeks and narrow mouth The nose is not pear-shaped.



and the mother had an unusually broad andprominent nasal tip. Both parents had normal high-resolution (650 band) karyotype and thyroid func-tion tests. Three maternal aunts and uncle haveisolated thyroid dysfunction: onewithhypo- and twowith hyperthyroidism. The mother has subsequentlygiven birth to healthy boy and girl from two otherfathers.

A diagnosis of possible familial Ohdo syndromewas proposed for this family, despite the normalaspect of the nose. It was switched to probableYoung–Simpson syndrome after the discovery of thethyroid problem.

Family 7

Patient 8 (Fig. 7). This boy was born bycaesarean at 37 weeks of a pregnancy marked byoligohydramnios during the third trimester, weight-ing 2,135g (�3.2 SD) (Fig. 7). BLwas 45 cm(�2.5 SD)and OFC was 30.5 cm (�4.6 SD). He had a roundface, blepharophimosis, stubby nose with a flat,large tip, thick columella, wide alae nasi, short,smooth philtrum, narrow mouth, mild retrognathia,prominent cheeks, posteriorly rotated ears withdysplastic conchae (thick helix, prominent anthelix,softened antitragus), and a cleft soft palate. Thumbswere adducted and palmar creases were unusually

deep. The penis had an unusual shape: the shaftwas angulated, there was a ring constriction of itsproximal part, and cleft prepuce with glandularhypospadias. Renal and cardiac ultrasounds scanswere normal. Neurological examination in theneonatal period was unremarkable. CNS imagingrevealed bilateral small-sized cysts of the choroidsplexus, a left paraventricular cyst in the area of thecaudate nucleus, and mild enlargement of the lateralventricles. Visual and somatosensory evoked poten-tials showed non-specific immaturity. Auditoryevoked potentials revealed an important latency ofthe wave I, and abolished waves IV and V.

At the age of 6 months, he was 59.5 cm long (�3.4SD), weighted 5,970 g (�2.3 SD), and had an OFCof 38.5 cm (�4.3 SD). The face was ‘‘more roundedthan normal,’’ wider than high. Initial psychomotordevelopment was moderately delayed. At 9 months,he was 63 cm tall (�2.7 SD) and had an OFC of40.6 cm (�3.1 SD). He was admitted to the intensivecare unit for hypsarrhythmia resistant to vigabatrinand ACTH treatment. Brain MRI at that time showedleucomalacia along the walls of the occipital horns ofthe lateral ventricles. He died after 17 days of statusepilepticus. Autopsy was declined.Patient 9 (Fig. 8). The second boy was born

after an uneventful pregnancy (Fig. 8). No anomalieswere noted by antenatal ultrasound scan. BWwas 3,090 g (�0.8 SD), BL was 48 cm (�1 SD), OFCwas 31.5 cm (�3.4 SD). The facial appearance wasstrikingly similar to the elder brother, including a cleftof the soft palate. The penis has an unusual shape:long curved shaft with a proximal constrictionextending to the first half, extremely long glans,absence of foreskin, and normal urethral meatus. Histhumbs were short and adducted. The fourth andfifth toes appeared proximally placed. CNS, cardiacand renal US scans were normal. The eyes werenormal, including their size measured by ultrasono-graphy. Hypsarrhythmia appeared at the age of12 months. It was successfully treated with nitraze-pam. He had gastroesophageal reflux and constipa-tion. Development was severely delayed: at the ageof 4 6/12 years, he was 91 cm tall (�3.1 SD), weighted12 kg (�2.8 SD), and had an OFC of 43.2 cm(�6.6 SD). He was unable to speak and had poorvisual contact. He crawled but did not walk on allfours. Seizures were kept under control withvalproate and vigabatrin. The parents were healthyand nonconsanguineous. Family history was unre-markable. Conventional and high-resolution karyo-types (650 bands) were normal in both children.FISH analysis with probes for 22q11 deletion and forthe 3p region and chromosome 3 painting failed todemonstrate deletion or rearrangement in Patient 8.Subtelomeric FISH screen was normal in patient 9.Neonatal screening for hypothyroidism was normalin both (TSH and T4) and control of thyroid functionin patient 9 was normal at age 4 years.

FIG. 7. Patient 8 soon after birth. a, b: Microcephaly, severe blepharophi-mosis and narrow mouth; (c) abnormally grooved root of the penis, (d) cleftpalate.

1290 VERLOES ET AL.


A diagnosis of severe Ohdo syndrome wasinitially proposed for this family. However, theircatastrophic evolution and severe microcephalywere nevertheless considered incompatible with thisdiagnosis.

Family 8

Patient 10 (Fig. 9). The first patient of thisfamily was previously reported in this journal asOhdo syndrome (Patient 2 in [Maat-Kievit et al.,

1993]). This patient died at age 25 years of metastaticprostate cancer (Fig. 9).Patient 11 (Fig. 10). This child is the son of

the sister of patient 10 (Fig. 10). The parentsare nonconsanguineous. He was born at 37 weeksvia caesarean because of a complicated breechposition. His birth weight was 2,960 g (�1.1 SD).Hewas irritable in theneonatal periodwithmoderatefeeding problems that gradually diminished. He wasnoted to have apparent hypertelorism with appar-ently short palpebral fissures, a low bridge of thenose with a short nose, and anteverted nostrils, thickalae nasi, markedly grooved philtrum, micrognathia,low set protruding ears with rounded helices, foldedon the right side. The hands and feet were normal.He had normal male genitalia with normally des-cended testes. At age 14 weeks, his muscle tone hadimproved. The patient had splints for right-sided hipdysplasia. His weight was 4.2 kg (�1.7 SD), and hisOFC was 39 cm (�0.15 SD). There was persistentmarked blepharophimosis, hypertelorism, and epi-canthus. The inner canthal distance was 28 mm(>>þ 2 SD) and the outer canthal distance was of

FIG. 8. Patient 9 soon after birth. a, b: Similar facial features as patient 8; (c) blepharophimosis; (d) abnormal penile shape; (e) abnormal position of toes; (f) adductedthumbs.

FIG. 9. Patient 10 during adolescence. a, b: Note triangular shape of the face,upturned nose with thick alae nasi, and thick facial appearance; (c) abnormallyshaped fingers with enlarged joints and clinodactyly of the fifth digit.

FIG. 10. Patient 11 in infancy: a,b. Note blepharophimosis, swollen aspect ofperiorbital tissues, thick philtrum folds, thick earlobes with uplifted lobules,thick alae nasi with a marked angulation between the nares and the nasal tip.



70 mm (þ1 SD). At follow-up at age 9 months, con-tact was adequate for age. The patient was bimanu-ally manipulating objects. The feeding problems hadresolved. Hearing was considered normal, but aformal hearing test was scheduled at age 11 months.

Investigations showed normal male karyotype onG-banding (650 bands), normal telomere screen byMLPA, and normal results of a X-chromosome full-coverage BAC array screening for submicroscopicdeletions and duplications [Veltman et al., 2004].

Because of the striking resemblance to his uncle, adiagnosis of Ohdo was considered. After exclusionof unbalanced subtelomeric translocations, X-linkedrecessive inheritance is the most likely explanationfor the recurrence.

DISCUSSION

In 1986, a particular combination of blepharophi-mosis and mental retardation allowed Ohdo todelineate a MCA syndrome in two sibs and one oftheir cousins [Ohdo et al., 1986; Madokoro et al.,1987]. This initial paper was followed by several casereports describing children with this combination. Atthis moment, approximately 20 cases have beenreported as Ohdo syndrome, including familial[Ohdo et al., 1986; Madokoro et al., 1987; Dawsonet al., 1997; Mhanni et al., 1998] and sporadic cases[Say and Barber, 1987; Biesecker, 1991; Melnyk,1994; da Silva Lopes and Guion-Almeida, 1997;Lopez and Guion-Almeida, 1997; Rasmussen andStromme, 1998; Stoll, 1999; Day and Fryer, 2004].Twelve patients with blepharophimosis and heartdefect were reported by Ohdo’s team, including theoriginal Ohdo family and three other patients(patients 4, 5, and 12) with mental retardation [Ohdoet al., 1986; Sonoda et al., 1988, 1989]. These patientswere not sufficiently described to allow preciseclassification. The combination of blepharophimosisand hypothyroidism due to thyroid hypoplasiadescribed by Young and Simpson was seen inseveral sporadic patients [Young and Simpson,1987; Fryns and Moerman, 1988; Cavalcanti, 1989;Nakamura and Noma, 1997; Masuno, 2001]. Theeight reportedpatients showathyreosis or congenitalhypothyroidism, congenital heart defects (e.g., VSDand ASD), a facial dysmorphism (sloping forehead,bulbous nose, low set ears, micrognathia) reminis-cent of the syndrome reported by Ohdo (butless striking), cryptorchidism in males, hypotonia,mental retardation, and postnatal growth retarda-tion. All eight cases were sporadic, and most caseswere reported in stillborn or young infants. Parentswere consanguineous in the single case reported byBonthron.

Patients with terminal deletion of short arm ofchromosome 3 have microcephaly, blepharophimo-sis, epicanthus, upturned nose, long philtrum, andpolydactyly. Heart and kidney malformations are

often present [Maurer et al., 1979; Nienhaus et al.,1992]. Patients with interstitial deletions of the shortarm of chromosome 3, also delineated by Ohdo’steam have blepharophimosis, heart defect, and jointlimitation [Naritomi et al., 1988]. Patients withinterstitial deletions of the long arm of chromosome3 are characterized by blepharophimosis and epi-canthus inversus (due to hemizygocity for the BPESgene), ptosis, microphthalmia, heart defect, and clubfeet [Alvarado et al., 1987; Fujita et al., 1992].

To some observers, Ohdo syndrome, as definedclassically, is heterogeneous. The family reported byOhdo had an inheritance pattern that was suggestiveof a cryptic rearrangement. Moncla et al. [1995] firstpointed to the overlap of Young–Simpson syn-drome, Ohdo syndrome, and del(3)(pter) syndrome.Clayton-Smith et al. [1994] proposed to separateOhdo syndrome (for the original family) and Ohdo-like syndrome, an entity that encompassed most ofthe patients described as Ohdo syndrome. Finally,Marques-de-faria et al. [2000] make the assumptionthat Ohdo syndrome and Young–Simpson syn-drome may belong to the same clinical spectrum.

Blepharophimosis and mental retardation syn-dromes (BMRS) are not limited to Ohdo, Young–Simpson and chromosome 3 rearrangement syn-dromes. Indeed, this combination of features isrelatively non-specific, and may occur in manydevelopmental anomalies [Cunniff et al., 1998] Otherentities should be considered, because their over-lapping phenotype may relate them to the groupof patients discussed here, with the same caveaton possible cytogenetic etiology. These othersyndromes include: ROCA-Wiedemann syndrome[Wiedemann et al., 1985], Buntinx–Majewski syn-drome [Buntinx and Majewski, 1990], and a blephar-ophimosis syndrome with severe IUGR [de Die-Smulders et al., 1993]. Of special interest is thefamilial blepharophimosis syndrome reported byNowaczyk and Sutcliffe [1999]. These two sibshad blepharophimosis, ptosis, midface hypoplasia,dysplastic ears, trigonocephaly, fused incisors, lar-yngomalacia, sensorineural hearing loss, genitalanomalies (hypospadias or hypoplastic labiae), andmental retardation. Other well-defined clinical enti-ties show blepharophimosis and MR, as the blephar-ophimosis-lymphoedema syndrome (with intestinallymphangiectasis) [Hennekam et al., 1989], Dubow-itz syndrome, or the fetal alcohol syndrome.

The 11 patients reported here show an associationof blepharophimosis (11/11), round face withcharacteristic nasal shape (8/11), narrow mouth,and MR. These most obvious features (blepharophi-mosis and mental retardation) and Gestalt wereconsistent with Ohdo syndrome, in its ‘‘historical’’sense. Patients 1–3 have the typical aspect of Ohdosyndrome. Because of congenital hypothyroidism,patients 4 and 5 were diagnosed as Young–Simpsonsyndrome. In family 6, characterized by seizures,

1292 VERLOES ET AL.


severe speech delay, splenomegaly and normoce-phaly, the mild phenotype and borderline hypothyr-oidism make difficult to distinguish between mild/atypical Ohdo and mild Young–Simpson syndrome.In family 7, severe congenital microcephaly, abnor-mal brain structures with hypsarhythmia, cleft palate,adducted thumbs, and abnormal penile shapeseemed unusual and/or too severe for Ohdosyndrome. In family 8, the clinical features of patient11 were consistent with mild Ohdo, whereas hisuncle (patient 10) has a syndrome reported initiallyas Ohdo, but with distinctive coarsening of the faceand, in retrospect, different Gestalt, at least inadulthood. These inconsistent observations and ourdithering diagnoses lead us to review the literatureand controversies on BMRSs, and lead us to considerthat ‘‘Ohdo syndrome’’ and ‘‘Young–Simpson syn-drome’’ were both obsolete and misleading diag-nostic categories.

A Clinical Classification of Blepharophimosis-Mental Retardation Syndromes (BMRS)

Based on our review of the literature and on ourexperience, we suggest the following clinical classi-fication for the syndromes commonly classified asOhdo, Ohdo-like, or Young–Simpson syndromes(Table II).BMRS due to del(3)(pter). None of the

patients reported as Ohdo or Young–Simpson havea known chromosome 3 anomaly, but it seems likelythat some of them may have cryptic rearrangements.The 3pter deletion has some distinguishable fea-tures, as trigonocephaly and postaxial polydactyly,but those signs are not common. Congenitalhypothyroidism was not reported in children withdel(3)(pter). Patients with congenital hypothyr-oidism are less likely to carry an overlookeddel(3)(pter) but coincidental anomaly or low pene-trance of this trait may reconcile athyreosis andchromosome 3 anomaly. For instance, the patientreported by Cavalcanti [1989] as Young–Simpsonsyndrome with trimelic postaxial polydactyly couldhave a 3p deletion.BMRS, Ohdo type. This form is limited to the

original patients of Ohdo, and may indeed corre-spond to a cryptic familial rearrangement. Shortphiltrum, mild blepharophimosis, normal growthparameters, absenceof limbdefects, proteinuria, andabsence of hypotonia distinguish this type from thefollowing ones. Interestingly, Ohdo never men-tioned any abnormalities of the nose in his five cases,which is the second most important hallmark of theother BMRS.BMRS SBBYS type (or Say–Barber/Bie-

secker/Young–Simpson type). This entrymerges Ohdo syndrome in the common sense(corresponding to the Ohdo-like syndrome deli-neated by Clayton–Smith) and Young–Simpson

syndrome. Table I summarizes literature cases,separated into two groups by their original diag-noses. Although the facial phenotype is particularlystriking in some patients (for instance in Biesecker’sreport), most reported patients have milder, thoughdistinctive facial traits: round face, nose with a largeto bulbous tip, small and/or dysplastic, thick, simpleor overfolded pinnae, thick, swollen cheeks, andretrognathia. This facial appearance changes overyears, but these changes have seldom been men-tioned. Figure 1 shows changes of the facial pheno-type during infancy in one of our patients. Thepattern of malformations observed in BMRS typeSBBYS iswidebut variable: heart defects, cleft palate,and auricular pits are common. Several patients haveorthopedic problems, including patellar hypoplasia,joint stiffness, camptodactyly, or talipes. Opticatrophy and conductive or sensorineural deafnessare repeatedly reported, but few are known of thenatural history of these sensory problems. Patient 1and to a lesser extent Patient 3 have severeswallowing deficiency, which have not been men-tioned before. The teeth in patients with Ohdo-likesyndrome were reported to be small and sometimeswidely spaced, but normally shaped, without den-tine or enamel dysplasia. The diagnostic value of this

TABLE I. Comparison of 22 Patients With BMRS, SBBYS Type,Subdivided Into Two Groups Based on Their Original Diagnosis:14 Patients Reported as Ohdo or Ohdo-Like Syndrome (OLS), andEight Patients With Young–Simpson (YSS) Syndrome, Illustrating the

Clinical Overlap and Distinction of the Syndromes

Features OLS YSS

Sex 7M:7F 5M:3FGrowth retardation (post natal) 5/13 6/7Mental retardation 13/13 7/7Hypothyroidism 0/14 8/8Hypotonia 10/11 7/7Microcephaly (postnatal) 3/13 3/7Seizures 2/14 2/6Brain structural abnormalities 1/7 3/8Blepharophimosis 14/14 8/8Eyes abnormalities 8/9 2/6High-nasal bridge 1/11 3/7Wide/depressed nasal bridge 10/11 4/7Bulbous nasal tip 11/13 8/8Thin lips 6/13 3/6Long philtrum 5/14 4/7Small mouth 9/14 6/8Cleft palate 1/14 3/8Hypoplastic teeth 11/13Micrognathia 9/13 8/8Preauricular pits 2/13 3/7Low set/dysmorphic ears 10/14 8/8Clinodactyly of the fifth finger 6/14 3/7Camptodactyly 3/14 2/7Polydactyly post axial 0/14 1/6Overlapping toes 5/14Single palmar creases 5/14 5/7Heart defects 5/14 5/811 pairs of ribs 1/7 2/7Undescended testes 7/7 5/5Asphyxia 6/8Polyhydramnios 2/8



feature is nevertheless questionable, as appraisal ofthismicrodontia remains subjective. Furthermore, nomorphometric analysis is available for the dentitionin this group. The degree of mental retardation isvariable, from mild to moderate. Interestingly,several patients in this series have disproportionatespeech delay despite normal hearing. Hypothyroid-ism and polydactyly (in some) seem the onlydistinctive features of Young–Simpson syndrome.Microdontia was not reported, but this is age-dependent and may have been overlooked. Hypo-plastic patellae were seen in one patient with Ohdosyndrome [Day and Fryer, 2004] and in patient5 (present report), who warrants a diagnosis ofYoung–Simpson syndrome. Patient 4 showspreaxialpolydactyly, instead of postaxial. Family 6 in thisreport, with mild, late onset thyroid dysfunctionappears to fill the gap between those with normaland those with congenitally defective thyroidfunction.

BMRS type SBBYS, as defined here, remains aclinically heterogeneous condition. Some clinicaltraits show remarkable variability, in particular theOFC. As all published cases but one were sporadic,we have no way to appreciate intrafamilial varia-bility. In the same manner as for any purelydysmorphic syndrome, the setting of minimal criteriato retain or reject a diagnosis of BMRS relies on asubjective impression, which can vary with age orethnicity, but also with the experience and theconviction of the dysmorphologist. The experienceof the authors is that for years, in each dysmorphol-ogy meeting, there are some case reports of possible/probable Ohdo leading to discordant opinions inthe audience. Patients 6 and 7 in this series, forinstance, have a slightly different phenotype withsplenomegaly and a face, which is less characteristic.Because this family is the only one in whichautosomal recessive inheritance is likely (XLR orgonadal mosaicism are other possibilities), it may bethe seed for the delineation of a distinct AR typeof BMRS. On the other hand, the main clinicaldifferences among these two patients and the othersare qualitative (less-striking phenotype, not discor-dant phenotype). For this reason, we have tabulatedthem separately, but under the same heading, inTable II.

Furthermore, BMRS type SBBYS is likely to becausally heterogeneous. Several arguments point tothe possibility of autosomal dominant inheritance.Parental age is high in some reports, but theinformation is lacking in most of them. Autosomaldominant single gene mutation or de novo chromo-somal rearrangement seems possible in many cases.The family reported by Mhanni et al. [1998] is theonly one to show mother-to-child transmission,reinforcing the latter hypothesis. By contrast, par-ental consanguinity was reported in one sporadicYoung–Simpson case and recurrence is now shown

TABLE

II.

Signifi

cantEle

ments

forth

eD

iffe

rential

Dia

gnosi

softh

eBM

RS

Syndro

mes

Type

ofBM

RS:

Del3

pO

hdo

SBY

SSM

aat–

Kie

vit–

Bru

nner

Verloes

Pat

ientre

port

——

1–5

6.7

8.9

10.1

1Ble

phar

ophim

osi

sM

ild

tose

vere

Mild

Mild

tose

vere

Mild

Mild

Sever

eLa

rge,bulb

ous

nose

Abse

ntto

Mild

Abse

nt

Mild

toch

arac

terist

icM

ild

Mild

Char

acte

rist

icEar

pits

Som

etim

es

No

Com

mon

Abse

nt

Abse

nt

Abse

nt

Pro

gnat

his

mAbse

nt

Pre

sent

Abse

nt

Abse

nt

Abse

nt

Abse

nt

Mic

roce

phal

yPre

sent

Var

iable

Var

iable

Abse

nt

Sever

eThic

kenin

goffa

cial

trai

tsAbse

nt

Abse

nt

Abse

nt

Abse

nt

Pre

sent

Bra

inM

alfo

rmat

ion

Unco

mm

on

Abse

nt

Unco

mm

on

Abse

nt

Abse

nt

Pre

sent

Men

talre

tard

atio

nM

odera

teto

seve

reM

ild

tom

odera

teM

ild

tom

oder

ate

Mild

tom

oder

ate

Moder

ate

tose

vere

Sever

eH

ypoto

nia

Pre

sent

Abse

nt

Pre

sent

Pre

sent

Pre

sent

Pre

sent

Seiz

ure

s?

Abse

nt

Unco

mm

on

Pre

sent

Abse

nt

Sever

eH

ypoth

yro

idis

mAbse

nt

Abse

nt

Var

iable

Pre

sent,

late

onse

tAbse

nt

Abse

nt

Poly

dac

tyly

Pre

sent,

inco

nst

ant

Abse

nt

Pre

sent,

inco

nst

ant

Abse

nt

Abse

nt

Abse

nt

Oth

erdis

tinct

ive

feat

ure

sTrigonoce

phal

ySh

ort

philtrum

,pro

tein

uria

Smal

lteeth

,optic

atro

phy,j

oin

tankylo

sis

Sple

nom

egal

yAdduct

ed

thum

bs,

genital

anom

aly

SBBY

Sty

pe

issu

bdiv

ided

intw

ose

ts(s

ee

dis

cuss

ion).

1294 VERLOES ET AL.


(family 6). Thus, both autosomal dominant BMRStype SBBYS and autosomal recessive BMRS typeSBBYS could be delineated. Unfortunately, up tonow, there is no clinical clue to distinguish betweenthe two varieties, and presence or absence of thyroiddysfunctionorpolydactyly cannot beused to achievethis. Subtle differences in the phenotype mayemerge: The autosomal recessive form may haveless severe dysmorphic features (as illustrated byfamily 6) and thyroid dysfunction or polydactyly maybe limited to (but not characteristic of) this type.Practically, the distinction between autosomal reces-sive and dominant types is currently impossible insporadic patients.

As stressed before, we suspect that some patientspublished as Ohdo or Young–Simpson syndromemay indeed have cryptic chromosome 3 rearrange-ments. It is of major importance that any new reportof BMRS type SBBYS should only be accepted if 3pdeletion and/or telomeric rearrangements are prop-erly excluded. Kondoh’s patients, reported asYoung–Simpson syndrome, had thyroid hypoplasia,bilateral macular degeneration, talipes, and patellardislocation [Kondoh et al., 2000]. The retinal anomalyseems distinct from the optic nerve atrophy reportedin other BMRS type SBBYS cases. Additional reportsare needed to confirm whether Kondoh’s report isrecessive BMRS type SBBYS or another distinctrecessive entity.

BMRS, MKB (Maat–Kievit–Brunner) Type

This type is basedon amaternal uncle-nephewpairthat seems compatible with an X-linked mode ofinheritance (although a cryptic interstitial rearrange-ment is still a possibility). Whereas young patientswith this syndrome do resemble mild BMRS syn-drome SBBYS type, the phenotype in adulthood isclearly distinct: Patient 10 had coarse facial features,thick alae nasi, triangular face, and a Gestalt that isnot of the SBBYS type, whereas this man, in infancy,and his young nephew had a BMRS type SBBYSphenotype.

BMRS, V (Verloes) Type

This entry is proposed for the family 7, whichshows distinctive anomalies such as severe micro-cephaly, severe epilepsy, adducted thumbs, abnor-mal genitalia, and normal thyroid function. Thisfamily is suggestive of AR autosomal recessive orX-linked inheritance. Only Nowaczyk’s report of twosibs [Nowaczyk and Sutcliffe, 1999] can be comparedto our probands. The children reported by Now-aczyk, born to unrelated parents, had very mildblepharophimosis, ptosis, midface hypoplasia,abnormal palate, trigonocephaly, dental anomalies,laryngomalacia, sensorineural hearing loss, genitalanomalies, hypotonia, and mental retardation. Their

facial anomalies were much less striking than thecases reported here. Telomeric screen was notperformed.

The previously delineated Ohdo syndrome was aclinically and genetically heterogeneous entity thatshould be removed from the dysmorphology litera-ture, and Young–Simpson syndrome was artificiallydelineated because a facultative anomaly (hypothyr-oidism) was considered to be a mandatory key sign.We present here a more analytic appraisal of theBMRS phenotype. A definite etiologic classificationof syndromes with blepharophimosis and mentalretardation is still needed: our tentative classificationinto five groups should be viewed as a preliminarystep in the revision of this family of disorders.Although this classification scheme is not definitive,two conclusions are clear. First, it is not the case thatall patients with blepharophimosis and mentalretardation have the same syndrome (Ohdo blephar-ophimosis-mental retardation syndrome). The sec-ond is that geneticists and counselors should giverecurrence risks for BMRS with the understandingthat some cases may be autosomal recessive or X-linked recessive.

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