Brief Clinical Report

Acro-Oto-Ocular Syndrome: Further Evidence for aNew Autosomal Recessive Disorder

Debora R. Bertola, Linda M. Wolf, Helga V. Toriello, and Michael L. Netzloff*Department of Pediatrics and Human Development, Division of Medical Genetics, Michigan State University,East Lansing, Michigan

We report on a patient born to consanguin-eous parents and presenting with pseudo-papilledema, mixed hearing loss, and minorfacial and limb anomalies. To our knowl-edge, there is just one similar description ofthis syndrome in three members of a Brazil-ian kindred whose parents were also con-sanguineous, suggesting autosomal reces-sive inheritance. We compare the findings ofour patient with these previous reportedcases and discuss the differential diagnosesof this new syndrome, which we suggest benamed the acro-oto-ocular syndrome. Am. J.Med. Genet. 73:442–446, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: pseudopapilledema; mixedhearing loss; consanguinity;autosomal recessive inheri-tance

INTRODUCTION

In 1991, Paes Alves et al. reported on three patientsin two sibships in a large kindred from Brazil with apossible new autosomal recessive syndrome comprisingpseudopapilledema, mixed hearing loss, absence of sul-cus orbitopalpebralis superior, apparent ocular hypo-telorism, downslanting palpebral fissures, broad baseof the nose, malformed external ears and micrognathia;short fingers, partial cutaneous syndactyly, hypoplasiaof thenar, hypothenar, and interdigital areas, palmarkeratosis; small feet with peculiar shape, broad spacebetween the first and second toes, and zygodactyly. Theparents of these three patients were consanguineous.

We describe here a man who has many of the anoma-

lies of this new syndrome. He is also a product of aconsanguineous mating, providing further evidence forautosomal recessive inheritance.

CLINICAL REPORT

DF is a 23-year-old man who was born at term (39weeks) to a 16-year-old mother after an uncomplicatedpregnancy. Birth weight was 2,430 g (3%), length 49.5cm (25%), and head circumference 34 cm (<50%). Apgarscores were 7 and 10 at 1 and 5 minutes, respectively.He was adopted at age 1 day. The patient’s biologicalmother was 165 cm tall (75%) and weighed 56 kg (50%)and his father was 172.5 cm tall (25–50%) and weighed65 kg (75%) at age 17. They are brother and sisterwithout evident defects.

During his first 6 months, he had reported episodesof choking and blue spells. Chest radiograph, electro-cardiogram, electroencephalogram (EEG), and sweatchloride test were normal. His first teeth did not eruptuntil 15 months. As a child, he had several hospital-izations for failure to thrive and bronchitis. From theage of 5 to 9, he essentially did not grow. During thistime, multiple episodes of otitis media were diagnosed.At age 5, he was found to have papilledema; results oftwo cranial computed tomography (CT) studies werenormal. When the patient was 11 years old, he wasseen for the first time by the Genetics Service of theUniversity of Michigan and a diagnosis of Johanson-Blizzard syndrome was suggested, based on his failureto thrive (his height was 126 cm and his weight 24 kg,both below the third centile) and facial anomalies.Chromosomes and results of urine metabolic screenswere normal. It was concluded that he had a pseudo-papilledema. He was also seen by an endocrinologistand a growth hormone profile was requested, includinggrowth hormone releasing factor and arginine insulintolerance tests, which showed suboptimal responses.He received growth hormone therapy for 3 years (fromage 13 to 16 years), with some improvement in hisgrowth. His psychomotor development is not known indetail, but he was educated in a special education pro-gram. At age 18 years, he had a measured verbal IQ of90 and a performance IQ of 88, with a full scale of 88.

*Correspondence to: Michael L. Netzloff, Pediatrics and Hu-man Development, B-240 Life Sciences Building, East Lansing,MI 48824-1317.

Received 25 March 1997; Accepted 10 June 1997

American Journal of Medical Genetics 73:442–446 (1997)

© 1997 Wiley-Liss, Inc.

The patient has been followed for his hearing loss.Originally this was essentially conductive, but his lastaudiogram, performed last year, showed normal hear-ing through 2,000 Hz, gradually sloping to a moderatemixed hearing loss in the right ear and sloping mildlyto moderate mixed hearing loss in the left ear. He cur-rently uses a hearing aid in his left ear. In the last 4years, two EEGs were requested because of visual andaudiologic disturbances. The patient reported seeingflashing lights or fully formed figures which speak tohim and, at times, give him commands. Both studiesshowed an abnormal pattern of sharp theta and spikewave activity seen in the anterotemporal and centro-parietal regions.

PHYSICAL EXAMINATION

DF was seen by the Genetics Section of MichiganState University at age 23 years. He had a height of163.8 cm (<5%), weight of 48.3 kg (<3%), and head cir-cumference of 53 cm (<2%). He also had bitemporalnarrowing, synophyrs, slightly downslanting palpebralfissures, prominent nose with long columella extendingbelow the nasal tip and hypoplasia of the alae nasi,high arched palate, teeth with a red-brown coloration,coned second incisors and short canines, micrognathia,and relatively small and asymmetric ears. Right earlength was 6 cm (50%) and the left ear was 5.5 cm (1 SDbelow the mean). Although he appeared to have hypo-telorism, inner and outer canthal measurements (at 2.9cm and 8.6 cm, respectively) were within normal limits(Figs. 1, 2). Ophthalmoscopy showed bilateral pseudo-papilledema. Neck, cardiac, abdominal, and genitalfindings were normal. He had bilateral hypothenar hy-poplasia, palmar keratosis, short fingers and broadthumbs bilaterally (Fig. 3), short fifth metacarpal, es-pecially on the right hand; small feet, wide space be-tween the first and second toes, cutaneous syndactylyof the second and third toes, shortness of toe four on theright and shortness of the third and fourth toes on theleft foot, dysplastic nails (Fig. 4), and protruding cal-caneus.

DISCUSSION

The first description of patients with mixed hearingloss, pseudopapilledema, malformation of face, ears,hands, and feet inherited as an autosomal recessivesyndrome was published by Paes Alves et al. in 1991(MIM no. 264475).

The patient described here has most of the physicalmalifestations in common with the ones described inthe Brazilian kindred, although the facial anomalies inour patient are not so striking (Table I). It is especiallyinteresting to note that they all had a birth weightbelow the tenth centile and, during the first 6 monthsof life, two of the three Brazilian patients and our pro-positus had episodes of choking. Sometimes these epi-sodes could be severe, requiring a nasogastric tube toimprove food intake. Our patient’s growth during thefirst 6 months was consistently on the third centile, butdropped off after that. Partial growth hormone defi-ciency was diagnosed by formal growth hormone stimu-lation testing at 10 8⁄12 years, although his bone age at

that time was equivalent to 11 1⁄2 years. Of the threepatients described in the Brazilian kindred, only onehad a height below the third centile. Endocrine studiesto check for the possibility of a growth hormone defi-ciency in that case were not reported.

Another important characteristic that seems consis-tent in this syndrome is the history of delayed denti-tion. The first teeth usually erupted after age 15months. The permanent teeth also show abnormalitiesin number (supernumerary teeth or anodontia), color(reddish-brown), and shape (coned incisors and shortcanines).

Hearing loss in the Brazilian family was congenitaland mixed in type. Probably part of the component inthese patients is a consequence of the atresia of theexternal acoustic meati. This is not present in our pa-tient. Actually, his hearing loss was initially conduc-tive, probably aggravated by recurrent otitis media inhis childhood. It has been progressive, although not assevere as in the patients described by Paes Alves et al.[1991]. His most recent audiogram showed a mixedhearing loss. A CT scan of the temporal area could give

Fig. 1. Frontal view of the patient at the age of 23 years showing bi-temporal narrowing, synophrys, prominent nose, micrognathia.

Acro-Oto-Ocular Syndrome 443

us more information about which structures are in-volved in the hearing impairment presented by thesepatients.

One characteristic presented by our patient and notdescribed before are apparent hallucinations. Duringthe investigation, an EEG was performed on two occa-sions and showed an abnormal pattern secondary toirritative processes in the anterotemporal and centro-parietal regions. Although these abnormalities are in-dicative of cortical irritability and could be the site of aseizure focus, his symptoms are more consistent with apsychiatric disorder.

The three patients described by Paes Alves et al.[1991], a brother, a sister, and a cousin, were productsof a consanguineous marriage. In both sibships, theparents were first cousins. An autosomal recessive pat-tern was suggested based on this pedigree. Our pro-positus is a product of a brother/sister incestuous rela-tionship, which reinforces this pattern of inheritance.

Some of the anomalies in this disorder are quite un-usual, especially as a cluster, making the diagnosis ofthis new syndrome straightforward. One of theseanomalies is pseudopapilledema, which is a nonpro-gressive anomalous elevation of the optic nerve head,without the peripapillary edema, hemorrhages, andthe exudation into the physiologic excavation normallyseen in the true papilledema [Nelson, 1984]. In the

latter, there is a passive edema of the optic disk, re-sulting from increased intracranial pressure. In the pa-tient described here, two CT scans were performed andruled out intracranial hypertension.

Pseudopapilledema (MIM no. 177800) can occur asan isolated trait, inherited in an autosomal dominantpattern [Singleton et al., 1973].

Genetic syndromes with pseudopapilledema as amanifestation include Wildervanck syndrome (MIMno. 314600), which is characterized by hearing loss(usually sensorineural due to developmental inner earanomalies), ‘‘Klippel-Feil’’ anomaly, and Duaneanomaly [Keeney et al., 1992]. In 1969, Kirkham de-scribed two patients with the full triad of this conditionwho also presented with pseudopapilledema. There isan overwhelming preponderance of female cases, whichfavors X-linked dominant inheritance with lethality inthe hemizygous male [Cremers et al., 1984]. This syn-drome can be easily discarded in our patient since he ismale and does not have vertebral or eye movementanomalies. Bannayan-Riley-Ruvalcaba (MIM no.153480) syndrome is characterized by macrocephaly,pseudopapilledema, multiple hemangiomata, intesti-nal polyposis, and pigmented spotting of the penis

Fig. 2. Lateral view of the patient at the age of 23 years.

Fig. 3. Palmar keratosis, short fingers, broad thumb.

444 Bertola et al.

TABLE I. Clinical Findings in the Present Case Compared to the Ones Described byPaes-Alves et al. [1991]*

DescriptionCase 1

10 yearsaCase 2

8 yearsaCase 3

24 yearsaOur patient

23 years

GeneralConsanguineous parents + + + +Birth weight <10th centile + + + +Choking crises during

first year of life + + − +Short stature + − − +Mixed hearing loss + + + +Speech problems + + + −Retarded and incomplete

dental eruption + + + RetardedAbnormal EEG + − − +Mental retardation − − − −

HeadSmall head and face + + + +Low-set and malformed

external ears + + + AsymmetricPrehelicine fistulae − + − −Atresia of external

acoustic meati + + + −Synophrys − − − +Absence of sulcus

orbitopalpebralissuperior + + + −

Ocular hypotelorism + + + −Downward palpebral slant + + + +Blepharophimosis + + + −Epicanthal folds + + + −Pseudopapilledema + + + +Broad base of nose + + + +Hypoplasia of alae nasi − − − +High arched palate + + + +Abnormal shape of teeth − − − +Dark teeth + − − +Malocclusion of teeth + + + −Micrognathia + + + +

Neck and chestMultiple pigmented nevi − + + −Cafe-au-lait spots − + + −Pectus excavatum + − − −Kyphoscoliosis − − + −

LimbsShort fingers + + + +Broad thumbs − − − +Hypoplasia of thenar,

hypothenar, andinterdigital areas

+ + + Hypothenarhypoplasia

Abnormal palmar creases + + + +Single flexion crease on

finger 2, 3, and/or 5 + + + −Hypoplasia of

interphalangeal muscles + + + −Palmar keratosis + + + +Cutaneous syndactyly + + + +Small feet with peculiar

shape + + + +Broad space between toes

1 and 2 + + + +Shortness of toes 3 and 4 + − + +Zygodactyly + + + +Protruding calcaneus + + + +Abnormal knees and

bowed legs − − + −

*+ 4 present; − 4 absent. Modified from Paes-Alves et al. [1991], with permission of the publisher.aPatients described by Paes Alves et al.

Acro-Oto-Ocular Syndrome 445

[Dvir et al., 1988; Gorlin et al., 1992]. Our patient doesnot have any of these manifestations, besides the pseu-dopapilledema.

On the other hand, deafness is a common componentof many syndromes. It is estimated that about 30%among known hereditary examples of hearing loss aresyndromal [Reardon and Pembrey, 1990]. Otopalato-digital syndrome type I (MIM no. 311300) is an X-linked recessive condition characterized by distinctivefacial appearance, conductive hearing loss, short stat-ure, cleft palate, and generalized bone dysplasia [Gor-lin et al., 1990]. Another syndrome that presents withdeafness and craniofacial and limb anomalies is acro-cranio-facial dysostosis (MIM no. 201050). In this con-dition, affected persons have craniosynostosis, abnor-mal auricles and preauricular pits, mixed hearing loss,and craniofacial and digital anomalies [Kaplan et al.,1988]. The patient described here shows some of themanifestations of these two syndromes, but lacks im-portant characteristics, such as generalized bone dys-plasia and craniosynostosis. Besides, our patientpresents with pseudopapilledema and palmar kerato-sis, not described in these syndromes. Michels syn-drome (MIM no. 257920) is a rare disorder character-

ized by craniosynostosis, eye involvement, cleft lip andpalate, skeletal defects, mild mental retardation, anddeafness [Guion-Almeida and Rodini, 1995]. In thiscondition, the eye anomaly consists of a developmentdefect of the anterior segment of the eye and our pa-tient, as well as the patients described in the Braziliankindred, have abnormality in their fundi. Craniosynos-tosis, hypertelorism, eyelid anomalies, and cleft lip andpalate are other characteristics not seen in our patient,clearly differentiating Michels syndrome from the onedescribed here.

We suggest the name of this new syndrome, de-scribed originally by Paes Alves et al. [1991], to be acro-oto-ocular syndrome, based on the most striking mani-festations.

REFERENCESCremers CWRJ, Hoogland GA, Kuypers W (1984): Hearing loss in the

cervico-oculo-acoustic (Wildervanck) syndrome. Arch Otolaryngol 110:54–57.

Dvir M, Beer S, Aladjem M (1988): Heredofamilial syndrome of mesoder-mal hamartomas, macrocephaly, and pseudopapilledema. Pediatrics81:287–290.

Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA (1992): Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 44:307–314.

Gorlin RJ, Cohen MM Jr, Levin LS (1990): ‘‘Syndromes of the Head andNeck,’’ 3rd ed. New York: Oxford University Press, pp 686–670.

Guion-Almeida ML, Rodini ESO (1995): Michels syndrome in a Braziliangirl born to consanguineous parents. Am J Med Genet 57:377–379.

Kaplan P, Plauchu H, Fitch N, Jequier S (1988): A new acro-cranio-facialdysostosis syndrome in sisters. Am J Med Genet 29:95–106.

Keeney G, Gebarski SS, Brunberg JA (1992): CT of severe inner earanomalies, including aplasia, in a case of Wildervanck syndrome.AJNR 13:201–202.

Kirkham TH (1969): Cervico-oculo-acusticus syndrome with pseudopapill-edema. Arch Dis Child 44:504–508.

McKusick VA (1992): ‘‘Mendelian Inheritance in Man,’’ 10th ed. Baltimore:The John Hopkins University Press.

Nelson LB (1984): ‘‘Pediatric Ophthalmology.’’ Philadelphia: W.B. Saun-ders Company, pp 165–166.

Nover A (1981): ‘‘The Ocular Fundus. Methods of Examination and TypicalFindings,’’ 4th ed. Philadelphia: Lea and Febiger, p 78.

Paes-Alves AF, Azevedo ES, Sousa MGF, Almeida-Melo N, Oliveira-FilhoOJ (1991): Autosomal recessive malformation syndrome with minormanifestations in the heterozygotes: A preliminary report of a possiblenew syndrome. Am J Med Genet 41:141–152.

Pazzaglia UE, Beluffi G (1986): Oto-palato-digital syndrome in four gen-erations of a large family. Clin Genet 30:338–344.

Reardon W, Pembrey M (1990): The genetics of deafness. Arch Dis Child65:1196–1197.

Singleton EM, Kinsbourne M, Anderson WB Jr (1973):Familial pseudopap-illedema. South Med J 66:796–802.

Fig. 4. Wide space between the first and second toes, shortness of toefour on the right, and shortness of the third and fourth toes on the left foot,dysplastic nails.

446 Bertola et al.