fronto-otopalatodigital osteodysplasia: clinical evidence for a single entity encompassing...

Fronto-Otopalatodigital Osteodysplasia:Clinical Evidence for a Single Entity EncompassingMelnick-Needles Syndrome, Otopalatodigital SyndromeTypes 1 and 2, and Frontometaphyseal Dysplasia

Alain Verloes,1* Sylviane Lesenfants,1 Mason Barr,2 Dorothy K. Grange,3 Hubert Journel,4Jacques Lombet,5 Gert Mortier,6 and Elisabeth Roeder7

1Wallonia Center for Human Genetics, Liege University, Liege, Belgium2Division of Pediatric Genetics, University of Michigan Medical Center, Ann Arbor, Michigan3Division of Medical Genetics, Department of Pediatrics, Cardinal Glennon Children’s Hospital, St. Louis UniversitySchool of Medicine, St. Louis, Missouri

4Department of Pediatrics and Genetics, Vannes University Hospital, Vannes, France5Neonatal Intensive Care Unit, Liege University, Liege, Belgium6Center for Human Genetics, Ghent University, Ghent, Belgium7Medical Genetics, Prenatal Detection Unit, Valley Children’s Hospital, University of California San Francisco,Fresno, California

Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression incarrier females and comprises typical facialanomalies and a generalized bone dysplasiawith osteodysplastic changes, brachydac-tyly, and impaired survival. Recently sev-eral other severe malformations were re-ported in the condition. Melnick-Needlessyndrome is an X-linked dominant disorder.Affected males are usually sporadic cases.The exceptional males born to symptomaticwomen present with a lethal disorder com-prising generalized osteodysplasia, defi-ciency of the first ray, and facial anomaliesstrikingly similar to those of otopalatodigi-tal syndrome type 2. We report here on threeboys with classical, severe, and lethal oto-palatodigital type 2 syndrome, and threeboys with severe (lethal) Melnick-Needlessyndrome, born to affected mothers. Wesuggest that otopalatodigital type 1 and 2,Melnick-Needles syndrome and frontome-taphyseal dysplasia, sharing many clinicalmanifestations and a similar mode of inher-itance, are variants of the same condition:fronto-otopalatodigital osteodysplasia. Therelationships to similar syndromes (i.e.,Saint-Martin–Gardner–Morrisson syn-drome, serpentine fibula syndrome, atelo-steogenesis type 3, boomerang dysplasia,

and Yunis-Varon syndrome) are discussed.Am. J. Med. Genet. 90:407–422, 2000.© 2000 Wiley-Liss, Inc.

KEY WORDS: otopalatodigital syndrome;frontometaphyseal dyspla-sia; Melnick-Needles syn-drome; omphalocele; halluxhypoplasia; thumb hypopla-sia

INTRODUCTION

We report on a mild case of otopalatodigital syn-drome type 2 (OPD2), a severe case of OPD2 with cen-tral nervous system (CNS) anomalies and some mani-festations of frontometaphyseal dysplasia, a lethal caseof OPD2 similar to Melnick-Needles syndrome (MNS),and three unrelated boys born to mothers with MNS,one with a severe form, one with a lethal form, and anaborted fetus, in order to demonstrate that these phe-notypes are clearly related and may constitute a singleentity.

CLINICAL REPORTSFamily 1

Patient 1 is the only affected child of normal parents,who were 33 and 31 years old at the time of his birth.The family history was unremarkable. Pregnancy wasuneventful. He was delivered at term with a length of55 cm (>90th centile), a birth weight of 2,465 g (<10thcentile), and an occipitofrontal circumference (OFC) of34 cm (50th centile). The face was round (Fig. 1A) withbulging forehead, very large fontanels, hypertelorism

*Correspondence to: Prof. Alain Verloes, Centre UniversitaireWallon de Genetique, CHU Sart Tilman, B-4000 Liege, Belgium.E-mail: [email protected]

Received 19 July 1999; Accepted 1 November 1999

American Journal of Medical Genetics 90:407–422 (2000)

© 2000 Wiley-Liss, Inc.

with narrow, downslanted palpebral fissures, short,stubby nose with prominent root, microstomia witharched upper lip and downturned corners of the mouth,micrognathia, cleft palate, and posteriorly angulated,apparently low-set, abnormally modeled ears. Therewere redundant skin folds at the back of the neck. Thetrunk and limbs were normal but the hands were short,the thumbs were proximal, and the fingertips broad.There was cutaneous syndactyly II–IV bilaterally, andcamptodactyly of the index fingers. Nails were normal.The toes were fanned out, with a very short first ray,short, wide halluces with normal nails, cutaneous syn-dactyly II–IV and short toes V (Fig. 1B).

At 41⁄2 years, he was 105 cm tall (−2 SD), weighed 16kg, and had an OFC of 51.7 cm (mean). Numerous op-erations had been undertaken to correct oral and limbanomalies. He had a round face (Fig. 1C), hypertelor-ism with minor downslant of palpebral fissures, full,sagging cheeks, small, downturned mouth and pointed,mildly receding chin. Feeding was difficult and he stillrefused most solid food. He had recurrent urinary tractinfections (without structural anomalies) and multipleupper and lower respiratory tract infections, partiallyrelated to chronic tracheobronchomalacia. Psychomo-tor development was normal. Walking was hamperedby genua valga. Language was not delayed, but velo-pharyngeal insufficiency resulted in severe speechproblems.

Radiographs obtained soon after birth showed bowedlong bones, presence of both fibulae, and brachydactylywith brachymetapodia (Fig. 2A). The second to fifthmetacarpals were short, with a half-moon-shaped sec-ond metacarpal. The phalanges were undertubulatedand short, particularly the distal ones. In the feet,

metatarsal shortness was much more severe in rays IIand I: in ray I, the metatarsal and the proximal pha-langes were ovoid; in ray II, the proximal part of themetatarsal was not ossified (Fig. 2B). There was incom-plete duplication of the fifth ray. All phalanges werepresent.

The final diagnosis was typical OPD2.

Family 2

Patient 2 was a white boy born normally at 34 weeksof gestation to a then 29-year-old G3P2 mother. Be-cause of polyhydramnios and a history of a previouspregnancy that resulted in an abnormal male infantwho died shortly after birth, amniocentesis was per-formed and showed a normal 46,XY karyotype. Apgarscores were 3 at 1 min, 4 at 5 min, and 7 at 10 min.Birth weight was 2,435 g (75th centile), length 50.5 cm(90th centile), and OFC 30.5 cm (25th centile). The an-terior and posterior fontanels were large and confluentand the metopic and sagittal sutures were open fromthe glabella to the occiput. There was a bony ridge pal-pable across the lower forehead and superior orbitalregion. The palpebral fissures were downslanting (Fig.3A,B). There was marked hypertelorism. The ears weresmall, apparently low-set, and posteriorly angulated.The mouth and tongue were small. The palate was higharched, but there was no cleft. The neck was short. Thechest was bell shaped with costal flare and small, in-verted, wide-spaced nipples. The abdomen was normal.The genitalia were normal except for a relatively smallscrotum with palpable inguinal testes. There were flex-ion contractures of elbows, knees, and digits. There

Fig. 1. Patient 1. A: Facial appearance at birth. B: Feet (note syndactyly 2/3). C: Face at age 2.

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was ulnar deviation of the hands at the wrist. Thethumbs were small. There was overlap of the fifth digitover the fourth and of the second over the third digits.Partial syndactyly of digits III to V was present bilat-erally. The right fifth digit had a duplication of themiddle phalanx. There were only four toes on each foot,and the digits were medially deviated.

He required prolonged hospitalization after birth for

choanal stenosis, severe respiratory distress, and tra-cheomalacia requiring tracheostomy. At 31⁄2 months,he developed obstructive hydrocephalus requiring ven-triculoperitoneal shunt. A gastrostomy tube was placedfor feedings as he refused to take solids or liquids bymouth. Auditory brainstem evoked response tests per-formed at 4 and 16 months showed severe to profoundsensorineural hearing loss.

Fig. 2. Patient 1. Radiographs of (A) the hands and (B) the feet soon after birth.

Fig. 3. Patient 2. Appearance (A) soon after birth and (B,C)at age 5 months. Striking prominence of the orbital ridges, absence of proptosis, and severehypertelorism with downslanted palpebral fissures. Nose and mouth are similar to these of Patient 1.

Fronto-Otopalatodigital Osteodysplasia 409

At 3 1/2 years, he weighed 16.8 kg (+1 SD), was 94cm long (−1 SD), and had an OFC of 54 cm (+3 SD).Appearance was consistent with OPD2. There wasmarked macrocephaly with tall, wide forehead, frontalbossing, prominent bony supraorbital ridges, hypertel-orism with ptosis and downslanting palpebral fissures,depressed nasal bridge with a flat midface, and full andround cheeks. The mouth was small with downturnedcorners, and was usually held in an open position. Theteeth were normal in number for age, but werecrowded, and the palate was narrow and high arched.The ears were very small, apparently low set, and hadthick helices. At the age of 3 1/2 years, he was still ona home ventilator and was slowly weaning. He vocal-ized around the tracheal tube, but had no speech anddid not use signs. Developmentally, he was able to sitwhen propped up in a chair or a walker but could not sitindependently and was unable to ambulate. He playedactively with toys and turned the pages of a book.

Skeletal surveys performed at birth and at 18months showed very poor mineralization of the frontaland parietal bones, which has improved over time. Thesella was small. The mastoids were dense. The lowercervical spine was hypoplastic. There was an increasedinterpediculate distance in the lumbar spine, with de-creased antero-posterior diameter and flattening of thethoracic vertebral bodies. The chest was bell shaped.The ribs were thin and wavy with acute angulation ofthe fourth through the seventh ribs. There was hypo-plasia of the inferior iliac bones and bilateral coxavalga with subluxation. There was bowing of femora,tibiae, fibulae (which were not hypoplastic), radii, andulnae, and to a lesser extent, humeri. The distal hu-merus was hypoplastic. The radial heads were roundwith bilateral dislocation. The left thumb (Fig. 4) was

proximally placed. The second through fifth metacar-pals were short, with a half-moon shape of the secondmetacarpal. The proximal phalanges of the fifth digitswere also ovoid. The other phalanges were undertubu-lated and shortened, particularly the distal phalanges.On the right, there was duplication of the middle pha-lanx of the fifth finger. There was diffuse osteopenia.

The mother’s first pregnancy resulted in term maleinfant who survived for 3 hr and who had multipleanomalies similar to those of Patient 2, including digi-tal abnormalities, with only four toes on each foot, andcleft palate. No X-ray studies or autopsy were per-formed and no photographs are available. The mother’ssecond pregnancy resulted in a normal boy. The motherhas the facial changes seen in carriers of the otopalato-digital syndrome, including prominent orbital ridgesand marked fifth-finger clinodactyly (Fig. 5).

The final diagnosis was severe OPD2.

Family 3

Patient 3 was the first child of normal nonconsan-guineous parents. Spontaneous labor at 35 weeks ofgestation led to the birth of a boy (Fig. 6) with birthweight of 2,170 g (25th–50th centile), length of 45 cm(25th–50th centile), OFC of 33.2 cm (75th–90th cen-tile), and thoracic circumference of 30.5 cm. Craniumwas disproportionately large, with an anterior fontanelof 5 × 5 cm. The infant had hypertelorism (inner inter-canthal distance 29 mm), downslanted palpebral fis-sures, short, stubby nose, small mouth with down-turned corners, micrognathia, posterior cleft palate, avery small, bifid tongue (the tip of which did not reachthe lower gingiva), and small, apparently low-set, pos-teriorly angulated ears with thick, triangular-shaped

Fig. 4. Patient 2. Radiographs of hands at the age of 5 weeks. Shortness of metacarpals and phalanges. Note partial duplication of fifth finger, andhalf-moon–shaped second metacarpal.

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pinnae, with absent lobules and hypoplastic anthelix.The thorax was shield-shaped, with widely set, hypo-plastic nipples, and mild hypospadias (cleft prepuce).The arms were somewhat short. The thumbs were verysmall, with absent (right) or vestigial (left) nail, andthe left fifth finger was small. There was camptodac-tyly II to V and duplication of the third phalanx of theleft index finger and of both fifth fingers. The lowerlimbs were short and bowed, with ankylosis at kneesand ankles. The feet were short with symmetricequinovarus deformity, syndactyly IV–V, and absenthalluces. The child was very hypotonic and areactive.Despite intensive care and assisted ventilation, he diedon day 1. Necropsy findings were normal (no lung hy-poplasia) and brain was macroscopically unremark-able.

Radiographs (Fig. 7) showed a generalized osteodys-plasia, with bowed, dense long bones, and thick cortex.The fibulae were present. The metacarpals were short,dense, and undertubulated. The second metacarpal didnot show the half-moon shape noted in previous cases.The phalanges were short and wide, with a dense me-taphyseal rim. There was duplication of the distal pha-langes of fingers II and V, and apparent absence ofterminal phalanges of the thumbs. The pelvis was nar-row; the clavicles were long and the ribs were some-what irregular. Fibulae were present. Cranial vaultwas undermineralized, without wormian bones.

The Belgian mother was 27 years old. Her personaland family history were unremarkable. She had a largeface with hypertelorism (inner intercanthal distance:37 mm), slight antimongoloid slant of palpebral fis-sures, pointed chin, and normal palate (Fig. 8). She was172 cm tall, with normal hands and feet. Findings onskeletal survey were completely normal. She was con-sidered to have the typical facial appearance of anOPD2 carrier.

The final diagnosis was lethal OPD2.

Family 4

Patient 4 was a Hispanic boy born at 37 weeks ofgestation by cesarean section (breach presentation) to aG1, 28-year-old mother. Pregnancy was marked bypolyhydramnios. At age 27 days, he was 51 cm long(75th centile), weighed 2,700 g (10th centile), and OFCwas 34.2 cm (50th centile). The sutures were wide andthe anterior fontanel was large (7 cm). Facial anoma-lies (Fig. 9) included low frontal hair line, hypertelor-ism (which became more severe with skull growth),downslanting palpebral fissures, sparse eyelashes onthe lower lid, prominent cheeks, high nasal bridge,square nasal tip, deep philtrum, indentation in themiddle of the upper lip, downturned mouth corners,thick gingivae, normal palate, impressive microretrog-nathia, and normally set and mildly abnormal auricleswith prominent anthelix. The eyes were abnormal,with bilateral vascularized peripheral sclerocorneae,megalocorneae, and white pupils. There was pectus ex-cavatum, umbilical hernia, penile chordee with mildhypospadias, and cryptorchidism. There were bilateralcontractures at the elbows, and a connatal fracture ofthe left humerus. Anomalies of the limbs were symmet-ric. They included long, “spatulate” fingers, clenchedthumbs, ulnar deviation of finger II, ankylosis of thedistal interphalangeal joint in fingers II and III, clino-dactyly V, metatarsus adductus, laterally deviated,short halluces with extreme hypoplasia of the corre-sponding nails, prominent heels, and overlapping toes.Progressively, the skull became acroturricephalic, withocular proptosis. Failure to thrive was marked, withrecurrent chest infections. Development was delayed.At 81⁄2 months, he did not smile, roll over, sit, or coo. Aheart murmur was not investigated. Cooperation of thefamily was problematic, and several important exams[magnetic resonance imaging (MRI), complete cardiacand ophthalmologic investigations] were never per-formed, as he died suddenly at age 9 months. Necropsywas denied.

X-ray survey showed the following anomalies: mac-rocrania with midface hypoplasia and mandibular hy-poplasia, hypoplastic tooth buds, increased skull basedensity, scoliosis, flared ilium, dysplastic ischium withmedial deviation of its midportion, hypoplastic acetab-ular roofs, laterally hooked clavicles, bowed/angulateddiaphyses of humerus, radius, and tibiae, overmodeledfemora, serpentine fibulae, narrow, bell-shaped chest,and 13 pairs of thin ribs. Hands were normal. Therewere short halluces.

The mother has typical MNS. She was 132 cm tallwith small head (OFC 52.2 cm), widely spaced eyes

Fig. 5. Mother of Patient 2: flat face, broad nasal bridge, and prominentforehead.


(intercanthal distance 75th–97th centile), proptosis,prominent cheeks, and micrognathia (Fig. 10). Therewas rhizomelic shortness of the arms, bowed forearms,long, slender fingers with camptodactyly II–III–IV onthe right hand, curved fingers, and genua valga. Shehad had a stillborn brother (no other information avail-able). There was no parental consanguinity. Skeletalsurvey showed kyphoscoliosis, scalloped anterior end ofvertebrae, midface hypoplasia, mandibular hypoplasia,increased skull base density, flared ilium, hypoplasticpubis, bell-shaped thorax with thin, wavy ribs, over-modelled, and constricted, S-shaped diaphyses of longbones.

The final diagnosis was severe male MNS.

Family 5

Patient 5 is the first child of a 26-year-old Caucasianwoman. He was described briefly by Krajewska-Walasek and Kozlowski [1994]. The patient (Fig. 11)was stillborn at 36 weeks of a gestation marked by

oligohydramnios: Growth parameters included birthweight 1,400 g (<<10th centile), length 38.5 cm (<<10thcentile), OFC 29 cm (<<10th centile), and foot length63 mm. The skull was scaphocephalic, hypomineral-ized, and disproportionately wide. The infant hadhypertelorism (inner intercanthal distance 26 mm),downslanted, short palpebral fissures, wide beakednose, apparently low-set ears, microstomia with bowedupper lip and downturned corners, micrognathia, cleftpalate, and grooved tongue. The neck was short andwebbed; the thorax was short and deformed, with tho-racolumbar scoliosis. There was a large omphalocele(5 × 3 × 4 cm). The upper limbs were long, with bowedhumeri and forearms, shoulder and elbow ankylosis,and axillary and antecubital webbing. The thumbswere hypoplastic, and nails were lacking. Lower limbswere short and bowed. There was ankylosis of hips,subluxation of knees, and talipes equinovarus. The hal-luces were short and proximally placed, medially devi-ated, lacking the distal phalanx and nail. Cutaneous

Fig. 6. Patient 3, soon after birth. A: Face (postmortem). B: Shape of the anterior fontanel. C: Close-up of the abnormally modeled left ear. D:Appearance of the foot. E: Hypoplastic thumb with minute nail. F: Abnormal digital tips (note wide, biconvex nail of index finger and duplicated digit V).

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syndactylies extended from fingers III to V. Genitaliawere abnormal: small penis with hooded prepuce, bifidscrotum, and no urethral meatus. Karyotype was nor-mal, 46,XY. Necropsy showed tracheal stenosis, cystickidney dysplasia, hypoplastic ureters and bladder,

atretic urethra and nonregression of Mullerian ductswith uterus and atretic vagina. The testes were locatedin the abdomen. Macroscopic examination of the brainwas normal except for arhinencephaly.

X-ray (Fig. 12) studies showed hypomineralized cal-varia, gracile ribs, absence of first ribs, narrow pelvis,bowed femora, tibiae, and fibulae (which were not hy-poplastic), wide metaphyses, and wide metacarpalsand metatarsals. No phalanges were ossified in onethumb, and only the proximal phalanx was visible inthe other thumb and both halluces.

The mother had MNS. This diagnosis was made afterbirth of the propositus and confirmed by skeletal sur-vey. Based on family photographs, the mother’s sisterwas also affected.

The final diagnosis was lethal MNS.

Family 6

Ultrasonographic examination during the pregnancyof Patient 6 at 18 weeks showed a fetus with short,bell-shaped thorax, ascites, bowing of femora and ab-normal widening of thoracolumbar spine. On follow-upevaluations, the ascites became more pronounced witholigohydramnios, leading to fetal death at 24 weeks.The male fetus was severely macerated (Fig. 13). Afterremoval of the abdominal ascitic fluid, weight was 321g, crown-rump length 18 cm, crown-heel length 26.4cm, and OFC 15 cm. Remarkable were the webbedneck, subcutaneous edema, protuberant abdomen,small, dysplastic thorax, hypertelorism (inner inter-canthal distance 18 mm; OCD 36 mm), downslantingpalpebral fissures, hypoplastic and flat nose, appar-ently low-set ears, and micrognathia. There was a mid-line fusion defect of the mandible, U-shaped cleft pal-ate, and hypoplastic tongue apparently fixed to thefloor of the mouth. The abdomen was severely dis-tended with normal insertion of the umbilical cord,suggesting prune belly sequence. The genitalia were

Fig. 7. Patient 3. Radiographs of (A) narrow pelvis and thick, bowed femora and (B) hand: distal duplication of fingers II and V. Bones of relativelynormal length (compare with Patient 2). Note the shape of the second metacarpal.

Fig. 8. Mother of Patient 3. Prominent forehead, mild downslant of thepalpebral fissures (ptosis and facial asymmetry are artifacts).


male with an empty and small scrotum. Both thumbswere small, lacked a nail, and gave the impression thatthey were distally amputated. At the tip of boththumbs a horizontal groove was visible. The distal pha-

langes of the second and third fingers were ulnary de-viated and the distal phalanx of the fourth fingershowed radial deviation, most pronounced on the righthand. Partial cutaneous syndactyly was present be-tween fingers II to V. Both feet showed varus deformi-ty. The halluces were very small. Postaxial hexadactylywas bilaterally present with syndactyly V–VI. Autopsyshowed hypoplastic anterior abdominal wall muscles,malrotation of bowel, dilatation of left kidney with cys-tic appearance, dilatation of bladder and proximal partof the urethra, and absence of cervical spinous pro-cesses.

Radiographs of the skeleton (Fig. 14) showed ossifi-cation defects of the posterior part of the skull aroundand posterior to the foramen magnum, the major partof the orbits, and the midline of the mandible. Thespine was widened in the cervical region (probably dueto failure of fusion of some neural arches) and scolioticin the thoracolumbar part. The thorax was bell shapedwith 12 pairs of short ribs. The pelvis was character-ized by a flat acetabular roof and a widened appearanceof the iliac wings. The long tubular bones showed me-taphyseal widening and cupping with bowing of thediaphyses. Mainly the tibiae and ulnae were S-shaped.The metacarpals and proximal phalanges were mildlyshort and broad. The middle phalanges were roundedand half-moon–shaped and the distal phalanges hypo-plastic. The distal phalanx of the thumbs was absent.In the feet, only the metatarsals and proximal phalanxof the halluces were ossified. In both feet, five metatar-sals were visible.

The mother of Patient 6 was a 33-year-old womanwho was previously diagnosed as having MNS. She wasthe oldest daughter of healthy parents who were sec-ond cousins once removed. She had three unaffectedsisters and an unaffected, elder child. Psychomotor de-velopment was normal. When she started walking,bowing of the legs was noted. As a teenager, she un-

Fig. 9. Patient 4 at 8 months. A: Face showing proptosis, prominent supraorbital ridges (compare with Patient 2). B: Hands showing camptodactyly.

Fig. 10. Mother of Patient 4. Moderately facial expression of MNS.

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derwent surgery for severe scoliosis. At the age of 26years she had a height of 170 cm with a span of 173 cm,weight of 51 kg, and OFC of 56 cm. Remarkable werethe exophthalmia, pronounced micrognathia, fullcheeks, hypertelorism, and malalignment of numerous

teeth. She had a short thorax with pectus carinatumand kyphoscoliosis. The fingers had a long and slenderappearance and the lower limbs were bowed. On radio-graphs of the skeleton, tall vertebral bodies with ante-rior concavity at the thoracic level, cortical irregularity

Fig. 11. Patient 5. A: General appearance showing severe micrognathia, omphalocele, and dysplastic ears. B: Facial appearance similar to that ofPatient 2. Note absence of apparent proptosis. C: Hands with short thumbs. D: Feet with short halluces.

Fig. 12. Patient 5. Postmortem (disarticulated) fetal X-rays of (A) rib cage and axial skeleton, illustrating thin, wavy ribs; (B) upper limb; and (C) lowerlimb, illustrating variable bowing and undertubulation.


and ribbon appearance of the ribs, flat acetabular roofs,coxa valga with long femoral necks, and bowing of thelong tubular bones were noted.

The final diagnosis was lethal MNS.

DISCUSSION AND REVIEW

We review here the literature on OPD2 and MNS inorder to determine whether they represent a single en-tity, and discuss two other, genetically probably relatedsyndromes, otopalatodigital syndrome type 1 (OPD1)and frontometaphyseal dysplasia.

OPD2

OPD2 is a severe, X-linked disorder with minimalexpression in carriers and comprises a typical facialappearance, generalized osteodysplasia, and poor sur-vival. Initially reported by Fitch et al. [1976], the syn-drome was later designated as OPD2 by the same au-thor [Fitch et al., 1983]. Inheritance is usually consid-ered X-linked recessive, with mild expression in carrierfemales. At least 29 male cases have been reported in-sofar, some very incompletely [Fitch et al., 1976, 1983;Kozlowski et al., 1977; Andre et al., 1981; Kaplan andMaroteaux, 1984; Brewster et al., 1985; Shi, 1985;Farhud et al., 1989; Ogata et al., 1990; Stratton andBluestone, 1991; Blanchet et al., 1993; Holder and Win-ter, 1993; Young et al., 1993; Preis et al., 1994; Eccleset al., 1994; Nishimura et al., 1997]. The cases of Gen-dall and Kozlowski [1992] are now considered maleMNS cases (Robertson et al. [1997], vide infra).

In OPD2, intrauterine growth is usually normal andaffected infants have large anterior fontanels, broadforehead and lateral fullness of the supraorbital ridge,hypertelorism, downslanting palpebral fissures, stubbynose with a flat root, microstomia with typical down-turned bow of the upper lip, micrognathia, and mal-

formed and/or apparently low-set ears (24 of 24 pub-lished cases with sufficient data). Posterior cleft palatewas noted in 20 of 24, but glossoptosis or Robin se-quence only in two [Andre et al., 1981 (Patient 1);Ogata et al., 1990] . Thorax may be narrow [Andre etal., 1981 (Patient 1); Brewster et al., 1985 (Patients 1and 2); Farhud et al., 1989; Ogata et al., 1990; Nish-imura et al., 1997 (Patient 2)], sometimes with pectusdeformity [Brewster et al., 1985 (Patients 1 and 2);Preis et al., 1994] . Limbs are short and bowed, withrockerbottom or equinovarus feet. The hands and feethave a typical fanned appearance. Syndactyly is pres-ent frequently and usually involves fingers III and IVin the hands and toes II to V in the feet. Clenchedfingers or true camptodactyly is noted or visible on pub-lished pictures in most patients. The facial appearanceevolves with time, as illustrated in Family 1 and inFitch’s report [1983]: Cheeks become saggy, and micro-gnathia becomes less obvious.

X-ray films show hyperostotic, bowed long bones(femora, tibiae, forearms) that sometimes resembleboomerang dysplasia [Nishimura et al., 1997 (Patient1)]. Short, stubby, undertubulated metapodia are con-spicuous, with brachytelephalangy, severe hypoplasiaof the first ray and, to a lesser extent, of the second andfifth rays, often with a swollen aspect of the corre-sponding metapodia. Fibulae are absent or severely hy-poplastic (10/16). Accessory ossification centers may beseen in the second metacarpal, and second and thirdmetatarsals. Carpal or tarsal coalition has been notedin some survivors [Kozlowski et al., 1977 (Patient 1);Fitch et al., 1983 (Patient 1)]. The cranium showsthick, sclerotic base and delayed ossification of thevault. Ribs and clavicles are usually thin and irregularor wavy. Platyspondyly [Andre et al., 1981 (Patient 1);Fitch et al., 1983 (Patient 1)], scoliosis [Andre et al.,

Fig. 13. Patient 6. A: General appearance. B: Close-up of the hands showing brachydactyly, camptodactyly, and hypoplastic thumbs. C: Close-up ofthe face, disclosing the hypertelorism and downslant of the palpebral fissures (compare with Patients 2 and 5).

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1981 (Patient 1); Ogata et al., 1990; Blanchet et al.,1993], sacral defect [Blanchet et al., 1993], and coxavalga [Preis et al., 1994 (Patient 1)] may occur. Spon-taneous fracture was noted once [Preis et al., 1994 (Pa-tient 1)]. Skeletal deformities tend to diminish withtime: Femora straighten, platyspondyly regresses, andsclerosis diminishes [Kozlowski et al., 1977; Fitch etal., 1983].

Survival was less than 1 year in 11 of 18 reportedcases. Surviving children reach at least 10 years [Ko-zlowski et al., 1977] and have short stature. Psychomo-tor development varies from normal [Fitch et al., 1983(Patient 1); Kaplan and Maroteaux, 1984] to mild men-tal delay [Kozlowski et al., 1977 (Patient 2); Preis et al.,1994 (Patient 1)]. Petit mal seizures were noted in onepatient [Preis et al., 1994]. Deafness was noted in somepatients [Kozlowski et al., 1977; Andre et al., 1981;Fitch et al., 1983; Shi, 1985; Stratton and Bluestone,1991; Preis et al., 1994].

Whereas the disorder is fairly typical in many cases,several inconstant anomalies have recently been iden-tified in the condition (Table I). Many of them affect themidline. Some malformations seem to bear importantintrafamilial recurrence risk: omphalocele was ob-

served in three relatives of Young’s Case 1, and in thetwo brothers described by Riconda et al. [1991]; hydro-cephalus was present in all three cases in the familyreported by Stratton, and hallux was absent in the pro-positus and his maternal uncle in Shi’s report.

Expression of OPD2 in female carriers was reviewedby Preis et al. [1994] and clinical pictures were pre-sented by Young et al. [1991] and Preis et al. [1994].Wide forehead, hypertelorism, and downslanting pal-pebral fissures are the more obvious signs (4/7). Bifiduvula or cleft palate were noted in Fitch’s family, andabnormal eruption of teeth was present in Preis’scases. Skeletal survey is usually normal, except forminimal broadening of metacarpals [Preis et al., 1994(Patient 1)]. Obligate carriers may be totally asymp-tomatic [Ogata et al., 1990].

MNS

MNS or Melnick-Needles osteodysplasia is a rare X-linked dominant (or possibly autosomal dominant, sex-limited) condition with short stature and typical facialanomalies (prominent forehead, bulging eyes, fullcheeks, small chin with dental misalignment) reported

Fig. 14. Patient 6. A,B: Radiographs of the skeleton.


in less than 50 persons. X-ray images show delayedclosure of the anterior fontanel, sclerosis of the skullbase, micrognathia with an increased mandibularangle, thin wavy ribs, increased height of the vertebralbodies, and an S shape to the long bones [Krajewska-Walasek and Kozlowski, 1994]. No linkage analysis isavailable for this condition.

In familial reports of MNS, most cases are women,and the disorder in males is thought to be usually early

lethal in utero. Males with MNS usually are sporadiccases, with a disorder similar to what is seen in women.The topic was reviewed critically by Krajewska-Walasek and Kozlowski [1994]. Among 13 male casesreported as MNS, they considered ten to lack the mini-mal characteristics of MNS. Those patients were sug-gested to have other conditions, such as frontome-taphyseal dysplasia or serpentine fibula syndromes, orwere even normal. The “affected males” from the origi-nal families of Melnick and Needles were actually un-affected [Gorlin and Knier, 1982]. They concluded thatonly five bona fide sporadic male cases were known[Grosse and Bowing, 1980 (Patient 2); Theodorou et al.,1982; Fryns et al., 1988; van der Lely et al., 1991; Kra-jewska-Walasek and Kozlowski, 1994].

In four families, affected boys born to MNS mothersare known, including the early, partial report of Pa-tient 5 in this report. In contrast to the female charac-teristics, they show a variable pattern of anomalies,including curved, dysplastic bones with thin, irregularcortex, and vault hypomineralization similar to what isseen in female MNS cases. Intrauterine growth is nor-mal or retarded. In the report of Theander and Ekberg[1981], the affected premature stillborn boy (birthweight 1,300 at 27 weeks of gestation) had kyphosco-liosis, hypo/aplasia of the second phalanx of the thumb,absence of the first metacarpal bone and of the greattoes, and wide phalanges. Dense, homogeneous calcifi-cations surrounded the diaphyses of the long bones andwidespread calcified foci were present in the vicinity ofthe phalanges, mandible, clavicles, and ribs. An om-phalocele was present. Facial anomalies were not welldescribed, but “low-set” ears, micrognathia, and bilat-eral sclerocorneae were present. In the report of vonOeyen et al. [1982], the facial appearance of the af-fected child is strikingly similar to that of our Case 5(hypertelorism, sagging cheek, small mouth withdownturned corners, micrognathia). He also had om-phalocele, multicystic kidneys, nail hypoplasia ofthumbs and toes, and thick metacarpals. In the Don-nenfeld et al. report [1987], tetralogy of Fallot, atrio-ventricular canal, and urethral atresia with prunebelly sequence were present in a 16-week-old fetuswith protuberant eyes and micrognathia, but normalhands and feet.

The male stillborn infant reported by Deleporte et al.[1985] born to an MNS woman, and often quoted as anexample of male MNS, was likely to have trisomy 13(intrauterine growth retardation, cleft lip and palate,microcephaly, aplasia cutis of the vertex, urinary tractmalformations, and kidney hypoplasia).

OPD1

OPD1 is an X-linked disorder characterized by hy-pertelorism, prominent supraorbital ridges, abnormalpinnae, broad nasal bridge with small nose and mouth,and downward slant of palpebral fissures. Various digi-tal anomalies are present (brachydactyly with cone-shaped epiphyses, cutaneous syndactyly, flattened tipof thumbs, splayed “frog” feet with a short hallux, anda large gap between the first and second toes, and lat-

TABLE I. Rare Manifestations in OPD2

Manifestation References

Tracheal stenosis Preis et al. [1994], Patient 2Ventricular septal defect Andre et al. [1981], Patient 1Aortic stenosis Preis et al. [1994], Patient 1Hydronephrosis ±

urethral valve/refluxFitch et al. [1983], Patient 2;

Stratton and Bluestone [1991],Patients 2 and 3; Young et al.[1993]; Preis et al. [1991],Patient 1

Renal duplication Preis et al. [1994], Patient 2Short penis Young et al. [1993], Patient 2Hypospadias Farhud et al. [1989]; Stratton and

Bluestone [1991], Patient 3;Blanchet et al. [1993]; Young etal. [1993], Patient 3; Preis et al.[1994], Patient 1

Epispadias Stratton and Bluestone [1991],Patient 2

Cryptorchidism Fitch [1979], Patient 1; Preis et al.[1994], Patient 1

Omphalocele Riconda et al. [1991]; Blanchetet al. [1993]; Young et al.[1993]; Nishimura et al.[1997], Patient 2

Adrenal aplasia Blanchet et al. [1993]Ventral wall defect Eccles et al. [1994]Corneal clouding Stratton and Bluestone [1991]

Patient 3Iridoretinal coloboma Stratton and Bluestone [1991]

Patient 1Cerebellar hypoplasia Stratton and Bluestone [1991]

Patient 1Myelomeningocele/

encephaloceleStratton and Bluestone [1991],

Patient 2 and 3Hydrocephalus Fitch et al. [1983], Patient 1;

Stratton and Bluestone [1991];Young et al. [1993], Patients 1and 3; Nishimura et al. [1997],Patient 1

Articular ankylosis ofelbow, hip, and knees

Fitch et al. [1983], Patient 1;Ogata et al. [1990]; Stratton andBluestone [1991], Patient 1;Blanchet et al. [1993]; Young etal. [1993], Patient 1

Postaxial polydactyly Fitch [1979], Patient 1; Andre etal. [1981], Patient 3; Kaplan andMaroteaux [1984]

Thumb duplication Holder and Winter [1993]Duplicated third phalanx

of indexAndre et al. [1981], Patient 2;

Preis et al. [1994], Patient 2;Eccles et al. [1994]

Hallux aplasia Brewster et al. [1985], Patient 2;Shi [1985]; Ogata et al. [1990]

Thumb hypoplasia withnail hypoplasia

Stratton and Bluestone [1991],Patient 1

Anterior cleft palate Stratton and Bluestone [1991],Patient 1

418 Verloes et al.

eral curvature of the toes). The gene was mapped toXq26-28 [Biancalana et al., 1991; Hoar et al., 1992].

Frontometaphyseal Dysplasia (FMD)

This syndrome comprises patchy sclerosis and bonyovergrowth of the supraorbital ridges with a general-ized dysostosis that resembles MNS: undermodeledlong bones, thin and wavy ribs, wavy and bowed, back-ward-curved tibiae and fibulae. Inheritance is mostlikely X linked. Reardon et al. [1991] reported a some-what similar syndrome in two mentally retarded sibs:The girl was less severely affected than the boy. An-other ill-classifiable observation probably falling in thescope of FMD is the report of two half-brothers withsevere mental handicap, microcephaly, micrognathia,and massive supraorbital ridges [Jervis and Jenkins,1975].

Lumping FMD, MNS, OPD1, and OPD2

Lumping MNS and OPD2.

Combining OPD2 and MNS as a single disorder hasbeen suggested by some [Blanchet et al., 1993; Holderand Winter, 1993; Verloes et al., 1996; Robertson et al.,1997; Corona Rivera et al., 1999] and contested by oth-ers [Young et al., 1993]. This hypothesis relies on ge-netic similarity, and on two clinical arguments: resem-blance between unrelated cases with one or the otherdiagnosis, and presence of both phenotypes in the samefamily.

Classical OPD2 and MNS have distinct phenotypesbut the more severe OPD2 cases and male offspring ofMNS women have similar facial anomalies (comparePatients 4 and 5 of this report or the patients of Andreet al. [1981] with the patient of von Oeyen et al. [1982]),with a “fetal” appearance (compare Eccles et al. [1994]and Patient 6 or Donnenfeld et al. [1987]) and similarmalformations (omphalocele, urogenital anomalies).Interestingly, the bulging eyes that characterize MNSseem to be a progressive trait, as illustrated by Patient4. Facial and radiological findings of OPD2 and MNSmothers differ considerably in their “classical” expres-sion, being almost normal in the former, and severe inthe latter. Nevertheless, the most obvious carriers ofOPD2 (as Patient 3’s mother) facially resemble themildest cases of MNS. The degree of proptosis, so strik-ing in typical MNS carriers, is sometimes very mild,leading to a milder appearance, with large forehead,hypertelorism and mild micrognathia, without asym-metry, as illustrated in several reports [Fryns et al.,1979; de la Cruz Sevilla et al., 1980; Dereymaeker etal., 1986]. Conversely, some cases of OPD2 have strik-ing micrognathia [Holder and Winter, 1993].

Skeletal anomalies in male MNS are extremely vari-able. General “osteodysplasty,” deficiency in thumbsand halluces, the hypoplasia of fibulae, and the wavyribs are similar to OPD2. An important point is vari-ability in hand anomalies: Whereas OPD2 patientsusually show a consistent complex pattern of defects,hands in male MNS vary from normal to severe. Thevery specific half moon shape of the second metacarpal

is sometimes considered a hallmark of OPD2, but thismark may be lacking, as illustrated by Patient 3 of thisreport.

Recently, Robertson et al. [1997] described an inter-esting Maori pedigree, in which four males were bornto three sisters with a mild form of MNS (both radio-logically and facially). The four children died within 1month of birth. Striking anomalies included IUGR (4/4), craniofacial traits similar to those of previous re-ports (large fontanel, downslanting palpebral fissures,broad forehead, micrognathia; 4/4) and cleft palate (2/4), gastroschisis (1/4), or omphalocele (2/4), urinarytract anomalies (4/4), fanned out toes (3/3), camptodac-tyly (3/3), short hypoplastic or absent halluces (4/4) orfibulae (2/4). X-ray films showed several anomalies(broad and/or hypoplastic metacarpals and metatar-sals, bowed long bones, hypoplastic ilia, ribbon-likeribs). This family shows clearly overlapping pheno-types, and the facial anomalies of the depicted carriermother (who has radiological anomalies associatedwith MNS) strikingly resemble the mother of Young etal.’s [1993] Case 1. Interestingly, two of those childrenwere previously reported as OPD2 cases [Gendall andKozlowski, 1992] and this led to some debate betweenthe authors [Kozlowski, 1999; Robertson, 1999].

Lumping OPD1 and OPD2.

Although OPD1 and OPD2 share many findings,clinical differentiation is usually easy. The presence ofbowed long bones, lacking fibulae, fanned-out toes,flexed fingers, syndactyly, polydactyly, and the generalseverity of the acral X-ray anomalies usually allowclear distinction between the two phenotypes [Fitch etal., 1983]. Nevertheless, the overall similarity of phe-notype and similar inheritance lead to the hypothesisthat OPD1 and OPD2 are allelic. Indeed, the largepedigree published by Le Marec et al. [1988] as OPD1seems a perfect intermediate type. The propositus hasfacial traits almost identical to those of our Patient 1;changes of the hand radiographs are similar to those ofclassic OPD2; one of the patients has postaxial poly-dactyly, but the patients have straight, nonstubby di-aphyses and fibulae were present in all cases. Anotherpossible phenotypic overlap is the family reported byHorn et al. [1995], with OPD1 in one brother and OPD2in one other, but the clinical descriptions are inad-equate to form an opinion. We are not completely con-vinced by the case of Stoll and Alembik [1994]: He mayrepresent a transitional from between OPD2 andOPD1, or another entity, most likely Larsen syndrome.It should be noted that this clinical overlap betweenLarsen and OPD1 has been stressed by Spranger[1985]. Also notable are the foot deformity in mildMNS, which clinically and radiologically resemblesOPD1 [Dereymaeker et al., 1986].

Lumping FMD and MNS.

The clinical overlap of FMD with OPD1 and MNS,and a common mode of inheritance are strong argu-ments to consider FMD as an (allelic?) variant of the


latter conditions. Patient 2 of this report illustratesthis point: Skeletal appearance is typically OPD2-like,whereas the prominence of the supraorbital ridges re-calls FMD. Overlap of FMD with OPD1 and MNS isexemplified by the family reported as FND by Danks etal. [1972] and later re-published as OPD1 [Superti-Furga and Gimelli, 1987] and by the patient of Sellarsand Beighton [1978]. Glass and Rosenbaum [1995] re-ported a mildly affected mother with two severely af-fected sons, who died in infancy of congenital heartdisease (complex atrioventricular malformation).

Differential Diagnosis

Several entities share anomalies with the OPDs,MNS, or FMD, but, for several reasons, are likely to begenetically unrelated to them.

Other forms of osteodysplasia.

A precocious form of osteodysplasia has been delin-eated [Kozlowski et al., 1973], which is recessively in-herited, without minor anomalies, and with general-ized hypoplasia of fingertips and nails. Precociousosteodysplasia is clearly different from MNS, and rep-resents a possible variant of Yunis-Varon syndrome,similar to Patient 1 in Garrett et al. [1990].

The syndrome published as recessive MNS [ter Haaret al., 1982] probably is similar to the syndrome wedefined as megalocornea–mental retardation type 2syndrome [Verloes et al., 1993], but with glaucoma andsecondary megalocorneae rather than primary megalo-cornea.

Serpentine fibula syndrome (SFS).

Further complication in the nosology came from thedelineation of this entity consisting of growth retarda-tion, deafness, facial anomalies (arched eyebrows,blepharophimosis, long philtrum, “dysplastic” pinnae)hirsutism, short neck, metatarsus adductus, bowed ra-dii, S-shaped (“serpentine”) fibulae, and polycystic kid-neys [Exner, 1988]. The three reported cases are fe-male. Despite some overlap, the general gestalt andspecific differences make it unlikely that SFS is a vari-ant of MNS [Majewski et al., 1993].

Atelosteogenesis type 3.

This sporadic condition, delineated in males and fe-males [Stern et al., 1990] comprises skeletal anomalies(rhizomelic shortness and bowing of the limbs, absentor hypoplastic fibulae, multiple joint dislocations, andabnormalities of the hand bones), broad forehead, hy-pertelorism, flat nasal bridge, cleft palate, platyspon-dyly, and vertebral anomalies. Differentiation fromOPD2 relies on normal ossification of the skull, differ-ent shape of pelvis, segmentation defect and coronalcleft of vertebrae, quasinormal ribs, club-like femora,tombstone-shaped proximal phalanges, and differentcartilage histology.

Atelosteogenesis type 1 (AO1) and boomerangdysplasia (BD).

Nishimura et al. [1997] discussed this overlap. Clini-cally, these two lethal short-limbed dwarfisms are eas-ily discarded: The facial anomalies of OPD2 are lack-ing, and micromelia is much more severe, butradiological aspects deserve some comments. AO1 is asporadic disorder. Undertubulation of the long bones islimited to the proximal femora and humeri (with distaltapering and proximal clubbing giving the appearanceof a golf club). Platyspondyly with coronal clefts andossification defects of the spine are much more pro-nounced in AO1 than in OPD2. Absent or hypoplasticcarpals, tarsals, metacarpals, metatarsals, and proxi-mal and middle phalanges are also distinctive.

BD is characterized by a boomerang-shaped tibia.The femora, humeri, ulnae, and radii are extremelyhypoplastic, or absent. Ossification of the spine, pubicbones metacarpals, and proximal and middle pha-langes is deficient. Hunter and Carpenter [1991] andGreally et al. [1993] suggested that AO1 and boomer-ang dysplasia are a single entity.

Slaney et al. [1993] reported on an affected male withBD, and his maternal uncle. Reviewing the literature,they suggested X-linked inheritance for this condition,thus opening the discussion to possible allelism withOPD2/MNS.

Saint-Martin–Gardner syndrome.

Two stillborn brothers were reported with bowedlong bones, and normal spine [Saint-Martin et al.,1978]. Skull was not ossified. Facial anomalies in-cluded hypertelorism, small nose, triangular-shapedmouth, micrognathia, tongue agenesis (1/2), and cleftpalate. In the elder child, halluces were absent andthere was unspecified syndactyly. In the second one,there were four fingers on each hand (thumb present),missing hallux (right), and two missing (unspecified)toes (left). Other anomalies included omphalocele andlack of fibulae. Multiple fractures (long bones, ribs)were present. The mother was 163 cm tall, and de-scribed as oxycephalic, with a prominent forehead. Herroentgenograms showed frontal hyperostosis. She losttwo brothers neonatally of unknown cause.

Gardner et al. [1983] described a newborn girl, whodied at 5 weeks, with a unique combination of polymi-crogyria and craniofacial anomalies (hypertelorism,frontal bossing, coloboma of lower eyelid and nasalalae, cloudy corneae, and cleft palate), syndactyly III–IV and oligodactyly of the foot (absence of hallux andsecond toe), hydronephrosis, bicornuate uterus, om-phalocele, and abnormal X-rays (undermineralizedvault, osteodysplasia with curved, short and abnor-mally modeled long bones, sheathing along the femora,vertebral anomalies) and rib fractures.

There is strong resemblance between the cases ofSaint-Martin et al. and Gardner et al., although ocularanomalies are more severe, and fractures less severe inthe latter. It has been suggested that Gardner et al.’scase could represent severe MNS, due to some skewed

420 Verloes et al.

inactivation of the normal X. Although the general fa-cial appearance, curved limbs, and missing fibulae areevocative of OPD2, the nasal and palpebral clefts, andthe strange pattern of oligodactyly, are against bothdiagnoses. Sheathed femora, sclerocornea, and oligo-dactyly were seen in male MNS, but nothing in the casereports suggests MNS in the mothers, and multiplefractures were never reported in OPD2 nor in MNS.

Both reports are included in the MNS entry of theLondon Dysmorphology Database [Winter and Barait-ser, 1999], a classification with which we disagree atthis point. We rather suggest those reports represent adistinct clinical entity, different from OPD2 and MNS,for which we suggest the name Saint-Martin–Gardnersyndrome.

CONCLUSION: LUMPING OF OPD2 AND MNS?

OPD2 and MNS probably are X-linked disorders, al-though definite molecular demonstration of this pointis still awaited. For clinical and genetic reasons, wesuggest that OPD2 and MNS are likely to be due tomutations in the same gene. The difference in expres-sion would be explained by allelic heterogeneity in ex-pression. We postulate that in OPD, most mutationsreduce (OPD1) or abolish (OPD2) protein activity, lead-ing to the expression of the disorder in hemizygousmales, whereas, in MNS, other mutations with domi-nant-negative effect and/or gain of function would re-sult in the expression in both sexes; in males, the ab-sence of the normal allele could lead to early lethality,or, in “milder” mutations, to a more variable and wide-spread expression, depending on the alteration of thenormal function of the mutated allele. Similar reason-ing could probably be applied for FMD.

In order to maintain a consistent nomenclature, wesuggest the name of fronto-otopalatodigital osteodys-plasia to describe the entity encompassing MNS,OPD2, OPD1, and FMD.

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