American Journal of Medical Genetics 35:360-369 (1990)

Oral-Facial-Digital Syndrome Type VI (Varadi Syndrome): Further Clinical Delineation Maximilian Munke, Donna M. McDonald, Amy Cronister, Janet M. Stewart, Robert J. Gorlin, and Elaine H. Zackai T h e Children$ Hospital of Philadelphia, Division of H u m a n Genetics and Molecular Biology, Philadelphia, Pennsylvania (M.M., D.M.McD., E.H.Z.); University of Colorado, Health Sciences Center, Denver, Colorado (A.C., J.M.S.); and University of Minnesota, School of Dentistry, Minneapolis, Minnesota (R.J.G.) Cerebellar anomalies are consistent findings in patients with the oral-facial-digital syndrome type VI (Varadi syndrome) in addition to variable facial and oral changes, and polysyndactyly of hands and feet. We report 3 unrelated patients with this entity who have a hypoplastic cerebellar vermis shown by magnetic resonance imaging (MRI),as well as clinical signs of cerebellar defect. Polydactyly of the hands is characterized by a central Y-shaped metacarpal. Clinically recurrent episodes of tachypnea and hyperpnea are remarkable. Postnatal growth is delayed with short stature in all 3 patients possibly due to growth hormone deficiency in one of them. In contrast to reported patients who are all severely mentally retarded, one of our patients is of normal intelligence. Type VI oral-facial-digital syndrome is an autosomal-recessive trait and may be detected prenatally.

KEY WORDS: oral-facial-digital syndrome type VI, Varadi syndrome, cerebellar vermis hypoplasia, polysyndactyly, Y-shaped metacarpal.

INTRODUCTION The oral-facial-digital syndromes (OFDS) have in common anomalies of the palate, hypertelorism, and pol ydactyly, brachydactyly, clinodactyly andlor syndactyly of hands and feet. Two types were delineated previously on the basis of distinct clinical manifestations and different inheritance patterns (X-linked dominant versus autosomal-recessive) [Rimoin and Edgerton,

Received for publication March 10, 1989; revision received August 25, 1989. Address reprint requests to Maximilian Munke, University of Pennsylvania School of Medicine, Department of Human Genetics, Philadelphia, PA 19104-6072.

0 1990 Wiley-Liss, Inc.

19671. Further clinical descriptions have led to a new classification of OFDS with 4 [Baraitser, 19861 and recently with a t least 7 different types [Toriello, 19881. Varadi syndrome or OFDS type VI [Varadi et al., 19801 differs from other OFDS because of cerebellar anomalies. Here we further delineate the clinical spectrum of this rare autosomal recessive disorder in 3 additional, unrelated patients.

CLINICAL REPORTS Patient 1 The propositus was the product of a 39-week uncomplicated gestation and delivery, born to a 34-year-old white woman (gravida 11, para I) and a n unrelated 34year-old white man. Family history was negative for any birth defects or pregnancy wastage. Apgar scores were 10 a t 1 min and 10 a t 5 min. Birthweight (3,000 g), length (49.5 cm), and head circumference (OFD at age 2 months: 39.5 cm) were all between the 10th and 25th centiles. Physical examination showed anomalies in the oral cavity, face, hands, and feet. There were multiple frenula a t the base of the tongue and sublingual masses bilaterally. A high-arched palate and superior alveolar ridge with a n indentation in the midline were evident. The mandible was hypoplastic (Fig. 1A).The right hand had 7 fingers; the left hand had 5 with soft tissue syndactyly between fingers 4 and 5 (Fig. 1B). Radiography showed a forked third metacarpal with a n extra, fully formed central digit and a postaxial digit on the right side (Fig. 1C). Bony structures on the left hand were normal, with the exception of a duplication of the distal fifth phalanx, which was fused distally. Both feet had preaxial hexadactyly (Fig. 1D) with duplication of the medial cuneiform bones, first metatarsals, phalanges of the hallux and soft tissue syndactyly of the first 2 toes bilaterally (Fig. 1E). In addition, there was partial duplication of the fifth metatarsal (left), which was fused distally. The left foot was clubbed. The genitalia were unremarkable as was the remainder of the clinical exam. Chromosomes were 46,XY. The neonatal period was marked by failure to thrive with weight and length falling below the 5th centile. At 2 months, episodes of head and arm shaking and abnormal eye movement were observed. At age 9 months,

OFD VI (Varadi Syndrome) oculomotor apraxia, mild fixed esotropia, and bilateral conductive hearing impairment were noted. Gross motor development a t 20 months was that of a 10-monthold child. Psychomotor development, such as walking, was achieved a t age 3 years, and there was a significant delay in language. At 6% years, gross motor activities were described a s clumsy, the gait being wooden and stiff. The neurologic examination a t age 11 years confirmed the oculomotor apraxia and poor gross motor coordination. Mentally, the patient appeared to be normal, although he did not have formal I.&. testing. He attended a regular school and was in age-appropriate grade. Fluoroscopic studies demonstrated a poor apposition of the left lateral wall of the hypopharynx secondary to paresis or paralysis of this region. On magnetic resonance imaging (MRI) of the brain, the cerebellar vermis was hypoplastic with only a small superior portion of the vermis present. In addition, there was a n isointense mass within the hypothalamus, most consistent with a hypothalamic hamartoma. In association with this abnormality, there was no evidence of a n anterior lobe of the pituitary gland. Olfactory bulbs and tracts were considered normal. At age 10 years, 4 months, he was severely growth retarded with a height of 115 cm (50th centile for 5 years, 9 months), and a weight of23 kg (50th centile for 6 years, 3 months), whereas his OFC was normal for age. Thyroid function tests were normal. Bone age was delayed approximately 2 years, when tested a t a chronological age of 5 years, 11months; a t 6 years, 7 months; and a t 10 years, 4 months. Serum somatomedin C was low for age. Results of growth hormone provocative tests (propranolol glucagon and arginine stimulation) were abnormal and consistent with a partial growth hormone deficiency.

Patient 2 The propositus was the product of a 40-week uncomplicated gestation born to a 28-year-old white woman (gravida 11, para I) and a n unrelated 32-year-old white man. There was no family history of birth defects or pregnancy wasting. Apgar scores were 6 a t 1min and 9 a t 5 min. Birthweight (3,500 g), length (51 cm), and OFC (34 cm) were between the 25th and the 75th centiles. Physical examination demonstrated a prominent and broad nasal bridge, hypertelorism, and micrognathia (Fig. 2A). There was unilateral complete cleft of lip and palate, incomplete cleft lip at the midline, a detached band between the upper segments with neonatal teeth in each segment, multiple frenula, a tiny cystlike mass on one side, and lobulated tissue on the other side of the dorsal surface of the tongue. He had bimanual central hexadactyly and a postaxial minimus on one side (Fig. 2B). Hand radiographs showed the extra digit to be central with a bifid, Y-shaped metacarpal on one side, with a n individual additional metacarpal on the other side (Fig. 2C). Both feet had preaxial polydactyly with duplication of the first metatarsal and triplication of the first phalanges of the hallux with soft tissue syndactyly bilaterally (Fig. 2D,E). In addition, there was a n extra postaxial phalanx on one side. The penis was below 2 SD in length but structurally normal. An endocrine workup

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a t 4 months because of micropenis demonstrated markedly decreased serum testosterone, decreased serum luteinizing hormone (LH), and decreased serum folliclestimulating hormone (FSH) levels. Chromosomes were normal: 46,XY. The clinical course was remarkable for recurrent episodes of tachypnea and apnea. Thermistor studies showed both central and obstructive apnea. He demonstrated severe failure to thrive, with a weight of 8.0 kg a t 18 months (50th centile for 6V2 months). At this time, a gastrostomy tube was inserted. With a n ageappropriate caloric intake, his weight increased slowly, but it stayed below the 5th centile. At 23 months, weight and length were 50th centile for 12 and 14 months, respectively. OFC was normal for age. The neurologic examination was normal at age 2 months and was first noted t o be delayed at 6 months. At age 23 months, he had generalized hypotonia and motor development at a 6-month level. By contrast, the child was very alert and understood and followed simple commands at a l-year-oldlevel. MRI ofthe brain at 6 months showed a prominent cisterna magna and a cerebellar vermis which was decreased in size, especially inferiorly. The remaining brain structures, including olfactory tracts and bulbs, were normal. At 1 4 months, fluoroscopy showed tracheomalacia.

Patient 3 The proposita was the product of a 38-week gestation, born to a 27-year-old white woman (gravida V, para 11, SAB 11)and a 25-year-old white man. The family history was unremarkable but limited, as the mother was adopted. Apgar scores were 7 a t 1min, but only 4 a t 5 min because of a n episode of bradycardia and apnea. She responded well to resuscitation, and her score at 10 min was 8. The sepsis workup was negative, and she subsequently did well in the nursery. Birthweight (4,170 g), length (55.5 cm), and OFC (38.5 cm) were above the 98th centile. She had a midline cleft lip and a n intact but highly arched palate. The tongue was small and lobulated without frenula. The eyes appeared to be small (palpebral fissure length 1.8 cm) and wide set, with epicanthal folds, a high nasal bridge, and a glabellar hemangioma. She had micrognathia with a prominent chin (Fig. 3A). Both hands showed preaxial and central polysyndactyly (Fig. 3B). In addition to 2 syndactylous first digits on both hands, there were 6 other fingers on the left hand with syndactyly of digits 3-5 and a postaxial minimus. There were 5 other digits on the right hand with ulnar deviation of the index and radial deviation of the last fingers. Radiographs showed complete duplication of the right thumb, duplication of the distal left thumb, a n additional central metacarpal on one side, and a forked fourth metacarpal on the other side with 2 fully formed digits each. Middle phalanges of all digits were short (Fig. 3C). Both feet had preaxial polysyndactyly with duplication of the first metatarsals bilaterally and duplication and triplication of the first syndactylous phalanges, respectively (Fig. 3D,E). Studies at birth included normal skull films. Head ultrasound and CT were considered normal. By contrast, MRI showed a hypoplastic cerebellar vermis with a small superior vermis and no detectable inferior vermis. Olfactory

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Figs. 1 A-C.

tracts and bulbs were considered normal. Chromosomes were normal: 46,XX. The early clinical course was extremely stormy with several hospitalizations for respiratory syncytial virus and reactive airway disease necessitating tracheostomy at 13months. She also had severe feeding problems with marked failure to thrive, and a gastrostomy tube was

inserted a t 13 months, when weight was 5.4 kg (50 centile for a 3-month-old child). At 10 months, generalized hypotonia was noted, and gross motor development was that of a 4-month-old child. At age 17 months, she was functioning at a 9-month level, with good social interaction. When seen last a t 20 months, weight (9.64 kg) had

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Fig. 1.Patient 1.A: Face. At age 2 months (left) and 10 years (right).B: Hands with polysyndactyly. C: Hand films with forked metacarpal. D: Foot with preaxial hexasyndactyly. E: Foot films.

increased to the 10th centile, but height (73 cm) remained far below the 3rd centile, corresponding to the 50th centile for a n 11-month-old child. OFC (47.5 cm) was age appropriate. The child was alert and playful, sitting independently, reaching out, grasping and transferring objects, but still mildly hypotonic. She had normal vision and a 45 db conductive hearing loss with a history of recurrent otitis.

DISCUSSION We report here 3 unrelated patients with OFDS type VI (Varadi syndrome), who had the following anomalies: midline or unilateral cleft lip and/or highly arched or cleft palate, multiple frenula and lobulated lingual tissue, hypertelorism, broad nasal bridge, and micrognathia. Hands showed central polydactyly with a Y-shaped metacarpal, as well as preaxial and postaxial polydactyly. Feet had preaxial polydactyly. One foot had a postaxial phalanx in addition to preaxial polydactyly. Although birthweight and length were normal, there was postnatal growth delay in all 3 patients, leading to severe short stature, due to growth hormone deficiency in one of them. One patient had hypogonadotrophic hypogonadism with micropenis. Two of the 3 patients had conductive hearing loss. Further evaluation showed abnormal breathing patterns, including hypernea, tachypnea, and apnea. There were varying degrees of developmental delay in all 3 patients. Neurologic findings, such as rotary nystagmus, oculomotor apraxia, esotropia, ataxia, generalized hypotonia, and poor gross motor coordination, were suggestive of a cerebellar defect. This was confirmed by MRI, which showed a cerebellar midline defect with vermis hypoplasia in all 3 patients. One also had a hypothalamic mass, most likely a hamartoma, and the anterior lobe of the pituitary gland was missing. Most of these manifestations have been described in patients by Varadi et al. [19801 and in 7 other publications [Gustavson et al., 1971, same as patient 3 of Anneren et al., 1984; Egger et al., 1982; GenEik and GenEikova, 1983; Haumont and Pelc, 1983; Mattei and

Ayme, 1983; Silengo et al., 19871. In addition, several patients were reported who did not display all the characteristics [Lyons, 1939; Hooft and Jongbloet, 1964;Joubert et al., 1969, patient in Fig. 8; Poznanski, 1984, patient in Figs, 13-251; Fried et al., 19891. When comparing the findings in patients with Varadi syndrome to those with other types of oral-facial-digital syndrome [Table I] it appears that the 2 differentiating features are Y-shaped metacarpals with central polydactyly and cerebellar anomalies. Syndactyly, brachydactyly, clinodactyly, and occasionally preaxial and/or postaxial polydactyly have been described in patients with OFD VI. However, the most frequent hand anomaly is central polydactyly [Varadi et al., 1980; Gustavson et al., 1971; A n n e r h et al., 1984; GenEik and GenEikova, 1983; Haumont and Pelc, 1983; Mattei and Ayme, 1983; Silengo et al., 19871. We define central polydactyly as a fully developed extra digit arising from a n additional central metacarpal or from a bifid or Y-shaped, usually third, metacarpal. In central polydactyly, the Y-shaped metacarpal represents incomplete duplication. This is best seen in o u r patients 2 and 3 with a n incomplete split of a partially duplicated metacarpal bone on one hand and a n additional central metacarpal bone on the other hand (Figs. lC, 2C, 3C). Although polydactyly as a n isolated malformation or as part of a syndrome is not uncommon [Temtamy and McKusick, 19781, polydactyly due to a Y-shaped central metacarpal is extremely rare. We are aware of only one such report in association with other anomalies LKaufman et al., 19721.By contrast, congenital fusion of either metacarpal or metatarsal bones with a normal number of digits has been reported frequently [Hooper and Lamb, 1983; Holmes et al., 1972; Robinow et al., 1982; Niebuhr and Ottosen, 1973; Le Merrer et al., 1988; Pfeiffer and Karpferer, 19881. We are aware of only one animal model with central polydactyly. Continuous release of retinoic acid from small beads implanted into the wing buds of 3.5-day-old chick embryos results in a 432234 digit pattern (normal 234) [Tickle et al., 19851which is similar to polydactyly

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Figs. 2 A-C

due to a Y-shaped central metacarpal. In humans, effects of retinoid teratogenicity are well known not only as the cause of limb anomalies but also craniofacial defects [Lammer et al., 19851. It is tempting to speculate that alterations of the retinoic acid receptor gene, located on the short arm of chromosome 3 ( 3 ~ 2 4[Mattei )

et al., 19881,may be involved in midline defects such as the holoprosencephaly sequence, since this forebrain defect has been associated nonrandomly with the duplications of 3p in some patients [for review see Munke, 1989.1 Cerebellar anomalies, mostly vermis hypoplasia and/

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Fig. 2. Patient 2. A Face with hypertelorism and unilateral cleft lip and palate. B Hands with hexadactyly. C: Hand films with bifid, Y-shaped metacarpal. D: Foot with preaxial polysyndaetyly. E: Foot films.

or clinical findings suggestive of cerebellar involvement, have been described in every patient with OFD VI: absent cerebellum lEgger et al., 19821, absent or hypoplastic cerebellar vermis [Varadi et al., 1980; Haumont and Pelc, 1983; Mattei and Ayme, 1983; present report], enlarged fourth ventricle [Gustavson et al., 1971;Egger et al., 19821, and Dandy-Walker malformation [Haumont and Pelc, 19831. Absence of olfactory bulbs and tracts has been described in 2 of 21 patients only [Varadi et al., 19801. In addition to the cerebellar vermis anomalies typical of OFDS type VI, our patient 1 had an isointense mass within the hypothalamus that was most consistent with a hypothalamic hamartoma and an absent anterior lobe of the pituitary gland. Congenital hypothalmic hamartoma has been described as a consistent finding of the Pallister-Hall syndrome [Haas et al., 1980; Hall et al., 1980; Clarren et al., 1980; Huff and Fernandes, 1982; Culler and Jones, 1984; Graham et al., 1985 and 1986; Donnai et al., 1987; Iafolla et al., 1989; Pallister et al., 19891. Additional manifestations include cleft palate, cleft lip, and/or highly arched palate (frequency 8/13), postaxial polydactyly (11/13)>renal ectopiaidysplasia (81131, congenital heart defects (61131, lung segmentation anomalies (611l), imperforate/anteriorly placed anus (71131, pituitary aplasia/dysplasia, and resulting panhypopituitarism (11/13)[from a review by Iafolla et al., 19891.The similarity of some of these features (craniofacial and digital anomalies, endocrine findings, e.g., testicular hypoplasia with micropenis) to those of the OFDS type VI is intriguing. Thus, Pallister-Hall syndrome is one of the differential diagnoses in OFDS. However, 2 consistent findings ofthe OFDS type VI have not been described in patients with Pallister-Hall syndrome: cerebellar vermis anomalies and central polydactyly with a Y-shaped metacarpal. By contrast, Pallister-Hall syndrome is almost always a lethal condition with manifestations not reported in OFDS type VI, e.g., anal defects and lung anomalies. Testicular hypoplasia

and/or cryptorchidism with micropenis in 7 of 8 males with Pallister-Hall syndrome has also been described in patients with OFDS type VI in the absence of hypothalamic hamartoma [Varadi et al., 1980; patient 2 in this report]. All patients with OFDS type VI so far reported have had severe developmental delay and mental retardation. By contrast, our patient 1had normal intelligence. Although the gross motor development was delayed in patients 2 and 3, intellectual development cannot be assessed properly at this time. Thus, severe mental retardation may not necessarily be a constant manifestation of the OFD type VI and may not be predictable in a newborn infant with this clinical entity. Postnatal growth delay and severe short stature, as in our 3 patients, has been reported previously in affected individuals who survived the neonatal period. The severe failure to thrive may in part be due to inadequate nutrition because of oral anomalies. However, the growth delay may be due to a partial hypopituitarism with growth hormone deficiency, as in patient 1.Endocrine studies in patient 2 because of micropenis demonstrated hypogonadotrophichypogonadism. Although no further studies were done, cryptorchidism in the 3 males reported by Varadi et al. [19801 may be attributable to the same endocrine dysfunction. In this respect, it is of interest that pituitary dysfunction such as LH/FSH deficiency has been described in association with cerebellar hypoplasia [McKusick, 19881. Type VI of OFDS seems to have autosomal-recessive inheritance. Consanguinity was present in at least one family Waradi et al., 19801, and several affected sibs with varying severity were described in other families [Varadi et al., 1980; Gustavson et al., 1971; Egger et al., 1982; GenEik and GenEikova, 1983; Haumont and Pelc, 1983; Mattei and Ayme, 1983; Silengo et al., 19871. For counseling purposes, a clinical differentiation between OFDS types VI and I is essential since the latter is an X-linked dominant trait, lethal in the male. Thus, af-

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Fias. 3 A-C.

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Fig. 3. Patient 3. A Face with midline cleft lip. As infant (left) and at 20 months (right).B: Hands with polysyndactyly. C : Hand films with forked metacarpal. D: Feet with preaxial polysyndactyly. E: Foot film.

fected girls with OFDS type I are mostly due to a new mutation with a very low recurrence risk, in contrast to the high recurrence risk in type VI. Prenatal diagnosis in pregnancies at risk for OFDS has not yet been reported. However, detection of individual signs the presence of which may be suggestive for the full syndrome has well been documented. Sonographic assessment of fetal extremities is feasable before the middle ofthe second trimester ([Mahony and Filly, 1984; Jeanty et al., 19851.In addition, facial anomalies such as hypertelorism or micrognathia have been described prenatally LChervenak e t al., 1984; Pilu et al., 19861.Fetal cleft lip and palate has been diagnosed repeatedly between 16 and 20 weeks [Savoldelli et al., 1982; Seeds and

Cefalo, 1983; Saltzman et al., 19861. Even such subtle anomalies as partial agenesis of the cerebellar vermis as seen in type VI OFDS were suspected by ultrasound in a fetus a t risk of Joubert syndrome at 20 weeks and confirmed a t 25 weeks gestation [Campbell et al., 19841.

ACKNOWLEDGMENTS We are indebted to the 3 families for their cooperation and to the following individuals involved in the patients’ care: D.L. Eunpu, P. Borns, R. Wetmore, P. Randall, H.S. Caplan, A. Spitzer, D. Hackney, R. Clancy, S.H. Tucker, R. Mayro, and R.W. Furlanetto.

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Munke et al. TABLE I. Comparative Findings in the Oral-Facial-Digital Syndromes*

Findings Oral anomalies

Facial anomalies

OFDS I Highly arched or cleft palate Dental anomalies Tongue clefts Frenula Telecanthus or hypertelorism Median cleft lip Alar hypoplasia

Hand anomalies

Clinodactyly BrachydactYlY Syndact yly

Foot anomalies

Preaxial polydactyly, usually unilateral Corpus callosum agenesis Porencephaly

Cerebral anomalies

Miscellaneous anomalies

Inheritance

OFDS I1 (Mohr syndrome)

OFDS I11 (Sugarman syndrome)

Highly arched or cleft palate Frenula Tongue nodules Tongue clefts Median cleft lip Broad nose with bifid tip Telecanthus or hypertelorism Clinodactyly BrachvdactYlY” Syndact yly R e - or Dostaxial -polydactyly

Clef uvula Tongue nodules Cleft tongue Small teeth

OFDS IV (Baraitser-Burn syndrome)

OFDS V (Thurston syndrome)

OFDS VI (Varadi syndrome)

OFDS VII (Whelan syndrome)

Highly arched or cleft palate Lobed tongue Tongue nodules Frenula Hypertelorism Epicanthal folds Micrognathia Low-set ears

Frenula

Highly arched or cleft palate Lobed tongue F’renula

Highly arched or cleft palate Frenula Tongue nodules

Median cleft lip

Hypertelorism Median or unilateral cleft lip Broad nasal tip

Hypertelorism Unilateral cleft lip Facial asymmetry

Postaxial polydactyly

Pre- or postaxial polydactyly BrachydactY’Y Clinodactyly Syndactyly

Postaxial polydactyly

Postaxial Preaxial polydactyly polydactyly (usually bilateral)

Pre- or postaxial polydactyly Syndact yly

Postaxial polydactyly

Central poly- Clinodactyly dactyly R e - or postaxial polydactyly BrachsdactYlY Clinodactyly Syndact yly Preaxial polydactyl y

Porencephaly Hydrocephaly

See-saw winking Myoclonic jerks

Porencephaly Cerebral atrophy

Short sternum Hyperconvex nails

Tibia1 dysplasia Pectus excavatum Short stature

Autosomalrecessive

Autosomalrecessive

A1opecia Miliary skin lesions Adult-onset polycystic kidneys X-linked Autosomaldominant recessive or new mutation

Hypertelorism Low-set ears Bulbous nose

Cerebellar anomalies DandyWalker anomaly

Autosomalrecessive

Autosomalrecessive

Coarse hair Congenital hydronephrosis Preauricular skin tag Autosomal or X-linked dominant

*Modified from Toriello 119881.

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