American Journal of Medical Genetics 38:574-582 (1991) Variability of Expression of the Orofaciodigital Syndrome Type 1 in Black Females: Six Cases Carlos F. Salinas, G. Shashidhar Pai, Christian L. Vera, Jovan Milutinovic, Richard Hagerty, Joel D. Cooper, and David R. Cagna Department of Pediatric DentistrylOrthodontis (C.F.S., J.D.C.), Division of Craniofacial Genetics (C.F.S., D.R.C.); Department of Pediatrics, Division of Genetics (S.G.P.); Department of Neurosurgery (C.L.V.); Department of Medicine, Division of Nephrology (J.M.); Department of Surgery, Division of Plastic Surgery (R.H.); Medical University of South Carolina, Charleston Orofaciodigital syndrome type I (OFD I) includes striking orodental, facial, digital, renal, and central nervous system (CNS)abnormalities. Frequently associated with mental retardation, OFD I is inherited as an X-linked dominant trait, lethal in males. Here, we report the variable expressivity of OFD I in 6 black U S . females and review findings in 2 previously reported black patients. Only these 8 of over 160 reported cases involve blacks. Abnormalities observed in black patients are similar to those observed in whites, but with specific differences. Only 25% of the blacks had cleft palate and none was observed with midline cleft of the upper lip. Among whites, 80% have cleft palate and 45% midline cleft of the upper lip. These findings suggest that racial genetic factors may protect lip and palate development in blacks, even in the presence of the OFD I gene. CNS abnormalities, including agenesis of the corpus callosum, hydrocephaly, cystic brain lesions, seizures, and mental retardation, were present in 50% of our the cases. This figure is greater than previously reported. Polycystic kidneys were present in 3 of our patients. Including a previously reported patient, 50% of the black OFD I patients show polycystic kidneys. Hyperplastic and supernumerary frenula, with or without brachydactyly, have been shown to be strong diagnostic criteria in our patients. New findings reported here include intracranial berry aneurysm, periodontal disease, and lip pits. Clinicians treating these patients should be aware of the pleiotropic manifestations of the Received for publication November 12, 1989; revision received June 22, 1990. Address reprint requests t o Carlos F. Salinas, D.M.D., Department of Pediatric DentistryiOrthodontics, Division of Craniofacial Genetics, College of Dental Medicine, Medical University of South Carolina, 171 Ashley Avenue, BSB 344, Charleston, SC 29425. 0 1991 Wiley-Liss, Inc. syndrome, which may include renal and CNS anomalies. Ultrasonic and computed tomography scan studies are indicated in patients diagnosed with OFD I. KEY WORDS: cleft palate, polycystic kidney, CNS abnormalities INTRODUCTION The orofaciodigital syndrome type I (OFD I) is an X-linked dominant trait, lethal in males, characterized by hyperplastic buccal frenula, ankyloglossia, asymmetric cleft of the palate, bifid or lobate tongue, absence of lower lateral incisors, median cleft or pseudocleft of the upper lip, hypertelorism or telecanthus, hypoplasia of the nasal alae, variable sparsity of hair, transient milia on face and ears, brachydactyly, syndactyly, polycystic kidney, mental retardation, and variable central nervous system (CNS) abnormalities [Gorlin, 1979; Doege et al., 1964; Baraitser, 19861. This disorder can be recognized at birth; however, due to its great variability, diagnosis may be difficult. Often, these patients are treated for isolated defects, such as cleft tongue, and no further diagnosis is made. Furthermore, for mildly affected females, there is a high risk of producing offspring with the full spectrum of OFD I. More than 160 OFD I patients have been reported; only 2 of them [F’ruzanskyet al., 1966,l case; Harrod et al., 1976,l case], were black. We have identified 6 black U.S. females with OFD I ranging in age from 4 months to 32 years. These include 2 familial cases and one isolated case. The scarcity of data on black patients, the apparent variability of expression of the disorder in this group of patients compared with whites, and the finding of previously unreported associations prompted us to present the following cases. PATIENT 1 The proposita was referred, at age 5 months, for evaluation of bifid tongue. The patient’s mother (patient 2) was found to be affected with OFD I. No additional family history of birth defects was reported. The mother OFD Q p e 1 in Black Females has had 4 pregnancies, which resulted in one abortion, one liveborn male, and 2 liveborn females. Six years later, the mother gave birth to a third liveborn female also affected with OFD I (patient 3). All these children were full brothers and sisters. Birth weight was 2.0 kg (<5th centile). Birth length is not known. Abnormalities noted at birth included bifid tongue and syndactyly of the second and third digits on the right hand. At age 5 months, the child was lethargic and irritable, with proportioned head and no apparent sutural defects. OFC was 41 cm (25th centile) “ellhaus, 19681. The infant had a high forehead; fine, sparse, curly hair; a flat, broad nasal bridge; milia on cheeks and ears, simple external ears, with narrow auditory canals; and esotropia (Fig. 1). Intraoral abnormalities included bifid tongue, with a whitish and firm mass emerging from between the tongue halves; ankyloglossia; and serrated lower alveolar ridge particularly at the level of the lower lateral incisors, with multiple hyperplastic frenula. In the upperjaw, broad bands of tissue connect the alveolar ridge, posterior to the cuspid area, and the lip. The hard palate appeared normally arched, with no evidence of clinical clefts or submucous clefts, but showed bilateral, longitudinal grooves extending from the midline toward the lateral aspects of the alveolar ridge in the cuspid areas. The soft palate was intact (Fig. 2). 575 Bilateral clinodactyly ofthe distal phalanx of the fifth digits and syndactyly of the second and third digits on the right hand were present. Brachydactyly was clinically evident on the right hand. The left thumb appeared malimplanted. The feet showed syndactyly of the second and third digits. Skeletal survey was normal except for clinodactyly of the fifth fingers and brachydactyly on the right hand. Lateral skull films showed a normal nasion-sella-basion angle. At age 1year, 10 months, the child was developmentally delayed. She could not walk, and her vocabulary was limited to simple sounds. Examination at age 2 years, 7 months, found the child continuously suffering from nasal congestion and ear infections. The mother reported that the child occasionally “stares off into space.” Lower lateral incisors were absent, corresponding to the serrations noted in the alveolar ridge during the first examination. Hyperplastic frenula had practically eliminated the vestibular sulcus. The maxillary arch was divided into 3 segments by grooves at the level of the cuspids and in relation to the hyperplastic frenula. These shallow grooves divided the palate into an anterior segment, which included the cuspid teeth, and 2 posterior segments. The premaxillary area was somewhat protruded, and the maxillary central incisors were in mesioversion. This child died at age 5 years in an accident; no autopsy was done. Fig. 1. Patient 1. A. Lethargic child, high forehead, broad nasal bridge, and abundant milia. B. Hypotrichosis and fine hair. C. Palatal grooves, alveolar notching, and bifid tongue with hamartoma. D. Brachydactyly and syndactyly of second and third digits. 576 Salinas et al. PATIENT 2 This 32-year-old black woman is the mother of both patients 1 and 3. Her parents are reportedly nonconsanguineous, with no isonomy in their families. Other than the 2 affected daughters and one miscarriage, her family history is unremarkable. The patient appeared healthy, with normal mental development. Medical history was unremarkable. The eyebrows were sparse and scalp hair was straight, with normal density, except in the region just above the ear, where it was scant. Lips were normal. She had multiple hyperplastic fre- A nula in the upper and lowerjaws, a serrated upper alveolar ridge, and normal hard palate, without clefts. There was a history of multiple extractions, apparently due to caries and periodontal disease. Numerous teeth had caries, and she had advanced periodontal disease. The tongue was reportedly repaired a t age 6 months, but remained bifid, with a whitish mass emerging between the tongue halves (Fig. 3). There was clinodactyly of the right third, fourth, and fifth fingers, with brachydactyly. The right fourth metacarpal was shorter than the left fourth metacarpal. The skeletal survey was otherwise normal. Computed tomography (CT) scan showed polycystic B Fig. 2. Patient 1.A. Serrated alveolar ridge, multiple frenula and shallow sulcus. B. Same patient at age 2 years with hyperplastic frenula, alveolar notching, and missing lower lateral incisors, with a hypoplastic alveolar ridge. Fig. 3. Patient 2. A. Clinodactyly of the third, fourth, and fifth digits. B. Multiple frenula and clinical signs of periodontal disease. C. Bifid tongue with remnants of a hamartoma. OFD Qpe I in Black Females 577 patient’s mother has had 2 pregnancies, resulting in one miscarriage a t 4.5 months and the present child. The parents are phenotypically normal. The patient was born at term. The birth weight was PATIENT 3 3.0 kg (>25th centile), and birth length was 47.0 cm At age 5 months, this child was well developed, (50th midline indentation of the soft palate, preaxial polydaccentile) and OFC was 42.5 cm (>50th centile). She was tyly of the left foot, syndactyly of the right hand, and alert and responsive. She had frontal bossing and mid- bilateral notching of the maxillary and mandibular alline linear hypopigmentation of the skin of the forehead, veolar ridges. At age 2 months, the child’s weight was 5.8 kg (>98th black and curly scalp hair, and mild facial lanugo hair was present. Face was symmetrical and normognathic. centile), height was 54.0 cm (<25th centile), and OFC Milia were present on ears, especially the left. There was 40.0 cm (98th centile). The child was well developed was hypertelorism (IP = 5.3 cm; >97th centile), bilateral and normally proportioned. The child reportedly had constant upper airway congestion. Eyebrows were epicanthal folds and a markedly flat nasal bridge. Intraorally she had multiple hyperplastic frenula in sparse, transient milia were observed on the face, and the lower jaw markedly reducing the depth of the ves- the mouth appeared to have downturned corners. She tibular sulcus. Thick fibrotic bands originating from the had preaxial polydactyly on the left foot and incipient lips were seen to run through the alveolar ridge at the preaxial polydactyly on the right foot with no bone inlevel of the lateral incisors resulting in its serration. volvement, syndactyly of the right second and third Fibrotic hyperplastic frenula were also noted in the up- fingers, broad fingers, and marked hypoplasia of fingerper jaw, running through the alveolus a t the level of the and toe nails (Fig. 5). cuspid on the right side and the lateral incisor on the left Hyperplastic buccal frenula were present in the upper side, again resulting in a serration of the alveolar ridge. and lower jaws, with serrations in the mandibular alveoDental arches had a U-shaped appearance, and no teeth lar ridge a t the level of the lateral incisors. The hard were present. The hard and soft palates were intact. The palate appeared normally arched, with grooves extendtongue was bifid, witth a confirmed hamartoma emerg- ing from the posterior border to the rugae palatinae, ing at the midline. A shortened lingual frenulum re- then laterally through the alveolar ridge resulting in sulted in ankyloglossia (Fig. 4). notching a t the level of the cuspids (Fig. 5). The soft CT scan of the head demonstrated no abnormalities. palate showed a midline submucosal cleft. The child was Examination of the limbs showed bilateral brachydac- loosing fluids through the nose during feeding. No teeth tyly of the fingers and syndactyly of the left second and had yet erupted. third digits. CT scan of the kidneys showed no cystic At age 10 months, the child’s OFC remained a t the lesions. 98th centile. Teeth present included the primary upper and lower central incisors. The CT scan results were PATIENT 4 suggestive of agenesis of the corpus callosum. This girl was referred at age 2 months for evaluation At age 4 years, 10 months, her OFC was 55.5 cm of bifid uvula. The family history is unremarkable. The (>98th centile). The child was mentally delayed and had kidney. CT scans of her oldest normal daughter, normal son, and youngest daughter affected with OFD I (patient 3) were normal. A B Fig. 4. Patient 3. A. Patient at age 4 months, with flat nasal bridge, bifid tongue, ankyloglossia, and serrated alveolar ridge. B. Milia. 578 Salinas et al. C D Fig. 5. Patient 4. A. Note large head, frontal bossing, midline ridge, andstrabismus. B. Palatal grooves. C. Brachydactyly and clinodactyly of the third, fourth, and fifth digits. D. Same patient at infancy, showing unilateral preaxial polydactyly. a n awkward, waddling gait. She had prominent frontal bossing. The maxilla had 11 primary teeth, including one supernumerary cuspid, and wide diastemata distal to the cuspid teeth. One of the cuspids was wide in the mesiodistal dimension, compatible with tooth gomination. The mandible had 8 primary teeth and hyperplastic frenula extending through the alveolus at the level of the missing lateral incisors. CT scan of the kidneys failed to demonstrate polycystic lesions. PATIENT 5 The proposita is a 10-year-old black girl. Her mother (patient 6) also has OFD I. Family history is otherwise unremarkable. The patient’s mother had had 2 pregnancies, resulting in one liveborn, unaffected female and the proposita. The patient was born at term. Her birth weight was 3.8 kg (95th centile). Birth length is not known. No abnormalities were noted a t birth. At age 2 months, her weight was 5.2 kg (>75 centile), height was 54.0 cm (>50th centile), and OFC was 45.5 cm (>98th centile). She had gross hydrocephalus, with enlargement of the right ventricle and probable aqueductal obstruction. A ventriculoperitoneal shunt was inserted. The child was irritable, with no head control and poor visual awareness. Milia covered the face and extended up onto the scalp and ears. The tongue was bifid, with a short, hypertrophic lingual frenulum. Sev- eral small, whitish, firm masses were present on the tongue, one at the tip, one on the ventral surface, and one associated with the lingual frenulum. At age 2 years, 4 months, she developed seizures, with abnormal electroencephalograms (EEG). CT scan showed diminished density over the right basal ganglia and parietal lobe, with atrophic changes suggesting the presence of a hamartoma within the right frontal lobe. Esotropia and nystagmus were noted, and the child underwent bilateral medial rectus recession. Intraoral examination showed 2 whitish and firm masses; one on the tongue and one on the soft palate. The teeth appeared dysmorphic, widely spaced, and discolored. An irregular, hyperpigmented skin lesion was present on the left cheek. An irregular, hyperpigmented skin lesion was present on the left cheek. The hands showed short, broad-based fingers. The child was able to talk in sentences; however, motor development was determined to be mildly slow for her age. CT scan at age 3 years, 2 months, demonstrated marked hydrocephalus, lucent areas in the right frontal region suggestive of infarction or cyst development and, atrophy in the right frontal and parietal lobes. By age 4 years, OFC 52.0 cm (>50th centile) was recorded. The child had developed a clumsy but effective gait and was able to handle objects well. CT scan showed the appearance of a large mass in the right parietal and temporal regions, asymmetry of the ventricular system, ventriculomegally, and a midline shift to the left. Oral OFD Type I in Black Females C D C D Fig. 6. Patient 5. A. Patient at age loyears, showing large head and hypertelorism. B. Hyperpigmented skin lesion, milia have cleared up. C. Lobated tongue. D. Clinodactyly. Fig. 7. Patient 5. A. Lower lip pit. B. Pedunculated soft palate lesion. C. Note upper hyperplastic frenula and lower serrated alveolar ridge. D. Note normally arched and intact palate and alveolar notching. 579 580 Salinas et al. examination noted a 5 mm rose-colored lesion of the soft palate and three 2 mm whitish lesions on the ventral surface of the tongue. Examination a t age 9 years showed OFC 55 cm (>98th centile). Both CT scan and magnetic resonance imaging (MRI) surveys suggested a right frontoparietal mass to be of heterotopic grey matter, with considerable mass effect distorting the right frontal horn and body of the right lateral ventricle, shifting midline structures to the left. Also noted were probable obstruction of the left lateral ventricle, enlargement of the third and fourth ventricles, encephalomalacia in the right frontopariental region, increased thickness of the calvarium, and atrophy of the right cerebral peduncle. Examination a t age 10 years showed weight 45.8 kg (>90th centile), height 145.5 cm (>75th centile), and OFC 55.5 cm (98th centile). Cytogenetic analysis of peripheral blood showed no gross chromosomal abnormalities detectable with the QFQ-banding technique. The child was very cooperative; however, mental development was delayed, and special education was presently required. There was hypertelorism, with a n interpupillary distance of 7.0 cm (>98th centile). The belly appeared large, and gait remained clumsy but effective. Skeletal examination showed brachydactyly and clinodactyly of the digits. Oral examination showed paramedian lip pits on the vermillion border. Multiple hyperplastic buccal frenula were present, most notable in the lower anterior region and a t the level of the upper cuspids. A hypertrophic lingual frenulum resulted in ankyloglossia. The lower alveolar ridge was serrated. The teeth show generalized spacing, localized enamel hypoplasia, and gemination of the lower right cuspid, and a supernumerary tooth was present mesial to the lower left cupid (Figs. 6, 7). Ultrasonic examination a t age 10 years, 8 months, demonstrated the existence of 2 small cysts a t the superior pole of the right kidney. This observation suggested the earliest findings of polycystic kidney disease. CT scan confirmed the presence of polycystic kidney (Fig. 8A). PATIENT 6 This is a 30-year-old black woman, the mother of patient 5. Her family history is unremarkable. At age 27 years, the patient suffered a subarachnoid hemorrhage (grade I clinical stage). CT scan and arteriography demonstrated a 4 mm berry aneurysm a t the junction of the left anterior cerebral and anterior communicating arteries. This condition was corrected surgically. On initial examination, the patient was well developed and nourished and normally proportioned. She had frequent severe headaches. On evaluation she was found to have brachydactyly, alopecia of scalp hair, and epicanthal folds. Milia were not present. Intraoral examination showed hyperplastic buccal frenula, a markedly hypertrophied lingual frenulum, intact soft palate, normally arched hard palate, and serrations of the mandibular alveolar ridge located distal to the central incisors and associated with thick fibrotic frenula running from the lips through the al- Fig. 8. A. CT scan of patient 5, showing polycystic lesions of the kidney. Patient is 10 years of age. B. CT scan of patient 6, showing polycystic lesions of the kidney and cystic lesions of the liver. Patient is 30 years of age and is the mother of patient 5. veolus a t that level. Heavy calculus deposits, with associated periodontal disease, were present. Dental malocclusion was present, with anterior crossbite, anterior open bite, and tooth rotations. An upper midline diastema and spacing associated with the lack of a lower lateral incisor were observed. Ultrasonic examination showed enlargement of the kidneys with multiple cysts consistent with polycystic kidney disease. Recently, this patient has developed late-onset seizures that apparently are not related with the surgical correction of the berry aneurism. DISCUSSION Since Papillon-Leage and Psaume [19541 described the syndrome of abnormal frenula, cleft tongue, hypertelorism, median cleft of the lip, cleft palate, hypoplasia of the nasal alae, digital malformations, and mental retardation, a considerable number of abnormalities have been added to the clinical description of OFD I. Table I summarizes the clinical findings of our patients and 2 black patients previously reported [Harrod et al., 1976; Pruzansky et al., 19661. These, as far as we know, OFD Q p e I in Black Females 581 TABLE I. Manifestations Among 8 Black Females Diagnosed With OFD I* -_ Clinical findings 1 2 Present cases 3 4 5 6 Harrod et al. [19761 Pruzansky et al. [1966] ~~ Total CNS + n a + + + 418 Mental retardation Microcephaly + 1I8 Macrocephaly + 218 Corpus callosum agenesis -- +- 1I8 Hydrocephaly + I18 Seizures + + + 318 Infarcted areas with cystic + 1I8 degeneration Head + + + + + + Hypotrichosis 618 + + + + Transient milia 418 + + + + +Broad nasal bridge 518 Alar cartilage hypoplasia 018 + + + + Hypertelorism 418 + + + + + + Sparse eyebrows 618 + + + Frontal bossing 318 + + + Strabismus 318 Mouth Midline cleft upper lip 0 I8 True cleft palate + 1I8 Submucous cleft palate + 118 Palatal grooves + - + + 318 Alveolar notching + + + + + + + + 818 Hypertrophied frenula + + + + + + + + 818 Multiple frenula + + + + + + + + 818 Anky loglossia + + + + nr nr 418 Lip pits - + 118 Lobatedibifid tongue + + + + + + 618 Tongue hamartomas + + + + + 518 Missing lower lateral incisors + n r n a + + + + + 618 Missing lower central incisors na + +2I8 Supernumerary teeth n a + + + 318 Enamel hypoplasia n a + + nr nr 218 Periodontal disease + + a + + + + + 218 Malocclusion + n a n a + + + + + 618 Extremities Brachydact yly + + + + + + + + 8 I8 Clinodact yly + + + + + +618 t + + + -+ Syndactyly 518 Unilateral polydactyly of hallux - + 1I8 Kidney + + + + Polycystic kidney 418 Other Conductive hearing loss + + +318 + + Irritability + 318 Micrognathia + + 218 + + History of miscarriages nr 214 Berry aneurysm + 118 Unusual gait d na + nr nr 1I8 * + , Clinical feature is present; - ,clinical feature is not present; na, clinical feature is not applicable;nr, clinical feature is not recorded;d, delayed motor development. are the only black females reported with OFD I. The clinical manifestations and their frequency demonstrate that the pleiotropic manifestation of the disorder is similar to that observed among white patients. At the same time, it is apparent that there are differences in expression that may be in part due to the ethnic background of the population sample. The low frequency of cases observed in blacks may represent a n ethnic predilection. At this time, however, we cannot disregard the variable expressivity of the disorder as a factor in the number of unreported cases in the black population. Patient 2, for example, was treated for bifid tongue 25 years ago. Aside from bifid tongue and thick, multiple oral frenula, she had no other gross anomalies that would suggest the diagnosis of OFD I. Only a detailed family history and physical examination provided the necessary evidence to diagnose her case. The intraoral manifestations of the disorder are quite striking and include serrated alveolar ridges, multiple frenula, hyperplastic frenula, maxillary alveolar cleft, 582 Salinas et al. palatal grooves, cleft palate, hypodontia, upper midline pseudocleft of the lip, lobate tongue, hamartomas, and a n unusually divided maxillary arch [Gorlin, 19791.All our patients had hyperplastic frenula, confirming the conclusion of Melnik and Shields [ 19751 that “multilobated tongue or hyperplastic frenula with or without brachydactyly is the minimum diagnostic criterion for the OFD I syndrome.” The major difference in our patients, compared with reports on whites is with regard to the type and incidence of cleft observed. Fuhrmann et al. 119661reported that, in 80% of the white patients, the soft palate was completely and asymmetrically cleft. Patient 4 had bifid uvula and submucous cleft, and patient 7 [Harrod et al., 19761had cleft of the soft palate. These cases represent only 25% of the black patients. In addition, Gorlin [1979] suggests that about 45% of the reported patients show upper midline cleft or pseudomidline cleft lip. However, our patients show no cleft of the lip. It is widely recognized that cleft lip and palate are more frequent among whites (1 : 850) than among blacks (0.4 : 1,000). The frequency of cleft palate is also higher in whites (0.32 : 1,000) than in blacks (0.23 : 1,000) in the United States [Shapiro, 19761. The low frequency of lip and palate defects found in the OFD I cases reported here appears to follow this same pattern of racial frequency. This finding suggests the presence of racial genetic factors that act to protect palatal development, even in the presence of the OFD I gene. We are well aware that the number of patients reported herein is small; however, they represent 5 unrelated black families, and we think that the observed tendency is not coincidental. Patients 2,5, and 6 were diagnosed as having polycystic kidney disease. Patient 5, now age 10 years, 8 months, was asymptomatic and was ascertained only following the diagnosis of polycystic kidney disease in her mother (patient 6). In addition, patient 6 was also shown to have small cysts in the liver. This motherdaughter set as well as patient 2 and a case reported by Harrod et al. [1976], affected with OFD I and polycystic kidney disease, represent 50% of the black cases reported to date and appear to demonstrate once more than polycystic kidney disease is a manifestation of the disorder [Doege et al., 1964; Harrod et al., 1976; Melnick and Shields, 1975; Tucker et al., 1966; Connacher et al., 1987; Donnai et al., 1987; Stapleton et al., 19821. These findings support the need for ultrasonic and CT scan studies of the kidneys in patients diagnosed with OFD I. Yearly follow-up examinations are necessary because cystic lesions appear during childhood and are assymptomatic. The association of periodontal disease with OFD I has not been previously reported and may represent a n additional expression of the disorder in young adults. The presence of periodontal disease is suggestive of a connective tissue disorder. Patient 6 was diagnosed a t age 27 years with intracranial berry aneurysm that subsequently was surgically corrected. It is pertinent to note that the association of berry aneurysms and polycystic kidney disease has been reported previously [Levey et al., 1983; Steh- bens, 19621, but not in association with OFD I. Several authors have postulated that aneurysms are complications or secondary manifestations of a primary connective tissue defect [Stehbens, 19831. Pope et al. [19811 reported type I11 collagen deficiency in 7 of 12 patients with berry aneurysm associated with connective tissue disorders. The berry aneurysm associated with polycystic kidney and periodontal disease in this patient suggest a connective tissue defect. 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