American Journal of Medical Genetics 41:83-88 (1991)
Nager Acrofacial Dysostosis: Male-to-Male Transmission in 2 Families Arthur S. Aylsworth, Angela E. Lin, and Patricia A. Friedman Department of Pediatrics and the Brain and Development Research Center, School of Medicine, University of North Carolina at Chapel Hill (A.S.A., P.A.F.); Department of Medical Genetics, West Penn Hospital, Pittsburgh, Pennsylvania (A.E.L.)
We describe 2 unrelated familieswith male-tomale transmission of Nager syndrome. All 5 affected individuals have moderate expression of the phenotype. One affected boy also has Hirschsprung disease. Although Nager acrofacial dysostosis usually occurs sporadically, both recessive and dominant inheritance have been suggested on the basis of reported familial cases. The 2 families described here with father-to-sontransmission strongly support the hypothesis that some cases of Nager acrofacial dysostosis occur in individuals who are heterozygousfor dominantly expressed, autosomal mutations.
KEY WORDS: mandibulofacial dysostosis, limb anomalies, Hirschsprung disease, neural crest, genetics, autosomal dominant INTRODUCTION Nager acrofacial dysostosis is characterized by malar and mandibular hypoplasia and preaxial upper limb defects, usually including hypoplasia or absence of thumbs. In addition, reported patients have had a variety of other findings including developmental delay, short stature, and other components of mandibulofacial dysostosis such as cleft palate, ear anomalies, hearing loss, absent or sparse eyelashes, and downslanting palpebral fissures [Bowen and Harley, 1974; Lowry, 1977; Gellis et al., 1978; Halal et al., 1983; Thompson et al., 1985; Meyerson and Nisbet, 1987; Byrd et al., 1988; Received for publication September 19, 1990; revision received February 5, 1991. Address reprints requests to Arthur S. Aylsworth, M.D., CB#7250, University of North Carolina, Chapel Hill, NC 27599-7250. Angela E. Lin’s current affiliation is the National Birth Defects Center, Franciscan Hospital, Brighton, Mass. Patricia A. Friedman’s current affiliation is The Durham Developmental Evaluation Center, Durham, NC.
0 1991 Wiley-Liss, Inc.
Chemke et al., 19881. This phenotype usually occurs sporadically but causal heterogeneity is suggested by families that are consistent with both recessive [Walker, 1974; Hecht et al., 1987; Chemke et al., 19881and dominant [Weinbaum et al., 1981; Hall, 1989; Kim et al., 1989;Le Merrer et al., 19891patterns of inheritance. No previous cases of male-to-male transmission have been reported.
CLINICAL REPORTS Family 1 The propositus (Fig. 1)is a black boy with hypoplasia of the zygomatic arches, downslanting palpebral fissures without lid colobomas, micrognathia, prominent upper lip, broad lateral palatine ridges, normal ear size with large fleshy lobes, and a mild pectus excavatum. Birth weight and length were normal. He had a poor suck in the newborn period and was a “noisy breather.” He had radial deviation of the left hand, a proximally placed, small left thumb, congenital absence of the right thumb, and medial deviation of the distal phalanges of the second toes. At age 2 years he had normal height, weight, and head circumference (OFC). He had 3 caf6-au-lait spots between 10 and 18 mm in maximum dimension. There was a moderate bilateral conductive hearing loss with type B tympanograms and delayed development of both receptive and expressive language. Limited testing documented gross and fine motor skills in a wide spread around his chronologicage. He was fitted with binaural hearing aids and had bilateral pollicization of index fingers. Follow-up testing at age 35/12 years showed moderate hypernasality, a severe articulation problem, and mildly to moderately impaired receptive and expressive language. Cognitive functioning was in the borderline normal range. Fingertip dermatoglyphics are AAUU on the right and WAAUU on the left. As shown in Figure Id, the thenar and proximal palmar creases did not develop and the distal palmar creases are prominent, running from between the index and middle fingers to the ulnar aspect of each hand. The father of the propositus (Fig. 2) has severe malar hypoplasia (L > R), downslanting palpebral fissures without lid colobomas, normal external ear size with small external auditory canals, micrognathia, very
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Fig. 1. Propositus in Family 1. a,b: Face at age 2 months. Palpebral fissures slant downward slightly and the mandible is somewhat small. Ear lengths were normal but the lobes were unusually large and fleshy. c: Face at age 2 years. d Hands at 2 years. The right thumb was congenitally absent and the left thumb was hypoplastic. e: Feet at 2 months showing bilateral medial deviation of the distal portion of the second toes.
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broad lateral palatine ridges, normal height and weight, and OFC at the 98th centile. At birth he had micrognathia, a short soft palate, apparent absence of the uvula, short radii with bilateral radial deviation of the hands, rudimentary left thumb, 4 metacarpals on the left, a hypoplastic right thumb, and bilateral metatarsus varus. Later in childhood he had a bilateral conductive hearing loss of 50-60 dB with a 40-50 dB airbone gap. Diagnosis at this time was Treacher Collins syndrome. At age 15, exploration of the left middle ear showed intact tympanic membranes, a small cartilaginous malleus, absence of the incus, absence of the stapes head and neck, and a normally positioned stapes footplate. The rudimentary left thumb, described as a “flail thumb” containing palpable bone but with no bony attachment, was removed a t 19 years. His proximally placed, hypoplastic right thumb was never functional. He had limited supination and extension of his forearms. As an adult, he has a moderate articulation problem, mild to moderate hypernasality, and overall intelligibility that is judged to be moderately impaired. There is no velar elevation or lateral pharyngeal wall activity during phonation. A single uvula is present without a palpable submucous cleft. Mandibular mobility is somewhat limited, especially lateral motion and protrusion. He has bilateral, moderate to severe conductive hearing loss with relatively good speech discrimination. The unaffected paternal grandfather of the propositus was 30 years old a t the time of the father’s birth. A cousin reportedly had unilateral hand polydactyly. The mother of the propositus had no significant dysmorphic features. No other relatives are known to have any manifestation suggestive of the Nager phenotype.
Fig. 2. Affected father of propositus in Family 1. a , b Face showing maxillary and mandibular hypoplasia with downslanting palpebral fissures. c: Hands. The left thumb was rudimentary and removed when he was a child; the right thumb was non-functional.
Family 2 The propositus (Fig. 3) is a white boy whose anomalies were noted in the newborn period. He had a low anterior hairline with tufts of hair extending down each cheek, mild hypoplasia of the zygomatic arches, moderate micrognathia, posteriorly rotated ears, right ear smaller than the left, small external auditory canals (left side smaller than the right), short palpebral fissures, absent lower lashes, no coloboma, and a small uvula with poor posterior movement. The thumbs were hypoplastic and pedunculated with some bone present on the right but not on the left. He was born to 20-year-old parents who reported normal fetal activity and growth. Apgar scores were 8 and 9 following a normal, spontaneous vaginal delivery a t 41 weeks. Height, weight, and OFC were all normal. The patient was admitted t o hospital at age 6 days with vomiting and abdominal distension. Hirschsprung disease was diagnosed and a colostomy was performed. The father of the propositus (Fig. 4)is short (163 cm), and has asymmetry with hypoplasia Of the right side, hair tufts extending down the cheeks, sparse lower eyelashes (especially in the medial aspect), and short, downslanting palpebral fissures. Both ears appear narrow and low-set with deep concha, hypoplastic anthelices, and small external auditory canals. The uvula is bifid and the vela are absent. He has marked
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Fig. 4. Father of propositus in Family 2. a,b Face showing marked malar and mandibular hypoplasia and downslanting palpebral fissures. c: Hands with congenital absence of both thumbs.
Fig. 3. Propositus in Family 2. a: Face in neonatal period showing micrognathia. b: Hands with bilateral hypoplastic, pedunculated thumbs.
malar and mandibular hypoplasia and had surgery on two occasions during childhood for ankylosis of the temporomandibular joint. His thumbs were congenitally absent. He had been born at 38 weeks gestation, presenting in breech position. The diagnosis of Treacher Collins syndrome was made during his 7 week hospitalization neonatally at which time his problems included poor feeding necessitating use of a nasogastric tube. He had problems with recurrent otitis media, hearing loss (for which he wears a hearing aid), dentition (for which he had prosthodontic appliances in childhood), and severely muffled, abnormal speech with poor articulation and nasal escape. He had refused additional speech therapy or reconstructive craniofacial procedures.
A younger brother (Fig. 5) was born 15 months after the propositus at 35 weeks of gestation. When examined at age 2 months, he had growth retardation (height, weight, and OFC less than 5th centile), hair tufts extending down each cheek, hypoplastic zygomatic arches, short, downslanting palpebral fissures with virtually absent lower lashes, small, apparently low-set pinnae with hypoplastic anthelices, prominent conchae, bilateral external auditory canal stenosis, flat philtrum, thin upper lip, thick palatine ridges with a narrow palatal groove, and severe micrognathia resulting in upper airway obstruction. There was radial deviation of the right hand, rudimentary thumbs which were ligated, and hypoplastic palmar creases with absent thenar creases. This child is more severely affected than his older brother and bears a striking resemblance to the more severely affected father. Because of the severe micrognathia, he had growth delay and required a tracheostomy and nasogastric tube feedings. No other relatives appear to be unequivocally affected. The paternal grandmother of the propositus (per-
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Fig. 5. Younger brother of propositus in Family 2, age 2 months. Face and arms showing malar and mandibular hypoplasia, downslanting palpebral fissures, radial deviation of the right hand, and absent thumb.
sonally examined) has a long, thin face with a narrow palate but her thumbs are normal. The paternal grandfather’s photograph did not suggest presence of the Nager syndrome. A paternal half-uncle reportedly had a long face, a “funnel chest,” and a 30%hearing loss bilaterally.
DISCUSSION The 5 patients described here all have typical Nager syndrome with mandibulofacial dysostosis and thumb anomalies. More severely affected cases have been described under the same eponym [Pfeiffer and Stoess, 1983; Kawira et al., 1984; Krauss et al., 1985; Hecht et al., 1987; Goldstein and Mirkin, 1988; Hall, 1989; Le Merrer et al., 1989; Palomeque et al., 19901 and the possible causal heterogeneity implied by this phenotypic variability has been pointed out by several authors [Carey et al., 1978;Weinbaum et al., 1981;Halal et al., 1983; Goldstein and Mirkin, 1988; Hall, 19891. Support for classifying all of these cases as Nager acrofacial dysostosis comes from observations that rather great intra-familial variability may occur [Le Merrer et al., 1989; Hall, 1989; Kim et al., 19891. Causal heterogeneity is suggested by families that are consistent with both dominant and recessive patterns of inheritance. The observation of affected monozygotic twins [Byrd et al., 19881is consistent with causation by a single mutant gene and either dominant or recessive expression. Reports of affected sibs with unaffected parents [Walker, 1974; Hecht et al., 1987; Chemke et al., 19881 and one sporadic case whose parents were first cousins [Burton and Nadler, 19771 suggest that some cases may be of autosomal recessive etiology. On the other hand, parent-to-child transmission has been observed. A mildly to moderately affected woman delivered, after 30 weeks gestation, a very severely affected son who died immediately after birth
because his limited jaw motion did not allow intubation [Hall, 19891. Another severely affected, phocomelic baby had a mother with thumb anomalies, downslanting palpebral fissures, and malar hypoplasia [Le Merrer et al., 19891. Observations of advanced paternal age in sporadic cases [Marden et al., 1964; Bowen and Harley, 1974;Lowry, 19771have also led to the suggestion that a dominantly expressed, autosomal mutation is responsible. The 2 families we report here with male-to-male transmission strongly support the hypothesis that some cases are caused by mutations in an autosomal gene (or genes) with dominant expression. One implication of these observations is that affected individuals may have as high as a 50%risk of having an affected child. Prenatal diagnosis for severe forms of radial dysplasia is feasible and prenatal ultrasound observations of this condition have been reported [Hecht et al., 1987; Benson et al., 19881. Hirschsprung disease is a developmental anomaly involving the neural crest [Webster, 19731and it has occasionally been observed in malformation syndromes that include anomalies of the limbs and/or craniofacial region [Bodian and Carter, 1963; Laurence et al., 1975; Goldberg and Shprintzen, 1981; Reynolds et al., 1983; Saul, 1985; Santos et al., 1988; Clayton-Smith and Donnai, 19891. To our knowledge, the association of acrofacia1 dysostosis with Hirschsprung disease, present in our second family, has not been reported previously. It may be a coincidental association or may represent a clue about the hypothesized, pathogenetic association between mandibulofacial dysostosis and the neural crest [Poswillo, 19751. Local inhibition of neural crestderived cell migration has been proposed for both a Hirschsprung-like animal model [Jacobs-Cohen et al., 19871 and mandibulofacial dysostosis [Herring et al., 19791. The hypothesis concerning enhancement of programmed cell death [Sulik et al., 1987, 19891 is also
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attractive and may explain better the association between craniofacial and limb defects seen in these patients. Nager acrofacial dysostosis is a somewhat variable but distinctive phenotype that is characteristic of a syndrome or community of syndromes about which knowledge is slowly evolving. We present this documentation of vertical transmission from father to son in 2 families as confirmatory clinical evidence in proving the hypothesis that some cases occur in individuals who are heterozygous for dominantly expressed, autosomal mutations.
Hecht JT, Immken LL. Harris LF, Malini S, Scott CI Jr (1987): The Nager syndrome. Am J Med Genet 27:965-969. Herring SW, Rowlatt UF, F’ruzansky S (1979):Anatomical abnormalities in mandibulofacial dysostosis. Am J Med Genet 3:225-259. Jacobs-Cohen RJ, Payette RF, Gershon MD, Rothman TP (1987): Inability of neural crest cells to colonize the presumptive aganglionic bowel of lsils mutant mice: requirement for a permissive microenvironment. J Comp Neurol 255:425-438. Kawira EL, Weaver DD, Bender HA (1984):Acrofacial dysostosis with severe facial clefting and limb reduction. Am J Med Genet 17:641-647. Kim HJ, Fragoso M, Chavez A (1989):Nager syndrome with autosomal dominant inheritance. Clinical Genetics Conference, Boston, p 39 (Abstract). Krauss CM, Hassell LA, Gang DL (1985):Anomalies in a n infant with Nager acrofacial dysostosis. Am J Med Genet 21:761-764. ACKNOWLEDGMENTS Laurence KM, Prosser R, Rocker I, Pearson JF, Richards C (1975): Hirschsprung’s disease associated with congenital heart malformaWe are grateful to Dr. Rodger Dalston for speech evaltion, broad big toes, and ulnar polydactyly in sibs: a case for fetosuation data on Family 1. This work was supported in copy. J Med Genet 12:334-338. part by NICHD grant HD-03110 and by a grant from the Le Merrer M, Cikuli M, Ribier J, Briard ML (1989): Acrofacial dysostoses. Am J Med Genet 33:318-322. North Carolina Department of Environment, Health, and Natural Resources, Division of Maternal and Child Lowry RB (19771: The Nager syndrome (acrofacialdysostosis):evidence for autosomal dominant inheritance. BD: OAS XIII(3C):195-202. Health. Marden PM, Smith DW, McDonald MJ (1964):Congenital anomalies in the newborn infant, including minor variations: a study of 4,412 babies by surface examination for anomalies and buccal smear for REFERENCES sex chromatin. J Pediatr 64357-371. Benson CB, Pober BR, Hirsh MP, Doubilet PM (1988):Sonography of Meyerson MD, Nisbet J B (1987):Nager syndrome: a n update of speech Nager acrofacial dysostosis syndrome in utero. J Ultrasound Med and hearing characteristics. Cleft Palate J 24:142-151. 7:163-167. Palomeque A, Pastor X, Ballesta F (1990):Nager anomaly with severe Bodian M, Carter CO (1963):A family study ofsirschsprung’sdisease. facial involvement, microcephaly, and mental retardation. Am J Ann Hum Genet 26:261-271. Med Genet 36:356-357. Bowen P, Harley F (1974):Mandibulofacial dysostosis with limb mal- Pfeiffer RA, Stoess H (1983):Acrofacial dysostosis (Nager syndrome): formations (Nager’s acrofacial dysostosis). BD:OAS 10:109-115. synopsis and report of a new case. Am J Med Genet 15:255-260. Burton BK, Nadler HL (1977):Nager acrofacial dysostosis: report of a Poswillo D (1975):The pathogenesis of the Treacher Collins syndrome case. J Pediatr 91:84-86. (mandibulofacial dysostosis). Br J Oral Surg 13:l-26. Byrd LK, Rogers RC, Stevenson RE (1988):Nager acrofacial dysostosis Reynolds JF, Barber J C , Alford BA, Chandler JG, Kelly TE (1983): in four patients including monozygous twins. Proc Greenwood GeFamilial Hirschsprung’s disease and type D brachydactyly: a report net Cntr 7:30-35. of four affected males in two generations. Pediatrics 71:246-249. Carey JC, Cox DR, Hall BD (1978):Nager acrofacial dysostosis: clinical Santos H, Mateus J , Leal MJ (1988):Hirschsprung disease associated and hereditary classification of a heterogeneous entity. Clin Res with polydactyly, unilateral renal agenesis, hypertelorism, and 26:192A (Abstract). congenital deafness: a new autosomal recessive syndrome. J Med Genet 25:204-208. Chemke J, Mogilner BM, Ben-Itzhak I, Zurkowski L, Ophir D (1988): Autosomal recessive inheritance of Nager acrofacial dysostosis. J Saul RA (1985): The nosology of megacolon. Proc Greenwood Genet Med Genet 25:230-232. Cntr 422-28. Clayton-Smith J, Donnai D (1989): A new recessive syndrome of unSulik KK, Johnston MC, Smiley SJ, Speight HS, Jarvis BE (1987): usual facies, digital abnormalities, and ichthyosis. J Med Genet Mandibulofacial dysostosis (TreacherCollins syndrome):a new pro26:339-342. posal for its pathogenesis. Am J Med Genet 27:359-372. Gellis SS, Feingold M, Miller D (1978):Picture of the month. Nager’s Sulik KK, Smiley SJ, Turvey TA, Speight HS, Johnston MC (1989): syndrome (Nager’s acrofacial dystosis). Am J Dis Child 132:519Pathogenesis of cleft palate in Treacher Collins, Nager, and Miller 520. syndromes. Cleft Palate J 26:209-216. Goldberg RB, Shprintzen R J (1981):Hirschsprung megacolon and cleft Thompson E, Cadbury R, Baraitser M (1985): The Nager acrofacial palate in two sibs. J Craniofac Genet Dev Biol 1:185-189. dysostosis syndrome with the tetralogy of Fallot. J Med Genet 22:408-410. Goldstein DJ, Mirkin LD (1988):Nager acrofacial dysostosis: evidence for apparent heterogeneity. Am J Med Genet 30:741-746. Walker FA (1974): Apparent autosomal recessive inheritance of the Treacher Collins syndrome. BD:OAS X(8):135-139. Halal F, Herrmann J , Pallister PD, Opitz JM, Desgranges MF, Grenier G (1983):Differential diagnosis of Nager acrofacial dysostosis synWebster W (1973): Embryogenesis of the enteric ganglia in normal drome: report of four patients with Nager syndrome and discussion mice and in mice that develop congenital aganglionic megacolon. J of other related syndromes. Am J Med Genet 14:209-224. Embryo1 Exp Morphol 30573-585. Hall BD (1989):Nager acrofacial dysostosis: autosomal dominant inWeinbaum M, Russell L, Bixler D (1981):Autosomal dominant transheritance in mild to moderately affected mother and lethally afmission of Nager acrofacial dysostosis. Am J Hum Genet 33:93A fected phocomelic son. Am J Med Genet 33:394-397. (Abstract).
Nager Acrofacial Dysostosis: Male-to-Male Transmission in 2 Families Arthur S. Aylsworth, Angela E. Lin, and Patricia A. Friedman Department of Pediatrics and the Brain and Development Research Center, School of Medicine, University of North Carolina at Chapel Hill (A.S.A., P.A.F.); Department of Medical Genetics, West Penn Hospital, Pittsburgh, Pennsylvania (A.E.L.)
We describe 2 unrelated familieswith male-tomale transmission of Nager syndrome. All 5 affected individuals have moderate expression of the phenotype. One affected boy also has Hirschsprung disease. Although Nager acrofacial dysostosis usually occurs sporadically, both recessive and dominant inheritance have been suggested on the basis of reported familial cases. The 2 families described here with father-to-sontransmission strongly support the hypothesis that some cases of Nager acrofacial dysostosis occur in individuals who are heterozygousfor dominantly expressed, autosomal mutations.
KEY WORDS: mandibulofacial dysostosis, limb anomalies, Hirschsprung disease, neural crest, genetics, autosomal dominant INTRODUCTION Nager acrofacial dysostosis is characterized by malar and mandibular hypoplasia and preaxial upper limb defects, usually including hypoplasia or absence of thumbs. In addition, reported patients have had a variety of other findings including developmental delay, short stature, and other components of mandibulofacial dysostosis such as cleft palate, ear anomalies, hearing loss, absent or sparse eyelashes, and downslanting palpebral fissures [Bowen and Harley, 1974; Lowry, 1977; Gellis et al., 1978; Halal et al., 1983; Thompson et al., 1985; Meyerson and Nisbet, 1987; Byrd et al., 1988; Received for publication September 19, 1990; revision received February 5, 1991. Address reprints requests to Arthur S. Aylsworth, M.D., CB#7250, University of North Carolina, Chapel Hill, NC 27599-7250. Angela E. Lin’s current affiliation is the National Birth Defects Center, Franciscan Hospital, Brighton, Mass. Patricia A. Friedman’s current affiliation is The Durham Developmental Evaluation Center, Durham, NC.
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Chemke et al., 19881. This phenotype usually occurs sporadically but causal heterogeneity is suggested by families that are consistent with both recessive [Walker, 1974; Hecht et al., 1987; Chemke et al., 19881and dominant [Weinbaum et al., 1981; Hall, 1989; Kim et al., 1989;Le Merrer et al., 19891patterns of inheritance. No previous cases of male-to-male transmission have been reported.
CLINICAL REPORTS Family 1 The propositus (Fig. 1)is a black boy with hypoplasia of the zygomatic arches, downslanting palpebral fissures without lid colobomas, micrognathia, prominent upper lip, broad lateral palatine ridges, normal ear size with large fleshy lobes, and a mild pectus excavatum. Birth weight and length were normal. He had a poor suck in the newborn period and was a “noisy breather.” He had radial deviation of the left hand, a proximally placed, small left thumb, congenital absence of the right thumb, and medial deviation of the distal phalanges of the second toes. At age 2 years he had normal height, weight, and head circumference (OFC). He had 3 caf6-au-lait spots between 10 and 18 mm in maximum dimension. There was a moderate bilateral conductive hearing loss with type B tympanograms and delayed development of both receptive and expressive language. Limited testing documented gross and fine motor skills in a wide spread around his chronologicage. He was fitted with binaural hearing aids and had bilateral pollicization of index fingers. Follow-up testing at age 35/12 years showed moderate hypernasality, a severe articulation problem, and mildly to moderately impaired receptive and expressive language. Cognitive functioning was in the borderline normal range. Fingertip dermatoglyphics are AAUU on the right and WAAUU on the left. As shown in Figure Id, the thenar and proximal palmar creases did not develop and the distal palmar creases are prominent, running from between the index and middle fingers to the ulnar aspect of each hand. The father of the propositus (Fig. 2) has severe malar hypoplasia (L > R), downslanting palpebral fissures without lid colobomas, normal external ear size with small external auditory canals, micrognathia, very
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Fig. 1. Propositus in Family 1. a,b: Face at age 2 months. Palpebral fissures slant downward slightly and the mandible is somewhat small. Ear lengths were normal but the lobes were unusually large and fleshy. c: Face at age 2 years. d Hands at 2 years. The right thumb was congenitally absent and the left thumb was hypoplastic. e: Feet at 2 months showing bilateral medial deviation of the distal portion of the second toes.
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broad lateral palatine ridges, normal height and weight, and OFC at the 98th centile. At birth he had micrognathia, a short soft palate, apparent absence of the uvula, short radii with bilateral radial deviation of the hands, rudimentary left thumb, 4 metacarpals on the left, a hypoplastic right thumb, and bilateral metatarsus varus. Later in childhood he had a bilateral conductive hearing loss of 50-60 dB with a 40-50 dB airbone gap. Diagnosis at this time was Treacher Collins syndrome. At age 15, exploration of the left middle ear showed intact tympanic membranes, a small cartilaginous malleus, absence of the incus, absence of the stapes head and neck, and a normally positioned stapes footplate. The rudimentary left thumb, described as a “flail thumb” containing palpable bone but with no bony attachment, was removed a t 19 years. His proximally placed, hypoplastic right thumb was never functional. He had limited supination and extension of his forearms. As an adult, he has a moderate articulation problem, mild to moderate hypernasality, and overall intelligibility that is judged to be moderately impaired. There is no velar elevation or lateral pharyngeal wall activity during phonation. A single uvula is present without a palpable submucous cleft. Mandibular mobility is somewhat limited, especially lateral motion and protrusion. He has bilateral, moderate to severe conductive hearing loss with relatively good speech discrimination. The unaffected paternal grandfather of the propositus was 30 years old a t the time of the father’s birth. A cousin reportedly had unilateral hand polydactyly. The mother of the propositus had no significant dysmorphic features. No other relatives are known to have any manifestation suggestive of the Nager phenotype.
Fig. 2. Affected father of propositus in Family 1. a , b Face showing maxillary and mandibular hypoplasia with downslanting palpebral fissures. c: Hands. The left thumb was rudimentary and removed when he was a child; the right thumb was non-functional.
Family 2 The propositus (Fig. 3) is a white boy whose anomalies were noted in the newborn period. He had a low anterior hairline with tufts of hair extending down each cheek, mild hypoplasia of the zygomatic arches, moderate micrognathia, posteriorly rotated ears, right ear smaller than the left, small external auditory canals (left side smaller than the right), short palpebral fissures, absent lower lashes, no coloboma, and a small uvula with poor posterior movement. The thumbs were hypoplastic and pedunculated with some bone present on the right but not on the left. He was born to 20-year-old parents who reported normal fetal activity and growth. Apgar scores were 8 and 9 following a normal, spontaneous vaginal delivery a t 41 weeks. Height, weight, and OFC were all normal. The patient was admitted t o hospital at age 6 days with vomiting and abdominal distension. Hirschsprung disease was diagnosed and a colostomy was performed. The father of the propositus (Fig. 4)is short (163 cm), and has asymmetry with hypoplasia Of the right side, hair tufts extending down the cheeks, sparse lower eyelashes (especially in the medial aspect), and short, downslanting palpebral fissures. Both ears appear narrow and low-set with deep concha, hypoplastic anthelices, and small external auditory canals. The uvula is bifid and the vela are absent. He has marked
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Fig. 4. Father of propositus in Family 2. a,b Face showing marked malar and mandibular hypoplasia and downslanting palpebral fissures. c: Hands with congenital absence of both thumbs.
Fig. 3. Propositus in Family 2. a: Face in neonatal period showing micrognathia. b: Hands with bilateral hypoplastic, pedunculated thumbs.
malar and mandibular hypoplasia and had surgery on two occasions during childhood for ankylosis of the temporomandibular joint. His thumbs were congenitally absent. He had been born at 38 weeks gestation, presenting in breech position. The diagnosis of Treacher Collins syndrome was made during his 7 week hospitalization neonatally at which time his problems included poor feeding necessitating use of a nasogastric tube. He had problems with recurrent otitis media, hearing loss (for which he wears a hearing aid), dentition (for which he had prosthodontic appliances in childhood), and severely muffled, abnormal speech with poor articulation and nasal escape. He had refused additional speech therapy or reconstructive craniofacial procedures.
A younger brother (Fig. 5) was born 15 months after the propositus at 35 weeks of gestation. When examined at age 2 months, he had growth retardation (height, weight, and OFC less than 5th centile), hair tufts extending down each cheek, hypoplastic zygomatic arches, short, downslanting palpebral fissures with virtually absent lower lashes, small, apparently low-set pinnae with hypoplastic anthelices, prominent conchae, bilateral external auditory canal stenosis, flat philtrum, thin upper lip, thick palatine ridges with a narrow palatal groove, and severe micrognathia resulting in upper airway obstruction. There was radial deviation of the right hand, rudimentary thumbs which were ligated, and hypoplastic palmar creases with absent thenar creases. This child is more severely affected than his older brother and bears a striking resemblance to the more severely affected father. Because of the severe micrognathia, he had growth delay and required a tracheostomy and nasogastric tube feedings. No other relatives appear to be unequivocally affected. The paternal grandmother of the propositus (per-
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Fig. 5. Younger brother of propositus in Family 2, age 2 months. Face and arms showing malar and mandibular hypoplasia, downslanting palpebral fissures, radial deviation of the right hand, and absent thumb.
sonally examined) has a long, thin face with a narrow palate but her thumbs are normal. The paternal grandfather’s photograph did not suggest presence of the Nager syndrome. A paternal half-uncle reportedly had a long face, a “funnel chest,” and a 30%hearing loss bilaterally.
DISCUSSION The 5 patients described here all have typical Nager syndrome with mandibulofacial dysostosis and thumb anomalies. More severely affected cases have been described under the same eponym [Pfeiffer and Stoess, 1983; Kawira et al., 1984; Krauss et al., 1985; Hecht et al., 1987; Goldstein and Mirkin, 1988; Hall, 1989; Le Merrer et al., 1989; Palomeque et al., 19901 and the possible causal heterogeneity implied by this phenotypic variability has been pointed out by several authors [Carey et al., 1978;Weinbaum et al., 1981;Halal et al., 1983; Goldstein and Mirkin, 1988; Hall, 19891. Support for classifying all of these cases as Nager acrofacial dysostosis comes from observations that rather great intra-familial variability may occur [Le Merrer et al., 1989; Hall, 1989; Kim et al., 19891. Causal heterogeneity is suggested by families that are consistent with both dominant and recessive patterns of inheritance. The observation of affected monozygotic twins [Byrd et al., 19881is consistent with causation by a single mutant gene and either dominant or recessive expression. Reports of affected sibs with unaffected parents [Walker, 1974; Hecht et al., 1987; Chemke et al., 19881 and one sporadic case whose parents were first cousins [Burton and Nadler, 19771 suggest that some cases may be of autosomal recessive etiology. On the other hand, parent-to-child transmission has been observed. A mildly to moderately affected woman delivered, after 30 weeks gestation, a very severely affected son who died immediately after birth
because his limited jaw motion did not allow intubation [Hall, 19891. Another severely affected, phocomelic baby had a mother with thumb anomalies, downslanting palpebral fissures, and malar hypoplasia [Le Merrer et al., 19891. Observations of advanced paternal age in sporadic cases [Marden et al., 1964; Bowen and Harley, 1974;Lowry, 19771have also led to the suggestion that a dominantly expressed, autosomal mutation is responsible. The 2 families we report here with male-to-male transmission strongly support the hypothesis that some cases are caused by mutations in an autosomal gene (or genes) with dominant expression. One implication of these observations is that affected individuals may have as high as a 50%risk of having an affected child. Prenatal diagnosis for severe forms of radial dysplasia is feasible and prenatal ultrasound observations of this condition have been reported [Hecht et al., 1987; Benson et al., 19881. Hirschsprung disease is a developmental anomaly involving the neural crest [Webster, 19731and it has occasionally been observed in malformation syndromes that include anomalies of the limbs and/or craniofacial region [Bodian and Carter, 1963; Laurence et al., 1975; Goldberg and Shprintzen, 1981; Reynolds et al., 1983; Saul, 1985; Santos et al., 1988; Clayton-Smith and Donnai, 19891. To our knowledge, the association of acrofacia1 dysostosis with Hirschsprung disease, present in our second family, has not been reported previously. It may be a coincidental association or may represent a clue about the hypothesized, pathogenetic association between mandibulofacial dysostosis and the neural crest [Poswillo, 19751. Local inhibition of neural crestderived cell migration has been proposed for both a Hirschsprung-like animal model [Jacobs-Cohen et al., 19871 and mandibulofacial dysostosis [Herring et al., 19791. The hypothesis concerning enhancement of programmed cell death [Sulik et al., 1987, 19891 is also
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attractive and may explain better the association between craniofacial and limb defects seen in these patients. Nager acrofacial dysostosis is a somewhat variable but distinctive phenotype that is characteristic of a syndrome or community of syndromes about which knowledge is slowly evolving. We present this documentation of vertical transmission from father to son in 2 families as confirmatory clinical evidence in proving the hypothesis that some cases occur in individuals who are heterozygous for dominantly expressed, autosomal mutations.
Hecht JT, Immken LL. Harris LF, Malini S, Scott CI Jr (1987): The Nager syndrome. Am J Med Genet 27:965-969. Herring SW, Rowlatt UF, F’ruzansky S (1979):Anatomical abnormalities in mandibulofacial dysostosis. Am J Med Genet 3:225-259. Jacobs-Cohen RJ, Payette RF, Gershon MD, Rothman TP (1987): Inability of neural crest cells to colonize the presumptive aganglionic bowel of lsils mutant mice: requirement for a permissive microenvironment. J Comp Neurol 255:425-438. Kawira EL, Weaver DD, Bender HA (1984):Acrofacial dysostosis with severe facial clefting and limb reduction. Am J Med Genet 17:641-647. Kim HJ, Fragoso M, Chavez A (1989):Nager syndrome with autosomal dominant inheritance. Clinical Genetics Conference, Boston, p 39 (Abstract). Krauss CM, Hassell LA, Gang DL (1985):Anomalies in a n infant with Nager acrofacial dysostosis. Am J Med Genet 21:761-764. ACKNOWLEDGMENTS Laurence KM, Prosser R, Rocker I, Pearson JF, Richards C (1975): Hirschsprung’s disease associated with congenital heart malformaWe are grateful to Dr. Rodger Dalston for speech evaltion, broad big toes, and ulnar polydactyly in sibs: a case for fetosuation data on Family 1. This work was supported in copy. J Med Genet 12:334-338. part by NICHD grant HD-03110 and by a grant from the Le Merrer M, Cikuli M, Ribier J, Briard ML (1989): Acrofacial dysostoses. Am J Med Genet 33:318-322. North Carolina Department of Environment, Health, and Natural Resources, Division of Maternal and Child Lowry RB (19771: The Nager syndrome (acrofacialdysostosis):evidence for autosomal dominant inheritance. BD: OAS XIII(3C):195-202. Health. Marden PM, Smith DW, McDonald MJ (1964):Congenital anomalies in the newborn infant, including minor variations: a study of 4,412 babies by surface examination for anomalies and buccal smear for REFERENCES sex chromatin. J Pediatr 64357-371. 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