American Journal of Medical Genetics 46:659-664 (1993)

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Mandibulofacial Dysostosis: Report on Two Brazilian Families Suggesting Autosomal Recessive Inheritance

A. Richieri-Costa, M.A. Bortolozo, J.R.P. Lauris, R.C.M.C. Lauris, M.L. Guion-Almeida, D. Marques, and D. Moreti Hospital de Pesquisa e Reabilitqh de Lescies Labw-Palatais, Universidude de S h Paulo, Bauru, S h Paulo, Brazil

We report on mandibulofacial dysostosis in 2 brothers born to normal nonconsanguineous parents, and a girl (F = 1/16) born to normal consanguineous parents. Normal clinical, skeletal, audiologic, and cephalometric studies in the parents, as well as the absence of limb anomalies in these children, exclude the autosomal recessive (Nager and Genee- Widemann) mandibulofacial dysostoses. The data of the present patients associated with the few additional reports on mandibulofacial dysostosis recurring in sibs, suggest the pos- sibility of an autosomal recessive Treacher Collins-like mandibulofacial dysostosis. 0 1993 Wiley-Lisa, Inc.

KEY WORDS: mandibulofacial dysostosis, Treacher Collins syndrome, germinal mosaicism, autoso- ma1 recessive inheritance

INTRODUCTION Typical mandibulofacial dysostosis occurring in sibs

and suggesting autosomal recessive inheritance is ex- ceedingly rare [Axelsson et al., 1963; Gollop, 1981, Lowry et al., 19851. Germinal mosaicism, chromosomal rearrangement or delayed mutation have been proposed as alternative genetic mechanisms. Here we report on a Treacher Collins-like phenotypes in 2 brothers born to normal parents, and in a girl born to normal consan- guineous parents, suggesting autosomal recessive in- heritance.

CLINICAL REPORTS Family A

Patient 1. GS (Fig. 1A-C), the 9-year-old propo- situs, was born in the State of Santa Catarina, Brazil. He is the first child of a 19-year-old G4P4 mother and

Received for publication October 13,1992; revision received Jan-

Address reprint requests to A. Richieri-Costa, M.D., HPRLLP- uary 25, 1993.

USP, P. 0. Box 620, 17043 Bauru, SBo Paulo, Brazil.

0 1993 Wiley-Liss, Inc.

her nonconsanguineous 22-year-old husband. The pa- ternal family has a remote Swiss origin (3rd genera- tion), and the maternal family has a remote Portuguese origin (8th generation). Pregnancy was normal. There was absence of trauma or exposure to toxic or infectious agents and/or to X-rays. There was normal, term deliv- ery. Birth weight (BW) was 900 g (<3rd centile), length (TBL) 38 cm (<3rd centile), and occipitofrontal circum- ference (OFC) was not recorded. Neuropsychological de- velopment was normal. The outcomes of the other preg- nancies were an equally affected brother (patient 21, a normal sister, and a normal brother. There were no related anomalies in other relatives.

Clinical examination at age 8 years: height 133 cm (75th centile), weight 24,4 kg (50th centile), OFC 51 cm (25th centile), inner canthal distance (ICD) 3.3 cm (75th centile), outer canthal distance (OCD) 8.5 cm (75th cen- tile). He had deep-set eyes, downward slant of the pal- pebral fissures, lower lid coloboma, abnormal eyelashes, hypoplastic left ear with absence of the external ear canal, small and cup-shaped right ear, with a hypoplas- tic external ear canal, bilateral extension of the hair on the upper cheek, malar hypoplasia, receding chin, highly arched palate, and normal limbs. Derma- toglyphics: Lu, As, Lu, Lu, Lu, atd angle 41", a-b count 42 at left, and Lu, At, Lu, Lu, Lu, atd angle 45", a-b count 45 at right. Audiologic examination showed bilateral conductive hearing loss, markedly a t left.

Roentgenograms was unremarkable. Orthopantomo- gram showed open bite. CT scan was normal. Results of routine blood tests were normal. Cytogenetic analysis showed normal chromosomes.

Patient 2. JS (Fig. 2A-C), the propositus's brother, was born in 1989. Pregnancy was normal. There was absence of trauma or exposure to toxic or infectious agents and/or to X-rays. He had a normal, term delivery. BW was 2,800 g (<loth centile), TBL 46 cm (<loth centile), OFC was not recorded. There was normal neu- ropsychological development. Clinical examination at age 3 years: height 96 cm (50th centile), weight 13 kg (25th centile), OFC 49 cm (<50th centile), ICD 3.1 cm (<97th centile), OCD 8.0 cm (<97th centile). He had deep-set eyes, downward slant of the palpebral fissures, lower lid coloboma, abnormal eyelashes, hypoplastic left ear with absence of the external ear canal, small and posteriorly angulated right ear with hypoplastic exter-

660 Richieri-Costa et al.

Fig. 1. A-C: Patient 1.

nal ear canal, malar hypoplasia, highly arched palate, and normal limbs. Dermatoglyphics: Lu, As, Lu, Lu, AS, atd angle 43", a-b count 46 at left; Lu, As, Lu, Lu, Lu, atd angle 42", a-b count 41 at right.

Audiologic examination showed bilateral conductive hearing loss. Roentgenograms was unremarkable. Or- thopantomogram showed open bite. Results of routine blood tests were normal.

Family data. The examination of the 27-year-old mother (Fig. 3A-C), and of the 30-year-old father (Fig. 4A-C) showed no clinical, audiological, or skeletal anomalies. Cephalometric findings are shown in Table I.

Family B Patient 3. MSB (fig. 5A-C), the proposita, was born

in 1988. She is the first child of a normal 23-year-old mother and her related (first cousin) 34-year-old normal husband. Pregnancy was normal. There was absence of trauma or exposure to toxic or infectious agents and/or to

X-rays. Delivery was through cesarean section. Birth weight was 2,800 g (10th centile), TBL was 49 cm (25th centile), OFC was not recorded. Neuropsychological de- velopment was normal. In a previous nonconsanguine- ous marriage, the mother had 2 normal boys. There were no related anomalies in other relatives.

Clinical examination at age 38 months: height 95 cm (50th centile), weight 11 kg (<3rd centile), OFC 52 cm (97th centile), ICD 4.0 cm (>97th centile), OCD 8.3 cm (75<P<97th centile). She had deep-set eyes, hypertelor- ism, downward slant of the palpebral fissures, lower lid coloboma at left partial absence of the lower eyelashes, hypoplastic ears with absence of the external ear canal, bilateral projection of the hair on the lateral cheek, malar hypoplasia, receding chin, carp-like mouth, and normal limbs. Dermatoglyphics: Lu(20), Lu(14), Lu(14), Ws(a), Ws(7), main line formula 11, 11, 7, 3, 13-t, O.O.M.O.L., atd angle 41" at left, and Lu(18), Wd(8), Lr(8), Wd(15), Wd(17), main line formula 11, 11, 7, 5',

Fig. 2. A-C Patient 2.

Mandibulofacial Dysostosis 661

Fig. 3. A-C: The mother of patients 1 and 2.

Fig. 4. A-C: The father of patients 1 and 2.

13-t, O.M.O.O.L., atd angle 37" at right. Audiologic exam- ination showed bilateral conductive hearing loss. Roent- genograms were unremarkable. Cytogenetic analysis showed normal chromosomes (G-banded).

Familial data. The examination of the 27-year-old mother (Fig. 6A-C), and of the 38-year-old father (Fig. 7A-C) showed no clinical, audiological, or skeletal anomalies. Cephalometric findings are shown in Table I.

DISCUSSION Mandibulofacial dysostosis (Treacher Collins syn-

drome) is an autosomal dominant condition, with 60% of the cases representing new mutations [Pashayan, 1978; Gorlin et al., 19911. Expressivity is variable, ranging from minor signs such as mild malar hypolasia or down- slanting of the palpebral fissures to a full-blown clinical picture. Estimation of penetrance from genealogical data has shown different values in different papers, ranging from 0.91 to 1.0 [Pashayan, 1978; Pinsky, 1979; Gollop, 1981; Rogatko et al., 19861. However, many re-

ports have been published on mandibulofacial dysos- tosis in sibs with apparently normal parents, suggesting the existence of an autosomal recessive type [Gollop, 1981; Lowry et al., 19851, but in these cases the alterna- tive possibility of a germinal mosaicism cannot be ruled out, since in some autosomal dominant disorders with complete penetrance, recurrence in sibs with normal parents has been observed [F'ryns et al., 1983; Lowry et al., 1985; Allanson, 1986; Rollnick, 1988; Kreiborg and Cohen, 19901. Mandibulofacial dysostosis associated with chromosomal anomalies were reported in two in- stances: a de novo balanced translocation t(5;13)(qll; p l l ) in a girl [Balestrazzi et al., 19831, and in a mother and three children, two of them with a familial balanced translocation t(6;16)(p21.3l;pl3.11) [Dixon et al., 1991aI. The possibility of the locus on chromosomes 6 or 16 was excluded [Dixon et al., 1991a1, and a further report showed evidence demonstrating the localization of the Reacher Collins locus to 5q31-34 [Dixon et al., 199 1 bl .

662 Richieri-Costa et al.

TABLE I. Cephalometric Measurements Family 2 _ _ ~ _ _ _ Family 1 Linear and Angular

measurements Mother Father Mother Father

S-N-A* 76.Fib 84.8 79.7 74.7b S-N-B 78.4 78.4 77.6 73.2 A-N-B - 1.9b 6.4" 2.1 1.5 S-N-GN 80.1 80.2 78.2 73.9 N-S. ANS-PNS 11.3" 5.0 7.0 12.4" N-S. Me-Go 32.2 33.0 34.0 42.0" N-S-Ba 127.5 123.1 128.5 123.6 ANS-PNS. Me-Go 20.9 28.0 26.9 29.6 Ar-Go-Me 130.1" 129.3 126.7 130.1 S-N 75.1 74.9 73.1 79.5 S-Ba 47.7 50.2 44.8 52.1 N-Me 119.8 129.5 114.7 143.3 N-ANS 58.6" 56.5 52.1 61.1 ANS-Me 61.8b 75.0 63.2 82.9 ANS-PNS 54.1 58.3 51.9 48.0b

Ar-Go 44.1b 52.2 43.7b 51.9 * S-N-A = degree of maxillary protrusion; S-N-B = degree ofmandibular protrusion; A-N-B = difference between maxillary and mandibular protrusion; S-N-GN = facial angle; N-S. ANS-PNS = anterior cranial baselpalatal plate; N-S. Me-Go = anterior cranial base/ mandibular plane angle; N-S-Ba = cranial base angle; ANS-PNS. Me-Go = palatal plane/ mandibular plane angle; Ar-Go-Me = mandibular angle; S-N = anterior cranial base length; S-Ba = posterior cranial base length; N-Me = anterior facial height; N-ANS = anterior upper facial height; ANS-Me = anterior lower facial height; ANSPNS = maxcil- lary length; Go-Me = mandibular body length; Ar-Go = mandibular ramus height. a Larger than normal pattern. Lesser than normal pattern. Normal pattern compared with data from M.L. Riolo et al. 119741.

Go-Me 78.0 73.7b 73.1 74.gb

The cumulative evidence in the literature on cases of mandibulofacial dysostosis recurring in sibs born to nor- mal parents suggests the existence of an autosomal re- cessive form of a Treacher Collins-like mandibulofacial dysostosis. The present report brings the overall number of these reported cases known to us to 24 (17 males and 7 females). In 7 instances, recurrence was in brothers [De Lima and Monteiro, 1923; Sanvenero- Roselli, 1948; Stovin et al., 1960; family 1; Ammermann

et al., 1971; Ih-aser, 1976; Gollop, 1981; present family] and in four instances in sibs or daughters [Lievre, 1953; Zunin, 1957; Stovin et al., 1960, family 2; Axelsson et al., 1963; Lowry et al., 19853. Consanguinity with recur- rence was present in two instances [Sanvenero-Roselli, 1948; Lowry et al., 19851, and in one isolated case (Fam- ily 2 of the present report); however, in the latter, con- sanguinity ci3n be fortuitous, and germinal mosaicism or a new mutation cannot be ruled out.

Fig. 5. A-C Patient 3.

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Fig. 6. A-C: The mother of patient 3.

Fig. 7. A-C: The father of patient 3.

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