Craniofacial pattern profile (CFPP) evaluation of facial dysmorphology in a familial syndrome with corneal anesthesia and multiple congenital anomalies.код для вставкиСкачать
AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 74:465-471(1987) Craniofacial Pattern Profile (CFPP) Evaluation of Facial Dysmorphology in a Familial Syndrome With Corneal Anesthesia and Multiple Congenital Anomalies SUDHA S. SAKSENA, MARIA A. RAMOS-ARROYO,AND M.E. HODES Departments of Oral Facial Genetics (S.S.S.) and Medical Genetics (M.A.R-A., M.E.H.), Indiana University Medical Center, 1226 W Michigan St., BR026, Indianapolis, Indiana 46220 Familial syndrome, Craniofacial pattern profile (CFPP) evaluation, Facial dysmorphology KEY WORDS ABSTRACT Roentgencephalometric findings are presented for a family with an unusual facial morphology. Twenty measurements defining the size and shape of major anatomic areas of the head and face were taken. The measurements were transformed into Z-scores. Using the cZ (i.e., standard deviation of the Z-scores) value, an estimate of craniofacial pattern deviation from the norms was made for each family member. All members of this family have highly aberrant, i.e., dysmorphic, craniofacial pattern profiles. Familial as well as syndromic craniofacial similarities vs. dissimilarities between Z-score values of pairs of family members were assessed by the Pearson's correlation coefficient r,. Results of correlation coefficients demonstrate a high level (far in excess of the expected value of r, 0.50) of craniofacial pattern profile (CFPP) similarity between sibs and between sibs and their mother. This strongly suggests that the two sibs and their mother are the carrier of the same genetic syndrome. Two patients (proband and her brother) with multiple congenital anomalies were examined in o u r Medical Genetics Clinic, I.U. Medical Center for a possible genetic defect. They both had a history of congenital persistent ductus arteriosus (PDA), corneal anesthesia with resultant corneal ulceration, absence of the retinal pigment epithelium, moderate to severe sensorineural hearing loss, short stature, low weight, mild mental retardation, and similar unusual facies. Their mother had a somewhat similar face, and similar eye and hearing problems. The father also had an unusual face, but was examined to be normal and in good health. The parents are nonconsanguineous. Only other known member of the family with a history of corneal ulcers is the maternal grandmother, who also has a decreased visual acuity in the right eye. The purpose of this report is t o use roentgencephalometry in the evaluation of facial morphology of the proband, her brother, and her mother and father, in order 1)to identify 0 1987 ALAN R. LISS, INC. any family specific dysmorphic facial characteristics; and 2) to examine the extent of craniofacial similarities and/or differences, both familial as well as syndromic. DESCRIPTION OF THE FAMILY Case Report Patient 1:Proband at age 8 years (Fig. 1). Height: 120 cm (< 15th centile), 'weight 17.5 kg (< < 3rd centile). Head circumference: 49.4 cm (< 10th centile); inner canthal distance 3.1 (>6Oth centile); and outer canthal distance 8.0 cm (50th centile). Face: Square shape, broad flat forehead; ocular hypertelorism; slanted palpebral fissures; low and broad nasal root and bridge; prominent ramus and wide chin. 'Normal data values from Synder et al. (1977) (for height and weight), Nelhaus, (1968) (for head circumference), and Feingold and Bossert (19741(for inner and outer canthal distances). Received April 25,1986; revision accepted November 17,1986. 466 S.S. SAKSENA, M.A. RAMOS-ARROYO,AND M.E. HODES Fig. 1. Proband (patient 1) and brother (patient 2). tile); and outer canthal distance 8.6 cm (>85th centile). Face: Extremities and other clinical findings are very similar to those of the proband, with some differences: a cardiac murmur of PDA found soon after birth and the PDA closed spontaneously. Same eye problems as his sister but not so severe. Moderate bilateral sensorineural hearing loss. Severe speech impairment. Moderate mental retardation. I& 48. Mother: Mother at age 29 years (Fig. 2A). Height: 161 cm (30th centile);weight 39 kg (< < 5th centile). Head circumference: 53.2 cm (25th centile); inner canthal distance 3.25 cm (75th centile); and outer canthal distance 9.3 (75th centile). Face and extremities are very much like that of the two offspring. She had some kind of retinal epithelium abnormalities at age 7 years. Father: Father at age 31 years (Fig. 2B). Height: 170.2 cm (20th centile); weight 43 kg (<5th centile). Head circumference: 54.9 cm (5th centile); inner canthal distance 3.29 cm (75th centile); and outer canthal distance 8.94 cm (60th centile). Unusual face. Short and slender body build. All family members have normal karyotypes. Clinical findings are summarized in Table 1. Extremities: Long and slender. A large PDA surgically repaired at age 1 month. Ophthalmologic examination at 6 months of age showed multiple corneal ulcers owing to congenital anesthesia of the corneas. Poor visual acuity. Hearing examination at age 5 years revealed moderate to severe bilateral sensorineural hearing loss. Walked at 3% years of age. Speech pattern at 4'/2year level. Moderate mental retardation. I& 44. Patient 2: Brother at age 5 years (Fig. 1). MATERIALS AND METHODS Height: 99.9 cm (3rd centile); weight 13.4 Roentgencephalometric analysis kg (<3rd centile). A total of 20 linear and angular measureHead circumference: 48.2 cm (5th centile); inner canthal distance 3.35 cm (>97th cen- ments defining the size and shape of major Fig. 2. A Mother. B: Father. 467 CRANIOFACIAL PATTERN PROFILE EVALUATION TABLE 1. Comparison of the clinical features' Findings Eye and ear 1. Corneal anesthesia with corneal ulceration 2. Absence of the retinal pigment epithelium 3. Poor visual acuity 4. Sensorineural hearing loss Face 5. Square shape face, with prominent ramus and wide chin 6. Hyperterlorism 7. Slanted palpebral fissures 8. Low and broad nasal root and bridge Other features 9. Persistent ductus arteriosus 10. Short slender body build 11. Low weight 12. Moderate mental retardation I+, Proband Brother Mother + + + + + + + + + +- Father - + +- present; -, absent; ?, unknown. anatomic regions of the head and face were made on the lateral and frontal radiographs of the proband, brother, and parents (Table 2). The frontal radiographs are presented in Figure 3. Anatomic areas quantified were as follows: I) facial height; Ill facial depth; 111) cranial base; IV)facial profile; V) size and shape of the mandible; VI) head length; and VID facial width dimensions. Landmarks from the lateral and frontal radiographs were digitized directly from the x-ray headplates. To reduce landmark identification errors, each headplate was digitized on three separate occasions and the computer-generated linear and angular measurements were compared and verified. Linear measurements were read to the nearest 0.5 mm and angular to the nearest 0.5 degree. Facial height: The total facial height N-ME was significantly shorter ( 2 -2.2 S.D.) in the proband, her brother, and father. The total facial height was divided into two anatomic components, the upper facial height N-ANS and the lower facial height ANS-ME. The upper facial height was significantly shorter ( 2 -2.3 S.D.) in the proband and her father, but normal in her mother and brother. However, the lower facial height was only mildly reduced (-1.3 S.D.) in the proband, but it was markedly reduced in her brother and father. All the facial height dimensions were severely retarded in the proband's father, but only mildly affected in the mother. Facial depth: The total midfacial depth POA pt. was much underdeveloped (> - 1.7 S.D.) for all the family members except the father; but surprisingly, all had close to normal (< k0.5 S.D.) maxillary depth ANS-PNS. Cranial base: Dimensions of the cranial base (including the cranial base angle N-SBA) were small to very small in all the family members. Facial Profile: The relationship of maxilla to cranial base S-N-Apt. was highly recessed in the proband, brother, and mother. On the other hand, the proband's father had not only highly protruding maxilla but also a severely protruding mandible. Size and shape of the mandible: The mandibular dimensions of length and height GOAR and GO-PG were rather close to normal, but the mandibular angle AR-GO-PG was extremely small in the proband, brother, and mother. Head length: The maximum head length GL-OP was much shorter in the proband's brother, but was well within the normal range in the other family members. The proband, brother, and mother exhibited an extreme widening of the bony interorbital width MO-MO', interorbital width relative to head width MO-MO'/EU-EU', and face width ZY-ZY'; their respective mandibular and head widths were larger but not significantly. In the proband's father all facial widths were within the normal range. See the frontal radiographs in Figure 3. RESULTS The raw measurements were transformed into Z-scores (Table 2). Craniofacial pattern 468 S.S. SAKSENA, M.A. RAMOS-ARROYO,AND M.E. HODES TABLE 2. Z-scores Measurements’ I. Facial height 1. Total facial height N-ME2 2. Upper facial height N-ANS 3. Lower facial height ANS-ME 11. Facial depth 4. Facial depth PO-A pt. 5. Maxillary depth PNS-ANS 111. Cranial base 6. Total cranial base N-BA 7. Anterior cranial base S-N 8. Posterior cranial base length S-BA 9. Cranial flexure angle N-S-BA IV.Facial profile 10. Maxilla to cranial base S-N-A pt. 11. Mandible to cranial base S-N-PG V. Mandibular 12. Mandible length GO-PG 13. Mandibular height GO-AR 14. Mandibular angle AR-GO-PG VI. Head length 15. Maximum head length GL-OP VII. Facial width 16. Maximum head width EU-EU’ 17. Interorbital width MO-MO’ 18.Interorbital width (index head width) 19. Face width ZY-ZY’ 20. Mandible width GO-GO’ Abbreviation Proband (age 8 yr) Brother (age 5 yr) Mother Father TH UH LH -3.0 -3.0 - 1.3 -2.2 -0.6 -3.8 -0.8 0.6 -1.0 -4.8 -2.3 -3.2 FD MD -1.7 -0.3 -1.8 -0.1 -2.0 -0.5 -0.9 +0.4 BL AL PL FA -1.4 -1.3 -0.8 -0.6 -3.7 -3.4 -1.7 -2.8 -1.7 -0.01 -1.4 -1.9 -3.3 -1.3 -1.9 -3.2 AA PA -2.0 0.01 -2.4 2.5 -3.5 -0.5 3.5 ML MH GA 1.1 -0.1 -4.6 1.6 -0.5 -5.9 -0.7 -0.7 -2.0 0.5 1.7 -0.6 CL 0.7 -3.8 0.6 CW I1 1.3 5.1 5.0 1.5 3.6 3.1 0.8 3.9 3.4 ZW GW 3.2 1.0 3.5 1.8 1.4 Iw 1.6 5.2 -0.8 1.4 0.2 -0.2 1.9 1.0 ‘Normal data values from Saksena et al. (1987) (for variables 1 to 151, Costaras et al. (1982) (for variables 16, 17, and 18), and Woods (1950)(for variables 19 and 20). ‘Landmarks used in taking measurements: N, nasion; ANS, anterior nasal spine; ME, menton, PO, porion; A pt., subspinale;PNS, posterior nasal spine; BA, basion; S , sella; PG, pogonion; GO, gonion; AR,articulare; GL, glabella; OP, opisthoeranion; EU,EU’,euryon;MO-MO’, medioorbitale;ZY-ZY‘, zygoma. profiles (CFPP) of the proband, her brother, mother and father, based on the 20 Z-scores per individual are plotted in Figure 4A,B. The CFPP approach combines graphic and numerical measures of pattern variability and pattern comparison (Garn et al., 1984). Craniofacial pattern deviation measure u, (i.e., standard deviation of the Z-scores) for 20 measurements was estimated for each family member (Table 3). Standard deviation of the Z-scores gives an estimate of the variability of pattern of an individual from the norm. The more highly deviated a craniofacia1 pattern profile (CFPP) is of an individual, the higher is its a, score. On the other hand, a small a, value indicates a close clustering of the measurements around the mean. In a normal U.S.population sample of 1,500 individuals, Garn et al. (1985) found a a, range from 0.43 (for a least patterned individual) to 1.27 (for a most patterned individual). These a, values were based on 16 craniofacial measurements per person taken from the lateral radiographs only. According to data sample a a, of 1.3 or above signifies a highly aberrant craniofacial pattern profile, suggestive of a possible malformation syndrome. All individuals in this family have highly deviated CFPP profiles, with a, value of 2.49, 2.83, 1.89, and 2.45 for the proband, brother, mother, and father, respectively, indicating craniofacial dysmorphogenesis. Pattern profile similarities, i.e., correlation coefficient r,, were estimated using Z-scores of pairs of relatives (Table 4). The greatest CFPP similarity, r, 0.81, occurs in probandmother; followed closely by the probandbrother, r, 0.77; and the brother-mother, r, 0.72. Correlation coefficients for fatherbrother, father-proband, and father-mother were 0.52, 0.35, and 0.12, respectively. DISCUSSION Under the additive polygenic model of inheritance with no dominance and no environmental effects the expected level of corre- CRANIOFACIAL PATTERN PROFILE EVALUATION Fig. 3. Frontal radiographs. Note the presence of marked bony hypertelorism in the proband (A), her 469 brother (B),their mother (C), and the absence of it in their father (D). lation coefficient for CFPP between first-de- pair). The greatest CFPP similarity, r, 0.81, gree relatives (parent-offspringand sib-sib)is occurs between the proband-mother of like0.50 (Saunders et al., 1980).In a recent study sex, followed by the proband-brother, rz 0.77, (Garn et al., 1984) of normal families, the and the brother-mother, r, 0.72. The obtypical parent-child similarities averaged served correlation coefficients between the around 0.30, with a maximum of 0.85 (for a brother-father and father-proband agree well strikingly similar father-son) to a minimum with the expected value of 0.50. Age and of -0.47 (for a highly dissimilar father-son parity differences between sibs and mother 470 S.S. SAKSENA, M.A. RAMOS-ARROYO, AND M.E. HODES Ccphalomctric Mcnsurcment F a c 1 3 I H c i ~ h l FacI.1 Dopth Cranl3l O o s o I'Jc8aI PrDlile MJndiblo H o a d Lcnglh Facial Width --+---.---,-t--r-.t PATTERN DEVIATION 1.0 -- 2.0-. 3.0 -- 4.0 .. 5.0 -. * 0; P A T T E R N SIMILARITY, rz PR-MO 0.81 PR-0R 0.77 BR-MO 0.72 Ccphalcmctrlc Mcasurernent F a c i a l Heinhi F o i ~ a lD c D t h C r ~ o i o lDase f3caII Proliio Mandible Haad L s n g l h F3CI.I Widlh ---4-+-.- -6.0 -5.0 -4.0 -2 -3.0 -2.0 z 0 y 5 $ 2 ? $ N F 5 - -1.0 O 1.0 2.0 3.0 4.0 5 .O B 6.0 Fig. 4. Comparison of craniofacial pattern profiles A Proband, brother, and mother. B: Proband, brother, and father. and offsprings seem t o have little influence of proband-father (unlike-sex). As expected, on the CFPP similarities in this family; the the r, value between the parents is low, 0.12. correlation coefficient r, values between sibIndividuals with any syndrome resemble lings, and between mother and offsprings, each other despite the diversity of racial and are not much different. However, the degree ethnic background (Roberts et al., 1975).It is of CFPP resemblance between brother-father well known that the degree of craniofacial (like-sex)is greater Cr, 0.52) than that (rz 0.35) similarity is greater among syndrome-af- CRANIOFACIAL PATTERN PROFILE EVALUATION TABLE 3. Craniofacial pattern profile deviation (ad uv value' Proband Brother Mother Father 2.49 2.83 1.89 2.45 bz:i.e., standard deviation of 20 Z-scores per person. Normal range of uz is 0.43 to 1.27 (Garnet al., 1984). TABLE 4. Coefficient of' craniofacial pattern profile similarity (rJ r, value' Proband-mother Proband-brother Brother-mother Brother-father Proband-father Mother-father 0.81 0.77 0.72 0.52 0.35 0.12 'rc:i.e., Z-score currelation coefficientbetween pairs of relatives. fected than unaffected individuals in a single family. In this study, CFPP similarity between the proband, her brother, and mother is surprisingly high, rz 0.72. This high level of commonality of facial dysmorphogenesis, presence of retinal changes, and hearing loss shared by the two sibs and mother, can be attributed to their being the possible gene carriers of the same genetic disorder, which to our knowledge has not been previously described. The most likely pattern of inheritance is autosomal dominant (transmitted through the mother) with variable expressivity. Absence of consanguinity and equally severe expression of the syndrome in the two sibs (one female and one male) makes the Xlinked recessive mode of inheritance unlikely (Ramos-Arroyo et al., 1986). Roentgencephalometric analysis shows that all members of this family have highly deviant craniofacial pattern profiles, with a, values 2 1.9. Two distinct patterns of craniofacial dysmorphology were observed, one shared by the proband, her brother, and mother, while the other is rather unique to the father. Unusual facial features shared by the two sibs and mother include bony hypertelorism, large interorbital width relative t o 471 head width, decreased facia1 height and depth, marked maxillary retrusion, and very small mandibular angle. Features unique to the father are severe growth retardation of both facial height and cranial base dimensions, and prognathic mandible and maxilla. ACKNOWLEDGMENTS The authors wish to thank Drs. Bixler and P. Yu for reading an earlier version of this paper and making helpful suggestions. We would like to thank J. Robison for her help in typing this manuscript. Research for the senior author (S.S.S.) is supported by NIHNIDR Research Career Development Award, DE 00126. LITERATURE CITED Costaras, MS, Pruzansky, S, Broadbent, BH JR.(1982) Bony interorbital distance (BIOD), head size, and level of the cribriforme plate relative to orbital height: 1. Normal standards for age and sex. J. Craniofac. Genet. Dev. Biol. 25-18. Feingold, M, Bossert, WH (1974) Normal values for selected physical parameters: An aid to syndrome delineation. D Bergsma (ed): White Plains: The National Foundation-March of Dimes, Birth Defects X(13). Garn, SM, Smith, BH, LaVelle, M (1984)Applications of pattern profile analysis to malformations of the head and face. Radiology 150:683-690. Garn, SM, LaVelle, M, Smith, BH (1985) Quantification of dysmorphogenesis. Am. J. Roentgenol. 144:365-369. Nelhaus, G (1968) Composite international and interracial graphs. Pediatrics 41:106. Ramos-Arroyo, MA, Clark, GG, Saksena, SS, Hodes, ME (1987) Congenital corneal anesthesia with retinal abnormalities, deafness, unusual facies, persistent ductus arteriosus and mental retardation: A new syndrome? Am. J. Med. Genet., 26:345-354. Roberts, FG, Pruzansky, S, Aduss, H (1975) An X-radiocephalometric study of Mandibulo-facial Dysostosis in man. Arch. Oral Biol. 20.265-281. Saksena, SS, Walker, D, Bixler, D, Yu, P (1987) A Clinical Atlas of Roentgenocephalometry in Norma lateralis. New York: Alan R. Liss, Inc. Saunders, SR, Popovich, F, Thompson, GW (1980)A family study of craniofacial dimensions in Burlington Growth Center sample. Am. J. Orthod. 78:394-403. Synder, RG, Schneider, LW, Owings, CL, Reynolds, HM, Golomb, DH, Schork, MA (1977) Anthropometry of infants, children, and youths to age 18 for product safety design. Highway Safety Research Institute, The University of Michigan. Wood, GA Jr. (1950) Changes in width dimensions between certain teeth and facial points during human growth. Am. J. Orthod. 36:676-700.