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Craniofacial pattern profile (CFPP) evaluation of facial dysmorphology in a familial syndrome with corneal anesthesia and multiple congenital anomalies.

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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.
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profil, anomalies, corneal, cfpp, facial, anesthesia, syndrome, evaluation, dysmorphology, congenital, patterns, craniofacial, familiar, multiple
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