The Cleft Palate–Craniofacial Journal 51(1) pp. 83–89 January 2014 Ó Copyright 2014 American Cleft Palate–Craniofacial Association
ORIGINAL ARTICLE A Study of Facial Pattern in Patients With Fanconi Anemia ´ ˆ Lucia Fa´tima de Castro Avila, Ph.D., M.Sc., D.D.S., Wilson Denis Martins, Ph.D., D.D.S., Lisiane Candido, M.Sc., D.D.S., Sergio Aparecido Igna´cio, M.Sc., Ph.D., Carmen Maria S. Bonfim, M.D., Marina de Oliveira Ribas, Ph.D., M.Sc., D.D.S. Objective: This study is aimed to evaluate craniofacial features in patients with Fanconi anemia (FA) through cephalometric analysis and to classify the facial growth pattern to observe possible facial discrepancies. Design: This is a cross-sectional study which employed a quantitative approach to compare linear and angular measurements of cephalometric analysis in lateral teleradiographic images of a clinical type sample of patients with FA. A retrospective cephalometric study was performed using cephalometric analyses of Ricketts and Steiner; growth patterns according to Ricketts’ vertical growth pattern (VERT index) were also analyzed. Patients: Fifty patients diagnosed with FA who were undergoing anti-aplasia treatment at the outpatient Hematology service at the Federal University of Parana´, Curitiba, Brazil were included in the study. Interventions: The patients were evaluated in the School of Dentistry of the Pontifical Catholic University of Parana´ (PUCPR), Curitiba, Brazil. Exclusion criteria included patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. Main Outcome Measures: Cephalometric points were plotted in order to set up linear and angular cephalometric measurements. Angular and linear measurements from 17 factors proposed by Ricketts’ cephalometric analysis were assessed. Results: Dolicofacial appearance was observed in 52% of individuals; braquifacial in 28%, and mesofacial in 20%. Significant maxillary/mandibular discrepancy was observed. It was concluded that upon anteroposterior evaluation of facial bone structures, the FA sample presented smaller median measurements in most variables evaluated; it also presented mandibular micrognathism and mainly dolicofacial vertical growth pattern. These findings, together with other features such as skin pigmentation and microphthalmia, may lead to a possible recognition of a FA condition from a patient’s facial features. KEY WORDS:
cephalometric analysis, craniofacial growth pattern, Fanconi anemia
Several studies have reported growth delay in FA patients due to endocrine changes, in particular growth hormone deficiency (De Kerviler et al., 2000; Dokal, 2000; Wajnrajch et al., 2001; Massa et al., 2002; de Ilurdoz et al., 2003; Pasquini, 2003; Giri et al., 2007; Alter and Lipton, 2008). These osseous growth changes may affect skull and face bones and may be part of phenotypical features that help clinical diagnosis (Zago et al., 2001). Typical facial features, known as Fanconi facies, are described as delicate facial features, a large nasal base, epicanthal folds, microcephaly, microphthalmia, small mouth and chin (Dokal, 2000), anomalous sella turcica, and low-set ears (Alter, 1996; Dokal, 2000; Massa et al., 2002; Quintanilla et al., 2002). In many cases, FA patient facies facilitate the diagnosis of the disease (Green and Kupfer, 2009). Several researchers have used cephalometric analysis to assess osseous discrepancies and facial patterns in syndromic patients with the purpose of understanding typical features of each syndrome and helping surgical and dental
Fanconi anemia (FA) is an autosomal recessive genetic disorder with heterogeneous clinical manifestations. It is characterized by bone marrow failure, congenital anomalies, growth delay, and association with neoplasia. It progresses to pancytopenia, leukemia, and other solid neoplasias (Guerra et al., 2000; Pasquini, 2000; Pasquini, 2003; Green and Kupfer, 2009).
Dr. Martins is Professor, Oral and Maxillofacial Surgery, School of Dentistry of the Pontifical Catholic University of Parana´ ´ (PUCPR). Dr. Avila is Professor, Univille, Sa˜o Bento do Sul, Joinville, SC, Brazil. Dr. Ribas is Head, Oral and Maxillofacial Surgery, Dr. Igna´cio is Professor, PUCPR, Curitiba, PR, Brazil. Dr. Candido ˆ is private practice, Porto Alegre, Brazil. Dr. Bonfim is MD, Professor, Universidade Federal do Parana´. Submitted January 2012; Revised June 2012; Accepted July 2012. Address correspondence to: Dr. Wilson Martins, School of Dentistry of the Pontifical Catholic University of Parana´ (PUCPR), ´ Republica do Libano, 462 Curitiba, PR 82520-500, Brazil. E-mail [email protected]. DOI: 10.1597/11-321.1 83
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FIGURE 1 Skeletal measurements of cephalometric analysis.
treatment (Tarjan et al., 2005; Bindayel et al., 2008; Chong et al., 2008; Tuna et al., 2009; Leonardi et al., 2009). Skeletal facial patterns are known to vary according to age and race in normal individuals. The aim of this study was to evaluate craniofacial pattern in patients with FA through skeletal measurements of cephalometric analysis and vertical growth pattern as set by the VERT index. The hypothesis is that FA patients present lower mean measurements in relation to the skeletal standards compared. MATERIALS
AND
METHODS
This is a cross-sectional study that employed a quantitative approach to compare linear and angular measurements of popular cephalometric analysis in lateral teleradiographic images of a sample of patients diagnosed with FA. The study was approved by the Research Ethics Committee of the PUCPR. The study sample consisted of 50 patients diagnosed with FA (FA-G group), 25 female and 25 male patients, ages ranging from 3.8 years to 26 years (average age 10 years), who were undergoing treatment at the outpatient Hema-
tology service at the Federal University of Parana´, Brazil. All of the patients were undergoing anti-aplasia treatment because medullary aplasia is an ever present condition in these patients. Exclusion criteria were patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. Parents or guardians signed a free informed consent form for the research, giving permission for the researchers to abstract medical records. The radiographic images were obtained in the Department of Radiology of the PUCPR with an Orthophos XG Plus X-ray generator (Siemens, Berlin, Germany). Lateral teleradiographic images were scanned with a flatbed scanner model Color Page 6HRXc (Genius, KYE Systems Corp., Taipei, Taiwan) in line with the Orto Manager 6 software (Soft Manager, Curitiba, Brazil). Classic cephalometric points (Salzmann, 1958) were plotted in order to set up linear and angular cephalometric measurements analyzed: Ba - basion; Po - porion; XI – geometric center of the ramus; DC - condyle axis; Pt - pterygoid point; Or - orbitale; N - nasion; ENA - anterior nasal spine; Go - gonion; Me -
Martins et al., FACIAL PATTERN IN PATIENTS WITH FANCONI ANEMIA
TABLE 1
Three facial types are observed: mesofacial, with balanced growth and development, dolicofacial, and brachyfacial, depending on whether facial growth is vertical or horizontal, respectively. These angular measurements are used to calculate the indices: FA, FC, MP_A, IAFH, and AM_A from Ricketts’ cephalometric analysis. The tracings and measurements were done and repeated by two examiners. All lateral norm radiographic images were replotted, and tracings and measurements were redone after 2 months in order to detect Dahlberg error interrater reliability (Houston, 1983); no significant difference in discordant values of generated measurements was seen. For cephalometric assessment, the first measurement was used. Continuous variables were expressed through mean and standard deviation. Student’s t test was used to compare means between the FA-G group and the Ricketts standard for Americans (Ricketts et al., 1982) and the FA-G group and the Nobuyasu et al. (2007) standard for Brazilians. The same Student’s t test was used to compare SNA, SNB, ANB, GoGnSN, and SNGn values between FA-G and the norm of Steiner’s analysis (Steiner, 1959). Analysis of variance (ANOVA) was also carried out for these measurements. The value considered statistically significant was P , .05. For VERT (vertical growth pattern) assessment, a descriptive analysis with percentage values was used (Table 7).
Values of Cephalometric Norms Assessed*
CP‘‘A’’ - convexity at point ‘‘A,’’ mm IAFH - inferior anterior facial height, degrees FD - facial depth, degrees FA - facial axis, degrees FC - facial cone, degrees MD - maxilla depth, degrees MH - maxilla height, degrees PP - palatal plane, degrees MP_A - mandibular plane, degrees TFH - total facial height, degrees CD - cranial deflection, degrees ACL - anterior cranial length, mm PFH - posterior facial height, mm RP - ramus position, degrees PATM - position of ATM, mm AM_A - mandibular arc, degrees MCL - mandibular corpus length, mm SNA - sella-nasion point A, degrees SNB - sella-nasionpoint B, degrees ANB - point A-nasion point B, degrees GoGnSN - gonion-gnathion-sella-nasion, degrees SNGn - sella-nasion-gnathion, degrees
N
SD
CB
2 47 87 90 68 90 53 1 26 60 27 55 55 76 31 25 65 82 80 2 32 66
62.0 64.0 63.0 63.5 63.5 63.0 63.0 63.5 64.0 63.0 63.0 62.5 63.3 63.0 62.2 64.0 62.7 62.0 62.0 – – –
– – 0.33/y – – – 0.4/y – –0.3/y – – 0.8/y 1/y – 0.8/y 0.5/y 1.6/y – – – – –
* N ¼ norm (average value) of Ricketts’ cephalometric analysis; SD ¼ standard deviation of norm; CB ¼ biological correction.
menton; Gn - gnathion; Pm - mandibular axis; and CC cranial center (Fig. 1). For the cephalometric study, angular and linear measurements from 17 (skeletal factors) of the 33 factors proposed by Ricketts’ cephalometric analysis (Ricketts, 1961) were assessed. Sixteen dental factors were not assessed because most of the patients presented with mixed dentitions. Linear measurements are expressed in millimeters and angular factors, in grades (Table 1). Factors and respective fields compared were: field II - skeletal problems – maxillary/ mandibular relationship; field V - craniofacial relationships; and field VI - internal structure, of Ricketts’ analysis. SNA - sella turcica, nasion and point A angle; SNB - sella turcica, nasion and point B angle; ANB - point A, nasion, and point B angle; GoGnSN - gonion, gnathion, and sella turcica-nasion angle; and SNGn - sella turcica, nasion, gnathion angle of Ricketts’ and Steiner’s cephalometric analyses were also measured. Ricketts’ vertical growth pattern (VERT index) (Ricketts et al., 1982) was used to evaluate vertical craniofacial growth, which was calculated from measurements of factors FA, FC, MP_A , IAFH, and AM_A (Tables 1 through 4). All factors are defined in Table 1. TABLE 2
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RESULTS There were no differences between sexes. Skeletal Problems (Field II) Comparison of mean and standard deviation among FA-G, Ricketts et al. (1982), and Nobuyasu et al. (2007) showed significant differences, as can be seen in Table 2. Craniofacial Relationships (Field II) Comparison of mean and standard deviation among FA-G, Ricketts et al. (1982), and Nobuyasu et al. (2007) showed significant differences, as presented in Tables 3 and 4. Table 5 summarizes higher, lower, and similar values of the sample in relation to standards used for comparison.
Field II - Skeletal Problems (Maxillary/Mandibular Relationship) FA-G
Ricketts
Nobuyasu et al.
Linear and Angular Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
CP‘‘A’’, mm IAFH, degrees
3.82 44.71
2.89 4.24
2.00 47.00
2.00 4.00
.0000* .0001*
1 2
1.89 42.51
1.94 2.65
.0000* .0005*
1 1
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data. * Significant at P , .05.
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TABLE 3
Field V – Craniofacial Relationships FA-G
Ricketts
Nobuyasu et al.
Angular Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
FD FA FC MD MH PP MP_A
86.59 87.31 64.56 91.01 55.37 0.56 29.46
3.24 4.51 4.96 5.01 3.27 3.37 6.89
87.00 90.00 68.00 90.00 53.00 1.00 26.00
3.00 3.50 3.50 3.00 3.00 3.50 4.00
.3477 .0000* .0000* .0258* .0000* .0021* .0000*
3 2 2 1 1 2 1
89.23 93.11 68.11 91.09 56.22 0.63 23.42
3.25 3.18 3.30 3.37 3.54 3.06 4.70
.0000* .0000* .0000* .9151 .1778 .0430* .0000*
2 2 2 3 3 2 1
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data * Significant at P , .05.
individuals presented higher mean values, statistically significant, in the cephalometric measurements of variables CP’’A’’ MP_A, CD, and PATM.
Maxillary and Mandibular Anterior Posterior Relationship Comparison of mean and standard deviation between FA-G and Steiner (1959) showed significant difference in the relationship with mandibular angles (Table 6).
Maxilla and Maxillary/Mandibular Relationship The higher value of the measurement CP’’A’’ (field II skeletal problems) indicates that the maxilla lies slightly in a more anterior position than the one found in the studies used for comparison. As one of the references of the CP’’A’’ measurement is the facial line (N-Pg), the relationship with the Pg point must also be taken into account, which may undergo alteration due to the more posterior sagittal position of the menton as in mandibular micrognathia. This leads to a higher distance from the facial line (N-Pg) to point A, such as the case with FA-G.
Vertical Growth Pattern and Facial Type (Ricketts’ VERT index) The sample FA-G showed 28% (14/50) braquifacial individuals (7 medium and 7 mild), 20% (10/50) mesofacial individuals, and 52% (26/50) dolicofacial individuals (14 mild, 7 medium, and 5 severe) (Table 7). DISCUSSION Review of the literature failed to find studies that assessed craniofacial skeletal relationship and facial vertical growth pattern of individuals with FA, although some researchers state that there are craniofacial alterations in these patients (De Kerviler et al., 2000; Alter and Lipton, 2008; Green and Kupfer, 2009). Other syndromes were studied by cephalometric evaluation in order to observe variations in normality patterns (Quintanilla et al., 2002; Tarjan et al., 2005; Bindayel et al., 2008; Chong et al., 2008; Leonardi et al., 2009; Tuna et al., 2009). In relation to values from norms used for comparison (Ricketts et al., 1982; Nobuyasu et al., 2007), FA-G TABLE 4
Anterior/Posterior Maxillary/Mandibular Relationship SNA, SNB, and ANB angles were compared to respective norm values for these measurements. FA-G showed SNA mean values close to norm (82.528 6 4.20), lower SNB in relation to norm (77.888 6 3.85), and ANB (4.648 6 2.91) higher than the norm, therefore confirming a more posterior position of the menton in relation to the maxilla. The increased ANB angle could also be explained by the decreased mandibular corpus length by 88% (44/50) in FA-G individuals, when
Field VI – Internal Structures FA-G
Ricketts
Nobuyasu et al.
Angular and Linear Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
DC, mm ACL, mm PFH, mm AFT, mm PR, mm PATM, mm AM_A, degrees MCL, mm
27.91 50.23 49.77 60.88 74.06 27.73 29.29 59.70
3.10 3.96 6.13 5.51 4.20 4.29 5.50 5.88
27.00 55.00 55.00 60.00 76.00 31.00 26.00 65.00
3.00 2.50 3.30 3.00 3.00 2.00 4.00 2.70
.0369* .0000* .0000* .0551 .0000* .0000* .0000* .0000*
1 2 2 3 2 1 1 2
25.87 59.53 66.06 55.62 72.72 42.67 31.93 74.03
2.72 3.90 5.50 4.24 3.03 3.03 6.77 4.18
.0002* .0000* .0000* .0000* .0404* .0000* .0233* .0000*
1 2 2 1 1 1 2 2
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data. * Significant at P , .05.
Martins et al., FACIAL PATTERN IN PATIENTS WITH FANCONI ANEMIA
TABLE 5 Relationship Between FA-G Measurements and Norms for Comparison
TABLE 7
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Facial Growth Pattern - VERT†
FA-G Variable
Ricketts
Nobuyasu et al.
CP’’A’’* IAFH‡ PF‡ EF† CF† PM‡ AM‡ PP† MP_A* DC* CCA† AFP† AFT‡ PR‡ PATM* AM_A‡ CCM†
. , ¼ , , . . , . . , , ¼ , . . ,
. . , , , ¼ ¼ , . . , , . . . , ,
* Statistically significant values higher than 2 standards for comparison. † Statistically significant values lower than 2 standards for comparison. ‡ Statistically significant values higher, lower, or similar in one of the standards for comparison.
compared to norm standard for Brazilians, thus characterizing shorter mandibular length (mandibular micrognathia) and more posterior position of the menton. These findings corroborate clinical observations of micrognathia from several researchers (Gluckman et al., 1983; Auerbach, 1995; Alter, 1996; De Kerviler et al., 2000; Dokal, 2000; Koubik et al., 2006; Alter and Lipton, 2008). Craniofacial Relationships The MP_A angle (field V - craniofacial relationships) enables a vertical assessment of the mandible in relation to the Frankfort plane and, when increased, indicates dolicofacial vertical growth pattern, unlike findings of means for Brazilians (Nobuyasu et al., 2007), where the braquifacial growth pattern prevailed. Decreased FA and FC (field V - craniofacial relationships) angles show a more vertical growth in these individuals, unlike standards used for comparison. Values lower than the Ricketts norm for the palate plane angle (PP) (field V - craniofacial relationships) were also decreased in the Brazilian sample (Nobuyasu TABLE 6 Cephalometric Measurements of Maxillary/Mandibular Relationship† Norm
SNA, degrees SNB, degrees ANB, degrees GoGnSN, degrees SNGn, degrees † Source: study data. * Significant at P , .05.
FA-G
Value
SD
Mean
SD
P Value
82 80 2 32 66
62.0 62.0
82.52 77.88 4.64 35.2 68.31
64.20 63.85 62.91 66.60 63.63
.5878 .0620 .0900 .0000* .0000*
Braquifacial Mesofacial Dolicofacial
28% (14/50) 20% (10/50) 52% (26/50)
† Source: study data
et al., 2007). However, they were even lower in the FA sample, thus indicating a more horizontal position of this plane (anticlockwise) in relation to the Frankfort plane. FA-G individuals showed a lower mean value, statistically significant, of the FD variable (field V craniofacial relationships) only in relation to the standard for Brazilians. This result was similar to the Ricketts et al. (1982) standard for Americans. This lowered angle in relation to the standard for Brazilians, mainly braquifacial, also reinforces the trend of dolicofacial pattern of the sample. Lower MCL confirms the clinically observed micrognathism (Massa et al., 2002; Giri et al., 2007). MD and MH variables (field V - craniofacial relationships) showed higher mean values from cephalometric measurements, statistically significant, but only in relation to the pattern of Ricketts et al. (1982). This was similar to the standard for Brazilians (Nobuyasu et al., 2007), thus showing that maxillary position is in accordance with standards for Brazilians. IAFH (field II - skeletal problems) and RP (field VI internal structures), presenting higher values in relation to those found for Brazilians, show a dolicofacial growth pattern trend. This differs from results found in Nobuyasu et al. (2007), who reported a braquifacial standard for Brazilians. Internal Structures For the CD measurement (field VI - internal structures) increased mean values in the FA-G group show a more vertical growth trend of the midface and a more elongated facial midface. The PATM measurement (field VI - internal structures), which assesses medial position of the ramus, higher FA-G mean values found indicate a more posterior temporomandibular joint position. FA-G individuals presented lower, statistically significant mean values of cephalometric measurements for the EF, CF, PP, ACL, and PFH variables in relation to the norm for Americans (Ricketts et al., 1982) and to the standard for Brazilians (Nobuyasu et al., 2007). The reduced ACL (field IV - internal structures) reinforces clinical findings of microcephaly observed by researchers (Auerbach, 1995; Alter, 1996; De Kerviler et al., 2000; Dokal, 2000; Alter and Lipton, 2008). The PFH measurement (field VI - internal structures) is
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lowered in the sample, thus indicating that mandibular ramus is smaller than the one observed in compared patterns. Besides, the GoGnSN angle is higher in relation to the standard for Brazilians, confirming the vertical growth trend of the midface. The AM_A variable (field VI - internal structures) had a lower mean value, statistically significant, in relation to the standard for Brazilians (Nobuyasu et al., 2007), therefore confirming the dolicofacial growth pattern trend in the FA-G sample. This finding differs from braquifacial pattern findings for Brazilians. The TFH variable was higher in relation to the standard for Brazilians (Nobuyasu et al., 2007) and normal in relation to the standard of Ricketts et al. (1982) for Americans. This measurement relates mandibular corpus to total cranial base, and when increased, indicates dolicofacial vertical growth trend. These data are also corroborated by the increased GoGnSN (mean 35.208 6 6.60) angle in FA-G in relation to Steiner’s norm (Steiner, 1959). Upon a study of a sample of Brazilians, Nobuyasu et al. (2007) found a predominant braquifacial growth pattern (VERT), unlike the present study, which found predominant dolicofacial vertical growth pattern (VERT) in FA-G. Anterior Posterior Craniofacial Alterations The present study found anterior posterior craniofacial alterations, statistically significant, in relation to facial balance standards set by lateral cephalometric norm values of Ricketts et al. (1982) for Americans and in relation to the standard for Brazilians as described by Nobuyasu et al. (2007), such as: cranial base is smaller, normal maxilla in vertical length, and in relation to cranial base, the midface is elongated. These alterations included a smaller cranial base, normal maxilla in vertical length, and an elongated midface in relation to the cranial base. Furthermore, the mandible shows smaller corpus and ramus length but an increased mandibular angle, thus resulting in an elongated face. CONCLUSIONS Upon evaluation of anterior posterior bone structures of the face, the group of individuals with FA presented: 1. Lower mean measurements in most of the variables assessed in relation to skeletal standards compared; 2. Mandible with smaller corpus and ramus length and increased mandibular angle, leading to an elongated face and mandibular micrognathism; and 3. Smaller cranial base, normal maxilla in vertical length and in relation to the cranial base, and a predominant dolicofacial vertical growth pattern. These findings, together with other features, such as skin pigmentation and microphthalmia, may lead to a possible
recognition of the FA condition from facial features, significant in relation to facial balance standards set by both Brazilian and American norms. REFERENCES Alter B. Fanconi’s anemia and malignancies. Am J Hematol. 1996;53:99–110. Alter B, Lipton J. Anemia Fanconi. Available at: http://www. emedicine com/PED/topic 3022 htm. Accessed July 3, 2008. Auerbach AD. Fanconi anemia. Dermatol Clin. 1995;13:41–49. Bindayel NA, Ullbro C, Suri L, Al-Farra E. Cephalometric findings in ` patients with Papillon-Lefevre syndrome. Am J Orthod Dentofacial Orthop. 2008;134:138–144. Chong D, Murray D, Britto J, Tompson B, Forrest C, Phillips J. A cephalometric analysis of maxillary and mandibular parameters in Treacher Collins syndrome. Plastic Reconstr Surg. 2008;121:77e– 84e. De Kerviler E, Guermazi A, Zagdanski AM, Gluckman E, Frija J. The clinical and radiological features of Fanconi’s anaemia. Clin Radiol. 2000;55:340–345. Dokal I. Dyskeratosis congenita in all its forms. Brit J Haematol. 2000;110:768–779. Giri N, Batista D, Alter B, Stratakis C. Endocrine abnormalities in patients with Fanconi anemia. J Clin Endocrinol Metab. 2007;92:2624–2631. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol. 1983;54:431–440. Green AM, Kupfer GM. Fanconi anemia. Hematol Oncol Clin North Am. 2009;23:193–214. Guerra M, Barreirinho MS, Araujo ´ R, Costa E, Goncalves ¸ C, Porto B, Barbot J. Anemia de Fanconi: variedade fenot ´ıpica da doenca ¸ em duas irma˜s. Acta Pediatr Port. 2000;31:277–281. Houston WJ. The analysis of errors in orthodontic measurements. Am J Orthod. 1983;83:382–390. Koubik AC, Franca BH, Ribas M de O, de Araujo MR, Mattioli TM, de Lima AA. Comparative study of chronological, bone, and dental age in Fanconi’s anemia. J Pediatr Hematol Oncol. 2006;28:260– 262. Leonardi R, Licciardello V, Santarelli A, Ciavarella D, Bolouri S, Harle F, Caltabiano M, Lo Muzio L. Nevoid basal cell carcinoma syndrome: a cephalometric study of patients and controls. J Craniofac Surg. 2009;20:203–208. Massa GG, Heinrichs C, Vamos E. Van Vliet. Hypergonadotropic hypogonadism in a boy with Fanconi anemia with growth hormone deficiency and pituitary stalk interruption. J Pediatr. 2002;140:277– 286. Nobuyasu M, Myahara M, Takahashi T, Atizan A, Maruo H, Rino ´ W, et al. Padroes de Ricketts aplicados a indiv ´ıduos ˜ cefalometricos brasileiros com oclusa˜o excelente. Rev Dental Press Ortod Ortop Facial. 2007;12:125–156. Pasquini R. Bone marrow transplantation for aplastic anemia. Medicina (Ribeirao ¨ Preto). 2007;12:125–156. Pasquini R. Squamous cell carcinoma of the tongue due to Fanconi’s anemia after bone marrow transplantation. Rev Bras Hematol Hemoter. 2003;25:239–246. Quintanilla J, Biedma B, Rodr ´ıguez M, Mora M, Cunqueiro M, Pazos M. Cephalometrics in children with Down’s syndrome. Pediatr Radiol. 2002;32:635–643. Ricketts RM. Cephalometric analysis and synthesis. Angle Orthod. 1961;31:141–156. Ricketts RM, Roth H, Chaconas J, Schulhof J, Engel A. Orthodontic Diagnosis and Planning: Their Roles in Preventive and Rehabilitative Dentistry. Denver: Rocky Mountain Orthodontics; 1982.
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Tuna EB, Sulun T, Rosti O, El Abdallah F, Kayserili H, Aktoren O. Craniodentofacial manifestations in Hallermann-Streiff syndrome. Cranio. 2009;27:33–38. Wajnrajch MP, Gertner JM, Huma Z, Popovic J, Lin K, Verlander PC, Batish SD, Giampietro PF, Davis JG, New MI, et al. Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry. Pediatrics. 2001;107:744–754. Zago M, Falca˜o R, Pasquini R. Hematologia: Fundamentos e Pra´tica. Sa˜o Paulo: Atheneu; 2001:23–31.
ORIGINAL ARTICLE A Study of Facial Pattern in Patients With Fanconi Anemia ´ ˆ Lucia Fa´tima de Castro Avila, Ph.D., M.Sc., D.D.S., Wilson Denis Martins, Ph.D., D.D.S., Lisiane Candido, M.Sc., D.D.S., Sergio Aparecido Igna´cio, M.Sc., Ph.D., Carmen Maria S. Bonfim, M.D., Marina de Oliveira Ribas, Ph.D., M.Sc., D.D.S. Objective: This study is aimed to evaluate craniofacial features in patients with Fanconi anemia (FA) through cephalometric analysis and to classify the facial growth pattern to observe possible facial discrepancies. Design: This is a cross-sectional study which employed a quantitative approach to compare linear and angular measurements of cephalometric analysis in lateral teleradiographic images of a clinical type sample of patients with FA. A retrospective cephalometric study was performed using cephalometric analyses of Ricketts and Steiner; growth patterns according to Ricketts’ vertical growth pattern (VERT index) were also analyzed. Patients: Fifty patients diagnosed with FA who were undergoing anti-aplasia treatment at the outpatient Hematology service at the Federal University of Parana´, Curitiba, Brazil were included in the study. Interventions: The patients were evaluated in the School of Dentistry of the Pontifical Catholic University of Parana´ (PUCPR), Curitiba, Brazil. Exclusion criteria included patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. Main Outcome Measures: Cephalometric points were plotted in order to set up linear and angular cephalometric measurements. Angular and linear measurements from 17 factors proposed by Ricketts’ cephalometric analysis were assessed. Results: Dolicofacial appearance was observed in 52% of individuals; braquifacial in 28%, and mesofacial in 20%. Significant maxillary/mandibular discrepancy was observed. It was concluded that upon anteroposterior evaluation of facial bone structures, the FA sample presented smaller median measurements in most variables evaluated; it also presented mandibular micrognathism and mainly dolicofacial vertical growth pattern. These findings, together with other features such as skin pigmentation and microphthalmia, may lead to a possible recognition of a FA condition from a patient’s facial features. KEY WORDS:
cephalometric analysis, craniofacial growth pattern, Fanconi anemia
Several studies have reported growth delay in FA patients due to endocrine changes, in particular growth hormone deficiency (De Kerviler et al., 2000; Dokal, 2000; Wajnrajch et al., 2001; Massa et al., 2002; de Ilurdoz et al., 2003; Pasquini, 2003; Giri et al., 2007; Alter and Lipton, 2008). These osseous growth changes may affect skull and face bones and may be part of phenotypical features that help clinical diagnosis (Zago et al., 2001). Typical facial features, known as Fanconi facies, are described as delicate facial features, a large nasal base, epicanthal folds, microcephaly, microphthalmia, small mouth and chin (Dokal, 2000), anomalous sella turcica, and low-set ears (Alter, 1996; Dokal, 2000; Massa et al., 2002; Quintanilla et al., 2002). In many cases, FA patient facies facilitate the diagnosis of the disease (Green and Kupfer, 2009). Several researchers have used cephalometric analysis to assess osseous discrepancies and facial patterns in syndromic patients with the purpose of understanding typical features of each syndrome and helping surgical and dental
Fanconi anemia (FA) is an autosomal recessive genetic disorder with heterogeneous clinical manifestations. It is characterized by bone marrow failure, congenital anomalies, growth delay, and association with neoplasia. It progresses to pancytopenia, leukemia, and other solid neoplasias (Guerra et al., 2000; Pasquini, 2000; Pasquini, 2003; Green and Kupfer, 2009).
Dr. Martins is Professor, Oral and Maxillofacial Surgery, School of Dentistry of the Pontifical Catholic University of Parana´ ´ (PUCPR). Dr. Avila is Professor, Univille, Sa˜o Bento do Sul, Joinville, SC, Brazil. Dr. Ribas is Head, Oral and Maxillofacial Surgery, Dr. Igna´cio is Professor, PUCPR, Curitiba, PR, Brazil. Dr. Candido ˆ is private practice, Porto Alegre, Brazil. Dr. Bonfim is MD, Professor, Universidade Federal do Parana´. Submitted January 2012; Revised June 2012; Accepted July 2012. Address correspondence to: Dr. Wilson Martins, School of Dentistry of the Pontifical Catholic University of Parana´ (PUCPR), ´ Republica do Libano, 462 Curitiba, PR 82520-500, Brazil. E-mail [email protected]. DOI: 10.1597/11-321.1 83
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FIGURE 1 Skeletal measurements of cephalometric analysis.
treatment (Tarjan et al., 2005; Bindayel et al., 2008; Chong et al., 2008; Tuna et al., 2009; Leonardi et al., 2009). Skeletal facial patterns are known to vary according to age and race in normal individuals. The aim of this study was to evaluate craniofacial pattern in patients with FA through skeletal measurements of cephalometric analysis and vertical growth pattern as set by the VERT index. The hypothesis is that FA patients present lower mean measurements in relation to the skeletal standards compared. MATERIALS
AND
METHODS
This is a cross-sectional study that employed a quantitative approach to compare linear and angular measurements of popular cephalometric analysis in lateral teleradiographic images of a sample of patients diagnosed with FA. The study was approved by the Research Ethics Committee of the PUCPR. The study sample consisted of 50 patients diagnosed with FA (FA-G group), 25 female and 25 male patients, ages ranging from 3.8 years to 26 years (average age 10 years), who were undergoing treatment at the outpatient Hema-
tology service at the Federal University of Parana´, Brazil. All of the patients were undergoing anti-aplasia treatment because medullary aplasia is an ever present condition in these patients. Exclusion criteria were patients who had used or were using growth hormone medication, had undergone bone marrow transplant, or had been previously subjected to dental treatment. Parents or guardians signed a free informed consent form for the research, giving permission for the researchers to abstract medical records. The radiographic images were obtained in the Department of Radiology of the PUCPR with an Orthophos XG Plus X-ray generator (Siemens, Berlin, Germany). Lateral teleradiographic images were scanned with a flatbed scanner model Color Page 6HRXc (Genius, KYE Systems Corp., Taipei, Taiwan) in line with the Orto Manager 6 software (Soft Manager, Curitiba, Brazil). Classic cephalometric points (Salzmann, 1958) were plotted in order to set up linear and angular cephalometric measurements analyzed: Ba - basion; Po - porion; XI – geometric center of the ramus; DC - condyle axis; Pt - pterygoid point; Or - orbitale; N - nasion; ENA - anterior nasal spine; Go - gonion; Me -
Martins et al., FACIAL PATTERN IN PATIENTS WITH FANCONI ANEMIA
TABLE 1
Three facial types are observed: mesofacial, with balanced growth and development, dolicofacial, and brachyfacial, depending on whether facial growth is vertical or horizontal, respectively. These angular measurements are used to calculate the indices: FA, FC, MP_A, IAFH, and AM_A from Ricketts’ cephalometric analysis. The tracings and measurements were done and repeated by two examiners. All lateral norm radiographic images were replotted, and tracings and measurements were redone after 2 months in order to detect Dahlberg error interrater reliability (Houston, 1983); no significant difference in discordant values of generated measurements was seen. For cephalometric assessment, the first measurement was used. Continuous variables were expressed through mean and standard deviation. Student’s t test was used to compare means between the FA-G group and the Ricketts standard for Americans (Ricketts et al., 1982) and the FA-G group and the Nobuyasu et al. (2007) standard for Brazilians. The same Student’s t test was used to compare SNA, SNB, ANB, GoGnSN, and SNGn values between FA-G and the norm of Steiner’s analysis (Steiner, 1959). Analysis of variance (ANOVA) was also carried out for these measurements. The value considered statistically significant was P , .05. For VERT (vertical growth pattern) assessment, a descriptive analysis with percentage values was used (Table 7).
Values of Cephalometric Norms Assessed*
CP‘‘A’’ - convexity at point ‘‘A,’’ mm IAFH - inferior anterior facial height, degrees FD - facial depth, degrees FA - facial axis, degrees FC - facial cone, degrees MD - maxilla depth, degrees MH - maxilla height, degrees PP - palatal plane, degrees MP_A - mandibular plane, degrees TFH - total facial height, degrees CD - cranial deflection, degrees ACL - anterior cranial length, mm PFH - posterior facial height, mm RP - ramus position, degrees PATM - position of ATM, mm AM_A - mandibular arc, degrees MCL - mandibular corpus length, mm SNA - sella-nasion point A, degrees SNB - sella-nasionpoint B, degrees ANB - point A-nasion point B, degrees GoGnSN - gonion-gnathion-sella-nasion, degrees SNGn - sella-nasion-gnathion, degrees
N
SD
CB
2 47 87 90 68 90 53 1 26 60 27 55 55 76 31 25 65 82 80 2 32 66
62.0 64.0 63.0 63.5 63.5 63.0 63.0 63.5 64.0 63.0 63.0 62.5 63.3 63.0 62.2 64.0 62.7 62.0 62.0 – – –
– – 0.33/y – – – 0.4/y – –0.3/y – – 0.8/y 1/y – 0.8/y 0.5/y 1.6/y – – – – –
* N ¼ norm (average value) of Ricketts’ cephalometric analysis; SD ¼ standard deviation of norm; CB ¼ biological correction.
menton; Gn - gnathion; Pm - mandibular axis; and CC cranial center (Fig. 1). For the cephalometric study, angular and linear measurements from 17 (skeletal factors) of the 33 factors proposed by Ricketts’ cephalometric analysis (Ricketts, 1961) were assessed. Sixteen dental factors were not assessed because most of the patients presented with mixed dentitions. Linear measurements are expressed in millimeters and angular factors, in grades (Table 1). Factors and respective fields compared were: field II - skeletal problems – maxillary/ mandibular relationship; field V - craniofacial relationships; and field VI - internal structure, of Ricketts’ analysis. SNA - sella turcica, nasion and point A angle; SNB - sella turcica, nasion and point B angle; ANB - point A, nasion, and point B angle; GoGnSN - gonion, gnathion, and sella turcica-nasion angle; and SNGn - sella turcica, nasion, gnathion angle of Ricketts’ and Steiner’s cephalometric analyses were also measured. Ricketts’ vertical growth pattern (VERT index) (Ricketts et al., 1982) was used to evaluate vertical craniofacial growth, which was calculated from measurements of factors FA, FC, MP_A , IAFH, and AM_A (Tables 1 through 4). All factors are defined in Table 1. TABLE 2
85
RESULTS There were no differences between sexes. Skeletal Problems (Field II) Comparison of mean and standard deviation among FA-G, Ricketts et al. (1982), and Nobuyasu et al. (2007) showed significant differences, as can be seen in Table 2. Craniofacial Relationships (Field II) Comparison of mean and standard deviation among FA-G, Ricketts et al. (1982), and Nobuyasu et al. (2007) showed significant differences, as presented in Tables 3 and 4. Table 5 summarizes higher, lower, and similar values of the sample in relation to standards used for comparison.
Field II - Skeletal Problems (Maxillary/Mandibular Relationship) FA-G
Ricketts
Nobuyasu et al.
Linear and Angular Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
CP‘‘A’’, mm IAFH, degrees
3.82 44.71
2.89 4.24
2.00 47.00
2.00 4.00
.0000* .0001*
1 2
1.89 42.51
1.94 2.65
.0000* .0005*
1 1
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data. * Significant at P , .05.
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TABLE 3
Field V – Craniofacial Relationships FA-G
Ricketts
Nobuyasu et al.
Angular Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
FD FA FC MD MH PP MP_A
86.59 87.31 64.56 91.01 55.37 0.56 29.46
3.24 4.51 4.96 5.01 3.27 3.37 6.89
87.00 90.00 68.00 90.00 53.00 1.00 26.00
3.00 3.50 3.50 3.00 3.00 3.50 4.00
.3477 .0000* .0000* .0258* .0000* .0021* .0000*
3 2 2 1 1 2 1
89.23 93.11 68.11 91.09 56.22 0.63 23.42
3.25 3.18 3.30 3.37 3.54 3.06 4.70
.0000* .0000* .0000* .9151 .1778 .0430* .0000*
2 2 2 3 3 2 1
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data * Significant at P , .05.
individuals presented higher mean values, statistically significant, in the cephalometric measurements of variables CP’’A’’ MP_A, CD, and PATM.
Maxillary and Mandibular Anterior Posterior Relationship Comparison of mean and standard deviation between FA-G and Steiner (1959) showed significant difference in the relationship with mandibular angles (Table 6).
Maxilla and Maxillary/Mandibular Relationship The higher value of the measurement CP’’A’’ (field II skeletal problems) indicates that the maxilla lies slightly in a more anterior position than the one found in the studies used for comparison. As one of the references of the CP’’A’’ measurement is the facial line (N-Pg), the relationship with the Pg point must also be taken into account, which may undergo alteration due to the more posterior sagittal position of the menton as in mandibular micrognathia. This leads to a higher distance from the facial line (N-Pg) to point A, such as the case with FA-G.
Vertical Growth Pattern and Facial Type (Ricketts’ VERT index) The sample FA-G showed 28% (14/50) braquifacial individuals (7 medium and 7 mild), 20% (10/50) mesofacial individuals, and 52% (26/50) dolicofacial individuals (14 mild, 7 medium, and 5 severe) (Table 7). DISCUSSION Review of the literature failed to find studies that assessed craniofacial skeletal relationship and facial vertical growth pattern of individuals with FA, although some researchers state that there are craniofacial alterations in these patients (De Kerviler et al., 2000; Alter and Lipton, 2008; Green and Kupfer, 2009). Other syndromes were studied by cephalometric evaluation in order to observe variations in normality patterns (Quintanilla et al., 2002; Tarjan et al., 2005; Bindayel et al., 2008; Chong et al., 2008; Leonardi et al., 2009; Tuna et al., 2009). In relation to values from norms used for comparison (Ricketts et al., 1982; Nobuyasu et al., 2007), FA-G TABLE 4
Anterior/Posterior Maxillary/Mandibular Relationship SNA, SNB, and ANB angles were compared to respective norm values for these measurements. FA-G showed SNA mean values close to norm (82.528 6 4.20), lower SNB in relation to norm (77.888 6 3.85), and ANB (4.648 6 2.91) higher than the norm, therefore confirming a more posterior position of the menton in relation to the maxilla. The increased ANB angle could also be explained by the decreased mandibular corpus length by 88% (44/50) in FA-G individuals, when
Field VI – Internal Structures FA-G
Ricketts
Nobuyasu et al.
Angular and Linear Variables
Mean
SD
Norm
SD
P Value
Concl.†
Mean
SD
P Value
Concl.†
DC, mm ACL, mm PFH, mm AFT, mm PR, mm PATM, mm AM_A, degrees MCL, mm
27.91 50.23 49.77 60.88 74.06 27.73 29.29 59.70
3.10 3.96 6.13 5.51 4.20 4.29 5.50 5.88
27.00 55.00 55.00 60.00 76.00 31.00 26.00 65.00
3.00 2.50 3.30 3.00 3.00 2.00 4.00 2.70
.0369* .0000* .0000* .0551 .0000* .0000* .0000* .0000*
1 2 2 3 2 1 1 2
25.87 59.53 66.06 55.62 72.72 42.67 31.93 74.03
2.72 3.90 5.50 4.24 3.03 3.03 6.77 4.18
.0002* .0000* .0000* .0000* .0404* .0000* .0233* .0000*
1 2 2 1 1 1 2 2
† Conclusions: (1) Mean values in the study are statistically higher than the norm; (2) mean values in the study are statistically lower than the norm; and (3) mean values in the study are the same as the norm. Source: study data. * Significant at P , .05.
Martins et al., FACIAL PATTERN IN PATIENTS WITH FANCONI ANEMIA
TABLE 5 Relationship Between FA-G Measurements and Norms for Comparison
TABLE 7
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Facial Growth Pattern - VERT†
FA-G Variable
Ricketts
Nobuyasu et al.
CP’’A’’* IAFH‡ PF‡ EF† CF† PM‡ AM‡ PP† MP_A* DC* CCA† AFP† AFT‡ PR‡ PATM* AM_A‡ CCM†
. , ¼ , , . . , . . , , ¼ , . . ,
. . , , , ¼ ¼ , . . , , . . . , ,
* Statistically significant values higher than 2 standards for comparison. † Statistically significant values lower than 2 standards for comparison. ‡ Statistically significant values higher, lower, or similar in one of the standards for comparison.
compared to norm standard for Brazilians, thus characterizing shorter mandibular length (mandibular micrognathia) and more posterior position of the menton. These findings corroborate clinical observations of micrognathia from several researchers (Gluckman et al., 1983; Auerbach, 1995; Alter, 1996; De Kerviler et al., 2000; Dokal, 2000; Koubik et al., 2006; Alter and Lipton, 2008). Craniofacial Relationships The MP_A angle (field V - craniofacial relationships) enables a vertical assessment of the mandible in relation to the Frankfort plane and, when increased, indicates dolicofacial vertical growth pattern, unlike findings of means for Brazilians (Nobuyasu et al., 2007), where the braquifacial growth pattern prevailed. Decreased FA and FC (field V - craniofacial relationships) angles show a more vertical growth in these individuals, unlike standards used for comparison. Values lower than the Ricketts norm for the palate plane angle (PP) (field V - craniofacial relationships) were also decreased in the Brazilian sample (Nobuyasu TABLE 6 Cephalometric Measurements of Maxillary/Mandibular Relationship† Norm
SNA, degrees SNB, degrees ANB, degrees GoGnSN, degrees SNGn, degrees † Source: study data. * Significant at P , .05.
FA-G
Value
SD
Mean
SD
P Value
82 80 2 32 66
62.0 62.0
82.52 77.88 4.64 35.2 68.31
64.20 63.85 62.91 66.60 63.63
.5878 .0620 .0900 .0000* .0000*
Braquifacial Mesofacial Dolicofacial
28% (14/50) 20% (10/50) 52% (26/50)
† Source: study data
et al., 2007). However, they were even lower in the FA sample, thus indicating a more horizontal position of this plane (anticlockwise) in relation to the Frankfort plane. FA-G individuals showed a lower mean value, statistically significant, of the FD variable (field V craniofacial relationships) only in relation to the standard for Brazilians. This result was similar to the Ricketts et al. (1982) standard for Americans. This lowered angle in relation to the standard for Brazilians, mainly braquifacial, also reinforces the trend of dolicofacial pattern of the sample. Lower MCL confirms the clinically observed micrognathism (Massa et al., 2002; Giri et al., 2007). MD and MH variables (field V - craniofacial relationships) showed higher mean values from cephalometric measurements, statistically significant, but only in relation to the pattern of Ricketts et al. (1982). This was similar to the standard for Brazilians (Nobuyasu et al., 2007), thus showing that maxillary position is in accordance with standards for Brazilians. IAFH (field II - skeletal problems) and RP (field VI internal structures), presenting higher values in relation to those found for Brazilians, show a dolicofacial growth pattern trend. This differs from results found in Nobuyasu et al. (2007), who reported a braquifacial standard for Brazilians. Internal Structures For the CD measurement (field VI - internal structures) increased mean values in the FA-G group show a more vertical growth trend of the midface and a more elongated facial midface. The PATM measurement (field VI - internal structures), which assesses medial position of the ramus, higher FA-G mean values found indicate a more posterior temporomandibular joint position. FA-G individuals presented lower, statistically significant mean values of cephalometric measurements for the EF, CF, PP, ACL, and PFH variables in relation to the norm for Americans (Ricketts et al., 1982) and to the standard for Brazilians (Nobuyasu et al., 2007). The reduced ACL (field IV - internal structures) reinforces clinical findings of microcephaly observed by researchers (Auerbach, 1995; Alter, 1996; De Kerviler et al., 2000; Dokal, 2000; Alter and Lipton, 2008). The PFH measurement (field VI - internal structures) is
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lowered in the sample, thus indicating that mandibular ramus is smaller than the one observed in compared patterns. Besides, the GoGnSN angle is higher in relation to the standard for Brazilians, confirming the vertical growth trend of the midface. The AM_A variable (field VI - internal structures) had a lower mean value, statistically significant, in relation to the standard for Brazilians (Nobuyasu et al., 2007), therefore confirming the dolicofacial growth pattern trend in the FA-G sample. This finding differs from braquifacial pattern findings for Brazilians. The TFH variable was higher in relation to the standard for Brazilians (Nobuyasu et al., 2007) and normal in relation to the standard of Ricketts et al. (1982) for Americans. This measurement relates mandibular corpus to total cranial base, and when increased, indicates dolicofacial vertical growth trend. These data are also corroborated by the increased GoGnSN (mean 35.208 6 6.60) angle in FA-G in relation to Steiner’s norm (Steiner, 1959). Upon a study of a sample of Brazilians, Nobuyasu et al. (2007) found a predominant braquifacial growth pattern (VERT), unlike the present study, which found predominant dolicofacial vertical growth pattern (VERT) in FA-G. Anterior Posterior Craniofacial Alterations The present study found anterior posterior craniofacial alterations, statistically significant, in relation to facial balance standards set by lateral cephalometric norm values of Ricketts et al. (1982) for Americans and in relation to the standard for Brazilians as described by Nobuyasu et al. (2007), such as: cranial base is smaller, normal maxilla in vertical length, and in relation to cranial base, the midface is elongated. These alterations included a smaller cranial base, normal maxilla in vertical length, and an elongated midface in relation to the cranial base. Furthermore, the mandible shows smaller corpus and ramus length but an increased mandibular angle, thus resulting in an elongated face. CONCLUSIONS Upon evaluation of anterior posterior bone structures of the face, the group of individuals with FA presented: 1. Lower mean measurements in most of the variables assessed in relation to skeletal standards compared; 2. Mandible with smaller corpus and ramus length and increased mandibular angle, leading to an elongated face and mandibular micrognathism; and 3. Smaller cranial base, normal maxilla in vertical length and in relation to the cranial base, and a predominant dolicofacial vertical growth pattern. These findings, together with other features, such as skin pigmentation and microphthalmia, may lead to a possible
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