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Congenitalhypothyroidism.nl
Kempers, M.J.E.
Publication date
2006
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Citation for published version (APA):
Kempers, M. J. E. (2006). Congenitalhypothyroidism.nl.
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ABSTRACT T
Severall studies have reported an increased incidence of congenital anomalies in patients with congenitall hypothyroidism. Furthermore, in patients with congenital hypothyroidism with mutationss in genes known to be involved in thyroid development specific extra-thyroidal abnormalitiess have been observed. The goal of the present study was to gain insight in the typess and patterns of morphological characteristics depending on the type of congenital hypothyroidismm of thyroidal origin (CH-T).
Inn 231 Dutch CH-T patients with a thyroid agenesis, a dystopic thyroid or an eutopic thyroid gland,, a careful physical examination of the body surface directed to phenotypic abnormalities wass performed, and compared to a control group of 1,007 Dutch children.The percentage off patients with one or more abnormality in the total CH-T cohort (32.9%) and in patients withh CH-T dystopic thyroid (36.9%) was significantly higher than in the control population (21.7%;; p<0.001). Especially in the CH-T dystopic thyroid group specific abnormalities i.e. turricephaly,, bilateral ear pits, and oligodontia, were found significantly more frequent. Thee percentage of patients in the total CH-T group with one or more minor anomalies (95.7 %)) was significantly higher than in the control group (82.5%). A number of single as well ass combinations of minor anomalies and common variants occurred significantly more frequentt in the CH-T subgroups.
Thee careful grouping of patients according to their phenotype and the types and patterns in morphologicall findings, may be helpful in subsequent molecular studies in search for new geness involved in thyroid development.
INTRODUCTION N
Congenitall hypothyroidism (CH) is the most frequent congenital endocrine disorder. In thee Netherlands the incidence (including transient CH) is 1 in 1,800 newborns [Kempers et al.,2006b].. The most frequent subtype of CH is thyroid dysgenesis, and other major subtypes aree thyroid dyshormonogenesis and central CH [Kempers et al.,2006b]. In thyroid dysgenesis thee thyroid gland is either absent (thyroid agenesis) or located dystopically (dystopic thyroid). Inn thyroid dyshormonogenesis the gland is located at the normal position and its size is usually normall or hyperplastic, and thyroid hormone production is disturbed due to an inborn error off thyroid hormonogenesis. The classification of thyroid hypoplasia is somewhat ambivalent: dependentt on the molecular background it can be considered as thyroid dysgenesis [Macchia ett al.,1998], but also as thyroid dyshormonogenesis [Biebermann et al.,1997]. In central CH,, the regulation of thyroid hormone production is impaired due to a dysfunction of the hypothalamus-pituitaryy regulatory system.
Developmentall biologic studies in recent years have shown that early (human) thyroid gland developmentt is dependent on the interplay of proteins encoded by TITF1 (NKX2.1), FOXE1 (TITF2),, NKX2.5, and PAX8 [Macchia et al.,1998; De Felice et al.,2004; Dentice et al.,2006] andd possibly by GLIS3 [Senee et al.,2006]. I lowever, screening of large cohorts of patients withh thyroid dysgenesis for mutations of the above genes has yielded mutations in only a smalll percentage [Perna et al.,1997; Lapi et al.,1997; Macchia et al.,1998; De Felice et al.,2004; Tonaccheraa et al.,2004; Castanet et al.,2005; Dentice et a l , 2006], and in the majority of patientss the molecular background remains unknown at present.
Inn some patients with known mutations concomitant major malformations have been reported,, such as choanal atresia and cleft palate in FOXE1 mutations [Clifton-Bligh et al.,1998],, pulmonary anomalies and choreoathetosis in TITF1 mutations [Krude et al.,2002], renall agenesis in PAX8 mutations [Meeus et al.,2004], cardiac malformations in NKX2.5 mutationss [Dentice et al.,2006], and neonatal diabetes mellitus in GLIS3 mutations [Senee et al.,2006].. Furthermore, many studies have reported on the increased incidence of congenital anomaliess in CH patients. Olivieri et al [2002] found a high prevalence of additional congenitall malformations (6.9% in their population of 490 patients with permanent CH). Cardiacc anomalies were most frequent (5.5%) but also anomalies of nervous system, eye, musculoskeletall system and digestive system were found as well as cleft palate and/or lip [Olivierii et al.,2002]. The same percentage was found in a neonatal CH screening survey inn the United Kingdom: congenital anomalies (mainly cardiac defects and dislocated hips) weree found in 7% out of a population of 493 patients [Grant et al.,1988]. In Georgia 13 of 100 patientss with CH had congenital heart defects, 10 had non-cardiac malformations (mainly gastrointestinall tract and malformations of the genitourinary system) and 17 respiratory distresss [FernhofF et al.,1987]. Kreisner et al. detected malformations in 13.2% out of 76 patientss with permanent CH, predominantly cardiac malformations, but also cleft palate andd lip and bifid spine were found [Kreisner et al.,2005]. Other studies also reported a highh prevalence of congenital abnormalities mainly cardiac defects, pulmonary problems, neurologicall problems, cleft palate and/or lip, anomalies of urogenital, gastro-intestinal andd musculoskeletal system, as well as chromosomal abnormalities [Bamforth et al.,1986; Lazaruss et al.,1988; New England Congenital Hypothyroidism Collaborativel988; Rosenthal ett al.,1988; Majeed-Saidan et al.,1993; Chao et al.,1997; Roberts et al.,1997; Al Jurayyan et
al.,1997;; Devos et al.,1999; Castanet et al.,2001]. So, from literature it appears that the number off 'malformations' in CH patients is higher than reported in earlier studies on newborn infantss (2-3.6%) [Marden et al.,1964; Mehesl983; Merlob et al.,1985; Leppig et al.,1987]. Inn most of the above mentioned studies the presence of malformations was retrieved fromm the patients' medical files. Occasionally patients were physically examined for major malformationss for study purposes, but in none of the studies patients were evaluated for minorr anomalies. Morphological findings were not systematically correlated to etiological subgroupss of CH. This has prevented the recognition of specific patterns in phenotype inn subgroups of CH patients. Careful grouping of patients according to their clinical morphologicall phenotype allows establishing groups that are more homogeneous, and may bee helpful in subsequent molecular studies for causative genes.
Thee goal of the present study was to investigate a large group of well characterized CH patients forr morphological characteristics, and to correlate these finding with the type of CH.
METHODS S
Patients s
Thee present study is part of an ongoing national study of the evaluation of effects of CH screeningg in The Netherlands. The primary goal of this study is to test cognitive and motor outcomee of CH patients from three age cohorts born between 1981-1982 (n=136), 1992-19933 (n=141) and 2002-2004 (n=213), respectively. The characteristics of the cohorts are summarizedd in Table I. Due to the national registration the number of CH patients born eachh year and detected by screening in The Netherlands is known. Also the children with CH,, not detected by screening but later on found by clinical features, are registered.
Reasonss for exclusion of patients from the present study were: the presence of a known syndromee (n=37; specification in Table 1); moved abroad (n=9); early death (n=ll); euthyroidismm without T4-supplementation (n=4); expressed problems with Dutch language (n== 7); severe mental retardation due to perinatal encephalopathy (n=3); blindness (n=l); deafnesss not part of Pendred syndrome (n=l); (treatment for) brain tumor (n=l); lost to follow-upp (n=l); severe psychosocial problems (n-2); and non-cooperation of physician in chargee (n=l) (see also Discussion).
Inn all patients the cause of CH was determined, and classified in six categories [Vulsma ett al., 2006; Kempers et al.,2006a; Kempers et al.,2006c]: congenital hypothyroidism of thyroidall origin, due to thyroid agenesis (n=64); abbreviated as 'CH-T thyroid agenesis, congenitall hypothyroidism of thyroidal origin, due to dystopic thyroid gland (n=122); abbreviatedd as 'CH-T dystopic thyroid' congenital hypothyroidism of thyroidal origin, with normallyy located thyroid gland (n=45); abbreviated as 'CH-T eutopic thyroid' congenital hypothyroidismm of central origin, part of multiple pituitary hormone deficiencies (n=20) congenitall hypothyroidism of central origin, due to inadequately treated maternal Graves' diseasee during pregnancy (n=ll) congenital hypothyroidism of unknown origin (n=24) Becausee of the (possible) central origin of CH and small group size, the latter three categories weree excluded from the analyses.
Tablee I. Patient characteristics of the three cohorts with congenital hypothyroidism. Cohortt Total No. of excluded patients,
numberr with specification of the knownn syndromes
Invited// Mean age at Participatingg physical (%) ) examination n (yr) ) 1981-822 136 13 syndromes: : Trisomyy 21 (3) Pendredd (1)
46,XY,, dupl4 (pter->q24.3::q22-»q24.3:: q24.3-»qter)) (1)
1992-933 141 23 syndromes: : Trisomyy 21 (2) Triplee X (1)
Albrightt Hereditary Osteodystrophy (3) Congenitall Disorder of Glycosylation 1A (1)
123/722 (59%) 21.7 7 118/89(75%) ) 10.6 6 2002-044 213 41 syndromes: : Trisomyy 21 (15) Trisomyy 13 (1) 46,X,del(X)(p22.2).ishder(X)t(X;19)(p22.2; ; pl3.3)) (1) Corneliaa de Lange (1)
Duchennee Muscular Dystrophy (1) Prader-Willii (1)
Congenitall nephrotic syndrome (1) Beckwith-Wiedemannn (1) Septo-opticc dysplasia (1) Johansson-Blizzardd (1) Turnerr (1) 171/1255 (73%) 1.1 1
Morphologicall Examination
Alll patients were invited in writing to participate both to psychological assessments as to a physicall examination. All participating patients (or parents if children were aged <12 years) gavee written informed consent.
Thee primary investigator (MJEK) was a physician, trained in clinical morphology by a pediatrician-clinicall geneticist (RCMH). All patients had a careful physical examination of thee body surface directed to phenotypic abnormalities using detailed definitions, as discussed elsewheree [Merks et ah,2003]. Auscultation of the heart, abdominal palpation, examination off internal organs and of the external genitalia was not performed. All patients were seen by thee primary investigator; 18 patients (6.3%) were seen together with the second investigator (RCMH).. Digital photographs were taken from 218 patients of the 231 participating patients (94%)) and all were discussed with the second investigator (RCMH). All anomalies observed byy the primary investigator were photographed and discussed with the second investigator; onlyy when both agreed on the presence of an anomaly the item was scored positive.
Thee institutional review board of the Emma Children's Hospital AMC approved the study protocol. .
Controls s
Thee data of the present CH-T cohorts were compared to data obtained in a group of control childrenn (n=l,007), using the same methodology and set of definitions for phenotypic abnormalitiess [Merks et al.,2006]. The median age of the controls at examination was 11.0 yearss (range 8-14 years).
Definitions,, terminology, and classification of phenotypic abnormalities
Priorr to the study, definitions were set for all phenotypic abnormalities that can be scored byy body surface examination [Merks et al.,2003]. The phenotypic abnormalities were classifiedd according to their (presumed) pathogenesis [Merks et al.,2003], and subdivided into:: 1. Abnormalities, caused by abnormal development, and 2. Minor variants, caused by a defectt in phenogenesis, arising after 8 weeks of gestation, which can be subdivided into two categories,, based on their prevalence in the normal population A. Minor anomalies: having a prevalencee in the normal population by definition of < 4% and B. Common variants: having byy definition a prevalence in the normal population of >4%.Statisticall Analysis
Thee percentage of observed morphological characteristics in the total CH-T group, in the variouss categories of CH-T etiology, and in the controls were compared using Chi-square testss or Fisher's exact tests in case of small numbers. The following phenotypic abnormalities weree selected for analysis: 1) minor anomalies with a prevalence of >4%; 2) common variants withh a prevalence of >8% (the threshold for common variants of 8% was arbitrarily chosen); 3)) abnormalities occurring more frequent in the CH-T subgroups than in the controls. Statisticall significance was considered to exist if the two-tailed p-value was <0.05. Multiple testingg was addressed by applying the p-value correcting method of Benjamini and Hochberg
[Benjaminii et al.,1995], which minimizes the false detection rate (FDR).
Forr the minor anomalies with a prevalence >4%, common variants with a prevalence of >8% andd abnormalities occurring more frequent in the CH-T subgroups a multivariate model was performedd with discrimination analysis (stepwise method).
Tablee II. Biologic classification of the participating patients
CH-TT CH-T CH-T Total number of thyroidd dystopic thyroid eutopic thyroid patients agenesis s
2002-20044 cohort 24 40 18 «2 1992-19933 cohort 17 45 17 ^ 1981-19822 cohort 23 37 10 ^0_ Totall 64 122 45 23_1_
ibnormalities s
RESULTS S
AA total of 231 patients (162 females) were examined (Table II). The mean ages at the time of examinationn were 1.1, 10.6 and 21.7 years in the 2002-2004, 1992-93 and 1981-82 cohorts, respectivelyy (see Table I). Twenty-five patients were of non-Caucasian descent, 206 of Caucasiann descent (both parents).
Thee percentage of CH-T patients with one or more abnormality (apart from the thyroid condition)) was 32.9%. This was significantly higher than the percentage of 21.7% in the controll population (p<0.001). Analysis of the three CH-T etiology groups separately revealed thatt only the percentage in the CH-T dystopic thyroid group was significantly higher than inn the control group (p<0.001, Table III A). The types of abnormalities observed are indicated inn Table IIIB. There were no significant differences in the percentage of patients with abnormalitiess between the three CH-T etiology groups. Excluding children with hemangioma fromm the 2002-04 cohort (a malformation that will be more frequent in one year old children thann in the other groups), resulted in slightly lower percentages, but the percentages in the totall CH-T group, and the CH-T dystopic thyroid group were still significantly higher than in thee control group (p = 0.024 and p = 0.016, respectively).
Thee percentage of patients with one or more minor anomalies in the total CH-T group (95.7 %) wass significantly higher than in the control group (82.5%), see Figure 1. Also the percentages inn the three CH-T etiology subgroups were significantly higher than in the control group.
Tablee IIIA. Percentages of patients with abnormalities in the CH etiology groups and in the control group. Percentagee of patients with 1 or more abnormality CH-TT thyroid agenesis CH-TT dystopic thyroid CH-TT eutopic thyroid CH-TT total Controls s 28.11 % 36.9%% * 28.9% % 32.9%% * 21.7% % (95%% CI 16.8-39.4) (95%% CI 28.2-45.6) (95%% CI 15.1-42.7) (95%% CI 26.8-39.0) (95%% CI 19.2-24.3) ** p<0.001 compared to the control group
CII = Confidence Interval
Excludingg children of the 2002-04 cohort with hemangioma resulted in the following percentages for the CH-T thyroidd agenesis, dystopic thyroid, eutopic thyroid and total group of 26.6%, 32.0%, 24.4%, 29.0%
100 0 90 0 80 0
\\ 70
:: 50
CH-TT agenesis C H,T emopK t h y r o j d Controls
CH-TT dystopic thyroid CH-T total
Figuree 1. Prevalence of minor anomalies. For the three CH-T etiology subgroups, the total CH-T group, and the controll group the prevalence of minor anomalies is presented
Tablee IIIB. List of abnormalities in the three CH-T etiology groups
Shortt stature proportionate Trigonocephaly y
Turricephaly y Sloww hair growth Nosee alae coloboma Voicee dysarthria
Openn mouth appearance Upperr lip cleft non-midline Gumss hypertrophy Teethh oligodontia Teethh fusion incisors Earr crumpled Helicess pits Earr pits unilateral Earr pits bilateral Nippless supernumerary Backk scoliosis
Toess post-axial Polydactyly Jointss contracture
Hypomobilityy small and large joints Hypermobilityy small and large joints Skinn localized hypoplasia/aplasia Cafee au lait multiple
Capillaryy hemangioma Port-winee stam CH-T T thyroid d agenesis s CH-T T dystopic c thvroid d CH-T T eutopic c thyroid d
Abnormalitiess observed in the CH-T etiology subgroup are indicated by ' + '
Inn the total CH-T group 81.4% had 2 or more minor anomalies and 58.9% had 3 or more anomaliess compared to 55.7% and 32.7% respectively, in the control group.
Inn Table IV (shown at the end of this chapter) the prevalence of phenotypic abnormalities is shownn for the three CH-T etiology groups and the controls. Those minor anomalies occurring att a frequency >4%, and common variants >8% are separately presented in Table VA, B and C. AA number of minor anomalies and common variants occurred significantly more frequent inn the CH-T subgroups: 18 in the CH-T thyroid agenesis (Table VA), 18 in the CH-T dystopic thyroidd group (Table VB) and 23 in the CH-T eutopic thyroid group (Table VC), (Table 4A,4B andd 4C are shown at the end of this chapter). Some common variants or minor anomalies suchh as broad nose tip, prominent lower jaw, long philtrum and prominent/deep philtrum weree not specific for one CH-T etiology subgroup, but occurred significantly more frequently inn all three CH-T group(s) than in controls.
Off the abnormalities bilateral ear pits (p=0.006, corrected), oligodontia (p=0.006, FDR-corrected,, calculated for the 1992-93 and 1981-82 cohorts only), turricephaly (p=0.006,
FDR-corrected)) and nose alae coloboma (p=0.034, FDR-corrected) were significantly more frequentt in the CH-T dystopic thyroid group than in controls. Also hemangioma occurred significantlyy more frequent in the CH-T dystopic and CH-T eutopic thyroid groups, but the p-valuee became non-significant when the youngest cohort was excluded from analysis. Multivariatee analysis showed in each CH-T subgroup combinations of discriminating commonn variants and minor anomalies: 16 in CH-T thyroid agenesis, 17 in CH-T dystopic thyroidd and 23 in CH-T eutopic thyroid, indicated in Table VA, VB and VC.
DISCUSSION N
Wee have demonstrated a strikingly high prevalence of visual phenotypic abnormalities in aa large cohort of CH-T patients. Minor anomalies as well as abnormalities were seen more frequentt in the CH-T patients than in the control group and each CH-T subgroup was found too have a combination of several discriminating items. Especially in the CH-T dystopic thyroidd group specific abnormalities i.e. turricephaly, bilateral ear pits, and oligodontia were foundd significantly more frequent.
Thesee results are in line with previous reports in literature describing that extrathyroidal abnormalitiess are frequently found in CH patients [Bamforth et al.,1986; Fernhoffet al.,1987; Lazaruss et al.,1988; New England Congenital Hypothyroidism Coliaborativel988; Grant et al.,1988;; Rosenthal et al.,1988; Siebner et al.,1992; Majeed-Saidan et al.,1993; Chao et al.,1997; Robertss et al.,1997; Al Jurayyan et al.,1997; Devos et al.,1999; Olivieri et al.,2002; Kreisner et al.,2005]. .
However,, to explore the spectrum of phenotypic abnormalities in CH patients the interpretationn of previous studies proves to be difficult because: a. CH etiology was not well classified;; b. patients with transient CH (often due to external factors) were included; c. patients weree not physically examined by the investigators specifically for the study; d. only major malformationss were recorded, and not minor anomalies; e. lack of control data. The present studyy tried to overcome these problems. Only patients with permanent thyroidal CH were includedd and each patient was classified in of three major etiologic subgroups. Furthermore, inn the present study all patients underwent a clinical morphological examination by the same observer,, using a list of 683 well defined phenotypic abnormalities. Lastly, the prevalence of phenotypicc abnormalities could be compared to a large control group (n=l,007) that was recentlyy investigated by our group using a similar study protocol [Merks et al.,2006]. Thee use of three cohorts of CH-T patients with different ages can be considered a limitation becausee changes in phenotypes occur with age, and because the control group consisted of childrenn between the age of 8 and 14 years. We tried to overcome this shortcoming by scoring thosee items which were considered age-dependent, differently in the three cohorts, e.g. in the youngestt cohort (mean age 1.1 years) a flat nasal bridge which is commonly occurring at this age,, was scored only if unusually prominent in the infant, whereas in the oldest cohort (mean agee 21.7 years) eyebrow synophrys was scored only if prominent, as some synophrys is so commonlyy seen in adults.
Thee inclusion criteria of the study require some comments. This study was linked to the study evaluatingg cognitive and motor development. Therefore, patients were excluded when they
hadd a syndrome known to be associated with mental or motor retardation (such as Down syndrome),, or when such severe cognitive or motor disabilities were present that it seemed unlikelyy to be related to the neonatal hypothyroidism, but more likely to be part of another, syndromicc entity. Undoubtedly, in the excluded patients different phenotypic abnormalities and/orr known syndromes will have been present. Indeed, several syndromes (such as Down,, Kabuki, Young-Simpson, Johansson-Blizzard, Pendred and Williams syndrome, and Albrightt Hereditary Osteodystrophy) are known to be associated with CH [Gould et al.,1989; Masunoo et al.,1999; Kawame et al.,1999; van Trotsenburg et al.,2003; Glaser2003; Stagi et al.,2003;; Vulsma et al., 2006], However, it was not the goal to study CH in relation to various syndromes,, but to evaluate the phenotype of various forms of CH-T. The present data refer to thee majority of CH-T patients in whom in general no syndrome is suspected or established. Thee present results support our hypothesis that the prevalence of phenotypic abnormalities inn patients with CH-T due to thyroid dysgenesis is increased compared to controls. It seemss likely that genes involved in thyroid development have functions in other tissues ass well, and that one may expect that abnormal functioning of the involved genes during thyroidd development will go along with abnormal functioning of pathways important for thee development of other structures as well. In this respect the study can be compared to studiess in children with cancer, where similar results have been found [Merks et al.,2005]. Thee relatively high frequency of oligodontia in the CH-T dystopic thyroid group can serve as ann example of gene(s) involved in the development of two different tissues.
Itt may seem unexpected that also in the CH-T eutopic thyroid group phenotypic abnormalities weree found to be present. It is known however that genes may have different functions, beingg a structural gene in one tissue and act as an enzyme in another. Examples for this aree fibrillin-1 which acts as a structural protein in connective tissue and also has enzymatic functionss (up-regulation of TGFB1 signaling) [Neptune et al.,2003], and Albright Hereditary Osteodystrophy,, in which mutations in Gsa are involved in TSH signaling and patients also exhibitt a variety of structural anomalies [Vulsma et al ., 2006]. Thyroid hypoplasia, leading too CH-T, is an etiologically heterogeneous subgroup and has been related to mutations in transcriptionn factors as well as to TSH-receptor mutations [Biebermann et al.,1997; Congdon ett al.,2001]. One or more of these genes may have other functions elsewhere, which could explainn the increase in abnormalities in phenotype development. Lastly, some phenotypic abnormalitiess were found with increased frequency in all three CH-T etiology subgroups. Thiss may indicate that fetal hypothyroidism in itself can induce permanent morphological featuress as well.
Inn conclusion, we described a high prevalence of visual phenotypic abnormalities in CH-T patients.. In patients with CH-T due to a dystopic thyroid remnant minor anomalies and abnormalitiess were found most frequently, but also in patients with thyroid agenesis or with CH-TT and a normally located thyroid gland high percentages of phenotypic abnormalities were found.. The various associations should be helpful in further studies identifying underlying geneticc defects. The next step will be to match the specific phenotypic abnormalities found inn CH-T patients to known syndromes and animal knock-out models which may point to novell steps in developmental pathways.
Acknowledgements s
T h ee a u t h o r s t h a n k t h e p a t i e n t s , t h e i r p a r e n t s a n d p h y s i c i a n s for t h e i r p a r t i c i p a t i o n in t h i s study. .
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Tablee IV. List of phenotypic abnormalities and their frequencies {%) in the three CH-T etiology groups and in
thee control group.
Numberr of patients CH-T T thyroid d agenesis s 6 4 4 CH-T T dystopic c thyroid d 122 2 CH-T T eutopic c thyroid d 4 5 5 Controls s 1007 7 Build d Truncall obesity Generalizedd obesity 'Ihin/slenderr build Muscularr build ' Stature e Shortt (proportionate) Shortt (short limbs) Shortt (short trunk) Talll (proportionate) Talll (long limbs)
Neurocraniumm size Microcephaly y Macrocephaly y Neurocraniumm shape Brachycephaly y Dolichocephaly y Plagiocephaly y Trigonocephaly y Turricephaly y Kleebiattschedel l Neurocraniumm sutures Ridgedd sutures Widee sutures Smalll anterior fontanel Earlyy closure fontanels Delayedd closure fontanels Extraa fontanels Hairr growth Alopeciaa totalis Alopeciaa areata Sparsee implantation * Sloww growth Malee pattern baldness Highh anterior hairline Loww anterior hairline Widow'ss peak Cow'ss lick
Abnormall whorl (not frontal)
Hairr structure Fine e Dry--Softt * 0 0 3.1 1 1.6 6 0 0 4.7 7 0 0 0 0 3.1 1 0 0 1.6 6 0 0 0 0 1.6 6 3.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3.1 1 0 0 1.6 6 10.9 9 12.5 5 7.8 8 7.8 8 0 0 0 0 0 0 0 0 0 0 7.4 4 0 0 0 0 1.6 6 t) ) 0 0 2.5 5 0 0 0 0 3.3 3 1.6 6 0.8 8 0 0 0 0 2.5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.5 5 0.8 8 1.6 6 9.0 0 4.1 1 5,7 7 8.2 2 0 0 0.8 8 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.3 3 0 0 0 0 2.2 2 2.2 2 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 6.5 5 4.3 3 15.2 2 2.2 2 0 0 0 0 0 0 0 0 2.7 7 2.0 0 2.4 4 2.2 2 2.5 5 0 0 0 0 2.2 2 0 0 2.3 3 2.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.1 1 0 0 0 0 0 0 2.5 5 0.4 4 6.3 3 14,9 9 0.3 3 0.3 3 0.5 5 0.2 2
Coarse e Brittle e Uncombable e Kinky y Hairr p i g m e n t a t i o n Generalizedd h y p o p i g m e n t a t i o n Patchyy depigmentation P r e m a t u r ee graying Unusuall color Facee general Faciall cleft A s y m m e t r y y Coarse e Small l Narrow/elongatedd ' Broad d Round-shapedd 2 Squaree shaped Triangularr shaped Flat t Lipodystrophy y P r e m a t u r ee ageing Prominentt creases Expressionless/dull l Hypotonic c Hypoplasticc malae Midfacee hypoplasia Midfacee hyperplasia Fulll cheeks l Sunkenn cheeks Broadd lower 1/3 part
Faciall nerve Peripherall a s y m m e t r y Centrall a s y m m e t r y Forehead d Metopicc ridge Frontall bossing 2 P r o m i n e n t2 2 Prominentt glabella Glabellaa bone defect Sloping g Ridged d Broad/widee 1 Short t 1.6 6 Ü Ü 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3.1 1 0 0 0 0 6.3 3 4.77 c.v. / 1.6 0 0 6.3 3 Oc.v.. / 6 . 3 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10.9 9 9.44 c.v. / 1.6 0 0 0 0 0 0 0 0 4.7 7 3.1 1 m.a. . n.a. . m.a. . 1.6 6 1.6 6 4.9 9 c.v v c.v v c.v v 2.5 5 0 0 0 0 0 0 0 0 Ü Ü 0.8 8 0 0 0 0 4.1 1 0 0 0 0 5.7 7 . / 4 . 1 1 1.6 6 4.1 1 .12.5 .12.5 4.9 9 0 0 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7.4 4 m.a. . m.a. . .. / 2.5 m.a. 0 0 0 0 0 0 0 0 3.3 3 3.3 3 2.2 2 6.5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8.7 7 0 0 0 0 8.7 7 c.v.. / 6.5 m.a. 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 8.7 7 c.v.. / 2.2 m.a. 0 0 0 0 0 0 0 0 8.7 7 4.3 3 1.2 2 0 0 0 0 0.3 3 0 0 0.1 1 0.1 1 0.8 8 0 0 1.5 5 0.5 5 0.8 8 2.3 3 0.3 3 2.8 8 0.9 9 0.1 1 1.0 0 0 0 0 0 0 0 0 0 0 0 0.6 6 0 0 0 0 3.2 2 0 0 0 0 0 0 0 0 0 0 0.6 6 3.11 c v . / 0 m.a. 2.5 c.v. / 0.8 m.a. 4.3 c.v. / 0 m.a.
10.99 13.1 4.3 2.4 9.44 c.v. / 1.6 m.a. 9.8 c.v. / 3.3 m.a. 2.2 c.v. / 2.2 m.a.
00 0 0 0 00 0 0 0 00 0.8 0 0.5 00 0 0 0 1.66 0.8 0 1.6 Oc.v.. / 1.6 m.a. 0.8 c.v. / 0 m.a.
Bipanetall n a r r o w i n g
Hyperplasticc supraorbital ridges Hypoplasticc supraorbital ridges
Eyes s Cyclopia a A s v m m e t r v v Strabismus s N y s t a g m u s s D u a n ee (retraction) anomaly Deeply-set t Proptosis s M i c r o p h t h a l m o s s B u p h t h a l m o s s Cryy p t o p h t halmos Orbitall cysts Hypotelorism m Hypertelorism m Iris s Aniridia a Hypoplasia a Atrophia/dysplasia a C o l o b o m a a Brushfieldd spots H e t e r o c h r o m i a a H y p o p i g m e n t a t i o n n Iriss stellata Iriss bicoloris P u p i l s s Ectopic c A b n o r m a ll size or movement A s y m m e t r y y Persistentt pupillary m e m b r a n e Lens s Ectopiaa lentis Size/shapee abnormality C a t a r a c t t C o r n e a a M i c r o c o r n e a a M a c r o c o r n e aa * Cloudy y Anesthesia a C o n j u n c t i v a a Noduli i Teleangiectasia a Epibulbarr dermoids Sclerae e Bluee colored Nevuss of Ota Eyelids s Ptosis s 0 0 t) ) 0 0 0 0 3.1 1 1.6 6 0 0 0 0 1.6 6 3.1 1 0 0 {) ) 0 0 0 0 1.6 6 0 0 0 0 I) ) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 I) ) 0 0 0 0 0 0 0 0 3.1 1 3.3 3 1.6 6 0 0 0 0 4.1 1 0 0 0 0 0 0 0.8 8 2.5 5 0 0 0 0 Ü Ü 0 0 4.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6.6 6 2.2 2 2.2 2 0 0 0 0 6.5 5 2.2 2 0 0 0 0 4.3 3 2.2 2 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 Ü Ü 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Ü Ü 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.2 2 0 0 0 0 0 0 0.3 3 0.1 1 0 0 0 0 4.5 5 0.9 9 0.2 2 0 0 0 0 0 0 1.8 8 2.1 1 0 0 0 0 0 0 0.5 5 0.1 1 0 0 0 0 0.2 2 0.5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6.5 5 4.2 2
C o l o b o m a a Ectropion n Entropion n Synechiae e Edema a Fullnesss 1 Fulll lateral p a r t s 2 Palpebrall fissures Blepharophimosis s Palpebrall fissures short Wide e A s y m m e t r y y Mongoloidd slant Antimongoloidd slant A l m o n dd shaped Boww shaped Periorbitall skin Epicanthii 2 Telecanthi i Blepharochalasis s Peri-oribitall skin tag Infra-orbitall skin folds Peri-orbitall fullness Eyelashes s Absent t Sparselyy implanted P r o m i n e n t t Double e C o l o b o m a a Two-colored d Eyebrows s Absent t Hypoplasia a Sparsee implantation Double e Synophryss ' Mediall Flare Laterall Flare
Mediall and lateral flare N a r r o ww laterally Arched d
C o n t i n u i n gg far laterally Fullness s
Lacrimall g l a n d s
Decreasedd tear production
Lacrimall d u c t s Absent t 0 0 4.7 7 0 0 0 0 0 0 3.1 1 Ü Ü 22 2 0 0 0 0 0 0 4.3 3 0 0 0 0 0 0 0 0 0 0 0.3 3
1.66 c.v. / 1.6 m.a. 0.8 c.v, / 1.6 m.a. 2.2 c.v. / 2.2 m.a. 10.99 7.4 4.3 00 c.v. ./ 10.9 m.a. 0 c.v. / 7.4 m.a. 0 c.v. / 4.3 m.a.
1.6 6 1.6 6 1.6 6 {) ) 1.6 6 3.1 1 0 0 1.6 6 77 8 88 c.v. / 0 m.a. 1.6 6 0 0 0 0 1.6 6 0 0 0 0 1.6 6 4.7 7 0 0 0 0 0 0 0 0 0 0 4.7 7 0 0 6.3 3 3.1 1 0 0 0 0 0 0 0 0 3.1 1 4.7 7 0 0 0.8 8 2.5 5 0 0 8.2 2 0.8 8 0 0 0 0 8.2 2 7.44 c.v. / 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0.8 8 1.6 6 0 0 0 0 0 0 0 0 0 0 2.5 5 0 0 1.6 6 3.3 3 2.5 5 0 0 0 0 0 0 1.6 6 4.1 1 19.6 6 0.8 8 0 0 0 0 2.2 2 0 0 10.9 9 2.2 2 0 0 0 0 0.6 6 0.3 3 0 0 0.1 1 4.3 3 0.9 9 1.6 6 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.3 3 2.2 2 0 0 0 0 0 0 2.2 2 2.2 2 0.5 5 0.1 1 0.1 1 0 0 1.8 8 0 0 0.1 1 15.8 8 0 0 0 0 0.1 1 0 0 0 0 1.6 6 0.4 4 1.4 4 0 0 1.1 1 0.1 1 0 0 0,6 6 1 1 1.2 2
Extra a A b n o r m a ll position N o s ee general Absent t C h o a n a ll atresia/stenosis Cleft t Large e Flat t Small/short t Long g Broad d Pinched d Loww h a n g i n g columella Profilee convex Profilee concave Tipp deviated S e p t u mm deviated Hairyy polyp Generall ridge p r o m i n e n t Generall ridge broad
N o s ee alae Hypoplasia a C o l o b o m a a N o s ee nares Broad d Single e Flare e Anteversionn * A s y m m e t r y y S u p e r n u m e r a r y y N a r r o w / t h i n n N o s ee bridge Flatt 4 P r o m i n e n t / h i g hh ~' W i d e e Thin n N o s ee tip Bifid d Broad d Flat t Bulbous s O v e r h a n g i n g g N o s ee s e p t u m Absentt cartilage Short t Broad d N a r r o w w N o s ee b a s e 0 0 0 0 0 0 0 0 0 0 3.1 1 0 0 7.8 8 0 0 0 0 1.6 6 10.9 9 0 0 0 0 0 0 4.7 7 0 0 0 0 0 0 0 0 6.3 3 3.1 1 0 0 1.6 6 9.4 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.7 7 0 0 1.6 6 1.6 6 15.6 6 1.6 6 0.8 8 0 0 3.3 3 0 0 0 0 0 0 2.5 5 4.9 9 0 0 0 0 0.8 8 8.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 4.3 3 10.9 9 2.2 2 0 0 0 0 6.5 5 0 0 0 0 0 0 4.3 3 2.2 2 2.2 2 0 0 2.2 2 11.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.5 5 0.3 3 9.2 2 0.1 1 1.0 0 1.4 4 4.8 8 2.3 3 2.9 9 0.5 5 0.7 7 0 0 0 0 0 0 0.6 6 1.2 2 0.3 3 0 0 0 0 4.0 0 0.2 2 0 0 0.5 5 0 0 3.3 3 2.55 c.v. / 0.8 m.a 17.2 2 14.11 c.v. / 3.1 m.a. : 1.6 6 1.6 6 0 0 9.4 4 0 0 3.1 1 0 0 0 0 0 0 0 0 0 0 7.4 4 '.. / 0 m.a. 6.6 6 0.8 8 3.3 3 9.8 8 0 0 1.6 6 0 0 0 0 0 0 0 0 0 0 10.9 9 10.9 9 c.v.. / 0 m.a. 6.5 5 0 0 2.2 2 13.0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 11.9 9 3.1 1 3.7 7 0.3 3 2.6 6 0.1 1 2.5 5 1.7 7 0 0 0.2 2 0.9 9 3.6 6
Broad d Narrow w Upperr jaw Cleft t Hypoplastic c Prominent t Narrow w Asymmetry y Absentt premaxilla Prominentt premaxilla Lowerr jaw Absent t Cleft t Asymmetry y Prominent t Retro/micrognathia a Chin n Dimpled/grooved d Pointed d Voice e Aphonia a Nasal l Dysarthria a Hoarse e Cat'ss cry/high-pitched Low-pitched d Philtrum m Long g Short t Smooth h Prominent/deep p Orall region
Extraa oral frenulae Synechiae e
Prominentt nasolabial folds Orall pigmentation Peri-orall pigmentation Mouth h Microstomia a Macrostomia a Asymmetry y
Openn mouth appearance Pouting g Upturnedd corners Downturnedd corners Upperr lip Cleftt midline Cleftt non-midline Thin n Fullness s 3.1 1 0 0 0 0 0 0 3.1 1 0 0 0 0 0 0 4.7 7 0 0 0 0 1.6 6 6.3 3 1.6 6 4.7 7 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 15.6 6 6.3 3 14.1 1 9.4 4 0 0 0 0 0 0 0 0 0 0 4.7 7 4.7 7 0 0 1.6 6 0 0 0 0 0 0 0 0 1.6 6 10.9 9 6.3 3 5.7 7 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 3.3 3 0 0 0 0 0 0 5.7 7 4.1 1 0.8 8 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 14.8 8 9.0 0 12.3 3 7.4 4 0 0 0 0 0 0 0 0 0 0 0.8 8 1.6 6 0 0 0.8 8 0 0 0 0 0 0 0 0 0 0 5.7 7 5.7 7 8.7 7 0 0 0 0 0 0 4.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.3 3 2.2 2 2.2 2 2.2 2 0 0 0 0 2.2 2 0 0 0 0 0 0 15.2 2 6.5 5 10.9 9 13 3 0 0 0 0 0 0 0 0 0 0 0 0 6.5 5 4.3 3 2.2 2 0 0 0 0 0 0 0 0 0 0 8.7 7 6.5 5 5.4 4 0.3 3 0 0 0.2 2 2.0 0 0.3 3 0 0 0 0 1.1 1 0 0 0.1 1 0 0 0.3 3 1.6 6 2.8 8 0.6 6 0 0 0.2 2 0.2 2 0 0 0 0 0 0 3.0 0 2.8 8 5.0 0 1.8 8 0 0 0 0 0 0 0 0 0 0 1.0 0 0.3 3 0.1 1 0 0 0.1 1 0 0 0.1 1 0 0 0 0 8.4 4 5.4 4
Tight t Everted d Pit(s) ) Cupidd bow Lowerr lip Cleft t Pit(s) ) Fullness s Thin n Tight t Everted/droopingg 4 Gums s
Fusionn and/or jaw Hypertrophy y Palate e Cleft t High/narrow w Short t Wide e Fistula a Cleftt uvula Absentt uvula Hypoplasticc uvula Longg uvula
Prominentt lateral ridg
Alveolarr ridges Thick k Cleft t Tongue e Aplasia a Hypoplasia a Cleft t Large e Lobulated d Smooth h Prominentt groove(s) Ankyloglossia a Glossoptosis s Protruding g Fasciculations s Geographic c Teethh 6 Macrodontia a Microdontia a Supernumeraryy teeth Oligodontia a Singlee central incisor Advancedd eruption Delayedd eruption
Neonatal l P r e m a t u r ee loss Dentall crowding Malocclusion n Widelyy spaced Abnormallyy shaped A s y m m e t r y y Fusionn incisors D i a s t h e m a a Dentinn a n o m a l i e s Enamell anomalies Ear r Agenesis s Small l Aplasia a Large e A s y m m e t r y y Long g Flat t
Roundd (incr AP) N a r r o ww (deer AP) Dysplastic c Simple e C u p s h a p e d d Lopp ear C r u m p l e d d Low-set t Posteriorlyy rotated P r o m i n e n t t Cysticc p i n n a Calcificationn cartilage Helices s H y p o p l a s t i c / t h i n n A b n o r m a l l yy modeled Overfolded d N oo fold N o t c h e d d
Horizontall upper ridg D a r w i n ss l u m p Pits s Earr l o b u l e s Hypoplastic/absent t Large e A t t a c h e d d Uplift t Crease e Cleft t Earr t r a g u s Absent t Hypoplastic c
Earr m e a t u s Absent t Atresia a N a r r o w w Earr pits Unilateral l Bilateral l Earr tags Unilateral l Bilateral l N e c k k Branchiall cyst/cleft/sinus Webbing g Cysticc hygroma Long g Short t T h i c k / b r o a d d Torticollis s Loosee skinfolds Thorax x Broad d N a r r o w w Increasedd AP d i a m e t e r A s y m m e t r y y Short t Long g Flat t Flaring g X i p h i s t e r n u m m Pectuss c a r i n a t u m P e c t u ss excavatum Shortt s t e r n u m S t e r n u mm a s y m m e t r y M a m m a e e Absent t Hypoplasia a H y p e r t r o p h y y A s y m m e t r y y G y n e c o m a s t i a a P s e u d o - g y n e c o m a s t i a a P r e m a t u r ee development N i p p l e s s Absent t Hypoplasia a Large e A s y m m e t r y y S u p e r n u m a r y y Wide-spaced d Inverted d S h o u l d e r s s 0 0 0 0 0 0 1.6 6 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 0.8 8 2.5 5 0 0 0 0 0 0 0 0 0 0 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 1.2 2 0 0 0.2 2 0.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.2 2 0.2 2 0.9 9 0 0 0 0 0 0 0 0 0 0 0.3 3 2.1 1 0 0 0 0 0 0 0 0 0 0 0 0 0.1 1 0.1 1 0 0 0 0 0 0 0 0 0.1 1 3.0 0 0.4 4 4.0 0
Broad d Narrow w Sloping g Anteriorlyy rotated Clavicles s Absent Absent Hypoplastic c Long g Horizontal l Scapulae e Absent t Small l High/sprengel l Winged d Pectorall muscle Absent t Hypoplasia a Ribs s Absent t Prominentt bows Abdomen n Diastasiss recti Musclee aplasia Musclee hypoplasia Protuberant t
Abnormall umbilicus position Herniaa umbilicalis
Omphalocele e Herniaa inguinalis
Back k
Decreasedd lumbar lordosis Decreasedd thoracic kyphosis Increasedd lumbar lordosis Increasedd thoracic kyphosis Scoliosis s Rigidd spine Buffaloo hump Spinall cord Spinaa bifida Meningocele/ / myelomeningocele e Syringomyelia a Pilonidall cyst/sinus/dimple Tetheredd cord Sacrum m Dimple/sinus s Caudall appendage Asymmetricc crease Fatt pads Upperr limbs
Absent t Proportionallyy short Rhizomelia a Mesomelia a Acromelia a Overgroww th Hemm i hyper trophia
Reductionn deformity (some digits) Reductionn detormitv (no digits) Constrictionn rings A s y m m e t r y y H u m e r u s s Absent t Bowed d Elbow w Valgus s \XX ebbing Acromiall dimple Forearm m Absent t Bowed d Madelungg deformity H a n d s s Absent t Smalll (malproportionate) Largee (malproportionate) N a r r o w w Broad d A s y m m e t r y y Ectrodactyly y Syndactyly y T'ndentt hands Clubb h a n d s Clenchedd hands H a n d ss deviation (ulnar/radial) H a n d ss long h a n d p a l m H a n d ss thenar hypoplasia H a n d ss h y p o t h e n a r hypoplasia H a n d ss edema d o r s u m hands H a n d ss isolated metacarpal s h o r t e n i n g P a l m a rr crease Sydneyy crease Simiann crease Bridgingg crease Absentt creases
Decreasedd flexion creases Deepp flexion creases
Fingers s Absent/oligodactyly y Hypoplastic c 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.7 7 l.fi i 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0 0 0 0 n.K K 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.6 6 0.2 2 0 0 0.1 1 0.6 6 0 0 0 0 0 0 0 0 0.4 4 0 0 0 0 0 0 0.1 1 0.3 3 2.1 1 2.7 7 0 0 0 0 0.2 2 0 0 0 0
Polydactylyy (pro-axial) Polydactylyy (post-axial) Polydactylyy (meso-axial) M i r r o rr image Polydactyly L o n g g Arachnodactyly y Short t Brachydactyly y Macrodactyly y Broad d C a m p t o d a c t y l y y Clinodactyly y
Ulnarr deviation dig II-II1 Ulnarr deviation dig V Radiall deviation dig IV-Y Overlapping g Syniphalangisni i Syndactyly y T a p e r i n g g Clubbing g Widee tips Fetall pads Shortt end-phalanges Absentt phalanges C o n s t r i c t i o nn rings T h u m b s s Absent t Hypoplasia a A s y m m e t r y y Broad d Addutt ted Proximall placement H i t c h - h i k e r s s Triphalangeal l Shortt end-phalanges Pelvis s Broad d X'arrrow w 11 lip dislocation Lowerr l i m b s Absent t Proportionallyy short KhizomcTia a Mesomelia a Acc romclia Sirenomelia a Duplication n A s y m m e t r y y ( ) v e r g r o w t h h H e m i h y p e r t r o p h y y 0 0 0 0 Ü Ü Ü Ü 1.6 6 0 0 0 0 0 0 (1 1 0 0 1.6 6 3.1 1 4.7 7 0 0 0 0 0 0 0 0 6.3 3 0 0 U U 0 0 32.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (I I (I I 0 0 4.7 7 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0 0 Ü Ü 0 0 0 0 0 0 Ü Ü 9.8 8 3.3 3 0 0 0 0 0 0 Ü Ü 2.3 3 0.8 8 o o 0.8 8 36.9 9 0 0 0 0 0 0 Ü Ü 0 0 0 0 (.) ) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (J J (J J 3.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.3 3 0 0 2.2 2 0 0 0 0 0 0 6.5 5 0 0 n n 0 0 34.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (J J t) ) 0 0 6.5 5 0 0 0 0 0.1 1 0 0 0 0 0 0 1.5 5 0 0 0.3 3 0.1 1 0 0 0.1 1 0.1 1 3.5 5 0.6 6 0 0 0.4 4 0 0 0 0 1.3 3 0.4 4 0 0 0.6 6 41.1 1 0.2 2 0 0 0 0 0 0 0.1 1 0 0 0.8 8 0 0 0.1 1 0 0 0 0 0 0 0 0 0 0 0 0 (J J 0 0 0 0 0 0 0 0 0 0 0 0 0.2 2 0 0 (J J
Reductionn deformity (no digits) Reductionn deformity (some digits) C o n s t r i c t i o nn rings F e m u r r Absent t Bowed d Patella a Absent t Hypoplastic c K n e e e V a r u m m Valgum m W e b b i n g g Tibia a Absent t Bowed d Feet t Absent t Malproportionallyy small Malproportionallyy large Short t Long g N a r r o w w Broad d A s y m m e t r y y Pess planus A Pess cavus Talipess equinovares Ectrodactyly y P r o m i n e n tt heel Rockerbottom m Deepp plantar creases Fetall pads Edemaa d o r s u m Isolatedd m e t a c a r p a l s h o r t e n i n g Toes s Absent t Hypoplastic c Pre-axiall Polydactyly Meso-axiall Polydactyly Post-axiall polydacryly M i r r o r - i m a g ee Polydactyly Long g Short t Broad d
Shortt terminal phalanges Syndactylyy 11 III Partiall syndactyly 11 111 Syndactylyy (not 11 II I) Partiall syndactyly (not II-III)
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 0 0 6.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Ü Ü 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0.8 8 3.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0 0 0 0 0 0 0 0 0.8 8 0 0 0.8 8 0.8 8 0 0 0 0 0 0 7.4 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 2.2 2 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.7 7 0.7 7 0 0 0 0 0 0 0 0 0 0 0 0 0.3 3 0.7 7 0.3 3 0.3 3 0 0 2.7 7 0.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.2 2 0.7 7 0 0 0.4 4 0.3 3 0 0 0 0
lj l- ' , , Symphalangism m Widelyy spaced A Sandall gap A Overriding g Clinodactylyy dig V H a m m e r t o e s s Toess 2nd longer t h a n 1st Fetall pads Clinodactylyy other t h a n V Halluces s Absent t Hypoplasia a Short t Long g A s y m m e t r y y Broad d Narrow w Varus s Valguss A Proximall implantation Dorsii flexed/ham mertoes
Joints s C o n t r a c t u r e e C o n t r a c t u r e s s Dislocation n Dislocations s Enlargement t
Hypomobilityy small joints Hypomobilityy large joints
Hypomobilityy small and large joints Hypermobilityy small joints Hypermobilityy large joints
Hypermobilityy small a n d large joints
M u s c l e s s Isolatedd agenesis Hypoplasia a Atrophy/dystrophy y Hypertrophy y Hypotonia a Hypertonia a Weakness s Fasciculations s Myotonia a N e u r o l o g y y Hemiplegia/paresis s Diplegia/paresis s Tetraplegia/paresis s Spasticity y Carniall nerve palsy Developmentall delay 0 0 1.6 6 20.3 3 1.6 6 3.1 1 4.7 7 4.7 7 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.7 7
o o
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9.4 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 21.3 3 4.1 1 1.6 6 3.3 3 2.5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 2.5 5 0 0 0 0 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.1 1 0.8 8 3.3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6.5 5 10.9 9 4.3 3 2.2 2 4.3 3 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (J J 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.4 4 26.7 7 0.3 3 4.5 5 0.2 2 3.1 1 0 0 2.4 4 0 0 0 0 0.2 2 0.1 1 0 0 0.9 9 0 0 0 0 2.5 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.2 2 0 0 0.2 2 5.6 6 3.8 8 1.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0S k i nn general Atrophy/dystrophyy 0 T h i n / t r a n s l u c e n tt 0 Thick/broadd 0 Hyperkeratosiss 0 Ichtyosiss 0 Dryy 0 Cutiss laxa 0 Hyperelasticityy 0 Excessivee skin folds 0 Sloww healing 0 A b n o r m a ll scarring 0 Photosensitvityy 0 Lipodystrophyy 0 Cutiss m a r m o r a t a & 0 Poikilodermaa 0 Lymphedemaa 0 Calcificationn 0 Dimpless 0 Eczemaa 0 Skinn l o c a l i z e d Hypoplasia/aplasiaa 0 Atrophyy 0 Striaee 0 Bullaee 0 Sclerodermaa 0 Fibromataa 0 Lipomataa 0 X a n t h o m a t aa 0 Scalpp defects 0 Skinn p i g m e n t a t i o n Albinismm 0 Generalizedd hypopigmentation 0 Generalizedd hyperpigmentation 0 Patchyy hypopigmentation 1.6 Patchyy hyperpigmentation 0 CALL solitary ¥ 6.3 CALL m u l t i p l e5 3.1 Solitaryy nevus 3.1 Multiplee nevi 1.6 Linearr sebaceus nevus 0 Axillaryy freckling 0 A c a n t h o s i ss nigricans 0 Skinn vascular Capillaryy h e m a n g i o m a 3.1 Port-winee stain 1.6 Teleangiectasiaa 0 Storkk bite 2 0 Angel'ss k i s s2 0 0
Arteriall malformation Venouss malformation (promm vessels)
Lymphaticc malformation Arterioo venous malformation Mixedd malformation Prominentt vessels Multiplee hematomata
Skinn body hair
Generalized d Localized d Nails s Absent t Hypoplasia a Short t Narrow w Concave e Hyperconvex x Thin/brittle e Thick k Pits s Striped d Bifid/double e Fused d Abnormall color 0 0 0 0 0 0 0 0 0 0 1.6 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.8 8 0.8 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2.3 3 0.3 3 0 0 0.2 2 0.8 8 0.1 1 0.9 9 0 0 0.3 3 0 0 0 0 0.2 2 0 0 0 0 0 0 c.v.. = common variant m.a.. = minor anomaly
11
Item considered a common variant at the age of 20 years and a minor anomaly at the age of 1 and 10 years
22
Item considered common variant at the age of 1 year and minor anomaly at the age of 10 and 20 years
33 Item considered a minor anomaly at the age of 1 and 10 years but at 20 years only when very extreme. 44
Item considered minor anomaly at the age of 10 and 20 years, but at 1 year only when very extreme
:
'' Item considered common variant at all ages but a minor anomaly when very extreme at the age of 1 year
66 Scoring of teeth phenotype is dependent on the stage of teeth eruption. Therefore, percentages are calculated
onlyy for the population of 10 and 20 year olds.
** Item is considered to be so common at the age of 1 year that it will not be scored unless very extreme. ** Item is common variant at all ages but will be somewhat more frequently seen at the age of 1 year
AA
Item will be less visible in 1 year olds when they do not walk yet
ss Item will be less visible in 1 year olds
Tablee VA. Most frequently found common variants and minor anomalies in CH-T thyroid agenesis and the
significancee of the difference as compared to the control group
LowLow anterior hairline EyelidEyelid ectropion
ForeheadForehead metopic ridge EyelidEyelid full lateral parts LowerLower jaw prominent ToesToes partial syndactyly ll-lll PhiltrumPhiltrum long
Hammertoes Hammertoes HighHigh anterior hairline LowerLower limbs asymmetry PhiltrumPhiltrum prominent/deep Macrostomia Macrostomia
PhiltrumPhiltrum smooth NoseNose tip broad
FingersFingers ulnar deviation dig ll-lll FingersFingers syndactyly
NoseNose septum deviated EyebrowsEyebrows synophrys
Feett pes planus Microstomia a
Nosee low hanging columella Helicess overfolded
Upperr jaw prominent premaxilla Nosee nares anteversion
Eyebrowss fullness
Eyebrowss sparse implantation Facee round-shaped
Philtrumm short
Palmarr crease simian crease Hallucess valgus
Fingerss fetal pads
Hypermobilityy small joints Toess sandal gap
Chinn dimpled/grooved Toess 2nd longer than 1st Upperr lip thin
Nosee bridge p r o m i n e n t / h i g h Upperr lip cupid bow
D.A.. = Discrimination analysis
CH-T T thyroid d agenesis s 12.5 5 4.7 7 4.7 7 10.9 9 6.3 3 6.3 3 15.6 6 4.7 7 10.9 9 4.7 7 9.4 4 4.7 7 14.1 1 9.4 4 4.7 7 6.3 3 4.7 7 6.3 3 7.8 8 4.7 7 10.9 9 9.4 4 4.7 7 9.4 4 4.7 7 4.7 7 6.3 3 6.3 3 4.7 7 4.7 7 32.8 8 9.4 4 20.3 3 4.7 7 4.7 7 10.9 9 14.1 1 4.7 7 Controls s 0.4 4 0.0 0 0.0 0 0.8 8 0.3 3 0.3 3 3.0 0 0.2 2 2.5 5 0.2 2 1.8 8 0.3 3 5.0 0 2.6 6 0.6 6 1.3 3 0.7 7 1.4 4 2.7 7 1.0 0 4.8 8 3.8 8 1.1 1 4.0 0 1.2 2 1.6 6 2.8 8 2.8 8 2.1 1 2.5 5 41.1 1 5.6 6 26.7 7 2.8 8 3.1 1 8.4 4 11.9 9 3.8 8
Thee items with a FDR-corrected p-value <0.05 are indicated in italics discriminatingg items (indicated by +) foi jndd by multh ariatee analysis
p-value e p-value e
Fisher'ss exact FDR-corrected test t <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 0.002 2 0.002 2 0.002 2 0.002 2 0.004 4 0.006 6 0.010 0 0.013 3 0.015 5 0.018 8 0.019 9 0.037 7 0.038 8 0.040 0 0.042 2 0.046 6 0.051 1 0.055 5 0.099 9 0.118 8 0.118 8 0.169 9 0.232 2 0.237 7 0.260 0 0.307 7 0.425 5 0.451 1 0.488 8 0.556 6 0.731 1
Thee last column alll p-values were
<0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 0.0069 9 0.0069 9 0.0069 9 0.0069 9 0.0127 7 0.0175 5 0.0271 1 0.0329 9 0.0356 6 0.0401 1 0.0401 1 0.0722 2 0.0722 2 0.0724 4 0.0725 5 0.0760 0 0.0808 8 0.0836 6 0.1447 7 0.1601 1 0.1601 1 0.2214 4 0.2905 5 0.2905 5 0.3088 8 0.3535 5 0.4750 0 0.4897 7 0.5151 1 0.5710 0 0.7310 0 D . A . . + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
showss the group of 16 most <0.01). .
Tablee VB. Most frequently found common variants and minor anomalies in CH-dystopic thyroid and the
significancee of the difference as compared to the control group
HelicesHelices over folded
ToesToes partial syndactyly II-II1 PhiltrumPhiltrum long
LowerLower jaw prominent EyelidEyelid full lateral parts NoseNose low hanging columella NoseNose tip broad
EyesEyes asymmetry LowLow anterior hairline
PhiltrumPhiltrum prominent/deep HighHigh anterior hairline GeneralizedGeneralized obesity PhiltrumPhiltrum short FaceFace square shaped LingersLingers clinodactyly PhiltrumPhiltrum smooth EarEar posteriorly rotated LowerLower Up fullness
Eyebrowss fullness Cow'ss lick Facee asymmetry Nosee nares anteversion Nosee bridge wide Retro/micrognathia a
Palpebrall fiss. mongoloid slant CALL solitary
Hypotelorism m Facee narrow/elongated Palatee long uvula Toess sandal gap Fingerss fetal pads Upperr lip cupid bow Earr small CH-T T dystopic c thyroid d 19.7 7 7.4 4 14.8 8 5.7 7 7.4 4 15.6 6 9.8 8 4.1 1 4.1 1 7.4 4 9.0 0 7.4 4 9.0 0 4.9 9 9.8 8 12.3 3 4.9 9 8.2 2 4.1 1 8.2 2 4.1 1 8.2 2 6.6 6 4.1 1 8.2 2 8.2 2 4.1 1 4.1 1 4.1 1 21.3 3 36.9 9 4.1 1 4.9 9 Controls s 3.8 8 0.3 3 3.0 0 0.3 3 0.8 8 4.8 8 2.6 6 0.3 3 0.4 4 1.8 8 2.5 5 2.0 0 2.8 8 0.9 9 3.5 5 5.0 0 1.4 4 16.1 1 1.2 2 14.9 9 1.5 5 4.0 0 3.1 1 1.6 6 4.3 3 14.1 1 1.8 8 2.3 3 2.3 3 26.7 7 41.1 1 3.8 8 5.3 3 p-valuee Fisher's exactt test <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 <0.001 1 0.001 1 0.001 1 0.001 1 0.001 1 0.002 2 0.002 2 0.003 3 0.003 3 0.003 3 0.015 5 0.023 3 0.029 9 0.053 3 0.056 6 0.057 7 0.061 1 0.067 7 0.067 7 0.090 0 0.093 3 0.216 6 0.216 6 0.230 0 0.382 2 0.802 2 1.000 0 p-value e FDR-corrected d <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 <0.0001 1 0.0001 1 0.0030 0 0.0030 0 0.0030 0 0.0030 0 0.0051 1 0.0051 1 0.0062 2 0.0062 2 0.0062 2 0.0291 1 0.0422 2 0.0504 4 0.0855 5 0.0855 5 0.0855 5 0.0875 5 0.0884 4 0.0884 4 0.1096 6 0.1096 6 0.2458 8 0.2458 8 0.2530 0 0.4066 6 0.8271 1 1.0000 0 D.A. . + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
D.A.. = Discriminationn analysis Thee items with a FDR-corrected p-val discriminatingg items (indicated by +)
uee <().05 are indicated in italics. The last column shows the group of 1 / most foundd by multivariate analysis (all p-values were <0,01),
