What Percentage of Families Do Abortion Because of Duane Syndrome

Trans Am Ophthalmol Soc. 2008 Dec; 106: 100–116.

Built Aberrant Tearing: A Re-Expect

Abstract

Purpose

Congenital aberrant tearing is characterized by tearing when eating ("crocodile tears"), lack of emotional tearing, or both. Near reported cases are associated with Duane syndrome. In our previous studies we observed aberrant trigger-happy in individuals with thalidomide embryopathy and Möbius sequence. This report summarizes the literature on the bailiwick and adds three new studies that give information on this unusual condition.

Methods

Xx-8 individuals with Möbius sequence were interviewed about tearing symptoms at a support grouping coming together in Italy. In Sweden 30 adults primarily from the original thalidomide series were reexamined. In this latter study, a Schirmer test was done at baseline and repeated 5 minutes later on eating. Twenty families in Brazil who have children with Möbius sequence were questioned most trigger-happy symptoms and exposure to misoprostol during pregnancy.

Results

In the 28 Italian individuals, either "crocodile tears" or lack of emotional tearing was noted in 7 cases. In the thalidomide study, 10 of thirty patients had tearing when eating and 7 had no emotional tearing. Low Schirmer scores or increased violent after eating was noted in a few asymptomatic individuals. Amongst the 20 Brazilian children with Möbius sequence, 10 had some tearing aberration.

Conclusion

Congenital anomalous lacrimation is rare simply usually associated with Duane syndrome or abduction deficits, as in Möbius sequence and, less often, facial nerve palsy. Studies implicate an early insult in evolution at iv to half dozen weeks. At that time the facial nervus, sixth nerve, and lacrimal nucleus are in close proximity in the embryo.

INTRODUCTION

Congenital abnormal (anomalous) tearing describes unexpected amending in lacrimation, such as trigger-happy when eating, absenteeism of emotional (psychic) lacrimation, or an unusual late onset in tearing. When this inappropriate trigger-happy is associated with eating or sucking, it is oftentimes referred to as paradoxical gustolacrimal tearing or crocodile tears, so named past Bogorad,^one who said "crocodiles cried when eating their casualty." However, the term crocodile tears likewise refers to feigned or misleading hypocritical tearing.^{2 , 3} Murubeⁱⁱ reviewed a large body of historical literature on the use of the term and points out that although crocodiles take lacrimal glands, the secretion seems more directed to glands of eating than to ocular structures, so the implication may be inappropriate. Darwin^iv believed that very few animals shed tears, with the possible exception of the India elephant and, questionably, some monkeys.

The condition of crocodile tears most often occurs as a complexity of acquired facial nerve palsy.^{ii , 3 , v} This report confines the word primarily to congenital forms, since the explanations of the neurologic implications are probably different.

Although the number of patients with both Duane syndrome and aberrant tearing is rare, the corollary of the association of anomalous violent with Duane syndrome is exceedingly potent, even when this combination is not role of a specific syndrome or caused by a known teratogen (Table one, Figure 1).^{6 – xxx} Some other type of anomaly of lacrimation is the congenital lack of emotional vehement in the presence of a normal cornea on exam. This finding is also often associated with crocodile tears and Duane syndrome. Congenital facial nervus palsy is reported with both aberrant neurologic conditions, but the linkage is non as strong. These combinations of malformations occur very rarely except in a few conditions: thalidomide embryopathy^{31 – 41} (Table 2), Möbius syndrome,^{42 – 45} and, to a lesser extent, Wildervanck syndrome^{46 – 48} (Table 3). At that place are a few isolated unusual associations^{49 – 51} (Table 3).

Summary timetable of thalidomide embryopathy. Timetable is based on observations in the literature. Sensitive period in pregnancy is twenty to 36 days after fertilization. If calculated from the final menstrual period, it would exist approximately days 34 to 50 (Kida,⁵⁵ Lenz⁵⁶).

TABLE 1

CONGENITAL ABERRANT Vehement REPORTED WITH DUANE SYNDROME BUT NO OTHER SYNDROME

SOURCE	Series TYPE	NO. OF CASES WITH Aberrant TEARING	Historic period (Year)/Sexual activity	Movement	CROCODILE TEARS	EMOTIONAL TEARING	seventh NERVE PALSY	COMMENTS
Agarwal6	Aberrant trigger-happy	ane	15/M	DS OU	OU	NI	0	Tearing with nearly sour foods, not sweet taste
Antonelli7	Aberrant tearing	1	NI	NI	OD	Absent	NI
Biedner and associates8	Abnormal tearing	1	6/M	DS OU	OU	NI	0	Mastication movements alone did non crusade vehement
Cricchi9	Aberrant tearing	1	16/NI	DS OU	OU	Absent-minded	0
D'Ermo10	Abnormal tearing	two	NI	DS OU	OU	Absent-minded	0	Facial asymmetry; oxycephaly
								Facial asymmetry
			NI	DS OD	OD	Absent	0
Ehlersxi	Aberrant violent	1	five/F	Abduction deficit OU	OU (sour)	Absent-minded OU	Weakness	Schirmer exam (mm) vii OD/23 Bone → 19/35 with vinegar; no modify with sweet
Hartwig and Kaufmann12	Abnormal trigger-happy	1	NI	DS OU	OU	NI	NI
Jacklinxiii	Aberrant violent	i	42/NI	Normal	Os	NI	50	↓ Hearing; nascence trauma L; Schirmer iii/12 mm; used chewing to treat dry eye OS
Jampel and Titonexiv	Aberrant fierce	1	6/F	DS OD	OD	Normal	R	Normal reaction to ammonia; tearing primarily to sucking and chewing; scoliosis; syndactyly; arachnodactylia; microstomia; leg bibelot
Karsenti and associates15	Aberrant violent	1	4/NI	DS + Brown syndrome	Yes	NI	NI	Internal and external ear
Komoto16	Abnormal violent	2	2/F	Normal	OD	Absent-minded OD	0
			5/M	Normal	OU	Normal	0
Lillie17	Aberrant tearing	1	NI	Lateral rectus palsy	Yeah	NI	NI
Lutman18	Aberrant fierce	2	NI	Limited abduction deficit	Unilateral	NI	NI
			NI	Limited abduction OU	OU	NI	NI
Magni and associatesnineteen	Aberrant tearing	1	5/F	DS OU	OU	NI	NI
Molinari20	Abnormal violent	1	29/1000	DS OD	OD	Absent OD	0
Nair21	Aberrant tearing	ane	30/M	DS OU	OU	NI	0	Fierce with chewing spicy nutrient
Pereira and Arts22	Aberrant violent	i	Infant/Thou	NI	OU	NI	NI
Ramsay and Taylor23	Aberrant tearing	2	3/1000	DS OU	OU	Absent-minded	Bilateral weakness	No lacrimation to irritants but ↑ to chewing; normal corneal sensation; finger bibelot; no stapedial reflex
			three/M	DS OU	OU	Absent	Bilateral weakness	Deaf, external ear; normal corneal sensation; no tearing to irritants
Regenbogen and Stein24	Aberrant tearing	1	7/F	DS Os	Os	Normal	0	Lacrimation with chewing, especially sour but not tasteless substances; ammonia fumes and corneal irritation stimulate vehement; Schirmer scores equal between eyes
Sannohe and associates25	Aberrant tearing	1	13/F	DS OU	OU	NI	0	Sensorineural hearing loss due to failed cochlear evolution
Sarda and associates26	Aberrant fierce	1	xiv/M	Abduction deficit OD	OD	Absent OD	0	Normal cornea response to irritation and ammonia fumes; equal normal Schirmer scores
Tachibana and assembly27	Aberrant violent	1	19/F	DS OU	OU	Absent-minded OU	0	Adopted; internal and external ear; scoliosis; hearing ↓, absence of oval window
Walsh and assembly28	Aberrant tearing	1	1/NI	Abduction deficit	OU	NI	NI
Zhang29	201 cases of DS	26 (12%)	NI*/99 One thousand; 102 F	All DS	26 (13%)	NI	NI	No pregnancy history given
Zhangxxx	Aberrant tearing	25	NI/8 M	15 DS OU	15 cases OU;	NI	NI	DS usually bilateral with bilateral tearing and unilateral DS with unilateral tearing
			NI/17 F	10 monocular	10 monocular

TABLE ii

THALIDOMIDE EMBRYOPATHY ASSOCIATED WITH Congenital ABERRANT TEARING IN SOME OR ALL CASES

SOURCE	Series TYPE	NO. OF CASES WITH Aberrant TEARING	Historic period/Sex	Motility	CROCODILE TEARS	EMOTIONAL TEARING	seventh NERVE PALSY	COMMENTS
Arimoto32	138 cases of thalidomide	23	NI	23 DS	23 cases	NI	xx
Maruo and associates33	266 cases of DS	27	NI/121 Grand; 145 F	23 bilateral DS; 4 unilateral DS	27 cases	NI	NI	18 of 23 cases with history of thalidomide had aberrant tearing
Miller34	86 cases of thalidomide	17	NI/12 One thousand; fifteen F	16 bilateral DS; one abduction ↓	xv cases	Absent-minded 10	12	Hearing 7; autism 2
Trieschmann37	Thalidomide	3	(i) 10 mo	(ane) DS OU	(1) OU	NI	(1) R/L	Schirmer test scores (mm) viii OD/v Os→ eating twenty/16
			(2) 9 year/F	(2) Abduction OU	(two) OU		(ii) R/L
			(3) 11 yr/F	(3) NI	(iii) OD worse than Os		(3) R
								Deaf; fierce ↑ with eating apple
Uemara and associates38	Abnormal tearing	10	3–half-dozen yr/iii F seven M	Bilateral 9; 1 OD	7 cases OU; 3 cases OS	NI	half-dozen	four thalidomide history; three CNS malformations; 1 deaf; Schirmer after eating on 2 cases, both ↑
Takemori and associates39	Thalidomide	xviii	NI/12 M; half dozen F	11 abduction deficits OU; i abduction arrears unilateral	7 cases	NI	3 OU	eleven external ears; absence
							3 unilateral	of stapes; inner ear 15; vestibular hypoplasia 15; 4 limb anomalies; Schirmer 11/8 mm → 34/28 mm after eating sour apple
Zetterstrom41	Thalidomide	iv	NI	three abduction deficit	NI	NI	NI	17 of 38 had abduction deficits; no details on type of vehement symptoms

TABLE 3

OTHER SYNDROMES REPORTED IN CASES OF Congenital Abnormal TEARING (NOT THALIDOMIDE)

SOURCE	SYNDROME	NO. OF CASES WITH ABERRANT Fierce	AGE/Sexual activity	Move	CROCODILE TEARS	EMOTIONAL TEARING	seventh Nerve PALSY	COMMENTS
Amaya and assembly42	18 cases of Möbius sequence	3	(1) iii mo/NI	Abduction deficit OU all*	3	NI	All*	(1) Microglossia
			(2) 6 mo/NI					(2) Cerebellum hypoplasia
			(3) iii½ yr/NI					(3) Foot and tongue; keratitis
Miller and Strömland43	25 cases of Möbius sequence	six–7	ii–7 year/all M	Abduction deficit all*	4 cases(3 with no emotional trigger-happy)	Absent 5* (3 with crocodile)	All*
Brik and Athayde46	Wildervanck	i	13 ½ yr/F	DS OU	OU	NI	0	Klippel-Feil; DS
Haciyakupoglu and associates47	Wildervanck	1	13 year/NI	DS OU	OU	NI	NI	Developmental delay; Dandy-Walker; Klippel-Feil; deaf
Brodsky48	Wildervanck	one	5 mo/NI	DS OU	Os	Absent OU	L	Klippel-Feil; deafened; brain stem hypoplasia; kyphosis hyperreflexia
Guirgis and associates49	Isotretinoin (Accutane)	1	10 mo/NI	Ophthalmoplegia (restrictive)	OU	Absent-minded OU	NI	Mother used isotretinoin early in pregnancy; middle and external ear anomalies; micrognathia; preauricular skin tags
Nigam50	Treacher-Collins	ane	11½ yr/M	Normal	OU	NI	NI	Microtia; deaf
Preisch and associates51	BOR	2	32 yr/G		OD	NI	NI	Schirmer exam negative OD, positive Os; patients are father and daughter
			four year/F		OD	NI	NI	BOR syndrome; hearing

Duane syndrome is a common instance of congenital aberrant innervation in which there is miswiring between the cranial nerves to the extraocular muscles, most commonly a branch of the medial rectus to the lateral rectus muscles. In addition to aberrant lacrimation, there are a few examples of less frequent congenital miswiring atmospheric condition, such equally Marcus Gunn syndrome (occasionally noted with Duane syndrome) and a case of an abnormal innervation of motor co-operative of trigeminal to the medial rectus muscle.^{52 , 53}

This report summarizes the literature on tearing aberrations, including the two Swedish studies previously reported by the authors, which were associated with thalidomide embryopathy and Möbius sequence.^{34 – 36 , 43 – 45} Additionally, the results of a new Swedish thalidomide study are reported, forth with the findings of a questionnaire obtained at an Italian Möbius support grouping, a Brazilian Möbius report, and an informal discussion at the Möbius Foundation meeting, which is a support group for patients with Möbius sequence and their families that is located primarily in the United States.

METHODS AND MATERIALS

The first Swedish thalidomide written report was conducted to focus on the ocular motility findings in patients (age range, 26 to 29 years) with known thalidomide embryopathy. Following a legal trial against the drug company, about 100 children were identified as meeting the criteria for thalidomide embryopathy, and in 1987 to 1989 a total of 86 patients were previously reported by 2 of the authors (One thousand.S., Yard.1000.),^{34 – 36} only the vehement data are reanalyzed for this report. Aberrant tearing, although mentioned in the literature, was a surprisingly frequent finding. Another unexpected finding was autism in 4 of the patients. Both of these functional disturbances were often accompanied by Duane syndrome, facial nerve palsy, and ear and thumb malformations that were the hallmark of the early effect (days 20 to 24 after fertilization) from thalidomide ingestion in pregnancy (Figure two). Considering of the similarity to the feature findings of Möbius sequence, it was decided to do a prospective multidisciplinary study of individuals in whom Möbius sequence had been diagnosed.^{43 , 44} This Swedish study (1995 to 1998) evaluated 25 cases of Möbius sequence, targeting non only the ocular findings but also the associated systemic and functional problems, with special attending to the autism spectrum disorders that had been reported in a few cases of Möbius sequence.

Summary estimates of sensitive periods for ophthalmic malformations. Estimates are based on associated anomalies manifested by well-nigh patients with Duane syndrome, the most frequent incomitant strabismus. These sensitive time blocks for evolution of center anomalies, facial nervus, and autism are estimations, and they may be shorter or slightly longer than indicated (Kida,⁵⁵ Lenz⁵⁶).

Our tearing data, collected during the previous Swedish thalidomide study of 86 patients and from the Swedish Möbius Study, were analyzed more closely and are summarized in Table 4. In these studies the diagnosis of abnormal lacrimation was fabricated past history alone, with simply a few patients tested with a Schirmer test.^{34 , 36 , 43 , 44} 15 years later, a multidisciplinary group decided to perform a more than detailed examination of every bit many patients as possible from the original Swedish thalidomide cohort.

TABLE 4

SUMMARY OF DATA FROM SWEDISH STUDIES

STUDY, Twelvemonth	NO. (%) OF CASES WITH ABERRANT TEARING	AGE (twelvemonth)/Sexual practice	ABDUCTION DEFICITS	CROCODILE TEARS SYMPTOMS + NO EMOTIONAL TEARING	CROCODILE TEARS ONLY	LACK OF EMOTIONAL TEARING ONLY	Late-ONSET TEARING	7TH NERVE PALSY	AUTISM (Total NO. IN Report)
First Swedish thalidomide report, 1987–1989 (due north = 84)	17 (20%)	26–29/12 M; 5 F	17 (16 DS OU; i abduction just OD)†	eight	7	2	NI	12 (five bilateral; five R; ii Fifty)	2‡ (n = iv)
Swedish Möbius study, 1997–1998 (north = 25)	6–7* (24%)	two–17/All Thousand	All by inclusion criteria	iii	one	2	3	All by inclusion criteria	four‡ (due north = six)

The written report described in this article was conducted in 2006 and 2007 and involved individuals with thalidomide embryopathy, now 45 to 47 years of age, who are registered in the Swedish Association of Thalidomide Embryopathy. This study was approved by the Sahlgrenska Academy at Göteborg University in Sweden, and each individual signed a consent form for photographs and participation in the report. All members were invited to participate in this study, but many did non concur to exist examined, so this new prospective study was done on a subset of individuals from the original cohort of Swedish patients with thalidomide embryopathy. The multidisciplinary study included orthopedics, speech communication and linguistic communication pathology, dentistry, psychiatry, and ophthalmology. Although in the 1989 study there were estimated to be 100 individuals affected with thalidomide embryopathy in Sweden, iv new patients had been identified more recently, and these were also examined. Two patients from the original group of 86 are deceased. Only 27 members of the original grouping plus the 4 new patients agreed to participate. The allotted fourth dimension for the ophthalmologic exam was 1½ hours. This included a routine general ophthalmologic evaluation (eg, slit lamp, dilated fundus evaluation, ocular motility [motor and sensory], refraction, intraocular tensions). The boosted ophthalmologic information added in this study was a more detailed history of tearing symptoms and a 5-minute Schirmer test without anesthetic, followed by a five-minute Schirmer test (also without coldhearted) while the subject was eating "chewy" cookies (Figures iii and ​ 4).

Baseline Schirmer I test. Patient was just get-go to chew. Notation limb anomalies.

Positive response (>ten-mm increase) on Schirmer test. Response occurred after chewing in patient with Duane syndrome.

Two of the authors (M.M., 50.V.) attended the 2007 meeting of Italia's Möbius Back up Grouping, which meets every 2 years. In 2007 the meeting was held in Piacenza, Italy; the organizing committee agreed that the investigators could ask families of children with Möbius sequence and a few adults participating in the plan if they would like to reply to a questionnaire. Later on signing consent forms, the participants answered some questions about ocular and systemic problems, with special attention to tearing characteristics (eg, dry optics, anomalous tearing, corneal complications). No ophthalmologic examinations were performed, except a basic ocular motility evaluation.

Breezy discussions and queries about lack of trigger-happy and anomalous trigger-happy took place at a Us Möbius Foundation meeting in San Francisco in 2006, led past one of the investigators (M.Thousand.). The respondents verbalized more than tearing problems than previously appreciated and precipitated further investigation. Many of the adults complained of dry out eyes requiring treatment, and a number of patients reported having crocodile tears.

In 2008 in Recife, Brazil, the organizers of the Permanbuco Möbius Support Group agreed that a questionnaire be given to families of children with known Möbius sequence while they attended a Möbius Support Group political party. After signing an appropriate consent form, those that volunteered to participate answered a few questions on violent. The information sought was elementary, asking just age and whether the children had decreased tearing, tearing when eating, and normal or absent emotional tears. Subsequently, the investigator (L.V.) supplied the data on misoprostol exposure by the mother in early pregnancy from information obtained in previous studies.

RESULTS

Table 4 (first row) summarizes the original Swedish thalidomide study. Seventeen patients (17 of 86) had a history of anomalous trigger-happy, with 15 individuals giving a history of crocodile tears (8 patients with both crocodile tears and lack of emotional violent) and ii having simply lack of emotional tearing.³⁴ All patients with abnormal tearing also demonstrated Duane syndrome or abduction arrears. Facial nerve palsy was present in 12 of the patients (total 17 of 86 in the report with 7th nerve palsy). Another surprise at the time of the study was the presence of obvious autism spectrum in 4 patients in the study, of which ii had dissonant tearing.

Table 4 (second row) summarizes the Swedish written report in 1997 and 1998 that evaluated 25 cases of Möbius sequence.^{43 , 44} A more detailed history of tearing symptoms was taken. The abnormal tearing symptoms were not as severe as in the thalidomide cases, merely there were iii cases of crocodile tears and no emotional vehement, 1 case of crocodile tearing only, and 2 cases of absent or reduced emotional fierce. Additionally, there were a few cases of late-onset tearing. The patient with the most farthermost example gave a history of no trigger-happy until age 8 years.

In the recent Swedish thalidomide study done in 2007 to 2008, information technology was decided to concentrate on the history of tearing characteristics and obtain more detailed information by doing a Schirmer I exam before and after eating. Tabular array 5 summarizes the findings from these patients. Although 31 individuals were recruited, one refused most of the ophthalmologic exam (patient fourteen), which made the final number 30. Likewise one (patient 18) was monocular because of an enucleated right eye. The Schirmer test seemed imprecise at times. There were a number of variables that could not be easily controlled, such as intolerance of irritation of the filter paper, movement of filter newspaper, and the amount of blinking of individuals. It would have been desirable to repeat the tests a few times to better control these variables, but that was impossible, as this group of patients are "research fatigued." Only fifty-fifty with these limitations, at that place were some very interesting findings in this recent Swedish thalidomide study:

1. Duane syndrome was nowadays in 11 patients, or 37% (44% in the original study).

2. Almost all of the individuals with a history of crocodile tears (9 of 11) were associated with Duane syndrome.

3. All patients with lack of emotional tears also had crocodile tears (7 of 7).

4. Facial nerve palsy was an associated finding in some patients (6 of 31).

5. If less than 10 mm of wetting on the first Schirmer test was chosen to indicate a low amount of trigger-happy, there were 15 cases, of which 8 had Duane syndrome.

6. If 10 mm or more increase in vehement betwixt the first and second Schirmer tests was taken as a measure of an abnormal response, 13 cases (21 eyes) were positive, of which 7 had Duane syndrome (14 eyes).

7. Of the patients with Duane syndrome and low initial vehement, seven showed increased tearing on eating (≥10 mm of wetting) and near gave a history of crocodile tears.

Tabular array 5

FINDINGS FROM Second SWEDISH THALIDOMIDE STUDY (north = 30)

CASE NO.	SEX	OCULAR MOTILITY	TEARING WHEN EATING	EMOTIONAL Fierce	7TH Nervus PALSY	SCHIRMER Test SCORES (MM, OD/Bone)			COMMENTS/DEFORMITIES
						INITIAL	5 MIN Subsequently EATING	≥x-MM Deviation
1	1000	DS OU	OU	Normal	0	2/two	12/12	OU	Hearing ↓, external ear, pollex
two	G	DS OU	0	Normal	0	two/two	xix/28	OU	Left upper limb, thumbs
three	Thousand	Comitant ET	OU	Normal	0	22/35	35/thirty	OD	Hearing ↓; upper limbs; lower limb thumbs
4	F	Normal	0	Normal	0	seven/28	23/xiv	OD	Upper limbs, easily and thumbs
5	M	Normal	0	Normal	0	5/5	5/v	–	Correct hand and thumb
half-dozen	F	Normal	0	Normal	0	16/thirteen	32/30	OU	Thumbs; lower limbs, hands
7	M	Normal	0	Normal	R	five/7	8/10	–	Hands; caused 7th nervus palsy
8	M	Normal	0	Normal	0	34/xvi	24/20	–	Upper limbs, thumbs
9	One thousand	DS OU	OU	Absent OU	0	27/20	35/26	–	Thumb
10	M	DS OU	OU	Absent OU	R/L	5/10	30/35	OU	–
11	F	Normal	0	Normal	R/L	v/18	12/17	–	Acquired 7th nerve palsy left, upper limbs, easily, thumbs
12	M	Normal	0	Normal	0	7/8	15/20	Os	Choanal atresia; manus, thumb, upper limbs, hypoplasia
13	F	Normal	0	Normal	0	18/22	19/twenty	–	Double vagina, upper and lower limbs, severe hands, thumbs
14	F								Refused examination
fifteen	F	DS OU	OD	Absent-minded OU	0	1/7	17/24	OU	Right inner ear, upper limbs and thumbs
16	F	DS OU	OD	Normal	L	15/25	24/31	–	–
17	M	↓ Abduction Normal Bone Enucleated	0	Normal	0	35/35	35/35	–	↓ Hearing, upper limbs, thumbs
xviii	K	OD	0	Normal	0	NA/28	NA/16	–	Upper limbs, thumbs
nineteen	F	DS OU	OU	Absent-minded OS	0	eight/two	23/16	OU	External ears, cataract OD
20	1000	Normal	0	Normal		7/11	9/13	–	Hands, thumbs
21	F	Normal	0	Normal	0	15/twenty	17/22	–	Hands, pollex, missing uterus and vagina
22	One thousand	Normal	0	Normal	0	0/0	0/13	Os	Thumb; kidney
23	M	Normal	0	Normal	0	35/35	35/35	–	Thumb
24	M	DS OU	OU	Absent OU	R	5/5	35/35	OU	↓ Hearing, hands, thumb
25	F	DS OU	OD	Absent OD	R	0/2	17/30	OU	↓ Hearing left ear
26	M	DS OU	0	Normal	0	nineteen/35	35/35	OD	Craniosynostosis, hand, thumbs
27	1000	Normal	0	Normal	0	15/25	12/35	–	Upper limbs, easily, thumbs, foot
28	M	Dark-brown S	0	Normal	0	35/25	21/35	–	Nystagmus, upper limb, paw, thumbs
29	F	Normal	0	Normal	0	27/29	25/34	–	Hands
30	Thousand	DS OU	OU	Absent OU	0	8/13	15/17	–	Upper limbs, hands, left pes, triphalangeal thumbs
31	F	Normal	0	Normal	0	14/30	9/ix	–	Thumbs, foot
Total
nineteen 1000, 12 F, age 44–46 y DS = 11; ↓ abduction = 1; Brown Due south = one; 1 comitant ET			10 of 30	7 absent	6

Information technology was interesting that a number of patients described specific nutrient items, such as sour or sweet, that result in the phenomenon of crocodile tears. One patient said that green apples were the prime inciting factor of the reflex, and nosotros observed this to be true after we gave her an apple tree to consume.

Table 6 summarizes the results of the interviews at the Italian Möbius back up group meeting. Anomalous trigger-happy was present in seven of 28 patients interviewed; both tearing when eating and lack of emotional tears were present in some patients, but these were not always combined.

Table half-dozen

RESULTS OF 2007 INTERVIEWS WITH THE ITALIAN MÖBIUS Support GROUP(north = 28)

Type OF Dissonant Violent	NO.
Crocodile tears and absent emotional tearing	2
Crocodile tears only	three/28
Lack of emotional tearing simply	2/25
Complaints of dry out eyes	eleven/28
Utilise of bogus tears	9/28
Onset >half-dozen mo	six/12

The recent questionnaire from a Möbius back up grouping in Brazil shows again a high number of some vehement anomaly (10 of xx). Additionally, information technology was known from previous research by Ventura and associates^{45 , 54} that five of 9 individuals with a history of misoprostol exposure during their mother'south pregnancy had dissonant vehement. In 4 individuals in that location was no data on the exposure to this drug.

Give-and-take

Axelsson and Laage-Hellman⁵ in 1962 reported 62 cases of crocodile tears in the literature and added sixteen cases of their own. All but a few followed caused known facial nervus palsy. By comparison, built anomalous fierce is a rarer condition, with the older literature unremarkably consisting of ane or 2 cases in each report (Table 1). Nearly cases of abnormal tearing are associated with Duane syndrome (Figure 5). Regenbogen and Stein²⁴ in 1968 could identify only 10 reported cases of anomalous trigger-happy in a Duane syndrome series. All cases were associated with involvement of the abducens nervus, usually Duane syndrome; a few were associated with facial nervus palsy, and none were associated with known syndromes. A few exceptions to a small number of instance reports are two large Chinese series of Duane syndrome, by Zhang,^{29 , 30} indicating a significant number of cases with aberrant tearing, but at that place was no mention of any association with specific syndromes (Tabular array i). Reports of the combination of these 2 aberrant neurologic weather have significantly increased post-obit the thalidomide tragedy and with the publication of a few Möbius sequence studies.^{42 – 45}

Child with exotropic-type Duane syndrome and tearing when eating. (Reprinted with permission from Trans Am Ophthalmol Soc. ³⁴)

Thalidomide (a-[Due north-phthalmido]-glutarimide) was introduced in the belatedly 1950s in Europe to treat anxiety, forenoon sickness, and insomnia. Information technology was a popular drug, and its usage spread worldwide with the notable exception of the United States, where it was not approved at that fourth dimension past the Nutrient and Drug Administration. It has been estimated that greater than 10,000 pregnancies and at to the lowest degree 6000 live births may have been affected by this drug, resulting in major malformations. This large number with many informative cases with narrow exposure history immune the establishment of a teratogenic timetable of sensitivity for certain malformations, such as limb anomalies, craniofacial structures, and cranial nerves.^{55 – lx} An increased number of limb defects were noted in 1959 by doctors in Germany, Austria, and Cracking Great britain.^{56 – 57 , 59 – 62} The drug was removed from the market in Europe starting in early 1961 and later in Japan. It is an extremely potent teratogenic agent, causing a wide variety of serious malformations during the known sensitive period of 21 to 36 days after fertilization. Since it is speedily hydrolyzed, information technology has an event in a very narrow fourth dimension frame in embryogenesis. It is recognized that the early exposure to thalidomide is associated with cranial nerve malformations, pollex, ear, and upper limb malformations. Thalidomide has proven to be a strong take a chance gene for the association of Duane syndrome, facial nerve palsy, and anomalous vehement occurring from exposure besides in the early on sensitive period—days xx to 24±.^{32 , 34} In the starting time Swedish thalidomide study, of 86 of the known 100 affected individuals, 44% had Duane syndrome, more than than 20% had abnormal lacrimation, and xx% had facial palsy (see Tabular array 4, showtime row).^{34 , 35} All cases of aberrant tearing were associated with Duane syndrome, and many were associated with facial nervus palsy. Two of the 4 patients with autism in this series as well had aberrant tearing (Figure 2).

A book summarizing the Japanese feel of a large number of individuals with thalidomide embryopathy was edited by Dr Mitsuhiro Kida.⁵⁵ Thalidomide was on the market in Japan for 5 years (1958 to 1963), only virtually no comprehensive inquiry was conducted until 1974. It was sold without a prescription. There were 309 cases registered as victims of thalidomide embryopathy, of which 137 (44%) were involved in the study.⁵⁵ A detailed eye test was performed by Arimoto³² on this subgroup. He reported Duane syndrome in 31 (23%), crocodile tear syndrome in 24 (18%), and facial nervus palsy in 38 patients (28%). All but 1 of the patients with the aberrant vehement had an associated Duane syndrome. Arimoto also postulated that the susceptible period was approximately 20 to 24 days later fertilization for these malformations. Table ii summarizes a number of studies involving thalidomide and anomalous violent.

It is interesting that Arimoto'southward findings are like to those of the Swedish thalidomide study. However, other reports on thalidomide investigations often do non even mention tearing symptoms or findings. One wonders whether the questions were asked. This absence of negative or positive history may also exist with the nonsyndromic Duane patients worldwide.

A further study of the Japanese feel was the report by Maruo and colleagues³³ of 266 cases of Duane syndrome betwixt 1963 and 1979. Gustatory-lacrimal reflex was observed in 27 cases (ten%). In this Duane series, there were 23 cases of thalidomide embryopathy.³³ Eighteen of the 23 cases of thalidomide embryopathy showed this type of aberrant trigger-happy. The study by Uemura and associates³⁸ of congenital gustatory-lacrimal syndrome described 10 patients with the association of aberrant tearing, with Duane syndrome in all cases. Six of these individuals had seventh nerve interest, and in 4 in that location was a history of thalidomide intake by the mother. There are another cases from Nihon reporting this association, and in that location may be some overlap of patients from the dissimilar studies.³¹

Zhang,²⁹ in an commodity from China in 1997, summarized 201 cases of Duane retraction syndrome, in which crocodile tears were noted in 26 cases (13%). The ratio of males to females in the full number was nearly 1:one. Although thalidomide may have been available in China during the time flow of the report, at that place is no mention of thalidomide intake past the mother. In 2002 Zhang³⁰ reported 25 cases of tearing when eating that were associated with Duane syndrome. It is unclear how many were from the 1997 cohort. It was as well noted that 15 cases were binocular. In general, if it was monocular vehement, it was associated with monocular Duane syndrome (Table one).

Wildervanck syndrome (cervico-oculo-acoustic syndrome) is a rare syndrome characterized by Klippel-Feil malformation, sensorineural deafness, and Duane syndrome.63 Inheritance has non been clearly established but is seen predominantly in females, and the presence of simply 2 parts of the triad may exist. Brik and Athayde46 reported a case of bilateral Duane syndrome, Klippel-Feil anomaly, and crocodile tears. A girl with the full triad and aberrant tearing while chewing was described by Haciyakupoglu and associates.47 Brodsky48 described a young daughter also with the triad, who had no emotional fierce in either eye, crocodile tears in the left centre, and brain stalk hypoplasia (Table iii).

It would certainly be intriguing and may be informative to study some of the unusual atmospheric condition associated with dissonant tearing, albeit a few may exist a run a risk occurrence (Table three). Branchio-oto-renal (BOR) syndrome is an autosomal inherited developmental complex characterized by branchial crevice cysts, renal anomalies, hearing deficits, and ear pits. Preisch and associates⁵¹ reported a family of 3 cases of BOR syndrome, with 2 of the patients (father, daughter) having gustatory lacrimation with normal reflex tearing on Schirmer test. They alluded to other families with this syndrome in the literature with excessive but not classic gustatory lacrimal tearing.⁵¹ They noted no abnormal ocular motion in the family. Still, in a report of BOR syndrome by Vincent and associates⁶⁴ of a example with 8q deletion, there was an association with Duane syndrome, only non abnormal tearing.

A teratogen, isotretinoin (Accutane), a vitamin A analogue used in the treatment of acne, has been frequently noted to take caused craniofacial and other malformations. Guirgis and associates⁴⁹ described a male child with restrictive external ophthalmoplegia, crocodile tear syndrome, and no emotional lacrimation. Karsenti and associates¹⁵ also described a case of Duane syndrome, Brown syndrome, and crocodile tears. Nigan^fifty reported a patient with Treacher-Collins syndrome (findings similar to Goldenhar syndrome), as well with anomalous fierce.

Lack of emotional (psychic) tearing is another unusual form of anomalous tearing. It was present in some patients in our thalidomide and Möbius series. This information will rarely be volunteered past the patient unless specific questions are asked. In our thalidomide series lack of psychic tearing was always associated with Duane syndrome and usually, but not always, with tearing when eating (Tabular array 4, first row). There was no mention of the presence or absence of emotional fierce in the large series past Maruo and associates³³ and Zhang.²⁹ Yet, the lack of emotional vehement has been noted in many cases in the literature.^{7 , 9 – 11 , 23 , 43 , 48 , 49}

The contempo Swedish thalidomide study (Table 5) was a multidisciplinary study with multiple areas of research interest. Because many members of the original accomplice of Swedish patients with thalidomide embryopathy declined to participate in the new comprehensive report, our results are for only a subset of the patients, and thus in that location may be some bias in the results. One goal of the ophthalmologic aspects of the study was to add more data on fierce symptoms in the older age-group and to document in more detail tear function past doing a baseline Schirmer I test and repeating the test while the patient is chewing. Although in that location were some reservations near the accurateness and reproducibility of the numbers obtained in the Schirmer tests, sure findings were very interesting. Nine of 11 individuals with symptoms of tearing when eating had Duane syndrome; the findings in the Schirmer exam of increased tearing greater than 10 mm after chewing was non as strong, yet still very suggestive. In that location were 7 patients with lack of emotional tears in this grouping, all of whom had Duane syndrome. Since our patients were anile 44 to 46 years, it would not exist unusual to have some individuals with decreased tearing, but the surprise was that at that place seemed to exist a greater number of individuals with Duane syndrome with a very depression Schirmer score but no history of dry out eyes. Of the 15 patients with decreased tearing, viii patients had Duane syndrome, merely 7 of these with Duane syndrome showed a 10-mm or greater increment on eating.

These observations raise interesting but unanswered questions. Do our routine adult patients with Duane syndrome accept a greater prevalence of "dry optics" with or without symptoms, and do some have increased tearing during eating that gives an overall total adequate vehement? Jacklin13 mentioned a patient with unilateral dry eye and crocodile tears who carried an apple to eat to save his low tearing symptoms. None of the patients without Duane syndrome who had x mm or more of wetting on the second Schirmer test had symptoms of tearing when eating. Many pediatric ophthalmologists stop seeing their patients with Duane syndrome as they grow older, because these patients come up to accept their condition and believe there is no reason to exist seen regularly, so we take piddling knowledge of their vehement characteristics.

The Möbius literature has little mention of tearing anomalies. One exception is an article past Amaya and associates,⁴² in which they noted crocodile tears in three of eighteen patients in their series on Möbius syndrome, only there was no mention of the status of emotional tears. However, the association of Möbius and aberrant fierce was strengthened in the Swedish Möbius study.^{43 , 44} This prospective, multidisciplinary study was actually designed to explore the possible association of autism spectrum disorder (ASD) with a group of patients with similar findings to the early outcome group of the Swedish thalidomide study (eg, 6th and 7th nerve involvement). Maternal pregnancy history in this Möbius report did not indicate exposure to drugs except in i patient. The findings were that autism syndrome was noted in a significant number of patients (6 of 25), and four of them had variations in tearing (Table 4, 2nd row). A few patients had some increased tearing that seemed related to balmy exposure from their facial nerve palsy, simply this was non considered every bit aberrant lacrimation. The anomalous tearing symptoms in the Möbius study ranged from isolated lack of psychic tearing (n = two) to no psychic tearing plus crocodile tears (n = 3) and crocodile tears alone (due north = 1). A few others had abnormal, late-onset tearing or less astringent symptoms.

In the interview of 28 patients with Möbius sequence (or their parents) at the Italian Möbius Support Group Meeting in 2007, further support of this association with abnormal lacrimation was noted. In response to our oral questions, 7 of 28 individuals reported some type of anomalous violent (Tabular array 6), and as well some had a history of tardily onset of tearing. No Schirmer tests were washed that might give more information as to the degree of dry out eyes.

Möbius syndrome is thought to be more correctly termed Möbius sequence, since the term sequence defines a cascade of secondary events that occur subsequently a single embryonic insult from heterogeneous causes. The accepted benchmark is bear witness of 6th and seventh nerve paralysis, although many other craniofacial and limb anomalies are frequently noted. Nigh cases are sporadic, and one theory is that Möbius sequence belongs to a grouping of "disruption syndromes," although various explanations are given for the causes of the disruption.^{65 – seventy} The caption is that there is a vascular disruption at a similar time early in embryogenesis causing hypoxia, ischemia, edema, and hemorrhage followed past a sequence of secondary events. Supporting this concept are cases of Möbius sequence with a history of drugs or events that could cause a hypoxic episode, usually due to uterine contraction early in pregnancy. The drugs misoprostol and cocaine, along with chorionic villi sampling, have been associated with infants with Möbius sequence.^{65 , 68 – 73}

Misoprostol is an abortifacient agent frequently used in S America for underground abortions. Many cases of Möbius sequence have been reported after unsuccessful attempts of abortions with misoprostol, in which the significant women describe one or 2 days of cramping and some bleeding, simply no abortion.^{45 , 74} Ventura and associates⁴⁵ take done extensive studies on patients with Möbius sequence, comparing systemic and functional findings in children whose mothers had taken misoprostol with findings in children with no gestational history of misoprostol exposure. Autism was noted in both groups, supporting the concept of Möbius sequence resulting from dissimilar causes (Figure half dozen).⁷⁵ Recently at a Möbius Support Group party, Ventura asked families of children with Möbius sequence to respond to a questionnaire on tearing characteristics (Tabular array 7). Findings from the 20 persons who agreed to participate support the determination that aberrant tearing occurs often with Möbius sequence, since 9 of 20 gave a history of crocodile tears, and 7 of 20 had lack of emotional tearing. There were besides a number of parents who said the children had a decreased amount of tears. There was a history of misoprostol exposure in some just not all children with absent fierce.

Patient from Brazilian Möbius report. Child has autism disorder, bilateral facial nerve palsy, and abduction deficits (sixth nervus). (Reprinted with permission from Miller MT, Strömland K, Ventura L, et al. Autism associated with weather condition characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci 2005;23:201–219.)

TABLE 7

RESULTS OF 2008 INTERVIEWS WITH THE BRAZILIAN MÖBIUS Back up Grouping (due north = 20)^*

Type OF ANOMALOUS Vehement	NO.
Crocodile tears and absent-minded emotional tearing	3/twenty
Crocodile tears only	6/20
Lack of emotional vehement only	one/20
Anomalous tearing with misoprostol exposure history	five/nine†

Support groups are often not a true random sample of whatever characteristic or finding, and then accurate prevalence information cannot be inferred, merely they do offer the opportunity to find out information on large numbers of individuals with rare weather. In the interviews conducted in Italy, Brazil, and the The states, at that place was strong bear witness that anomalous tearing of both the paradoxical gustatory lacrimal type and lack of psychic violent are common findings in Möbius sequence and that they may occur together or separately in any one patient with Möbius sequence. Additionally, the presence of autism syndrome is non a rare association.

In that location accept been a number of speculations for the link between these forms of anomalous trigger-happy with involvement of the sixth cranial nerve and, at times, the seventh cranial nerve. The near common explanation suggests a disturbance in normal evolution of the cells destined to form the sixth and seventh nervus nucleus and the superior lacrimal nucleus in the brain stem, which are thought to be in shut proximity in early embryogenesis. Ramsay and Taylor²³ suggested that the most logical explanation of this combination was nuclear damage or dysgenesis in the vicinity of the abducens nucleus, with the lacrimal finding existence the result of innervation of the lacrimal gland past fibers subserving salivation. The observations in thalidomide embryopathy of an overwhelming association with facial nerve palsy, Duane syndrome, and aberrant violent strongly support this theory of a nuclear location. In that location must too be some damage in the lacrimal nucleus to cells that are destined to be connected with college centers that would normally exist responsible for lack of emotional tearing. It appears that a variety of embryonic insults may affect these structures at the aforementioned crucial time in embryogenesis, resulting in the aberrant neurologic connections associated with Duane syndrome and aberrant tearing.

The time of the embryonic insult responsible for sixth nerve involvement and aberrant tearing in the thalidomide studies is quite accepted to exist near days 21 to 24 after fertilization simply seems to exist slightly afterwards in the Möbius-affected patients whose mothers took misoprostol in attempted only failed abortions (estimated time of gestation, 5 weeks). This raises the question of the relationship between Duane syndrome and the lateral rectus dysfunction seen in Möbius syndrome. Still, the fact that two unlike teratogens can implicate a fairly definite time of action does not prove that adverse embryonic events at other times could not cause the aforementioned effect. There is probably a period in development in which the organization is more plastic and a disturbance locally may lead to abnormal neurologic connections. Information on the length of this fourth dimension period would give of import information about developmental problems.

An important question is whether we are missing cases of anomalous tearing because we fail to ask specific questions virtually tearing of our patients with Duane syndrome, and because the parents or patients do non make the association between the ocular move disturbance and aberrant tearing. Although the prevalence is probably higher than recognized, anomalous tearing is still not a mutual characteristic of Duane syndrome. It does, however, give usa some insight into the time and location of the embryonic insult and, therefore, can be useful to amend understand some developmental bug associated with Duane syndrome.

PEER DISCUSSION

DR. MICHAEL C. BRODSKY

In this analysis, Dr. Miller accesses her vast database to estimate the prevalence of crocodile tears in children with Möbius sequence, a condition that has recently been classified as one of the built cranial dysinnervation syndromes.^ane This study is not a meta-assay but a combined literature review, patient questionnaire, and ophthalmologic test. The inherent limitations of this study are that it is more often than not retrospective and largely historical. If anything, this methodology would underestimate the prevalence of the association in question. Dr. Miller elicits a history of crocodile tearing in 33 to fifty% of patients with Möbius sequence.

And then what can we learn from this study? Offset, information technology is clear that crocodile tearing is an overlooked ophthalmologic sign of the Möbius sequence. After reading Dr. Miller'due south written report, I examined a child with Möbius sequence and asked the female parent if in that location was crocodile vehement. The mother said, "I don't call up and so, but I've ever wondered why we his nose runs and why we are e'er wiping information technology every fourth dimension he eats." Second, the range of stimuli that arm-twist this response in children with Möbius sequence however need to be elucidated. 3rd, we need to determine the range of weather in which abnormal tearing tin occur. The phenomenon of crocodile tears could fifty-fifty explain some cases of "refractory" congenital nasolacrimal duct obstacle.

As with any skillful study, Dr. Miller's paper raises as many questions equally it answers. Can exposure to the known teratogens for Möbius sequence produce crocodile tears equally an isolated condition? Do crocodile tears signify aberrant innervation (every bit in Duane syndrome) or augmentation of a normal physiologic synkinesis? Is the crocodile trigger-happy of Möbius sequence a cardinal or peripheral miracle? Jampel and Titone² considered the built gusto-lacrimal syndrome to outcome from failure of dispersion and differentiation of cells within the salivatory and lacrimal nuclei, which lie in shut juxtaposition within the pons.ⁱⁱⁱ Is the clinical expression of this synkinesis related to the timing or severity of injury? Is the observed response taste-specific (biochemical), stimulus-specific (eating), or psychic (thinking about nutrient)? Does the finding of crocodile tears correlate with congenital corneal anesthesia, some other recognized component of the Möbius sequence?⁴ Do these patients accept an underproduction of baseline tears? How often is crocodile fierce nowadays in patients with unilateral Duane syndrome?

In decision, Dr. Miller has demonstrated that crocodile trigger-happy is an integral component of the Möbius sequence. Every bit ophthalmologists, we need to be more attuned to crocodile trigger-happy, study its pathophysiology, determine its range of clinical expression, and examine its prevalence in other congenital cranial dysinnervation syndromes.

ACKNOWLEDGMENTS

Funding/Support: None

Financial Disclosures: None

REFERENCES

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DR. IRENE H. LUDWIG

Several years ago, I had the opportunity to examine a large series of children with congenital central hypoventilation syndrome, Ondine's Curse. I was struck by the similarity of heart findings in these children to those in Dr. Miller's series of thalidomide patients. This leads me to believe that maybe there is a teratogenic crusade of the congenital central hypoventilation syndrome. Our patients had strikingly high rates of attending arrears disorder, autism, and convergence insufficiency. I was wondering if y'all saw whatsoever of these traits in your grouping.

DR. BARTLEY R. FRUEH

I have no conflicts of involvement, but only a comment nearly crocodile violent. Nosotros see this in my practise largely in adults who have had VII nervus injuries with aberrant regeneration. We accept determined that injecting Botox® into the lacrimal gland can alleviate the symptoms of crocodile tearing. I wondered if this might besides exist helpful for these congenital cases.

DR. MARILYN B. METS

I am going to make a tangential annotate almost teratogenesis. I believe that information technology is important to accept every opportunity to make people aware of teratogens and to prevent their complications. I am referring to an organism called lymphocytic choriomeningitis virus, which is harbored in mice and hamsters and can produce dramatic CNS abnormalities, also as visual abnormalities. I mention this and then members will know to tell their patients or relatives who are young and having children that they should not purchase a pet, such every bit a mouse or a hamster for their 4 or five yr olds, if they are planning on having more children. These rodents can betrayal the significant woman to the organism and have dramatic effects on the unborn child. Cheers.

DR. MARILYN T. MILLER

Thank you, Dr. Brodsky and all of the discussants for your very interesting comments. I call back I am going to start with the last comment first, Dr. Brodsky. Interestingly enough, if y'all accept unilateral tearing and unilateral Duane syndrome they always occur on the same side. The literature does have cases of unilateral presentation, but y'all do not see a unilateral ptosis in one side and a unilateral Duane on the other, and then I call back that even brings us closer. I reviewed the published findings of built corneal anesthesia and they just do not seem referable to this group of patients. Furthermore, the corneas are really normal in our patients with built abnormal violent. We practice a very superficial test of corneal sensation, and it is normal. The question of sense of taste specific is too reported in the published literature; still, and I did not have the time to discuss this topic. Some patients lacrimate but when they taste sour food. Some volition not tear if they chew, but only if they experience a specific gustation sensation. One patient told us that she really cried when eating an apple. We confirmed this by observing her cry profusely while she ate an apple. Regarding the comment on the caused class of the condition, I also did non accept fourth dimension to hash out this. I believe that the most mutual cause of abnormal tearing with the crocodile tears is acquired facial nervus injury and occurs almost 4 to six months after the injury. This paper dealt only with the built type because the caption is different with respect to the neurological implications. I believe the congenital course is fundamental in origin mostly because of the combination with Six and Vii and the development at a certain time. We do not completely sympathize neurological development or why an insult at a sure fourth dimension results in actually two abnormal innervational situations, Duane syndrome and abnormal violent. I certainly agree that in that location is a wide range of symptoms. I practice not know if this might be related to refractory nasal duct problems.

Dr. Ludwig, we take talked nearly this often, although I think I previously discussed autism. Autism is present in this status. Since this was a thalidomide study, we evaluated for Möbius syndrome and were non looking for other findings. In that location is a 24% prevalence of the autism spectrum disorder in Möbius syndrome. In the Brazil grouping that included patients with a history of misoprostol and those of unknown etiology, nosotros observed autism spectrum disorder in both subsets of patients. The whole autism spectrum disorder is present in all of these. I mentioned the acquired form, and I agree with Marilyn that nosotros should be attuned to dangers of potential teratogens. They are very difficult to identify because and so oftentimes they are not very teratogenic. A combination of teratogens, genetic predisposition, and other environmental factors may result in a syndrome, the crusade of which is very difficult to decide in a serial.

ACKNOWLEDGMENTS

Funding/Support: Supported in office by grant U19HD/DC35466, Collaborative Programs of Excellence in Autism, National Plant of Child Health and Human Evolution, Rockville, Maryland; cadre grant EY 1792 from the National Middle Establish, Bethesda, Maryland; an unrestricted inquiry grant from Inquiry to Prevent Blindness, Inc, New York, NY; and the Lions of Illinois Foundation, Maywood, Illinois (Dr Miller). Also supported in part by the Göteborg Medical Society, Göteborg, Sweden (Dr Strömland), and the Altino Ventura Foundation, Recife, Brazil (Dr Ventura).

Financial Disclosures: None.

Author Contributions: All authors were very involved in this paper. All Swedish studies were done by Kerstin Strömland and Marilyn Miller. The Italian Möbius Support Group questionnaire was conducted past Liana Ventura and Marilyn Miller, and the Möbius Foundation questionnaire was given by Liana Ventura.

Conformity With Author Information: The Swedish Study was canonical by the Sahlgrenska Academy at Göteborg University, Sweden 2003.12.xviii, number Ö 556-03, and each patient signed a consent grade allowing photographs to exist used. All individuals in the Italian and Brazilian Support group questionnaire signed consent forms.

Acknowledgment: Dr Tatsuya Onguichi and Dr Yuri Kim assisted in translation of manufactures in Japanese.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646435/

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