792018 Nols - Victoria Madina - MyCrildrens at Boston Childers isaimer This documentation printed copy ony and not the oa Boston Chile's Hospital Mele! Record. I you wish copies of any documentation from the official Boston Children's Hospital Medical Record, please contact the Boston Children's Hospital HIM Department at 617-355-7546. Victoria Medina - MRN 4799270 2 Years O18 Gusyama, PR Female Dos S914 Otolaryngology Visit Da 7201s Oupeens, brygeiny Fe Sally Rea be i DATE OF BIRTH: 05/09/2014 Dear Dr. Quinones: {had the pleasure of seeing your patient Victoria taday. As you recall she isa 13-month-old with @ complex history significant for Mobius syndrome who has undergone tracheostomy back hom. She has remained n.p.0. due to her history of aspiration and neurological issues. She has 43.5 Shiley tach in place, Trach is changed twice a month without difficulty. She continues to be on levothyroxine because of her hypothyroidism as well. ‘On examination extemal canals are normal. There is no significant indication of effusion. Nasal passages are clear, Posterior pharynx is ‘lear, Palate elevation is symmetrical. I performed a tracheobronchoscopy. Distal tach from the trach tip down to the proximal right and left ‘main bronchus are normal. We also obtain an audiogram which again confirms flat tympanogram due to question of middle ear effusion, It was difficult to attempt hearing due tothe neurological issues however the testing reveals grossly normal hearing at 30 dB. For formal evaluation she js scheduled to undergo an ABR ‘Recommendations: [am pleased to see Victoria has done well. 1 have reviewed our findings with Mr and Mrs. Medina. Victoria will be coming to Boston in 8 months, Thave suggested to have an airway evaluation on the next visit for a complete evaluation ofthe airway. We will also consider scheduling an ABR at that time, Sincerely, Reza Rahbar, DM.D., MD. “Associate in Otolaryngology ‘Boston Children's Hospital tiipavimyhelincordchldrenshosptalcrgptint-poral-patont-viewerpaionNots seam ?mrn=4798270 ”Boston Children’s Hospital BCHMRN: 479-92-70 : 300 Longwood Avenue Patient Name: MEDINA, VICTORIA Bosom O11 DOB/Age/Sex: 5/9/2014 2years Female Admit Date: 7/6/2015 Patient Location: Ophthalmology Foundation scharge Date: 7/6/2015 Patient Type: Outpatient Financial #: 6116907394 DOCUMENT NAME: Ophthalmology Visit ‘SERVICE DATE/TIME: 71612015 00:00 EDT PERFORM INFORMATION: HUNTER MD,DAVID G (7/6/2015 15:27 EDT) SIGN INFORMATION: HUNTER MD,DAVID G (7/9/2015 22:18 EDT) RESULT STATUS: ‘Auth (Verified) DATE OF BIRTH: 05/09/2014 CHIEF COMPLAINT: Eyes drift out. HISTORY OF PRESENT ILLNESS: The patient is a 1-1/12-year-old girl who is here today with both parents, traveling from Puerto Rico for consultation regarding her complex strabismus. The patient is seen in the Congenital Cranial Dysinnervation Disorders Clinic together with Dr. Elizabeth Engle from the Department of Neurology. Dr. Engle has dictated a separate note that details her medical and neurologic history extensively. Briefly, she was born after a pregnancy that was notable for decreased fetal movements during the third trimester, born at term weighing 3120 grams (50th percentile.) She was intubated in the delivery room and has multiple medical problems including devlopmental delays, hypotonia, and arthrogryposis, and she is tracheostomy and G-tube dependent. Regarding her eyes, she has been noted to have exotropia of both eyes, right greater than left, since birth, but the misalignment has continued to increase over time. She is not able to close her eyes well She seems to prefer to use her right eye but will use her left eye at times. At 6 months of age, she came to Boston Children's Hospital for an evaluation and was seen by Dr. Janet Soul in Neurology, whose detailed note was reviewed. At that time, the spectrum of a CCDD variant was raised and a 3-Tesla brain MRI was obtained. At 10 months of age she had a follow-up visit with Dr. Soul and was also evaluated by Dr. Heidary in our department. The examination was notable for lack of infraduction of both eyes with limited adduction as well. There was no significant corneal exposure. Visual evoked potential testing was recommended but | do not believe that was performed. Patching of the right eye 1 hour per day was recommended and is being performed. The potential for surgery and spectacles was also discussed. THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48EDT Maxwell ,Yvette Report Request ID: 24815376* Boston Children's Hos| BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female n _ Ambulatory Documenta‘ Since then, the parents feel that the misalignment continues to increase, and mother is concerned that the aberrant eye positions are delaying her development. She is here for additional evaluation and the potential for obtaining a unifying diagnosis, Past medical history is further detailed in Dr. Engle's comprehensive report. Family history is negative for strabismus or amblyopia. Mother did require glasses at a young age. MAJOR FINDINGS The patient appears cooperative and is somewhat responsive to stimuli, especially visual stimuli, though she does respond slowly. On visual acuity assessment, she appears to fixate and follow with either eye, with somewhat of a preference for the right eye. She did not respond to OKN testing or to preferential looking testing. She will look at interesting, flashing lights at times and will slowly follow horizontally if given several seconds. Unable to assess dynamic retinoscopy today, either due to lack of effort or to lack of accommodation. Cycloplegic refraction shows less hyperopia than at the previous visit but there may have been partial cycloplegia, with astigmatism similar to that measured by Dr. Heidary. A sensorimotor evaluation was obtained. ~ There is a right eye fixation preference but the patient will fixate with the left eye. ~ There are some slow roving movements of the eyes. In addition, there are voluntary saccades though these are slow but conjugate with no evidence of dysinnervation. ~ Ductions show apparently full elevation and full abduction of both eyes with significant limitation of adduction and depression, though adduction may be slightly better on the right than on the left. Under no circumstances could down-gaze be elicited. An effort was made to elicit a Bell's phenomenon but the patient did not attempt to squeeze the lids in response to the forced eyelid opening or at least it was not palpable so we could not tell whether she was making an effort to resist. I do not see any evidence of intorsion on attempted down-gaze but could not confirm that there was an effort at down-gaze. = On Krimsky testing there is a large exotropia, greater than 80 prism diopters, and bilateral hypertropia, but with the right eye higher than the left eye and the patient unable to bring either eye down to the vertical midline. The sensorimotor impression is of a large angle exotropia with down-gaze paresis. (On external examination there is plagiocephaly. There does not appear to be ptosis but there is facial palsy with inability to close the eyelids. The corneas do cover nicely when the patient is at rest due to the hypertropia. THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell, Yvette Report Request ID: 24815376Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/AgelSex: 5/9/2014 2years Female Ambulatory Documentation ] Pupils are notably of normal size and reactivity with no afferent pupillary defect appreciated. The anterior segments appear to be within normal lit with exposure. There is no exposure keratopathy. Some ointmen except for mild hyperemia inferiorly consistent present in both eyes. Unable to assess visual fields. On dilated fundus examination, the left optic nerve is slightly larger than the right but the nerves themselves appear to have normal contour and appearance. There is +1-+2 intorsion of the right eye and +3 to +4 extorsion of the left eye. The exact amount of torsion was difficult to assess due to the upward and outward position of both eyes and the partially supine position of the patient but overall it did seem as though there was complementary intorsion on the right and extorsion on the left with abnormal extorsion on the left. The eye movements today were recorded on video and the eye position photographed to document the condition and follow it over time. IMAGING: The MRI scan was reviewed today together with Dr. Engle. The extraocular muscles were notable in that the medial and inferior rectus muscles seemed quite attenuated whereas the superior rectus muscles appeared to have closer to normal size and the lateral rectus muscles did appear to be essentially normal in size. The superior oblique muscles did appear to be somewhat attenuated. In the series with the thinnest cuts (0.5 mm), imaging of the midbrain did not go quite high enough to fully assess the extent of the third cranial nerve. The fourth cranial nerve is always difficult to visualize and was not present in this case. The sixth cranial nerve was present. There were numerous other abnormalities of the brain noted, detailed elsewhere. ASSESSMENT: . Congenital hypotonia with arthrogryposis. Multiple cranial nerve dysfunction, including partial involvement of Ill, IV, and Vil. Tracheostomy dependence. G-tube dependence. Global developmental delay. Plagiocephaly. Large angle exotropia. Limited depression of both eyes. Hyperopia with astigmatism, PPNOMEONS PLAN: THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815376BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female * Boston Children's Hospital Ambulatory Documentation | This patient does have a congenital cranial dysinnervation disorder, but we have not seen this pattern of findings in KIF21A or TUBB3 mutations to date. In particular, we rarely see the eyes resting above the vertical midline and we do not see inferior rectus muscle weakness. The other atypical feature with respect to this being a TUBB3 mutation is the lack of any sign of aberrant innervation such as, for ‘example, esotropia on attempted upgaze, hypertropia in attempted lateral gaze, or synergistic divergence = we could see none of these today. Indeed, when the patient did make an effort to move the right eye to the right, the left eye did follow in the same direction (but with the adduction limitation noted), in attempted left gaze both eyes moved leftward. Overall there appears to have partial involvement of the third cranial nerve involving the lower rather than the upper division, and most likely a fourth cranial nerve weakness as well, with some attenuation of the superior oblique muscle. The sixth cranial nerve appears intact, with normal appearing lateral rectus muscles. | wonder whether there is also a supranuclear contributor to the deviation pattern, given the complementary torsion of the two eyes, which is suggestive of skew deviation. Alternatively, the left inferior oblique muscle may have some residual innervation, explaining the extorsion and hypertropia (but this does not explain why the right eye is higher than the left eye.) For management, she is a borderline candidate for receiving glasses. Today | measure less hyperopia than was measured at the previous visit, but this may have been due to having partial cycloplegia today. | think in this situation | would like to try to assess the refraction under noneycloplegic conditions and then could consider prescribing based on the findings if the patient appears to be having difficulty accommodating. She does have normal pupillary function and so it could very well be that her accommodation is intact as long as she has an interest in the target. ‘She might benefit from strabismus surgery due to the magnitude of the exotropia, which is making it difficult for her to fixate without having to adopt a fairly large head posture to the side. However, considering the extent of her developmental delays and her medical status, | would like to defer surgery for the time being and give her condition a little bit more of a chance to evolve and a bit more time for us to review and consider the diagnosis in this case. Surgery would most likely consist of bilateral recess/resect procedures with significant resection of the medial rectus muscles and recession of the lateral rectus muscles, displacing both downward to try to reduce the amount of hypertropia. | explained to the parents that with such surgery, itis not likely that we would see conjugate horizontal movements but at least the eyes would be more in a straight-ahead position which would make it easier for her to. make eye contact. For the vertical misalignment, the downward displacement of the horizontal rectus muscles alone probably would not be enough. If the superior rectus muscles were tight or contractured then recession of those muscles would be the first step, combined with resection or plication of the inferior rectus muscles to try to hold the eyes in a more downward position. Depending on the forced duction findings of the oblique muscles, it might also be helpful to consider inferior oblique myectomies to further bring the eyes downward. The problem with bringing the eyes down, however, is that the patient does have a facial palsy and this will bring the eyes into a position where they will be much more susceptible to becoming dry due to corneal exposure. It is for this reason that | am somewhat hesitant to THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell, Yvette Report Request ID: 24815376Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female Ambulatory Documentation consider trying to address the vertical deviation, but at the same time the eyes are up far enough that it is probably interfering with her function, so it may be worth trying to find an in-between place where the eyes are brought down enough to improve function but not so much that there is a significant increase in the amount of corneal drying. If she did run into trouble with corneal exposure, then she might require much more frequent lubrication or even fitting with a PROSE contact lens to prevent long-term consequences of chronic exposure. In summary, considering the complexity of the case and the evolving understanding of her level of function, | do not recommend any intervention at this time but she may at some point require glasses, | horizontal strabismus surgery, and/or vertical strabismus surgery to improve her visual function and her eye alignment. THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell Yvette Report Request ID: 24815376* Boston Children's Hospital BCHMRN: 479-92-70 300 Longwood Avenue Patient Name: MEDINA, VICTORIA Boston, MA 02115 DOB/Age/Sex: 5/9/2014 2years Female Admit Date: 7/6/2015 Patient Location: Neurology Foundation Discharge Date: 7/6/2015 Patient Type: Outpatient Financial #: 6116673703 Ambulatory Documentation DOCUMENT NAME: Neurology Visit ‘SERVICE DATE/TIME: 7161/2015 00:00 EDT PERFORM INFORMATION: ENGLE MD,ELIZABETH C (7/6/2015 20:49 EDT) ‘SIGN INFORMATION: ENGLE MD,ELIZABETH C (7/8/2015 16:09 EDT) RESULT STATUS: ‘Auth (Verified) DATE OF BIRTH: 05/19/2014 Dear Dr. Quinones: had the pleasure of consulting on 13-month-old Victoria Medina in the CCDD Clinic at Boston Children's Hospital today. Victoria and her parents came to BCH from Puerto Rico for diagnostic evaluation, and were also seen in CCDD clinic by Dr. David Hunter from Ophthalmology, who will dictate a separate letter. Victoria has a complex medical history of global developmental delay, hypotonia, complex strabismus, facial weakness, oromotor dysfunction, hypothyroidism, arthrogryposis, and post-axial polydactyly, and is status post tracheostomy, gastrostomy and fundoplication. She was evaluated for encephalopathy at Boston Children's Hospital in November 2014 by Neurology, Orthopedics, Pulmonary Gastroenterology and the Feeding and Swallowing team. She was then seen in follow up in March of 2015 by Neurology and for the first time by Ophthalmology and ORL. As a result of these evaluations, neonatal neurology consultant Dr. Janet Soul diagnosed her as having a congenital cranial dysinnervation disorder (CCDD), and obtained a high resolution MRI which confirmed her clinical diagnosis, revealing hypoplasia or absence of cranial nerves Ill, Vil, and hypoplasia of V and likely lower cranial nerves. CLIA testing for mutations in the TUBB3 gene revealed normal sequence, and thus Dr. Soul referred her to the CCDD clinic. Her history is provided by her parents and through review of her medical records. Though you are familiar with her past history and it is summarized nicely by Dr. Soul and others in her Boston Children's Hospital notes, please allow me to relate pertinent portions of it for ‘our own records. Victoria was born at 39 weeks’ gestation to a 27-year-old gravida 2, para 0 to 1 mother who had one previous miscarriage. Her father was 33 years of age at delivery. Her mother had spotting once every two weeks for the first 13 weeks of pregnancy. From week 18 to 29, she describes strong fetal movements and ultrasounds showing fetal movements including sucking of the fetus’ fingers and movement when her mother tickled her abdomen. At 29 weeks of gestation, however, her mother noted a relatively abrupt decrease in fetal movements over a period of several hours. This was 4 days after a routine ultrasound which was read as normal. Although an Ob-Gyn examination was reassuring, the decreased or absent fetal movements persisted through the third trimester. Victoria's mother gained 40 pounds during the pregnancy. She had no known exposures during the pregnancy including lack of THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815377Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female Ambulatory Documentation _ exposure to cigarettes, alcohol prescription, over-the-counter or recreational drugs, environmental toxins or extreme temperatures. Victoria was born by C section under spinal anesthesia for a non-reassuring fetal heart tracing. Her Apgar's were 3, 6 and 8. She had a weak cry and an inability to handle secretions, and was intubated and taken to the neonatal intensive care unit, where she remained for two months. At birth, her measurements were appropriate for gestational age, but she was noted to have dysfunction of multiple cranial nerves with flexion contractures of her upper and lower extremities and polydactyly of the left hand and bilateral feet. Victoria's parents describe a lack of facial movement and an inability to close her eyes or to blink soon afer birth. In addition, she had a lack of spontaneous eye movements and they described her eyes as being in an exotropic and hypertropic position. They feel that her exotropic eye position has increased over time. Her parents feel that she can see objects and follow them but that recently she has begun using her right eye almost exclusively. They are now patching the right eye for about an hour a day. She failed her newborn hearing screen, and repeat testing has been delayed secondary to middle ear fluid. Her parents note that she has never been able to suck or swallow. She failed extubation trials on three occasions in the NICU due to inability to protect her airway and handle her secretions well extubated. She received a tracheostomy in June of 2014 and has been on room air since the end of August. She is still not able to swallow her secretions and she needs frequent suction. A flexible laryngoscopy in March of 2015 at Boston Children's found that she had patent nares anteriorly. Her septum was midline and her choana was patent. She had a normal appearing nasopharynx and hypopharynx. The laryngeal examination was somewhat limited because of moderate secretions but the examiners did not appreciate any cord function whatsoever. Victoria has not been able to take anything by mouth since birth. She was fed through an NG tube until she received a G-tube and fundoplication in June of 2014. She is noted to have gained excessive weight and was placed on PediaSure during her last visit to Boston Children's. Her mother says she gained another three pounds so she has now been giving her a lower calorie pureed food. Victoria has had generalized hypotonia, axial greater than appendicular, since birth. She was evaluated by Neurologists in Puerto Rico; a head ultrasound in May of 2014 had a small area of "increased echogenicity" at the right parietal occipital periventricular parenchyma, Her first MRI of the brain without contrast in May of 2014 showed a "enlarged left temporal and left posterior fossa extraaxial space", but was otherwise normal. She had three EEGs performed while in the initial hospitalization and no seizure activity was reported. They did, however, report low voltage and poorly disorganized background activity. She had an aldolase level which was borderline high and an EMG which was normal Victoria's parents describe her as sleeping for over 20 hours a day for the first eight months of her life. Indeed, she was referred to Boston Children’s in the fall for evaluation of encephalopathy. Her parents note, however, that in January, she began to have longer periods of wakefulness and currently she sleeps twelve hours at night and takes three 30-minute naps during the day, but is otherwise awake and THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815377479-92-70 MEDINA, VICTORIA 5/9/2014 2years Female BCH MRN: Patient Nam alert. As her wakefulness has increased, she has begun to move more and to gain a few milestones. She can follow objects sporadically to midline better with the right than the left eye, and regards faces and objects intermittently and with encouragement. She calms to mother's voice and can cry when her father speaks loudly or abruptly. She seems to like more lively music during her exercises. She doesn't smile (and continues not to have any facial movement) and she does not regard her own hand. She will hold objects to place in her hand but she does not bring her hands together in the midline. She has a speaking tracheostomy and, when in place, she can make "ah" sounds with expiration. Victoria has gained some axial tone and her parents feel she is trying more and more to hold her head up and is moving a lot more when being held on their lap. They note that she tends to move her right arm and left leg the most. She began rolling over recently and is able to spend some time prone. In prone, she can lift her head for a short period but doesn't have chest up or arm support. She can kick her legs against gravity and her mother feels she kicks a piano mat with some intention. She has no intentional movement of her arms. Of note, Victoria has not lost milestones. Victoria's parents have not had concerns of staring spells, repetitive movements or seizures. They do note, however, that she has jerky movements in sleep that are random and not rhythmic. Mother says that at the end of a flurry of such movements, she will arch her back stiffly and then wake up. In the last several months, when she has had longer periods of wakefulness, Victoria has developed somewhat gasping, short respiratory pattern when awake which does not occur in sleep. This is not accompanied by cyanosis and improves slightly with suctioning but doesn't resolve completely. Victoria has had multiple genetic tests. A karyotype that was normal and high resolution chromosomal analysis that was reported to be normal. In May of 2014, acylcarnitine levels and plasma showed several acylcarnitine species of varying chain lengths and nonspecific pattern. This was repeated in June and showed mildly elevated acylcarnitines in a nonspecific pattern again. Plasma amino acids x and urine organic acids x 3 in May and June of 2014 were nonspecific for any clear metabolic defect. Carnitine levels were within normal limits in May of 2014. Victoria had comparative genomic hybridization at Lab Core Reference Laboratory in 2015, that describes no significant gains or losses but a run of homozygosity on chromosome 12 that is 14.6 megabases. This is on 12q from 76, 404, 693 to 91, 036, 272. | reviewed this region and it contains multiple genes, some of which are intriguing candidates for an underlying etiology for her disorder (and can be pursued on a research basis). ‘As mentioned above, Victoria had high resolution brain MRI in March of 2015 at Boston Children's. | have reviewed the scan with Dr. Caroline Robson. The MRI revealed brachycephaly and left frontal and right parietal plagiocephaly. There was diffuse thinning of the corpus callosum and mild thinning of the anterior commissure. There was mild T2 prolongation within the dorsal aspect of the medulla and pons as well as in the dorsal mid-brain. The deep frontal and parietal white matter appeared somewhat THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815377Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/AgelSex: 5/9/2014 2years Female Ambulatory Documentation undermyelinated and there was mild prominence of the third and lateral ventricles. There was also a question of under-rotation of the hippocampal formation. Of note, the olfactory sulcus, bulbs and nerves appeared normal as did the optic nerve. Cranial nerve 3 was not identified; 4 was not clearly seen; 5 appeared somewhat smaller than expected, 6 appeared normal, 7 was absent and 8 was visualized. Cranial nerve 12 was fairly faintly seen but may be hypoplastic. The muscles of mastication and visual expression were hypoplastic and medial and inferior recti were small while the superior rectus and lateral recti and the superior oblique were more normal in size. No additional inner ear anomalies were appreciated. On review of systems, it is noted that Victoria is followed in Puerto Rico by Neurology, Genetics, Endocrinology, ENT, Ophthalmology, Audiology, Rehabilitation Medicine and Gastroenterology. Her Parents note that she remains on trach on room air and she suctioned every five minutes to several hours. She has had no history of aspiration pneumonias. She had a normal echocardiogram and EKG in May of 2014 and has had no cardiac concerns. She had a normal abdominal ultrasound in May of 2014. She was diagnosed with hypothyroidism in the NICU and is currently on replacement therapy with Synthroid. Testing apparently has not revealed any other hypothalamic or pituitary dysfunction. Victoria was transfused on at least two occasions in the NICU. She also was treated with several courses of antibiotics but has not had any infections since being discharged home. As noted above, her review of systems was positive for weight gain, visual abnormalities, difficulty swallowing, muscle weakness, inability to speak, myoctonus in sleep, trach with need for suctioning and she also has splints of her hands and feet and a soft body brace. Her review of systems is negative for ear infections, head injuries, sore throat, heart palpitations, or chest pains, episodes of fainting or passing out, abdominal pain, constipation, diarrhea, headaches, seizures, rashes, changes in mood or temper or urinary difficulties. She has had no skin, lymphatic, hematologic, immunologic or infectious disorders reported Hospitalizations: Initial NICU hospitalization. A second hospitalization last week in Puerto Rico for a question of fever and pneumonia. Testing was negative and she was discharged after an overnight stay. Surgeries: Gastrostomy tube, tracheostomy tube, fundoplication. Birth history: As above in HPI. Developmental History: Gross developmental delays as described above in HPI. Medications: Synthroid 25 meg daily. Allergies: None, SOCIAL HISTORY: Victoria lives with her parents in Puerto Rico. Mother's English is very good, while her father does not speak English and her mother served as the interpreter. Her mother has a Master's THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815377BCHMRN: 479-92-70 MEDINA, VICTORIA 5/9/2014 2 years Female Ambulatory Documentation nerve exam, Victoria had normal lid creases and did not appear to have ptosis. With bright light, her eyes became more superducted and the iris disappeared under non-ptotic lids. When light was turned off, they dropped down to only slightly elevated position. Her eyes at rest were bilaterally exotropic and hypertropic. With faces or light flashing toys, she tracked intermittently with adduction to just at or past midline, more frequently with the right eye than the left eye. On only rare occasions did she attempt to fixate with her left eye. She did not seem to track vertically and although she further elevated her eyes to bright light, she never depressed them to the midline. | did not witness any aberrant eye movements. She did not blink frequently. When she fell asleep, her eyes remained partially open with no iris visible. The pupils were normal in size, shape and reactivity and there was no evidence of an afferent pupillary defect. Her fundus exam is as per Dr. Hunter's note. Victoria has no movement of her forehead or her cheeks and only very minimal movements of her lips. She had no sucking movements and she kept her mouth slightly opened. | could not be certain that she responded to sounds although she did seem to alert to a bell. She did not clearly respond to touch or prick over the trigeminal distribution. Her facial expression and strengths were decreased bilaterally as. described above. She had absent gag reflex and her sternocleidomastoid and trapezius were weak bilaterally. Her tongue was in the midline and her gag reflex was absent bilaterally. On motor exam, Victoria showed significant and diffuse weakness and hypotonia that was more axial and proximal than distal. She made some mild anti-gravity movements of both legs and her right arm but | did not see antigravity movements of her left arm. Her deep tendon reflexes were 2+ throughout and symmetric in the upper and lower extremities and her toes were downgoing in the left and equivocal in the right. Her sensory testing appeared intact to light touch and to a sharp object in her upper and lower extremities. ASSESSMENT AND PLAN: Victoria is a 14-month-old girl who, by clinical exam and MRI, has a unique syndromic CCDD with absence and/or dysfunction of multiple cranial nerves including 3, likely 4, 7 and likely 5 and 9-12. This results in a complex form of CFEOM, bilateral facial weakness, absent suck, absent swallow, absent gag and a gasping respiratory pattern. Victoria's CFEOM is remarkable among patients | have seen because it appears to affect the inferior division of the oculomotor nerve to a much greater degree than the superior division. In contrast, other forms of CFEOM preferentially affect the inferior division. The functional superior division accounts for her lack of ptosis and together with absence of good inferior division or trochlear function accounts for the superducted eye position. Finally, the intact abducens nerve pulls the eyes into the exotropic position bilaterally. This is notably at odds with both CFEOM type 1 and type 3, in which the eyes are midline or infraducted with limited elevation. While CFEOM type 2 can result in a slightly hypertropic eye position, it is accompanied by significant ptosis. While Victoria does not fit the pattern of any of the currently defined forms of CFEOM, she is closest to CFEOM 3, that results from mutations in TUBB3. With TUBB3 mutations, affected individuals can have CFEOM accompanied by additional cranial nerve dysfunction, arthrogryposis and marked developmental delay. Her TUBB3 gene screening, however, was normal. THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell Yvette Report Request ID: 24815377Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA. DOB/AgelSex: 5/9/2014 2years Female Ambulatory Documentation Degree and is an administrator and the father has a technical degree and is a paramedic. There is no exposure in the house to tobacco smoke. Victoria's mother is currently 16 weeks pregnant and brought this appointment forward from November for this reason. FAMILY HISTORY: Both of Victoria's parents are of Spanish descent but do not believe they are related. Both families have lived in Puerto Rico for several generations. Mother's parents are cousins (second cousins she believes) and she has distant relatives with extra digits and strabismus but no other difficulties. Victoria's paternal grandfather is adopted and his family history is not known. There is no other family history of neurological problems except for migraine headaches in maternal grandmother and seizures during childhood in the maternal uncle. PHYSICAL EXAMINATION: Victoria was initially lying in her stroller in a remarkably hypotonic po: with her right arm flexed secondary to contractures. Her eyes are held in a hypertropic and exotropic Position, and she has no facial movement and a mildly open mouth position. Her trach and G-tube are in place and she is on room air. When awake, her respiratory pattern was often aberrant, with short staccato inhalations. This breathing pattern did not occur when very relaxed or asleep. She had no duskiness or cyanosis. n Her weight today is 11.9 kg (90th percentile) and her length is 78.2 cm (75th percentile). Head circumference is 44 cm (2nd percentile). Of note, the last HC | could find was at her Nov 2014 visit and she was then at the 10%; thus, she may be falling off her curve. Heart rate was 112 and her respiratory rate was irregular as described above. She has significant right positional plagiocephaly. Her right eye was slightly injected and her parents provided lubrication during the visit. Her fundus exam is per Dr. Hunter's note. Her nasal mucosa was not inflamed. Her lips and gums were without lesions although she has not had any teeth erupt yet to date. Her palate was intact but very high and her posterior pharynx was without exudate. Her neck appeared normal with no meningismus and with marked reduction in tone. Her chest was clear to auscultation although she reported frequent suctioning for upper airway transmitted noises. Her cardiovascular exam revealed a regular rate and rhythm without audible murmur. Her Gl examination showed an abdomen that was soft, nontender and without masses. There was no splenomegaly when palpated and her G tube site was without signs of inflammation. Her back and spine showed no abnormalities, with no dimples or hair tufts overlying her spine, She had post-axial polydactyly in the left hand and both feet. She had flexion contractures of the interphalangeal joints in both hands and more mild contractures of her wrists and a 45 degree contracture of her right elbow. Her feet were held in an extorted position without contractures. Her skin was without rashes or neurocutaneous stigmata. On neurologic exam, Victoria was reactive to stimulation with some visual tracking and head turning and limited movement of her right arm and leg. When her speaking trach was put in place, she made "ah" sounds with expiration but no other sounds were heard. When she was asleep, her respirations normalized but she developed irregular myoclonus of her limbs and at times her entire body. On cranial THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell ,Yvette Report Request ID: 24815377* Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female Ambulatory Documentation While Victoria has involvement of multiple cranial nerves, autonomic function seems relatively spared (pupils, cardiac, GI function), and she does not have evidence of general brainstem injury - she has not developed spasticity and hyperrefiecia to suggest CST dysfunction. The absence of cranial nerves in the setting of a relatively normal-appearing brainstem supports an early developmental etiology (4-6 weeks human gestation) for this aspect of her disorder. Of note, she does have subtle non-specific abnormalities of signal intensity in her brainstem and brain suggestive of a metabolic disorder. While metabolic testing has been unrevealing, it may be necessary to revisit this diagnostic category. In addition to multiple CN dysfunction, Victoria has significant developmental delay, hypotonia, and arthrogryposis. While absent eye and facial movement and severe oromotor dysfunction can result in an infant appearing to be more delayed intellectually and socially than they actually are, multiple data points provide evidence that Victoria also has significant cortical dysfunction. She has severe developmental delay, a smalll HC, thin corpus callosum and, on review of DTI, what appears to me to be a paucity of intrahemispheric association fibers. Her EEGs from a year ago also show poorly developed background rhythms. Finally, Victoria's postaxial polydactyly places her disorder in the category of a multi-organ congenital structural birth defect. Victoria's father asked if she might have Mobius syndrome. | explained how this was a label given to many children with different presentations of facial weakness combined with eye movement disorders and typically has no known etiology. Victoria does not meet classic Mobius diagnostic criteria because she has limitations of vertical gaze. Thus she is better classified as syndromic CFEOM. | agree with others that Victoria's findings are most consistent with a recessive or de novo dominant genetic disorder and are not consistent with an in utero hypoxia or ischemia event. To continue her evaluation and to attempt to identify an etiology, | have recommended a repeat EEG to evaluate her background rhythm awake and asleep and to evaluate her sleep myoclonus. This is scheduled for 12:30 p.m. tomorrow after her ORL appointment. She may also need a sleep study in the future to determine her sleep patterns and to make sure she is not desaturating in sleep. Victoria should also undergo a visual evoked potential test and a hearing test to further evaluate her vision and hearing. Patching and potential glossal and strabismus surgery were as per Dr. Hunter's recommendation. Finally, it will be important to follow her head growth to determine if she is beginning to plateau. Finally Victoria and her parents are enrolled in our ongoing research genetics studies of CCDD and we are proceeding on a research basis with exome and if necessary genome sequencing. If these research studies yield findings of interest, we will contact her family to provide CLIA diagnostic testing. THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell, Yvette Report Request ID: 24815377Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/AgelSex: 5/9/2014 2years Female ____ Ambulatory Documentation We would like to see Victoria back at her next scheduled ophthalmology appointment preferably by two years of age. | have invited her parents to please contact me via e-mail or phone if they have questions and also to update us on any new symptoms, worsening of her current symptoms or changes in her clinical status. Thank you again for referring Victoria to us for consultation. If you have questions based on this letter or if new information relevant to her care, please do not hesitate to contact me. Sincerely, Elizabeth C Engle, MD Professor of Neurology and Ophthalmology Boston Children’s Hospital ce: Dr. Jeffry Quinones Pediatrics La Fuente, Town Center Suite 1123 Guayama, Puerto Rico 00784 ce: Janet S Soul, MD 300 Longwood Avenue Boston, MA 02115 THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell, Yvette Report Request ID: 24815377“Boston Children's Hospital BCHMRN: 479-92-70 Patient Name: MEDINA, VICTORIA DOB/Age/Sex: 5/9/2014 2years Female Ambulatory Documentation cc: Dr. David Hunter THIS IS A COPY OF BCH ELECTRONIC MEDICAL RECORD Print Date/Time: 9/9/2016 11:48 EDT Maxwell, Yvette Report Request ID: 24815377