Dysmorphology Core Progress Report January 8, 2013 Kenneth Lyons Jones, M.D. Department of Pediatrics University of California, San Diego School of Medicine San Diego, CA

Specific Aim #1: Assure consistency and accuracy in recognition of FASDs at all CIFASD sites Use the previously established CIFASD physical examination protocol and classification system to perform and/or validate physical examinations of all infants and children who were participants in the CIFASD renewal project who have not previously been examined by the Core examination team. Use the previously established CIFASD examination training protocol to provide on - going training and re-training of local pediatricians/neonatologists/geneticists who are providing preliminary examinations at some CIFASD sites.

Accomplishments and Plans Specific Aim 1 Over the last 6 months we have provided accurate recognition of FASD at two sites in Ukraine. We have been very pleased to note that our examination of children at both sites has been completely consistent with the examinations performed at the time of birth by the pediatrician and geneticist that we have trained. We have also been involved in re-training pediatricians at both sites.

Specific Aim #2: To develop a training DVD to teach physicians to identify the structural features of FAS and to successfully diagnose or rule out that disorder . Will develop a training DVD Will compare effectiveness of that training DVD with a hands-on live training program done by a member of the Dysmorphology core. That will be accomplished by comparing pediatricians who have completed training with the DVD to pediatricians who have been trained by a member of the dysmorphology core. They will be compared based on their ability to correctly identify features of FASD as well as their ability to make a diagnosis of FASD.

Accomplishments and Plans Specific Aim #2 We have developed a 20 minute DVD of a neonate and a 20 minute DVD of a 6 year old child that demonstrates a careful Dysmorphology examination that focuses on minor malformations in structural development. Having shown that this can be developed and that it is effective in training Pediatric residents, we will develop a shorter version which focuses entirely on minor malformations that are diagnostic of FAS.

Specific Aim #3: To develop a methodology whereby long-distance consultation can be provided to physicians and other health care providers in outlying areas throughout the world. Will develop, with the help of the Telemedicine Communications Center at UCSD, a wireless, interactive, audiovisual tele-consultation system that would provide the opportunity for a practitioner in one remote locale to perform a comprehensive examination of a child being evaluated for FASD that could be viewed, commented upon and corrected by an expert dysmorphologist at a central location.

Accomplishments Plans Specific Aim #3 We are in the process of developing various alternative strategies in order to adapt to various geographic locals and population densities. Communicating with physicians in Ukraine in real time would be untenable Having sophisticated telemedicine equipment in remote areas of a country would be economically prohibitive. Those areas could be served in the following ways: 1. Take standard video according to a standard protocol of views 2. Send video to one of two geneticists in Rivne or Khmelnytsky on youtube 3. One of them would communicate with the clinician who sent the video by skype as they were simultaneously watching the video on youtube. 4. During development, all cases would be reviewed by me while discussing with the geneticist in Ukraine.

Accomplishments and Plans Specific Aim #3 In the two or three densely populated areas, sophisticated telemedicine technology will be implemented that will permit consultation regarding physical features of FASD with physicians at those sites, but will also make possible consultation with ultrasonographers who have performed prenatal ultrasound examinations. A digital subscriber line (DSL) exists in Ukraine. A DSl provides digital transmisson over the wires of the local telephone network. The data bit rate (number of bits conveyed or processed per unit of time) for consumer DSL in US typically range from 256 kbits to 40Mbit/sec. Data bit rates in Ukraine are 50Mbit/sec.

  Specific Aim #4: To document the prevalence of major malformations in children prenatally exposed to alcohol, and in so doing, delineate the extent of Alcohol Related Birth Defects (ARBD). For this specific aim the Dysmorphology core will determine the prevalence of ARBD in subjects ascertained through the prospective cohort study in Ukraine.

Accomplishments and Plans Specific Aim #4 12,000 pregnant women have been screened for alcohol consumption during pregnancy in Ukraine at the Rivne and Khmelnitsky sites. Two percent (240) of those women have been documented with heavy alcohol consumption. The newborn records of the children born to those women with heavy alcohol consumption will be screened in order to document the incidence of major birth defects

The Upper Labial Frenulum: Size and Variability In Normal Children and in Children with the Fetal Alcohol Syndrome Mikael Gold, Christina D. Chambers, Kenneth Lyons Jones Division of Dysmorphology/Teratology University of California, San Diego School of Medicine La Jolla, California

Alcohol’s Effect On Developing Face and Brain Face and forebrain of a normal Day 11 mouse embryo Three embryos affected to differing degrees by maternal ethanol treatment on Day 7. Note variability and loss of the "midline" tissues: abnormally close proximity of the nostrils, with absence of portions of the medial nasal prominences (m); abnormal proximity of the ganglionic eminences (g); and absence of the septal region (s). Modified from Sulik et al.

Purpose To document measurements of the volume of the upper labial frenulum in children prenatally exposed to alcohol compared to normal children Given the fact that alcohol on day 7 in a mouse causes holoprosencephaly, that FAS and holoprosencephaly in humans have similar facial features (Smooth philtrum and thin vermillion border), and that humans with holoprosencephaly lack their upper labial frenulum, we hypothesized that children with FAS would lack a frenulum or would have hypoplasia of their frenulum. In that measurement of the frenulum requires that the upper lip be everted with subsequent elongation and thinning of the frenulum we concluded that volume of the frenulum would be the best measure.

Methods The upper lip is extended and the cross sectional area of the frenulum is photographed using an Aranz Silhouette camera Embedded lasers shine on the mucosal surface which detect and then calibrate the image using computer software

With this image an area is calculated

Methods In addition, the width of the frenulum across the midline was measured using the frontal view Using both the area and the width of the frenulum, the volume was automatically calculated using the computer software

Subjects 22 children were evaluated In all cases the examiner was blinded to maternal alcohol exposure 7 were subsequently diagnosed as FAS 3 were subsequently diagnosed as PFAS 12 were diagnosed as No FAS, their mothers did not drink alcohol during pregnancy and they were classified as Normal Controls

Background FAS (N=7) AGE: (mean/range) 7yrs. (5-12) GENDER: F=5; M=2 ETHNICITY: African Amer = 4; White = 3 PFAS (N=3) AGE: (mean/range) 8yrs. (6-11) GENDER: F=1; M=2 ETHNICITY: African Amer = 1; White = 2 NORMAL CONTROLS (N=12) AGE: (mean/range) 11yrs ( 8-17) GENDER: F=5; M=7 ETHYNICITY: African Amer= 8; White=4

Volume of Labial Frenulum FAS: (N=7) Mean Volume: 32mm3 PFAS: (N=3) Mean Volume: 37mm3 Normal Controls: (N=12) Mean Volume: 71mm3

Conclusion and Summary A much larger sample size is clearly necessary to conclude with statistical significance that children with FAS have a decreased volume of their superior labial frenulum Decreased size of the upper labial frenulum should not be thought of as specific to prenatal alcohol exposure. Rather it should be considered a minor malformation indicative of an early defect in frontal brain development due to any cause. This observation provides the opportunity to consider the extent to which defects in facial development are a reflection of a defect in frontal brain development

Volume of Frenulum in Normal Controls by age 5 to 8 year olds – 63 mm3 9 to 12 year olds - 83 mm3 12 to 17 year olds – 79mm3