2002 David W. Smith Workshop on Malformation and Morphogenesis

Following is the itinuary of the workshop held August 7-12, 2002 in Clemson, South Carolina which featured Kabuki syndrome as one of it's main topics:

Friday Morning Kabuki Syndrome I Moderators: Judith Allanson & Connie Schrander-Stumpel

8:30 Linlea Armstrong: Kabuki Syndrome: A Collection of Your Patients

8:50     Dian Donnai: Kabuki Syndrome: Lessons from Longitudinal Patient Studies

9:10     Stavit Shalev: 12 Year Follow-Up of Individuals with Kabuki Syndrome that were the First Affected Children Presented at the D.W. Smith Meeting

9:25     Connie Schrander-Stupel: Kabuki Syndrome: Clinical Data in 21 Patients, Literature Review and Guidelines for Preventive Management

Friday Morning Kabuki Syndrome II Moderators: Judith Allanson & Connie Schrander-Stumpel

10:15     Keith Vaux: The Neonatal Phenotype of Kabuki Syndrome

10:30     Kathleen Leppig: Is Craniosynostosis Part of Kabuki Syndrome?

10:45     Angela Lin: Cardiovascular Malformations (CVMs) in Kabuki Syndrome (KS): Practical, Hierachical and Frequency-Based Analysis

11:00     Louanne Hudgins: Developmental Outcome in Kabuki Syndrome

11:15     Colleen Morris: Cognitive and Adaptive Behavior in Kabuki Syndrome

11:30     Albert Chudley: Kabuki Syndrome Network Survey Results. The Frequency of Birth Defects and Neurobehavioral and Social Challenges

11:45     Jeffrey Ming: Immune Dysfunction in Kabuki Syndrome

Friday Evening Special Presentation by Larry Shapiro Moderators: Marilyn Jones & Dian Donnai

Posters with Brief Presentations

Helga Toriello: Nocturnal Lagophthalmos in Kabuki Syndrome: Results of a Parent Group Survey

Micheil Innes: Polydactyly in Two Unrelated Patients with Kabuki Syndrome

Mark Hannibal: Hypoplastic Left Heart Syndrome Variant in Two Patients with Kabuki Syndrome

Alison Elliott: Cenani-Lenz Syndactyly in a Patient with Kabuki Syndrome

Suzanne Cassidy: Probably Kabuki Syndrome in a 32 Year Old Adult: Does Connective Tissue Involvement Worsen?


Marc Williams: Overlap of Clinical Features of Kabuki Syndrome and Branchio-Oto-Renal Syndrome: Contiguous Gene

Syndrome, Locus Heterogenety or Coincidence?

Mark Hannibal et al: Hypoplastic Left Heart Syndrome Variant in Two Patients with Kabuki Syndrome

Alison Elliott et al: Cenani-Lenz Syndactyly in a Patient with Kabuki Syndrome

Micheil Innes et al: Polydactyly in Two Unrelated Patient with Kabuki Syndrome

Helga Toriello et al: Nocturnal Lagophthalmos in Kabuki Syndrome: Results of a Parent Group Survey

Suzanne Cassidy et al: Probably Kabuki Syndrome in a 32 Year Old Adult: Does Connective Tissue Involvement Worsen?

Elizabeth McPherson: Paternal Age in Kabuki Syndrome: Further Evidence for Autosomal Dominant Inheritance

Note: Look for Dr. Ming's summary of conference presentations in the next Kabuki Journal issue

(Dec 2002).


Speech Study

Submitted to KSN's website by Sheila Upton on May 2001:

The Department of Human Genetics at the University of Maryland has completed its study evaluating speech characteristics in children with Kabuki syndrome both with and without cleft lip and/or cleft palate. Thank you very much to all those families who participated. We have finished the study and are in the process of publishing our findings. As soon as we have done this, we hope to put a posting in the Kabuki Journal newsletter summarizing our results.

Note: Study will be published next month (August 2002).


Kabuki Syndrome Genetic Research

Submitted to KSN's website by Karen L. Russell, M.S. on April 2000:

Researchers at The Children's Hospital of Philadelphia are interested in identifying the genetic etiology of Kabuki syndrome. They are collecting blood from individuals who have been clinically diagnosed with Kabuki syndrome and their parents, along with a clinical summary, family pedigree and photographs. There is no cost to participate and all information is kept confidential. For further information, please contact:

Karen L. Russell, M.S.
Certified Genetic Counselor
The Children's Hospital of Philadelphia
Clinical Genetics Center
34th St. and Civic Center Ave.
Philadelphia, PA 19104
Ph# 215-590-2920
Fax# 215-590-3298

Dr. Ming and Karen Russell are in the Division of Human Genetics at The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine. They and their colleagues have seen approximately 14 children with Kabuki syndrome. They are very interested in understanding what genes are involved in causing Kabuki syndrome.

Excerpt from letter from Dr. Ming (July 2002) to KSN in regards to study:

The goal of our research is to identify the gene that is involved in Kabuki syndrome. Finding the gene will help us understand what causes the different medical problems in the children. It could also potentially lead to new ways to think about treatment in the future. In addition, knowing what the gene is would be helpful for diagnosing those children in whom the diagnosis of KS is not clear. It could also provide information for recurrence risk for future pregnancies.

With some genetic syndromes, some of the children have a chromosomal difference that is picked up on routine chromosome analysis. For example, in some conditions, a proportion of children have part of one chromosome missing. We conclude from this that this chromosomal region must contain the gene or genes that are responsible for the syndrome. Once the part of the chromosome that is missing is identified, we can begin to see what genes in this region might be related to the syndrome. For KS, differences in several chromosomal regions have been noted. So, it is difficult to know for sure which chromosome has the KS gene. In our research, we are trying to see if there are consistent subtle differences in the chromosomes present in the KS children. Once we can find the chromosomal region that is involved, we can then narrow down the possible genes. We are performing the research with the samples that have been very generously provided by many of the families in KSN, including yours.

Our work is still in the early stages. We are actively working on the research now and are obtaining data from our studies. These early stages of research are important for laying the groundwork that is important for future advances. I wish I could tell you how long the research will take or when we will be able to identify the gene, but it is difficult to say. These studies do take a fair amount of time to do. Unfortunately, the rate of progress in research is very unpredictable. Sometimes the chromosomal region and gene can be found relatively quickly, and other times it takes many years.

As you know, there is a meeting next week that has KS as one of its main topics. There will be a number of geneticists there who have an interest in KS. Hopefully, we will all be able to collaborate on these studies. Certainly, the more samples that are available, the better chance we have of finding an important clue for figuring out the gene.


Sleeping with Eyes Open Study

The following abstract has been submitted to the 2002 David W. Smith Workshop on Malformations and Morphogenesis in Clemson, South Carolina (Aug 7-12) by Dr. Helga Toriello:


Helga V. Toriello, PhD1 and Patrick Droste, MD2

1Genetics Services and 2Department of Ophthalmology, Spectrum Health, Grand Rapids, MI

At the 2000 Smith Meeting in San Diego, we presented a poster noting that close to half of the parents of children with Kabuki syndrome reported that their children slept with their eyes open (nocturnal lagophthalmos). That prompted a follow up study to obtain more details about this phenomenon, particularly whether these children experienced any secondary complications.

In 2001, the Kabuki Syndrome Network sent a questionnaire to the members of the organization requesting information on various medical and developmental problems in these children. One of the questions asked if the child slept with his or her eyes open and required a yes or no answer. Of the 53 families who returned completed questionnaires, 51 responded to the “eyes open” question, with 36 responding that their child did sleep with the eyes open (72%). The 36 who responded positively were then sent more specific questionnaires asking for more details. Questions were posed regarding the child’s age when this was first noticed, the degree of aperture, frequency, and possible complications. To date sixteen families have responded. In general, approximately half (7/16) of the children were noted to have this finding before the age of 1 year, most (11/16) were reported to sleep with the eyes open every night, almost all (15/16) had openings of one quarter or greater, and only 6/16 reported possible complications, including keratitis or conjunctivitis.

We believe this is a frequent finding in Kabuki syndrome, which may precede the clinical phenotype becoming apparent. It occurs often enough to be a clue to diagnosis, particularly in younger children in whom the phenotype is less clear. In addition, ocular complications occasionally occur and families should be counseled to bring this to the attention of the child’s ophthalmologist.


Language/Behavioral Study

This study is being done by Dr. Schrander-Stumpel and Dr. Curfs through the Institution for Clinical Genetics of South-East Netherlands, the Universities of Nijmegen & Tilburg in the Netherlands, and the Universities of Gent and Leuven in Belgium.

The topics covered by the research are:

The emphasis has been on the first two.

The results have not yet been published but will be presented at the David Smith Workshop on Aug. 7-11.

Dr. Schrander? will also present a review of the 260 or so Kabuki cases in past published literature. This review was a joint effort of Dr. C. Schrander-Stumpel, Dr. J. Schrander, H. vande Ven, Prof. H. van der Vugt, Dr. T. Defloor, and Prof. L. Curfs.


Japanese Study

Due to language barriers I am not always so clear on what studies are being done in Japan. Here is what I know: Toshinobu Ozeki, who has a daughter with Kabuki, has started a Kabuki Syndrome Network in Japan. There are now 9 families involved. He translated the website and, more recently, KSN's survey results. The members requested that he continue to provide translations of any information available, especially in regards to behavior. No surprise?! He therefore asked his members to complete the Developmental, Neurological, and Sensory sections of KSN's survey and sent the results to us for comparison. See below - KSN's Survey Results.

On July 26, 2002 a study/conference was held called "The Study of Kabuki Make-Up Syndrome" in Saitama prefecture in Japan. The lecturer was Dr. Ohashi, who has co-authored several articles on Kabuki. Five of Japan's KSN members were involved.


KSN's Survey

A comprehensive questionnaire was mailed to 200+ families, 53 were completed. The percentages reflect the number of families who answered 'yes' for that particular characteristic. Most fields had 3 choices - yes, no, or unknown. Please keep in mind this is an informal survey, completed mostly by parents. 'Unknown' was chosen for many of the fields, either because the parent did not know if their child had the characteristic or the child is still too young.

Dr. Albert Chudley from the University of Manitoba Children's Hospital will present the results of KSN's survey at the David Smith Workshop. Following is his abstract, which is then followed by the results of KSN's survey.

Kabuki Syndrome Network Survey results. the frequency of birth defects and neurobehavioral and social challenges

Albert E. Chudley1, Bernard N. Chodirker1, Maureen Loftus2, Margot Schmiedge2, and members of the KSN.

1Section of Genetics and Metabolism, Children’s Hospital and University of Manitoba, Winnipeg, MB R3A 1R9. Ph# 204-787-4743 Email: achudley@hsc.mb.ca and 2Kabuki Syndrome Network

Parent and professional support groups are an important resource for families who have children with MCA and family physicians and other health care providers. In 2001, members of the Kabuki Syndrome (KS) Network, a support group for families of individuals with KS were surveyed by means of a questionnaire sent via e-mail or regular mail. The survey was to determine the frequency of various features in KS. 285 potentially present KS features were listed on the questionnaire and parents were asked to respond "Yes", "No" or "Unknown". 215 questionnaires were sent out and 53 were returned. The results were entered into an Access database for analysis. The frequency of a characteristic was calculated as number of "Yes" responses divided by the total number of responses excluding the "unknown" or non-applicable responses. Preliminary results were published on the KS network website (www.kabukisyndrome.com)

The mean age of the KS cases was 8.3 years with the age range from 1.2 to 29 years. 29 of 53 case were female. 98% were seen by a specialist in the area. 88% had chromosomal studies done. The most common facial/ cranial features identified include prominent ears (87%), long palpebral fissures (84%), highly arched palate (84%), thick eyelashes (76%), missing teeth (73%) and arched eyebrows (71%). Many showed fine motor delay (92%), gross motor delay (90%), hypotonia (87%), intellectual disability (85%), speech delay (82%), delayed toilet training (82%), tactile defensiveness (78%), excellent memory (75%), motor planning delay (73%) and sensory motor integration delay (71%). Sleeping with the eyes open (71%), decreased muscle tone (87%), small stature (75%), increased range of motion of joints (72%), poor sucking (78%) and abnormal finger pads (84%). 81% of cases were said to have a urogenital abnormality of any type and a small penis, was seen in 29% of males. 71% were said to have a hematological or immunological abnormality of which frequent infections (67%) were the most common. 64% reported cardiac anomalies: a murmur reported in 50%; and a VSD reported in 27%. KS cases were often said to have a happy disposition (89%), 75% were said to like routine. Poor eye contact (57%), excessive need for routines (55%), obsessions (55%), extreme sensitivity (47%), talks to self (53%) and repeating words or phrases (45%) were reported.

Although there are many limitations of this type of survey, these findings do represent an important contribution. For example, our own center used this database to determine the frequency of polydactyly/oligodactyly after our own encounter with KS patients with these features. No additional cases were identified confirming this to be a rare occurrence. It is clear KS is often associated with significant neurobehavioral and social problems in childhood including autistic-like behaviors.

KSN's Survey Results


53 Clients:
29 females, 24 males
Average age of birth: 1993
Surveys completed in 2001

Japanese results included for Developmental & Neurological sections

9 Japanese clients: average age 5 years, 3 months



Red face rashes: 25%

Small nails: 38%

Brittle nails: 26%

General hirsutism: 23%

Café au lait macules: 19%

Pygmentary dysplasia: 11%

Moles: 36%

Chalazion: 6%


Prominent ears: 87%

Low set ears: 42%

Prosteriorly Rotated Ears: 21%

Pre auricular dimple: 15%

Malformed pinnae/ears: 40%

Blue sclerae: 51%

Long palpebral fissures: 81%

Lower palpebral eversion: 49%

Arched eyebrows: 70%

Lateral thinning: 47%

Thick eyelashes: 72%

Ptosis: 45%

Droopy skin under eyes: 15%

Long philtrum: 23%

Trapezoid philtrum: 9%

Short nasal septum: 34%

Flat nasal bridge: 64%

Broad nasal root: 34%

Epicanthus: 38%

Mandibular hypoplasia: 17%

Retrognathia: 19%

Micrognathia: 26%

Overcrowding of Teeth: 19%

Widely spaced teeth: 55%

Missing teeth: 62%

Irregularly spaced teeth: 51%

Many cavities: 13%

Cleft lip: 4%

Cleft palate: 19%

Highly arched palate: 79%

Submucosal cleft palate: 21%

Bifid uvula: 21%

Velopharyngeal incompetence: 25%

Low posterior hairline: 38%

Clogged tear ducts: 25%

Pilli torti: 8%

Nasal tone to speech: 53%

Small head size: 40%


Sleeps w/ eyes open: 68%

Divergent squint: 19%

Strabismus: 47%

Nystagmus: 11%

Esotropia: 19%

Exotropia: 8%

Amblyopia: 30%

Corneal Abnormalities: 9%

Near sighted: 26%

Far sighted: 30%

Cleft optic nerve: 0%

Coloboma of the iris: 0%

Coloboma of the optic nerve: 2%

Optic nerve atrophy: 0%

Micro-opthalmia: 2%

Astigmatism: 21%

Cataracts: 0 %

Lens Abnormalities: 4%


Hearing Loss - Conductive: 32%

Hearing Loss - Sensorynueral: 28%

Hearing Loss - Progressive: 11%

Perforated Ear Drums: 40%


Respiratory Infections: 43%

Narrow Windpipe: 2%

Pulmonary Lymphangiectasia: 2%

Tracheomalacia: 4%

Laryngo Malacia: 4%

Asthma: 11%

Reactive Airway Disease: 9%

Broncho Pulmonary dysplasia: 2%

Bronchiectasis: 6%


Heart murmur: 49%

Interrupted aortic arch: 0%

Coarctation of aorta: 11%

Ventricular septal defect (VSD): 25%

Atrial septal defect (ASD): 15%

Patent ductus arteriosus (PDA): 6%

Double outlet right ventricle: 2%

Wolff-Parkinson-White Syndrome: 2%

Aortic valve abnormality: 8%

Tetralogy of fallot: 2%

Pulmonary artery atresia: 0%

Mitrial valve abnormality: 4%

Aortic hypoplasia: 2%

Hypoplastic left heart syndrome: 0%

Long QT syndrome: 0%

Pulmonic valve abnormality: 2%

Anomalous pulmonary venous return: 2%

Transposition of great vessels: 0%

Atrium abnormalities: 0%

Single ventricle: 0%

Subclavian vein abnormailities: 0%

Arrhythmia: 6%


Intellectual disability: 77%

Excellent memory: 62%

Attention Deficit: 42%

Dyslexia: 6%

Hyperactivity: 30%

Visual Motor Integration Delay: 51% Japan: 89%

Sensory/Motor Integration Delay: 58% Japan: 67%

Auditory Processing Difficulty: 34% Japan: 0%

Motor Planning Delay: 57% Japan: 22%

Gross Motor Delay: 83% Japan: 67%

Hypotonia/floppiness: 85% Japan: 78%

Hypertonia/Muscle stiffness: 8%

Dyspraxia of hands: 19%

Jaw winking: 9%

Synkinesis: 8%

Walks with wide based Stance: 40% Japan: 0%

Fine Motor Delay: 91% Japan: 56%

Speech Delay/no Speech: 75% Japan: 67%

Uses signing: 23% Japan: 0%

Stuttering: 9% Japan: 0%

Seizures: 30%

Muscle Spasms: 15%

Body Temp abnormalities: 23%

Recurrent fevers of unknown origin: 13%

Needs less sleep: 19%

How long does client sleep at night: 10 hours

Wakes up Often: 36%

How Often per Night: 3 times/night

Apnea: 15%

Hydrocephalus: 2%

3rd ventricle brain cyst: 2%

Other brain abnormalities: 11%

Neural tube defect: 2%

Spinal bifida Occulta: 4%

Dimple or sinus in tailbone/sacral area: 42%

Facial palsy/weakness: 13% Japan: 0%

Excessive drooling: 43% Japan: 78%

Delayed toilet training: 75% Japan: 56%

High pain threshold: 51% Japan: 56%


Decreased Spatial Awareness: 51%

Tactile defensive: 72% Japan: 44%

Chews on non-food items: 66% Japan: 56%

Food aversions: 60% Japan: 11%

Very selective in diet: 68% Japan: 44%

Decreased body awareness: 58%

Sensitivity to loud noises: 57% Japan: 78%

Self stimulatory behaviors: 47% Japan: 100%


Growth Hormone Deficiency: 9%

Short stature: 64%

Obesity: 15%

Failure to Thrive: 58%

Hypothyroidism: 2%

Hypoglycemia: 8%

Hyperinsulinism: 0%

Polyglandular AutoImmune Disease: 0%

Diabetes: 0%

Full Areolae: 13%

Premature Thelarche: 21%

Precocious Puberty: 6%

Early Menstruation: 2%

Irregular Menstruation: 4%


Immune Thrombocytopenic Purpura: 6%

Petechiae: 6%

AutoImmune Hemolytic Anemia: 4%

Anemia: 9%

IgA deficiency: 4%

Hypogammaglobulinemia: 4%

Immune Deficiency: 13%

Allergies: 34%

Frequent infections: 64%

What type: 53% ear, 28% respiratory, 2% eye, 8% gastro, 4% urinary

Ever require hospitalization for infections: 34%


Finger pads: 77%

Increase of ulnar loops: 23%

Absence of digital triadius c: 4% (many 'unknowns')

Absence of digital triadius d: 2% (many 'unknowns')

Increase of hypothenar loops: 6% (many 'unknowns')


Has Client been seen by a Specialist in this area?: 96%

Chromosomal analysis done?: 83%


Poor Sucking: 75%

Difficulty coordinating breathing, sucking and swallowing: 60%

Gags / Vomits while eating: 64%

Projectile vomiting: 34%

Low esophageal tone: 19%

Regurgitation: 23%

Reflux: 42%

G-Tube: 26%

Horizontal Stomach: 0%

Enlarged liver: 8%

Eventration of the diaphragm: 11%

Hernias: 21%

Intestinal absorption anomalies: 15%

Malrotation of intestines / colon: 4%

Imperforate anus: 4%

Constipation: 47%

Extreme pain while stooling: 25%


Electrolyte Imbalance: 8%

Structural renal abnormalities: 26%

Blocked kidney: 8%

Missing kidney: 2%

Extra kidneys: 4%

Pelvic kidney: 6%

Fused kidneys: 0%

Horseshoe shaped kidney: 8%

Enlarged kidney pelvis: 8%

Cross fused ectopic kidneys: 2%

Hydronephrosis of kidneys: 13%

Dual collection system: 8%

Kidney stones: 4%

Bladder Reflux: 11%

Bladder infections: 11%

Double urinary tract: 0%

Urethral reflux: 6%

Urethral abnormalities: 9%

One undescended testes: 8%

Two undescended testes: 8%

Wide set nipples: 25%

Umbilical cord abnormalities: 21%

Small penis: 13%

Hypospadias: 6%

Labial adhesion: 6%


Small stature: 74%

One side of body smaller than other: 2%

Decreased muscle tone: 85%

Decreased muscle strength: 62%

Increased range of joint motion: 68%

Dislocating joints: 25%

Osteoporosis: 0%

Delayed bone growth: 23%

Arthritis: 2%

Craniosynostosis: 13%

Coronal synostosis: 0%

Metopic synostosis: 0%

Jaw dislocations: 4%

Missing ribs: 4%

Other rib anomalies: 4%

Pectus carinatum: 4%

Pectus excavatum: 19%

Other sternum anomalies: 4%

Scoliosis: 19%

Kyphosis: 9%

Cervical spine deformities: 6%

Tethered cord: 0%

Other spine anomalies: 17%

Hip dislocations: 21%

Hip dysplasia: 25%

Subluxed hips: 17%

Kneecap dislocations: 13%

Missing knee ligament: 2%

Clinodactyly: 47%

Short 5th finger: 60%

Short phalanges: 47%

Extra finger or toes: 0%

Webbed finger or toes: 2%

Flat footed: 45%

Club foot: 2%

Pronated feet: 25%


Head Control: 7 months Japan: 5 months

Roll: 14 months Japan: 7 months

Sit: 12 months Japan: 13 months

Pull to Stand: 18 months Japan: 16 months

Walk: 26 months Japan: 28 months

First Words: 24 months Japan: 23 months

Feed Self: 38 months Japan: 33 months

Dress Self: 60 months (5yrs) Japan: 35 months

Pull On Socks: 63 months (5+yrs) Japan: 36 months

Button: 85 months (7+yrs) Japan: 39 months

Zipper: 89 months (7+yrs) Japan: 43 months

Tie Shoes: 110 months (9+yrs) Japan: 60 months

Toilet Trained Daytime: 52 months (4+yrs) Japan: 41 months

Toilet Trained Evenings: 68 months (5+yrs) Japan: 39 months

Hop on One Foot: 75 months (6+yrs) ) Japan: 37 months

Skip: 77 months (6+yrs) ) Japan: 54 months

Pedal: 68 months (5+yrs) ) Japan: 42 months


Signing: 19% Japan: 56 %

Communication Boards: 11% Japan: 11%

Gestures: 25% Japan: 22%


Tantrums: 34% Japan: 44%

Extremely hard to calm down when crying: 40% Japan: 33%

Excessive need to know routine: 55% Japan: 67%

Likes Routine: 74% Japan: 67%

Minimal interaction with others: 32% Japan: 11%

Very social: 57% Japan: 67%

Poor eye contact: 57% Japan: 11%

Obsessive over some things: 55% Japan: 67%

Happy disposition: 87% Japan: 89%

Extremely sensitive: 47% Japan: 33%

Excessive need for affection: 26% Japan: 0%

Excessive need for constant praise for motivation: 28% Japan: 11%

Self injurious behaviors: 19% Japan: 0%

Talks to self: 53% Japan: 56%

Repeats certain phrases/words over and over: 45% Japan: 56%