Patient

I

II

III

IV

V

Gender and age

Female, 2 yrs. 2
mOS.

Male, 5 yrs. 7 mos.

Male, 7 mos.

Female, 5 yrs.

Male, 3 yrs. 3 mos.

Pregnancy, term and mechanism of birth

1st pregnancy; detached placenta V 1.m. 39 g.w.
Emergency CS

3rd pregnancy; no abnormalities 39+6 g.w. PVN

1st pregnancy; 41 g.w.
Emergency CS (heart rate decelerations)

2nd pregnancy; 38 g.w., planned CS (maternal indications)

2nd pregnancy; IUGR; 35 g.w.,
Emergency CS (heart deceleration)

Neonatal period

No pathological findings

No pathological findings

Neonatal depression, muscular hy- potonia, heart murmur with left-to- right shunt and pulmonary stenosis

Neonatal depression; muscle hypotonia; atypical, mild pulmonary stenosis, systolic murmur, persistent foramen ovale

Hemodynamically insignificant foramen ovale

Anthropometric indicators at birth (WHO)

Weight

4th percentile, (-1.73 z-score)

17th percentile, (-0.96 z- score)

7th percentile, (-1.47 z-score)

15th percentile, (-1.03z-score)

<1st percentile, (-2.95 z-score)

Height

5th percentile, (-1.69 z-score)

52nd percentile, (0.06 z- score)

5th percentile, (-1.64 z-score)

27th percentile, (-0.62 z-score)

no data

Head circumference

37th percentile, (-0.32 z-score)

no data

17th percentile, (-0.95 z-score)

37th percentile, (-0.32 z-score)

no data

BMI

9th percentile, (-1.33 z-score)

6th percentile, (-1.55 z- score)

19th percentile, (-0.89 z-score)

15th percentile, (-1.05 z-score)

no data

Current Anthro- pometric Indicators (WHO)

Weight

27th percentile, (-0.47 z-score)

1st percentile, (-2.55 z- score)

<1st percentile, (-2.18 z-score)

9th percentile, (-1.34 z-score)

3rd percentile, (-1.85 z-score)

Height

25th percentile, (-0.87 z-score)

22nd percentile, (-0.76 z- score)

<10th
percentile,
(-1.27 z-score)

19th percentile, (-0.88 z-score)

39th percentile, (-0.27 z-score)

Head circumference (Hesse)

33rd percentile, (-0.45 z-score)

34th percentile, (-0.40 z- score)

44th percentile, (-0.14 z-score)

51st percentile, (-0.02 z-score)

5th percentile, (-1.64 z-score)

BMI

44th percentile, (-0.17 z-score)

<1st percentile, (-3.30 z- score)

42nd percentile,
(-0.19 z-score)

16th percentile, (-0.98 z-score)

<1st percentile, (-2.87 z-score)

Anthropometric indicators according to the adapted nomograms for UiB

Weight

around the mean percentile of the normal weight-to- age chart

below the mean but above the lower limit of the percentile range of the normal weight-to-age chart

above the mean percentile of the normal weight-to-age chart

within the lower half of the of the normal range on weight-to-age chart between the mean and -2SD

within the lower half of the percentile range, between the mean of the weight-to- age chart and -2SD

Height

around the mean percentile of the normal height-to- age chart

slightly above the mean percentile of the normal height-to-age chart

around the mean percentile of the normal height-to-age chart

around the mean percentile of the normal height-to- age chart

above the mean percentile of the normal height-to- age chart (between themean and +2SD values)

Head circum- ference (HC)

above the mean percentile of the normal HC-to-age chart

around the upper percentile range (+2SD) of the normal HC-to-age chart

slightly above the upper percentile range (+2SD) of the normal HC- to-age chart

within upper half of the percentile range (between the mean and +2SD values)

within upper half of the percentile range (between the mean and +2SD values)

Molecular genetic confirmation of the diagnosis

At the age of 2 years Screening for microdeletions

At the age of 4 years Screening for microdeletions

at 3 months Targeted analysis

at 4 months Targeted analysis

At the age of 3 yearsTargeted analysis

Phenotype

Typical for infants with WBS facial phenotype; synophrys; Dentition - 1st tooth at the age of 6 mos. diastema, microdontia

Typical for infants with WBS facial phenotype; bilateral epican- thus; Dentition - 1st tooth at 1 year + 7 months; diastema; microdontia

Typical for infants with WBS facial phenotype with a well distinguished stellar iris pattern; bilateral epicanthusi Dentition - absent

Typical for infants with WBS facial phenotype with a well distinguished stellar iris pattern; bilateral epicanthus; diastema, microdontia

Typical for infants with WBS with sparse stellar pattern of the iris, bilateral epicanthus, diastema, microdontia

Neurological and mental development

Started walking — at 20 months; Fine motor skills - impairment;
Speech understands when talked to, has difficulties in formulating entire phrases.

Started walking — at 4 yrs. Fine motor skills impaired; Speech - understands and answers questions, but has difficulty formulating whole words and phrases; Muscular hypotonia, highly vivid reflexes;

Active back tummy rolling; actively crawls; tracks objects; grasps objects actively and steadily; makes baby sounds; Increased muscle tone of the limbs, brisk tendon reflexes up to clonus of the feet

Started walking — at 2 yrs., after rehabilitation; Speech - first words at 2-yrs., very advanced, formulates sentences, communicates verbally, recites, sings, works with a speech therapist; Fine motor skills - difficult; Very advanced development in all areas for WBS;

Started walking - at 16 mos. Fine motor skills - impaired; First words - at 2 yrs., intonation is age adjusted, well developed.

Cardiovascular system

CVS - no pathological findings; BP not measured

CVS - no pathological findings; BP not measured

Cvs -
pulmonary stenosisi mild valvular pulmonary stenosis and bifurcation stenosis; BP not measured

CVS - pulmonary stenosis improv- ing with age and SVAS; BP — not
measured

CVS - foramen ovale (closed); BP - not measured

Gastrointestinal tract

No complaints

Feed difhculties - accepts only pureed foods, struggling with solids; Constipation

Feeding difficulties - rejects lumpy foods, eats slowly; frequent regur- gitation.

Feeding - requires more patience and time; the transition to some new foods takes longer.

Feeding difhculties in transition to solid foods in infancy, has trouble with textures such as fruits and purees, eats very well on biscuit-lilce foods. Tendency to constipation

Genitourinary system

A normal find

Cryptorchidism bilaterally; Ultrasound well differentiated pyra- mids, medullary nephrocalcinosis, unilateral hydronephrosis 1st degree

No data

Consistent follow- up; subtle bilateral nephrolithiasis

Primary nocturnal enuresis; normal findings on Ultrasound

Endocrine system; Calcium, Vitamin D, TSH

Calcium and phosphate homeosta- sis - normal; TSH — increased, with normal values of FT3/FT4 —
monitored

Hypercalcemia, hypercalciuria; Clinical hypothyroidism Hypovitaminosis D

Calcium and phosphate homeostasis normal; TSH — normal.

Calcium and phosphate homeosta- sis - normal; TSH — normal.
Hypovitaminosis D

Calcium and phosphate homeostasis - normal; TSH - no data.
Hypovitaminosis
D.

Connective tissue

Joint hypermobility

surgically repaired unilateral ingui- na1 hernia; Joint hypermobility

Joint hypermobility

surgically repaired bilateral ingui- nal hernias and
umbilical hernia; Joint hypermobility

surgically repaired umbilical hernia; Joint hypermobility

Vision and hearing

Hearing and vision not impaired, no medical data records available

Hearing and vision not impaired, no medical data records available

Hearing and vision not impaired, no medical data records available; hyperacusis

Vision - initial signs of myopia; hearing - not impaired; hyperacusis

Hearing and vision not impaired, no medical data records available; hyperacusis

Behavioral features

Loves music; Sleep difficulties; Hyperactivity

Loves music, plays with other children with pleasure; Previously sleep difficulties, resolved by still ongoing therapy: falls asleep more easily and sleeps through the night;

Sleep problems (difficulties in fall- ing asleep and sleeping through the night); Hyperactivity

Loves music; No sleep problems; very communicative and friendly; Hyperactivity; attention deficit

Loves music; Hyperactivity

Time since counseling

24months

17 months

16 months

11 months

9 months

Outcomes añer genetic counseling

Comprehensive parent education in WBS features and necessary followup schedule. Detailed plan for lifelong follow up for parents and pediatricians prepared.Individual growth charts for followup by the pediatrician prepared. Annual followup evaluation. Family further planning counseled.

Comprehensive parent education in WBS features and necessary followup schedule.
Detailed plan for lifelong followup for parents and pediatricians prepared.Individual growth charts for follow- up by the pediatrician prepared.

Comprehensive parent education in WBS features and necessary followup schedule.
Detailed plan for lifelong follow up for parents and pediatricians prepared.
Individual growth-charts for followup by the pediatrician prepared.

Comprehensive parent education in WBS features and necessary follow up schedule. Detailed plan for lifelong follow up for parents and pediatricians prepared.Individual growth-charts for follow up by the pediatrician prepared. Parents are exclusively compliant to the schedule and present annual reports of all check- ups to the genetic counselor.

Comprehensive parent education in WBS features and necessary follow-up schedule.Detailed plan for lifelong follow-up for parents and pediatricians prepared.Individual growth-charts for follow-up by the pediatrician prepared.Family further planning counseled.

Encountered complications

Subclinical hypothyroidism and followup.

Severe hypothyroidism identified - immediate supplementation.
Moderate hypercalcemia with hypercalciuria and nephrocalcinosisidentified dietary intervention; followup by nephrologist.

No

No

Severe dental problems and profound anxiety from doc- tors/dentists (anesthesia is discussed for treatment).

Intervention results

Physical therapy is very beneficial for development of motor skills.
Despite intensive speech therapy beginning of speech and speech development were very delayed. Very good integration among children.

The family is skeptical about working with any specialist and prefers not to address the problem to teachers, despite the school offered special counseling. No further contact with our geneticist (living in another city).

Very early intervention by physical therapy with incredible effect and very advanced motor skills development basic milestones
achieved within the normal (no WBS) range.
No further contact with our geneticist (living in another country).

Very early intervention by physical therapy with incredible effect and very advanced motor skills development basic milestones achieved within the normal (no- WBS) range. Very early intervention and working continuously with a speech therapist.
Speech is very well developed, rich; poems and songs reproduction is no problem. Very communicative, has no fear of doctors, very fast integration.

Early intervention by physical therapy with very good effect; very good motor skills development.
Speech development is good, loves singing songs. Very good integration among children.

Affected organ or body system: Symptoms for following-up

Early childhood

Child hood

Adult hood

Frequency
%

RECOMMENDATIONS

Thorough physical examination

Yes

Yes

Yes

NA

At each physician visit or at least once annually. Ensure that the growth delay is not drastic, take measures as necessary
Anesthesia counseling and specialist evaluation before any operation, sedation, etc

CAUTION by SEDATION or ANESTHESIA!!!

Yes

Yes

Yes

ViSÎOI1:

Ophthalmological examination lifelong once annually for any vision problems and for strabismus for all ages
Adults are also monitored for early cataractsall ages.

Strabismus (esotropia)

Yes

50

Hyperopia (hypermetropia)

Yes

Yes

50

Cataract

Yes

Otorhinolaryngology:

Otorhinolaryngology examination and audiogram, lifelong once annually.
Cerumen special care.
Antiphons (if necessary).

Recurrent otitis media; chronic otitis media

Yes

Yes

50

Progressive sensorineural hearing loss

Yes

Yes

65

Hypersensitivity to sounds

Yes

Yes

Yes

90

Dental status:

Regular dental examinations and professional dental cleaning every 6 months up to 12 years of age;
every 4 months after 12 years of age (anxiety is common).
Orthodontal examination/counseling for malocclusion after 6-8 years of age

Enamel hypoplasia

Yes

Yes

Yes

95

Microdontia, Diastema

Yes

Malocclusion

Yes

Yes

85

Basic examination at each physician

visit for elevated blood pressure (of

3 or 4 extremities), heartfrequency,

heart tones.

Once annually, lifelong:

electrocardiogram (ECG).

At least once annually for age 1 to 5

Cardiovascular problems:

years and once in every 2 years
thereafter (or as necessary):

thorough examination by a

cardiologist with blood pressure

measurement on 3 or 4

extremities,echocardiography,

Doppler sonography (for severe

stenosis incl. CT, MRI,

catheterization), ECG.

Basic examination

Yes

Yes

Yes

80

Supravalvular aortic

Yes

Yes

Yes

75

stenosis

Supravalvular pulmoniC

Yes

Yes

Yes

25

stenosis

Peripheral pulmonic

Yes

50

stenosis (PPS)

Stenoses of other arteries

Yes

Yes

20

Ventricular septal defect

Yes

10

(VSD)

Arterial hypertension

Yes

Yes

50

Prolonged QT interval

Yes

Yes

13

Screening at diagnosis - single

ultrasonographic (US) examination

(Doppler) of the kidneys and

renalarteries; US evaluation for

nephrocalcinosis; for bladder

malformations, diverticula. In adults

- USexamination once every 10

Genitourinary problems:

years.

Annually lifelong: serum BUN

(serum urea) and urinalysis; serum

creatinine - as necessary.In case of

complications (persistent

hypercalcemia, hypercalciuria,

nephrocalcinosis) -

consultationwith nephrologist.

Malformations

Yes

Yes

Yes

5

Enuresis (diurnal,

nocturnal)

Yes

50

Nephrocalcinosis

Yes

Yes

Yes

<5

Bladder diverticulosis

Yes

Yes

50

Gastrointestinal problems:

Continuous prevention of constipation. Each situation of abdominal pain should be addressed critically and having in mind that abdominal pain may be due to mesenteric artery stenosis(!) but alsoreflux, hiatal hernia, peptic ulcer, cholelithiasis, diverticulitis, ischemic bowel disease (due to motilityproblems, rectal prolapse, hemorrhoids, bowel perforation), and quite common - psychogenic (out offear).

Feeding difficulties

Yes

Yes

—

70

Constipation

Yes

Yes

Yes

50

Diverticula of the colon

Yes

Yes

30

Prolapse of the rectum

Yes

Yes

—

10

Skin and soft tissues:

At least once annually, lifelong: surgical examination for hernias;
At least once annually: check-up for joint contractures, spinal deformities, gait problems.

Soft and hyperelastic skin

Yes

Yes

Yes

90

Inguinal hernia

Yes

40

Umbilical hernia

Yes

50

Premature greying of hair

Yes

90

Musculoskeletal problems:

At least once annually, lifelong: orthopedic examination for joint hypermobility, contractures, scoliosis, kyphosis, lordosis.
Daily movement and exercise. Physical therapy and working with specialist on a regular basis arehighly recommended.

Joint hypermobility

Yes

Yes

90

Joint contractures

Yes

Yes

Yes

50

Radio-Ulnar Synostosis

Yes

Yes

Yes

20

Kyphosis

Yes

20

Scoliosis

Yes

Yes

18

Lordosis

Yes

Yes

40

Pathological gait

Yes

Yes

60

Calcium homeostasis and vitamin D:

Serum calcium levels: once every 4 months up to 2 years of age, once every 2 years thereafter (urinelevels only if necessary). Consultation on nutrition and dietary calcium intake; dietary calcium corrections are made only under physician supervision and never by parents alone!
Control of serum vitamin D levels. Control of vitamin D supplementary intake and caution for sunprotection too! Changes should be made at the discretion of a pediatrician.

Hypercalcemia

Yes

Yes

15—45

Hypercalciuria

Yes

Yes

Yes

30

Vitamin D hypervitaminosis

Endocrine problems:

Strict follow—up of TSH levels (+FT3, FT4) once annually up to 3 years of age; thereafter once in 12to 24 months lifelong (no TAT and MAT measurement necessary - the hypothyroidism is caused bygland hypo-/aplasia).
In case of puberty signs at 6-12 years
- counseling by endocrinologist. From the age of 13 years annual diabetes screening (serum glucose; tolerance test)

Hypothyroidism

Yes

Yes

Yes

5—10

Early (but not precocious) puberty

Yes

Yes

20

Diabetes mellitus

Yes

15

Obesity

Yes

Yes

30

Neurological problems:

Thorough neurological examination once annually for signs of muscle hypotension, hypertension,cerebe1lar symptoms. Head MRI if Chiari is suspected.

Hyperactive tendon reflexes

Yes

Yes

75

Chiari type I malformation (caudal retraction of the cerebellar tonsils through the foramen magnum)

Yes

Yes

Yes

10

Central muscular hypotension

Yes

-

80

Peripheral muscular hypertension

Yes

Yes

Yes

50

Cognitive and developmental problems:

Physical monitoring according to the age-adapted WBS nomograms for height, weight and head circumference at each visit by physician up to 5 years of age and once annually thereafter until adolescence.
Early intervention programs to support motor and language development, working with specialists(e.g. speech therapist, physical therapist), adapted schooling and learning programs, nutritional therapy if necessary

Motor and physical developmental delay

Yes

Yes

-

95

Intellectual impairment (normal intelligence in up to 5%)

Yes

Yes

75

Visuospatial cognitive impairment

Yes

Yes

95

Behavioral features:

Evaluation by psychologist/psychiatrist, symptomatic therapy if necessary (fear, depression, hyperactivity). Training in social skills.

Attention Deficit Hyperactivity Disorder (ADHD)

Yes

65

Anxiety disorder (specific phobias, generalized anxiety)

Yes

Yes

70

Sleep disorders

Yes

Yes

65