Table 3.

Synopsis for work-up and follow-up of patients with BBS.

FIRST VISIT
Family history	• Ask for: other family members with BBS clinical criteria, BBS typical features or proven BBS testing, parents with metabolic syndrome, obesity or T2D, parental height, other malformation or relevant medical event in the patient’s family including parental consanguinity.
General personal history	• Ask for: age at first symptom, presence of situs inversus, surgery for cryptorchidism, removal of accessory digits, symptoms of OSAS, eating behaviour such as hyperphagia.
	• Ophthalmic symptoms: nystagmus, night-blindness, photophobia, bumping into objects, clumsiness and low vision symptoms.
	• Uro-nephrological symptoms: night time drinking & abnormal daily fluid intake, enuresis, secondary enuresis, voiding problems.
	In addition: - Inspection of genitalia and urethra according to endocrinology workout: genital anomalies detection (males: micropenis, testicular position and volume measurement; females: vaginal atresia, hydrometrocolpos …) - Ultrasound kidneys (and urinary tract and internal genitalia if needed)
	• Endocrinology: Target height calculation (in children)
	• Developmental status: Initial morphological examination of the face and body
	In addition: - Search for polydactyly, bradydactyly, scoliosis, urogenital malformations/anomalies… - Any other (rare) associated malformations, situs inversus, cardiac anomalies (US at first visit), constipation…
Initial work-up & follow-up
Endocrinology
History taking	• *Eating behaviour • *Symptoms of OSAS • *Physical activity and sedentary time
Clinical Work-up	• *General status • *Pubertal staging
Growth and status	• *Height, weight, BMI • Adapted: Ambulatory BP 24 h (when blood pressure is above 95th percentile on three separate measurements)
Blood Test	• *Fasting lipid profile (TG, LDL, HDL, total cholesterol) • *Fasting glucose and insulin, HbA1c, uric acid • *Liver: AST, ALT, in adults: GGT, blood platelets for calculation of the FIB4 (index of liver fibrosis) • *Thyroid: TSH, freeT4 • IGF1 (in children with growth retardation or on treatment with recombinant GH, in adults) • In minipuberty, teenagers and adults (every 5 years when normal): FSH, LH, total testosterone/estradiol, prolactin, progesterone, SHBG, AMH (females), inhibinB (males) • Following transition to adulthood => Re-evaluation of gonadotroph and GH axis to search for reversibility
Imaging & Electro-physiology Testing	Adapted:
	• Body composition by DEXA (if available) when BMI SDS > 3
	• Abdominal US (for NAFLD) when liver tests are abnormal/hepatomegaly/ hepatomegaly
	• Testicular US in case of testicular ectopy
	• Pelvic US in case of dysmenorrhea, hyperandrogenism
	• In adults: - Bioelectrical impedance analysis - Resting ECG if obesity and/or diabetes - Osteodensitometry if hypogonadism - Polysomnography when BMI > 35 or suggestive signs, including questionnaire when BMI SDS > 3
Question-naires	Adapted: to age and neurodevelopmental context (presence of intellectual disability in adults): • Eating behaviour questionnaire: SEQ, DYKENS • Sleeping behaviour questionnaire (ESS Epworth sleepiness scale)
Urology-nephrology
History taking (Each visit)	*Ask for: night time drinking & abnormal daily fluid intake/balance, daily urine output (enuresis, secondary enuresis), voiding problems (frequency, pain, hesitation)
Clinical work-up (Each visit)	• *Presence of oedema, urinary continence attainment - urinary infection (fever) • *Ambulatory BP (in adults home BP if feasible), BP 24H*, Height, Weight, BMI • *ECG if high BP and/or diabetes
Blood test	• *Full blood count • *Creatinine, & Estimated glomerular filtration rate with a serum creatinine-based formula adapted to age • *Cystatin C (in case of growth retardation or obesity) • *Urea Nitrogen (BUN) • *Electrolytes: Na + , K + , bicarbonate, Calcium, magnesium, Phosphate, Alkaline phosphatase • *25 (OH) vitamin D, PTH
Urine test	• *Sediment • *Creatinine • *Protein, albumin (albumin to creatinine ratio to avoid false negatives due to polyuria), micro-albumin
Imaging*	• US kidneys (and urinary tract and internal genitalia if needed) done at first visit is then adapted to initial findings or intercurrent event • Adapted: MRI (teenagers/adults) in case US imaging is too limited due to obesity and technical equipment
Ophtalmology
History taking	*Ask for: nystagmus/strabismus, nyctalopia symptoms (not evident for parents), photophobia, loss of visual field symptoms (bumping into objects, clumsiness) & low vision symptoms (loss of daily visual skills, not recognizing people, …)
Basic ocular examination	• *Refraction (under cycloplegia for children and young adults) • *Visual Acuity (best corrected) testing with age-appropriated chart • *Slit-lamp (cataract detection in adults)
Functional testing	• *Visual field, adapted to age and level of vision
Imaging	• *Funduscopy (fundus photograph, if possible wide field or ultra-wide field imaging), • *OCT en face and transfoveal & Fundus Auto Fluorescence
Electroreti-nogram	• Adapted: Full field ERG only if needed and usually for initial diagnostic work-up & If needed under general anaesthesia (only for diagnostic value)
Developmental anomalies
Neurological examination	• *According to age • Adapted: If anomalies: MRI, EEG in case of convulsions
Neuro-psychological assessment (accounting for the patient’s visual impairment)	• *According to the age and patient: global level of development and search for slowness of ideation, adapted according to the patient’s age and abilities. • *Assessment of behavioural problems: emotional immaturity, hyperactivity, intolerance to frustration, disinhibition, obsessive-compulsive disorders, impaired affect • *Speech and language assessment
Orthopaedic assessment	• Adapted: If needed, for polydactyly, bradydactyly, scoliosis
Craniofacial	• *Dental examination (dental hygiene, crowding, …) • Adapted: If needed: Hearing test (Transient Evoked Oto Acoustic Emission test and audiometry) & ENT test to look for conductive or mixed hearing loss

*Yearly follow-up is recommended as baseline (but can be increased due to context)

If any associated condition is detected (CKD, severe obesity, diabetes, etc.) follow-up visits can be increased and adapted to medical field specialty current recommendations for children and for adults.

Adapted: means that the item is done only in specific conditions or situations.

Note 1: The main clinical manifestations follow the learned societies and current international guidelines for hypertension in children [59], management of CKD [56], Clinical Practice Guideline for obesity in children [40, 41].

Note 2: BBS1 mutations with no additional risk factors for CKD, normal BP and no kidney or urinary tract abnormalities on previous examination, this might be reduced to 3 years.