Williams syndrome: clinical guidelines

List of Abbreviations

DNA — deoxyribonucleic acid

WS — Williams syndrome

DM — diabetes mellitus

EchoCG — echocardiography

GI — gastrointestinal tract

MCD — major congenital defect

CHD — congenital heart defect

MRI — magnetic resonance imaging

Mb — megabase

US — ultrasound

CMA — chromosomal microarray analysis

MLPA — multiplex ligation-dependent probe amplification

FISH — fluorescence in situ hybridization

** — the drug is included in the list of vital and essential drugs (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on December 23, 2021) "On approval of the list of vital and essential drugs, as well as lists of medicinal products for medical use and the minimum assortment of medicinal products necessary for the provision of medical care")

# — off-label use, i.e., outside the indications registered in the drug's instructions, is carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the parents (legal representative) and the patient over 15 years of age

*** — a medical device implanted into the human body during the provision of medical care within the framework of the state guarantee program for the free provision of medical care to citizens

Terms and Definitions

Syndrome — a set of symptoms sharing a common etiology and pathogenesis

Megabase — a unit of DNA fragment length equal to 1 million nucleotides

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Williams syndrome (WS) — a multiple congenital malformation syndrome comprising characteristic features such as cardiovascular system lesions (typically supravalvular aortic stenosis, peripheral pulmonary artery stenosis, elastin arteriopathy), a distinct phenotype (the so-called "elfin facies"), intellectual disability (usually mild), behavioral features (typically a friendly disposition, social communication impairments, and a characteristic neuropsychological profile), short stature, and endocrine pathology (hypercalcemia, carbohydrate metabolism disorders, hypothyroidism, and early puberty are characteristic). Dental enamel and growth defects, full lips, and a hoarse voice are also common features [1-3]. It should be noted that the combination of symptoms in each individual patient may vary and is not necessarily complete; no single clinical symptom is obligate, and the syndrome is suspected precisely on the basis of the combination of characteristic clinical manifestations.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The disease occurs predominantly sporadically. The cause of WS is a heterozygous deletion of 1.5 to 1.8 megabases (Mb) on chromosome 7q11.23, which includes 26-28 genes.

To date, the contribution of several of these genes to the formation of the WS phenotype is known in more detail [3]:

• ELN — cardiovascular pathology;

• LIMK1 — impairment of visual-spatial cognitive abilities;

• GTF2I — reduced intelligence, impaired social communication ability;

• STX1A — involved in neurotransmitter release and insulin secretion, may play a role in the development of diabetes in WS;

• BAZ1B — the protein product of the gene binds the vitamin D receptor, likely contributing to the development of hypercalcemia in WS;

• CLIP2 — the gene is hypothesized to be involved in cerebellar dysfunction in WS;

• GTF2IRD1 — associated with craniofacial phenotypic features;

• NCF1 — associated with a reduced risk of hypertension.

The role of other genes in the development of the WS phenotype continues to be studied.

1.3 Epidemiology of the Disease or Condition

The prevalence of Williams syndrome is estimated at 1:10,000 newborns; in Norway, the prevalence is 1:7,500 newborns. Both sexes and all ethnic groups are affected equally [3, 7, 15].

1.4 Features of Coding the Disease or Condition

ICD-10: Q93.8 — Other deletions of autosomes.

ICD-11: LD44.70 — Chromosome 7 deletions.

1.5 Classification of the disease or condition

No.

1.6 Clinical presentation of the disease or condition

Early development. Infants are restless; a weak sucking reflex, frequent vomiting, constipation, and abdominal pain may be noted. Physical developmental delay is observed, with a growth rate of approximately 75% of normal, remaining at this level throughout the child's development period [33]. The final height of an adult patient with WS is typically below the third percentile, corresponding to a height SDS of less than -2. In the first year of life, poor weight gain is associated with feeding difficulties, sucking and swallowing disorders. Prolonged intestinal colic may develop as a result of gastroesophageal reflux, chronic constipation, and/or idiopathic hypercalcemia. Infants with WS are hypotonic and often exhibit joint hypermobility, which together lead to motor developmental delay. Independent walking begins before 24 months of age. There may be speech development delay [8].

The so-called "elfin facies" is a historically established definition of the external phenotypic features of WS patients. Upon examination at any age, the following features are noteworthy: broad forehead, periorbital eyelid puffiness, "starburst" iris pattern, blue eyes, fan-like hair growth at the inner edge of the eyebrows, depressed nasal bridge, short nose with a broad, flattened, and somewhat upturned tip, long philtrum, wide mouth, full lips, mandibular micrognathia, malocclusion, and large earlobes. Epicanthic folds, full cheeks, and small, widely spaced teeth are more obvious in early childhood; adult patients have a subjectively "gaunt" appearance, primarily due to a visually elongated face and neck, and pronounced sloping shoulders. Joint hypermobility, hyperlordosis, and scoliosis may be observed [3, 15].

Personality features. Patients with WS are very friendly, empathetic, socially active, and anxious. They have a "...good-natured disposition — they love everyone, are loved by everyone, and are very charming" [44]. Adaptive behavior does not correlate with intelligence level and turns out to be lower than expected in both children and adults [3], which negatively affects the ability of adults with WS to function independently.

Intellectual development. Most patients with WS have some degree of intellectual disability, which can range from mild to profound. In most cases (75%), a mild degree of intellectual disability is observed, with an average IQ of about 55. Overall, IQ ranges from 40 to 100; some patients have an IQ within the normal range [3]. No gender differences in intellectual abilities have been found [38].

Features of cognitive functions. Patients with WS have well-developed short-term verbal memory and speech, while simultaneously exhibiting visuospatial or constructive apraxia. Typically, children with WS score higher on verbal subtests than on tests measuring visuospatial constructive praxis [39, 45]. The cognitive profile in WS does not depend on the IQ level [3].

Learning abilities. Patients with WS master middle school-level reading skills relatively well, although the level of academic skills varies greatly. Reading skills correlate with cognitive abilities rather than language skills. Major difficulties arise with writing, drawing, and mathematics. Many adults with WS are capable of performing simple arithmetic operations [46].

Comorbid psychiatric and behavioral disorders. Difficulties with sensory modulation/sensory processing (e.g., intolerance to loud sounds), difficulties with emotional regulation, attention deficit hyperactivity disorder, generalized anxiety disorder, and specific phobias are found in 80% of patients with WS [3].

Some children with WS exhibit symptoms characteristic of autism spectrum disorder, such as restricted interests and repetitive behaviors [41].

In children with WS, attention deficit disorder occurs in 65% of cases, and anxiety disorder in 57% (usually specific phobias) [47].

Anxiety disorders are observed throughout life; longitudinal studies of anxiety indicate its prevalence in individuals with WS to be 80% [48]. The likelihood of phobic disorders correlates with a lower intellectual level and more pronounced behavioral difficulties [49, 50].

Sleep disorders. Sleep problems are observed in 65% of people and include difficulty falling asleep and reduced sleep quality (restless, interrupted sleep, prolongation of slow-wave sleep) [9].

Cardiovascular system. The most common problems are supravalvular aortic stenosis, which may worsen over time. If left untreated, it can lead to increased pressure in the left ventricle, its hypertrophy, and the development of heart failure [3, 11]. Other common problems include pulmonary artery branch stenosis, ventricular and atrial septal defects, renal artery stenosis, and aortic hypoplasia. Arterial hypertension, including secondary to renal artery stenosis, occurs in 40–50% of patients with WS and can manifest at any age. QT interval prolongation has been reported in 13.6% [3, 12, 18].

Sense organs. Hearing loss is detected in 63% of children and 92% of adults, and in about half of the cases, it is caused by progressive sensorineural hearing loss. Subclinical hearing impairments are widespread. Chronic otitis media and hypersensitivity to loud sounds are frequently observed [3, 13].

Most patients with WS have a husky or low-pitched voice, likely due to elastin deficiency leading to vocal cord anomalies. Malocclusion, dental enamel hypoplasia, hypodontia, and microdontia are also common problems [3].

Endocrine system. Short stature (height SDS less than -2) and early puberty are observed in the majority of patients with WS; some patients are diagnosed in childhood with primary hypothyroidism, carbohydrate metabolism disorders (impaired glucose tolerance and diabetes mellitus), as well as idiopathic infantile hypercalcemia. Hypercalcemia occurs in 15–50% of patients with WS, most prominently manifesting in the first two years of life (can lead to frequent constipation and vomiting, muscle cramps, irritability) [3, 14, 18].

Disease course. In most adult patients, symptoms progress: arterial hypertension, metabolic syndrome, diabetes mellitus, frequent recurrent urinary tract infections, and gastrointestinal diseases (chronic constipation, cholelithiasis) develop. Despite reports that some patients are able to lead an independent lifestyle, full independence is usually not achieved in most cases. Patients with WS continue to live either with their parents or in specialized facilities where constant care can be provided [3, 15].

Genotype-phenotype correlations. Large deletions in the WS critical region range in size from 1.5 Mb (90-95% of cases) to 1.84 Mb (5-10% of WS patients). A more severe phenotype with greater cognitive impairment is observed in individuals with larger deletions (2–4 Mb or more) compared to those with the standard deletion (1.5–1.8 Mb). Individuals with smaller deletions generally have a variable phenotype and may lack intellectual disability, but exhibit similar behavioral features. Penetrance is 100% [3].

Differential diagnosis (see Appendix A3.1). WS should be differentiated from other syndromes characterized by short stature, developmental delay, attention deficit hyperactivity disorder, facial features, and/or congenital heart disease. Primarily, these include: Noonan syndrome, 22q11.2 deletion (DiGeorge syndrome), Smith-Magenis syndrome, Kabuki syndrome, fetal alcohol syndrome. Individuals with supravalvular aortic stenosis should be evaluated to rule out WS [3].

For the main symptoms observed in WS patients at different ages, see Appendix A3.2 [33].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria.

The diagnosis is considered confirmed if a heterozygous deletion in the 7q11.23 critical region is detected by molecular genetic or molecular cytogenetic methods. The spectrum of clinical symptoms in patients may vary, and no single sign is obligate.

Please note that in accordance with the requirements for the development of clinical guidelines, each recommendation statement must indicate the strength of recommendations and the evidence base in accordance with the grading scales for the levels of evidentiary certainty (LEC) and the levels of recommendation persuasiveness (LRP). For many statements, the LRP and LEC will be low due to the lack of high-design clinical trials dedicated to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics.

2.1 Complaints and Anamnesis

When collecting anamnesis and complaints, attention should be paid to:

• cardiovascular system involvement — supravalvular aortic stenosis is the most significant condition, occurring in 75% of WS patients; peripheral pulmonary artery stenosis is generally more characteristic of infants;

• characteristic phenotypic features — "elfin facies";

• signs of connective tissue dysplasia (husky voice, inguinal or umbilical hernias, joint hypermobility, soft "velvety" skin);

• intellectual deficit of varying severity;

• behavioral features (hyper-sociability, anxiety, attention deficit hyperactivity disorder);

• growth retardation;

• endocrine system pathology (idiopathic infantile hypercalcemia, early puberty, carbohydrate metabolism disorders) [3, 8, 10, 12-14, 36, 58-62].

2.2 Physical Examination

Physical examination of patients with suspected WS:

• assessment of physical development — anthropometric measurements (height measurement, weight measurement);

• cardiovascular system examination: blood pressure measurement (on all four extremities);

• osteoarticular system examination: detection of joint hypermobility and spinal deformities (lordosis, kyphosis, scoliosis);

• assessment of behavioral disorders (hyper-sociability, attention deficit hyperactivity disorder, obsessive-compulsive disorders, autistic manifestations);

• assessment of cognitive functions: detection of visuospatial perception disorders [3, 8, 10, 28, 36, 58, 63].

Detailed physical examination findings are described in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Comments: a search for deletions in the 7q11.23 region is required. The MLPA method is more widespread and versatile for WS diagnostics; however, high-design clinical studies specifically dedicated to WS diagnostics have not been conducted. Despite this, it is rational to consider this method as the first-line diagnostic option. It is important to understand that negative DNA diagnostics results do not rule out WS itself or the hereditary nature of the disease in general. Only a medical geneticist can determine the tactics of DNA diagnostics and interpret its results. An initial and follow-up appointment (examination, consultation) with a medical geneticist is required.

Comments: in case of negative FISH diagnostic results, testing by the MLPA method is performed. In case of negative MLPA test results, performing diagnostics by the FISH method is impractical. Only a medical geneticist can determine the tactics of DNA diagnostics and interpret its results. An initial and follow-up appointment (examination, consultation) with a medical geneticist is required.

Comment: a search for deletions in the 7q11.23 region is required. FISH testing as a first-line option is possible if the MLPA method is unavailable. The diagnosis can be established through molecular genetic methods (MLPA method, in the nomenclature of medical services: "determination of structural gene variants in another or unspecified biological material sample, unclassified in other categories, by multiplex ligation-dependent probe amplification"), molecular cytogenetic methods (FISH method, in the nomenclature of medical services: "molecular cytogenetic study (FISH method) for one pair of chromosomes"; or CMA, in the nomenclature of medical services: "molecular karyotyping on DNA microarrays") or whole genome sequencing, in the nomenclature of medical services: "determination of gene variants in another or unspecified biological material sample, unclassified in other categories, by high-throughput sequencing"). The MLPA method is rational to consider as the first line of diagnostics or in case of negative FISH diagnostic results. WS cannot be confirmed by standard cytogenetic examination (karyotyping).

It is important to understand that negative DNA diagnostics results do not rule out WS itself or the hereditary nature of the disease in general. Only a medical geneticist can determine the tactics of DNA diagnostics and interpret its results. An initial and follow-up appointment (examination, consultation) with a medical geneticist is required.

Comment: hypercalcemia is one of the frequent conditions in patients with WS.

The study is performed at initial diagnosis and then dynamically every 4-6 months up to 2 years of age, and annually thereafter [3]. If necessary, testing for blood levels of phosphorus and ionized calcium is also performed.

Comment: monitoring of these parameters is necessary due to impaired glucose and lipid metabolism, and the frequent development of impaired glucose tolerance and diabetes mellitus in patients with WS. These tests are performed at the initial diagnosis and thereafter dynamically at least once a year.

Comment: regular monitoring of thyroid functional activity is necessary due to the high prevalence of morphological anomalies of the thyroid structure (hypoplasia, ectopia, hemiagenesis), which are frequently accompanied by subclinical or overt hypothyroidism. The tests are performed at the time of diagnosis and subsequently on a regular basis for all patients annually up to 3 years of age, and then on average once every 2 years [3].

Comment: monitoring of these parameters is necessary due to the high prevalence of urination disorders, lower urinary tract infections, chronic kidney disease, diabetes mellitus, and arterial hypertension in patients with WS. The test is performed at the time of diagnosis and subsequently on a regular basis for all patients at least once a year [3].

Comment: determining the calcium-to-creatinine ratio in a single portion of urine is a more accurate method for diagnosing urinary calcium excretion (see Appendix). Patients with WS must avoid vitamin D overdose, as it can further increase intestinal calcium absorption [3, 18, 19, 33]. The test is performed at the time of diagnosis and subsequently on a regular basis for all patients at least once a year [3].

Comment: monitoring of these parameters is necessary due to the high prevalence of urination disorders, lower urinary tract infections, chronic kidney disease, diabetes mellitus, and arterial hypertension in patients with WS. Patients also need to have their glomerular filtration rate calculated based on blood creatinine levels [37]. The test is performed at the time of diagnosis and subsequently on a regular basis for all patients at least once a year [3].

Comment: patients with WS must maintain an adequate vitamin D level while avoiding overdose. If vitamin D deficiency is suspected, it is important to check the vitamin D level before initiating therapy. Blood calcium levels must be monitored throughout the course of treatment [3, 20, 32].

2.4 Instrumental Diagnostics

Comment: measurement of the QT interval is mandatory. Various cardiovascular pathologies occur in 80% of patients with WS and are the leading causes of death. The most frequent ECG findings are left and right ventricular myocardial hypertrophy and QT interval prolongation (QTc). QTc is associated with a high risk of ventricular tachyarrhythmias, sudden cardiac death, and a high rate of perioperative mortality; therefore, an electrocardiogram must be recorded before any surgical intervention. It is also necessary to assess all risk factors for sudden cardiac death, including the use of medications that contribute to QTc prolongation, especially before starting drugs used for attention deficit hyperactivity disorder (ATC: N06B, Psychostimulants, agents used for attention deficit hyperactivity disorder [ADHD] and nootropics) [26, 27]. The test is performed at the time of diagnosis and subsequently at every visit to a pediatric cardiologist/cardiologist, as well as before any surgical intervention [3].

Comment: echocardiography is used for quantitative assessment of heart chamber dimensions, the severity of myocardial hypertrophy, aortic and mitral valve anomalies, cardiac septal defects, and tetralogy of Fallot. The test is performed at the time of diagnosis and subsequently on a regular basis annually until the age of 5, and then as needed, depending on the presence and severity of cardiovascular involvement [3].

Comment: the test is necessitated by the need for status monitoring due to the high risk of sudden cardiac death associated with a prolonged QTc interval. It is important to remember that a number of drugs that may be used in patients with attention deficit hyperactivity disorder, as well as in the perioperative period, including for anesthesia, lead to QTc interval prolongation [28]. The test is performed at the time of diagnosis and subsequently on a regular basis annually up to 5 years of age, and then once every 2 years [3].

Comment: annual audiological examination is recommended for children. Adults require an audiological examination at the age of 30, followed by repeat examinations every 3 years.

Comment: developmental anomalies (hypoplasia, ectopia, hemiagenesis) of the thyroid gland can be detected in patients with WS. The test is performed at the time of diagnosis and subsequently on a regular basis at least once a year [3].

Comment: structural developmental anomalies of the kidneys may be detected; performing a renal ultrasound is particularly important in the presence of arterial hypertension to timely identify renal artery stenosis. The test is performed at the time of diagnosis and subsequently at least once every 5 years or more frequently (if necessary) [3].

2.5 Other Procedures

Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comment: for the range of differential diagnostic search, see Appendix A3.1. Medical genetic counseling is the process of providing the proband, their family, or legal guardians with information about the etiology, mode of inheritance of the disease, and the consequences of genetic defects to help the family organize further follow-up, proper child care, rehabilitation, and social adaptation. Medical genetic counseling is also important for clarifying the genetic status of other family members, which is necessary for future reproductive planning and discussing the potential option of prenatal genetic testing.

WS is inherited in an autosomal dominant manner; most deletions arise de novo, although cases of parent-to-child transmission have been reported. In most cases, the proband's parents are unaffected. In the absence of clinical signs of WS in the parents, screening for the 7q11.23 microdeletion identified in the proband is considered impractical. The risk for the proband's siblings depends on the parental status. If one parent is affected, the risk for each sibling to inherit the 7q11.23 microdeletion is 50%. If the parents are unaffected, the risk for siblings is generally low, but higher than the general population risk due to the inability to rule out parental gonadal mosaicism. For the proband's offspring, the theoretical risk of having an affected child is 50% for each pregnancy, regardless of the sex of the unborn child. The optimal time for determining genetic risk and discussing prenatal/preimplantation genetic testing is prior to pregnancy.

Comment: WS is inherited in an autosomal dominant manner; most deletions arise de novo, although cases of parent-to-child transmission have been reported. In most cases, the proband's parents are unaffected. In the absence of clinical signs of WS in the parents, screening for the 7q11.23 microdeletion identified in the proband is considered impractical. The risk for the proband's siblings depends on the parental status. If one parent is affected, the risk for each sibling to inherit the 7q11.23 microdeletion is 50%. If the parents are unaffected, the risk for siblings is generally low, but higher than the general population risk due to the inability to rule out parental gonadal mosaicism. For the proband's offspring, the risk of having an affected child is 50% for each pregnancy, regardless of the child's sex. The optimal time for determining genetic risk and discussing prenatal/preimplantation genetic testing is prior to pregnancy.

Comment: height, weight, height SDS, growth velocity, BMI, and BMI SDS are assessed. Patients with WS most commonly exhibit postnatal growth restriction (below the 10th percentile) and moderate microcephaly. Postnatal poor weight gain is usually associated with feeding difficulties and frequent vomiting. The average adult height is 159 cm for males and 147 cm for females. This evaluation is recommended upon establishing the diagnosis and subsequently at every primary and follow-up clinical and diagnostic visit (consultation) with a pediatrician, general practitioner (family physician), medical geneticist, pediatric endocrinologist, or endocrinologist.

Comment: the need for consultations is due to the high risk of developing endocrine pathologies (impaired glucose tolerance, diabetes mellitus, hypothyroidism, obesity, precocious puberty, which worsens the final height prognosis), as well as for the treatment of persistent hypercalcemia.

Comment: typical audiological features include hyperacusis, cochlear dysfunction, and sensorineural, conductive, and mixed hearing loss (predominantly in the high-frequency range). Speech, play, and pure-tone audiometry, as well as tympanometry, may be performed [30, 31].

Comment: whenever possible, the management of patients with WS who have cardiovascular pathology should be carried out by a pediatric cardiologist/cardiologist experienced in treating children with WS. Patients are at high risk for arterial hypertension and other cardiovascular diseases. Lifelong follow-up by a pediatric cardiologist/cardiologist is advisable for regular monitoring of the cardiovascular system.

Comment: measurements should be taken on the peripheral arteries of all limbs. Arterial hypertension is observed in the majority of patients with WS; in some cases, it develops secondary to renal artery stenosis [3, 27, 32].

Comment: co-occurring mental and health behavioral problems requiring timely diagnosis and treatment are identified in 80% of patients with WS. The most frequently diagnosed conditions include intellectual disability, phobic and anxiety disorders, attention-deficit/hyperactivity disorder, behavioral disturbances, and sleep disorders.

Comments: intellectual disability, attention deficit, and visuospatial dyspraxia can hinder a child in acquiring daily living and social skills, as well as in learning. Diagnosis using standardized tools will help objectively assess the child's abilities and potential to determine an educational pathway and develop a habilitation program.

Comment: strabismus or refractive errors are diagnosed in approximately 40% of patients with WS.

Comment: patients with WS typically have small, irregular, widely spaced primary teeth. The prevalence of dental caries may be associated with enamel hypoplasia as well as difficulties children face in learning daily oral hygiene. The child's anxiety level and degree of intellectual deficit must be taken into account when developing appropriate skills. Issues of prevention and timely treatment of oral cavity diseases are particularly relevant for preventing infective endocarditis [32].

Comment: the disease is characterized by involvement of multiple organs and systems and requires comprehensive therapy. Initial and follow-up (as needed) diagnostic and treatment consultations/appointments are indicated with a geneticist, pediatric cardiologist, cardiologist, neurologist, gastroenterologist, pediatric endocrinologist, endocrinologist, pediatric urologist-andrologist/urologist, nephrologist, trauma surgeon-orthopedist, nutritionist, psychiatrist, pediatrician/general practitioner (family physician)/internist, ophthalmologist, anesthesiologist-resuscitologist, dentist; initial and follow-up appointments (testing, consultation) with a medical psychologist, as well as specialists in other fields for patients with Williams syndrome who have functional impairments of the respective organs and systems [3].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Symptomatic treatment

Comments: patients with Williams syndrome have been found to lack a noticeable pre-sleep increase in melatonin concentration and lack a nocturnal concentration peak. Nocturnal melatonin secretion promotes sleep onset and depth [10, 51, 100]. #Melatonin shortens sleep latency and increases sleep duration while having a favorable safety profile. The dose of #Melatonin is selected individually and ranges from 2 to 5 mg orally, once daily before bedtime. A prolonged-release formulation of #Melatonin may be effective for increasing sleep duration [10, 51, 54-56].

Comments: atomoxetine is used to treat ADD and ADHD in children older than 6 years. During treatment, ECG monitoring is critically important to detect signs of QT interval prolongation, given that patients with Williams syndrome have a tendency toward QT interval prolongation, and the drug may exert an additional effect on its duration. The daily dose is taken once in the morning. If the therapeutic effect is not achieved or in case of poor tolerability, the daily dose may be divided into two doses (morning and late afternoon).

Comments: treatment of complications and comorbid conditions is carried out in accordance with the relevant clinical guidelines. Appointments with medical specialists are indicated at least once a year or more frequently if clinically indicated. Patients with congenital heart disease are indicated for surgical treatment [12, 27]. The most common defects are supravalvular aortic stenosis, pulmonary artery branch stenosis, ventricular and atrial septal defects, renal artery stenosis, and aortic hypoplasia. Patients with Williams syndrome are at risk for developing long QT syndrome. Therefore, prior to surgical treatment, an initial and follow-up examination (evaluation, consultation) by a pediatric cardiologist/cardiologist is required, along with an electrocardiogram recording with mandatory measurement of the corrected QT interval. It should be kept in mind that a number of medications that may be used in patients with attention deficit hyperactivity disorder and in the perioperative period, including for anesthesia, additionally lead to prolongation of the QTc interval.

3.2 Other Treatment

Comments: depending on the manifestations of the disease, the patient may require clinical and psychological adaptation, clinical and psychological counseling, clinical and psychological correction, psychotherapy, procedures for adaptation to the microenvironment, procedures for adaptation to the macroenvironment, development of an individualized psychological rehabilitation program, etc. For example, hyperacusis and phobias can in many cases be effectively treated using cognitive behavioral therapy.

Comments: routine use of supplements (including multivitamins) containing vitamin D (ATC: A11CC Vitamins A and D, including combinations thereof) should be avoided [3, 20, 32].

Comments: surgical intervention for heart defects is performed according to indications.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: specific rehabilitation for Williams syndrome is not provided.

The physical and rehabilitation medicine physician leads the multidisciplinary rehabilitation team. The rehabilitation of patients with Williams syndrome must also involve the following specialists with higher professional (non-medical) education: ergotherapist/occupational therapist (ergorehabilitation, occupational therapy), medical speech-language pathologist [107, 108] (initial and follow-up medical speech-language pathologist appointments (consultations), development of an individualized speech-language rehabilitation program, medical speech-language pathology procedure for dysphagia, medical speech-language pathology procedure for aphasia, medical speech-language pathology procedure for dysarthria, medical speech-language pathology tonal-rhythmic procedure), medical psychologist (initial and follow-up medical psychologist appointment (testing, consultation)), neuropsychologist (initial and follow-up neuropsychologist appointment (consultation), in the national medical service register — initial and follow-up medical psychologist appointment (testing, consultation)). Rehabilitation measures are carried out based on specific clinical symptoms (neurological, psychiatric, speech-language, etc.) and in accordance with the relevant clinical guidelines.

5. Prevention and Dispensary Observation

5.1 Medical-genetic counseling and prevention

WS is generally sporadic; however, the theoretical risk of transmitting the 7q11.23 chromosome deletion to children is 50%. If parents have no clinical signs of WS, parental FISH testing is not warranted. The risk for the proband's siblings depends on the parental status: if one parent carries the deletion, the risk is 50%; when parents are clinically healthy, the risk for the proband's siblings is low. It is worth noting that gonadal mosaicism cannot be ruled out in the proband's parents, meaning the theoretical risk of recurrence of a child with WS in the proband's parents may be higher than the population risk. The risk for the proband's offspring is 50%, which falls into the high genetic risk category. Prenatal diagnosis may be performed [3].

5.2 Dispensary monitoring

For specific features of organizing follow-up care for patients with WS across different age groups and organ systems, see Appendix A3.3.

Comment: height, weight, height SDS, growth rate, BMI, and BMI SDS are evaluated. Patients with WS most commonly exhibit postnatal growth restriction (below the 10th percentile) and moderate microcephaly. Poor weight gain after birth is usually associated with feeding difficulties and frequent vomiting. The average height of adult males is 159 cm, and for females — 147 cm. The study is recommended upon initial diagnosis and subsequently at each initial and follow-up appointment (consultation) with a pediatrician, general practitioner/family physician, or geneticist, as well as an initial and follow-up pediatric endocrinologist/endocrinologist.

Comment: monitoring these parameters is necessary due to impaired glucose and lipid metabolism, and the frequent development of impaired glucose tolerance and diabetes mellitus in patients with WS. Tests are performed at initial diagnosis and subsequently monitored at least once a year.

Comments: the test is performed upon initial diagnosis and subsequently monitored every 4–6 months up to 2 years of age, and annually thereafter [3]. Additionally, serum ionized calcium levels are tested if clinically indicated.

Comments: monitoring these parameters is necessary due to the high prevalence of voiding dysfunction, lower urinary tract infections, chronic kidney disease, diabetes mellitus, and arterial hypertension in patients with WS. The test is performed upon diagnosis and subsequently monitored in all patients at least once a year [3].

Comment: regular monitoring of thyroid functional activity is necessary due to the high prevalence of structural thyroid anomalies (hypoplasia, ectopia, hemiagenesis), which are often accompanied by subclinical or overt hypothyroidism.

Comments: determining the calcium-to-creatinine ratio in a single random urine sample is a more accurate method for diagnosing urinary calcium excretion (see Appendix A4). Patients with WS should avoid vitamin D overdose, as it may further promote calcium absorption in the gut [3, 18, 19, 33]. The test is performed upon diagnosis and subsequently monitored in all patients at least once a year [3].

Comment: monitoring these parameters is necessary due to the high prevalence of voiding dysfunction, lower urinary tract infections, chronic kidney disease, diabetes mellitus, and arterial hypertension in patients with WS. Patients also need to have their glomerular filtration rate estimated based on blood creatinine levels using a calculation formula [37]. The test is performed upon diagnosis and subsequently monitored in all patients at least once a year [3].

Comment: the measurement is performed at every visit to a pediatric cardiologist/cardiologist. Blood pressure must be measured on the peripheral arteries of all four limbs.

Comment: measurement of the QT interval is mandatory. Various cardiovascular pathologies occur in 80% of patients with WS and are the leading causes of death. The most frequent ECG findings are left and right ventricular myocardial hypertrophy and prolonged QT interval (QTc). QTc prolongation is associated with a high risk of ventricular tachyarrhythmias, sudden cardiac death, and a high perioperative mortality rate; therefore, an electrocardiogram must be recorded prior to any surgical intervention. It is also necessary to assess all risk factors for sudden cardiac death, including the use of medications that promote QTc prolongation, especially before initiating medications used for attention deficit hyperactivity disorder [26, 27]. The test is performed upon diagnosis and subsequently at every visit to a pediatric cardiologist/cardiologist, as well as before any surgical intervention [3].

Comments: echocardiography is used to quantitatively assess cardiac chamber dimensions, the severity of myocardial hypertrophy, aortic and mitral valve anomalies, septal defects, and Tetralogy of Fallot. The test is performed upon diagnosis and subsequently monitored annually until 5 years of age, and thereafter as clinically indicated, depending on the presence and severity of cardiovascular involvement [3].

Comment: the test should be performed annually up to 5 years of age, and then every 2 years. Monitoring the cardiac conduction system is necessary due to the high risk of sudden cardiac death associated with a prolonged QTc interval. It is important to remember that a number of medications that may be used in patients with attention deficit hyperactivity disorder, as well as in the perioperative period, including for anesthesia, lead to QTc interval prolongation [28].

Comment: annual audiological evaluation is recommended for children. Adults require an audiological evaluation at 30 years of age, with repeat evaluations every 3 years.

Comment: the examination is performed at least once a year under the age of 3 years, then every 2 years.

Comment: the examination is recommended every 10 years. All patients with WS need follow-up by a multidisciplinary team of specialists due to the fact that the disease is characterized by multi-organ involvement and requires complex therapy, which dictates the need for joint management of the patient by specialists of various profiles [3, 33].

Initial and follow-up visits (consultations) are indicated with a geneticist, ophthalmologist, neurologist, gastroenterologist, pediatric endocrinologist/endocrinologist, cardiologist/pediatric cardiologist, nephrologist, pediatrician/general practitioner (family physician), trauma surgeon/orthopedist, pediatric dentist/dentist, otorhinolaryngologist-audiologist, as well as with other specialists for WS patients who have impaired functions of the respective organs and systems.

Comment: dispensary follow-up by a pediatric endocrinologist is required. Consultations with specialized specialists are necessary due to the prevalence of endocrine system pathology (impaired glucose tolerance, diabetes mellitus, hypothyroidism), as well as for the treatment of persistent hypercalcemia, hypercalciuria, and/or nephrocalcinosis.

Comment: dispensary follow-up by an otorhinolaryngologist-audiologist is required. Typical audiological features are characteristic, such as hyperacusis, cochlear dysfunction, sensorineural, conductive, and mixed hearing loss (primarily in the high-frequency range). Speech, play, pure-tone audiometry, and tympanometry can be performed [30, 31].

Comment: dispensary follow-up by a cardiologist/pediatric cardiologist is required. Whenever possible, the treatment of WS patients with cardiovascular pathology should be carried out by a pediatric cardiologist/cardiologist experienced in treating children with WS. Patients have a high risk of developing arterial hypertension and other cardiovascular diseases. Lifelong monitoring by a pediatric cardiologist/cardiologist is advisable for regular monitoring of the cardiovascular system.

Comment: measurements should be taken on the peripheral arteries of all limbs. Arterial hypertension is observed in the majority of patients with WS; in some cases, it develops secondary to renal artery stenosis [3, 27, 32].

Comment: dispensary follow-up by a psychiatrist is required. Co-occurring psychiatric and behavioral problems are identified in 80% of patients with WS, requiring timely diagnosis and treatment. Intellectual disability, phobic and anxiety disorders, attention deficit hyperactivity disorder, behavioral disorders, and sleep disorders are detected most frequently.

Comments: intellectual disability, attention deficit, and visuospatial dyspraxia can hinder a child in acquiring daily living and social skills, as well as in learning. Diagnosis using standardized tools will help objectively assess the child's abilities and potential to determine an educational pathway and develop a habilitation program.

Comment: dispensary follow-up by an ophthalmologist is required. Approximately 40% of patients with WS are diagnosed with strabismus or refractive errors.

Comment: dispensary follow-up by a pediatric dentist/dentist is required. Patients with WS typically have small, uneven, widely spaced primary teeth. The prevalence of dental caries may be associated with enamel hypoplasia and difficulties children face in daily oral hygiene. The child's anxiety level and degree of intellectual deficit should be taken into account when developing relevant skills. Issues of prevention and timely treatment of oral cavity diseases are particularly relevant to prevent the development of infective endocarditis [32].

6. Organization of Medical Care

Indications for scheduled hospitalization in a medical organization:

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis (including issuing a conclusion of a federal concilium / medical commission).

Indications for emergency hospitalization in a medical organization:

1. acute life-threatening conditions and conditions that may develop severe complications requiring emergency treatment, including intensive care, as well as 24-hour medical supervision and special diagnostic and therapeutic procedures.

Indications for discharging a patient from a medical organization:

1. Absence of a threat to the patient's life and the risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. Stabilization of the condition and basic clinical and laboratory parameters of the pathological process, absence of the need for prolonged medical observation (day or round-the-clock stay);

3. The patient's examination and treatment plan has been completed, and recommendations for further monitoring and treatment have been given.

4. Need to transfer the patient to another medical institution or social security institution.

7. Additional Information

Comment: the most frequent ECG findings in WS patients are left and right ventricular myocardial hypertrophy and QT interval (QTc) prolongation. QTc is associated with a high risk of ventricular tachyarrhythmias, sudden cardiac death, and a high rate of perioperative mortality, which necessitates electrocardiogram recording with mandatory measurement of the QT interval before any surgical intervention. It is also necessary to assess all risk factors for sudden cardiac death, including medications contributing to QTc prolongation, especially before starting drugs used for attention deficit hyperactivity disorder. It is important to remember that a number of drugs that may be used in patients with attention deficit hyperactivity disorder lead to QTc interval prolongation [27, 28].

Comments: when deficiency is suspected, it is important to check the vitamin D level before starting therapy. Calcium levels should also be monitored throughout treatment; if possible, postpone the initiation of therapy with "vitamin D and its analogues" until after the resolution of hypercalcemia, which typically occurs between 18 months and 2 years of age [3, 18, 19].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Inga V. Anisimova — Cand. Sc. (Med.), Medical Geneticist, Head of the Department of Medical Care Organization, Research Centre for Medical Genetics, Member of the Association of Medical Geneticists (AMG).

Berkutova Irina Yuryevna — Candidate of Pedagogical Sciences, Senior Researcher at the Federal State Budgetary Institution "Federal Scientific Center for Physical Culture and Sports (VNIIFK)", Chief Rehabilitation Specialist, Occupational Therapist at the Autonomous Non-Profit Organization "Center for Evidence-Based Non-Medical Rehabilitation of Persons with Disabilities and Other Health Impairments 'Special Garden'".

Grigorieva Veronika Vladimirovna — Founder of the Williams Syndrome Support Charity Foundation, Project Manager.

Kornoukhov Oleg Yuryevich — Candidate of Medical Sciences, Cardiovascular Surgeon, Cardiosurgical Department, N.F. Filatova Children's City Clinical Hospital of the Moscow Healthcare Department.

Kuvaldina Ekaterina Viktorovna — Pediatric Endocrinologist, Russian Children's Clinical Hospital — Branch of the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Sergey I. Kutsev — Academician of the RAS, Professor, D.Sc. in Medicine, Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists (AMG).

Anna A. Portnova — D.Sc. in Medicine, President of the Association of Psychiatrists and Psychologists for Evidence-Based Practice.

Valeria V. Sviridova — Medical Geneticist at the Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov; Junior Research Fellow at the Laboratory of Mutagenesis, Research Centre for Medical Genetics named after Academician N.P. Bochkov.

Dmitry M. Subbotin — Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists (AMG).

Svetlana P. Tsinovskaya — Pediatric Neuropsychologist, Certified Sensory Integration Specialist (CLASI), Curator of Educational Projects, "Territory of Speech" Speech Therapy Center, Moscow.

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

Target audience for these clinical guidelines:

1. Medical geneticist;

2. Pediatrician;

3. General practitioner (internist);

4. Neurologist;

5. Psychiatrist;

6. Pediatric cardiologist;

7. Cardiologist;

8. Pediatric endocrinologist;

9. Endocrinologist;

10. Pediatric surgeon;

11. Surgeon;

12. Traumatologist-orthopedist;

13. Pediatric dentist;

14. Dentist;

15. Medical psychologist;

16. Otorhinolaryngologist-audiologist;

17. Functional diagnostics physicians;

18. Residents;

19. Medical students.

Table 1. Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ of November 21, 2011 (as amended on December 25, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Order of the Russian Ministry of Health No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases."

3. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

4. International Statistical Classification of Diseases and Related Health Problems (ICD-10).

5. Order of the Russian Ministry of Health No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On approval of the Nomenclature of positions of medical workers and pharmaceutical workers".

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 (as amended on June 23, 2020) "On Approval of the Procedure and Timeframes for the Development of Clinical Practice Guidelines, Their Revision, the Standard Template of Clinical Practice Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Practice Guidelines".

Appendix A3.1 Main syndromes for differential diagnosis of WS [3]

Appendix A3.2 Main symptoms observed in WS [33]

Appendix A3.3 Dispensary follow-up in patients with WS across different age groups [33]

Appendix. Normal values of the calcium-to-creatinine ratio in a single urine sample [33]

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is Williams syndrome?

Williams syndrome (WS) (often referred to as "elfin face syndrome") is a condition resulting from a chromosomal abnormality (microdeletion on chromosome 7), characterized by a distinctive facial appearance, intellectual disability (usually mild), and specific behavioral features.

How does Williams syndrome manifest?

Most children with WS share similar facial features. These features may sometimes be subtle and can become more pronounced with age. Facial features include periorbital fullness, starburst (stellate) iris, short nose with a bulbous tip, wide mouth, full lips, and small mandible; older children and adults tend to have a long, narrow face and a long neck.

From birth, infants with WS most commonly have low birth weight; breastfed infants feed poorly and frequently suffer from vomiting, constipation, abdominal pain, and poor weight gain.

Many children with WS are diagnosed with congenital heart disease, most commonly aortic stenosis, requiring surgical intervention.

How is Williams syndrome inherited?

WS occurs sporadically, i.e., by chance. The recurrence risk for parents who already have a child with Williams syndrome is estimated to be extremely low (genetic risk counseling should be discussed with a geneticist).

How is Williams syndrome diagnosed?

A physician may suspect WS based on clinical symptoms. Physical examination reveals characteristic facial features, personality traits, and behavioral patterns. Serum calcium levels may be elevated on blood biochemistry. Echocardiography may reveal congenital heart disease. However, these signs can also occur in other genetic syndromes. Definitive confirmation requires DNA diagnostics. The gold standard is testing for deletions in the 7q11 region. The specific testing method is determined by a geneticist.

How is Williams syndrome treated?

Management centers primarily on symptomatic treatment and educational/rehabilitative support. Therapy for patients with WS is tailored individually. Special educational programs are developed for children with varying degrees of developmental delay. Behavioral counseling is provided, with options for pharmacotherapy for attention deficit and anxiety disorders. Surgical intervention may be performed for congenital heart defects. In cases of hypercalcemia, a modified diet and/or specific medications are prescribed. The prognosis is relatively favorable, and social adaptation is possible, which directly depends on early diagnosis, early intervention, and the prompt initiation of therapy.

Family support.

There are several organizations in Russia that can help you find answers to questions related to Williams syndrome.

Williams Syndrome Support Foundation website https://williams-syndrome.ru/

VKontakte open community for parents of children with WS https://vk.com/ws_russia_together

Center for Curative Pedagogics — assistance for parents and specialists https://ccp.org.ru/

Legal support for parents https://www.osoboepravo.ru/

Williams Syndrome Association (USA)

Website: http://www.williams-syndrome.org

Williams Syndrome Foundation Worldwide Web

http://www.wsf.org

The website lists support organizations in various countries at: http://www.wsf.org/family/support/orgsint.htm

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.