Williams Syndrome

Epidemiology and Genetics

Epidemiology

The incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of Williams syndrome (WS) is 1 in 10,000–20,000 live births.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

• The inheritance pattern is autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance.
• The majority of cases result from de novo mutations with no family history Family History Adult Health Maintenance of the condition.
• Results from a microdeletion in the small region of q11.23 on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 7 
• The deleted region includes approximately 25 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure:
  • Loss of the elastin gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, ELN, causes cardiovascular and connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology abnormalities.
  • Loss of the GTF2IRD1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics may contribute to the distinctive facial features often associated with WS.
  • Loss of CLIP2, LIMK1, GTF2I, and GTF2IRD1 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure may contribute to behavioral abnormalities, cognitive difficulties, and learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome (particularly visuospatial abilities).

Clinical Presentation

Outer appearance

• Distinctive facial features described as “elfin facies” (elf-like):
  • Broad forehead Forehead The part of the face above the eyes. Melasma
  • Short nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose Anatomy (External & Internal) with a flattened nasal bridge
  • Long philtrum
  • Wide mouth with full lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy
  • Full cheeks Cheeks The part of the face that is below the eye and to the side of the nose and mouth. Melasma
  • Medial flaring of the eyebrows (hair abnormally distributed more medially)
• Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus (crossed eyes)
• Short stature
• Dental abnormalities such as hypodontia (missing 1 or more teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth: Anatomy), diastema (a gap between the teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth: Anatomy), and malocclusion (misalignment of the teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth: Anatomy)
• Hoarse voice
• Low muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction
• Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive (lack of appropriate growth and weight gain) noted in the early years

Cognitive features

• Developmental delays
• Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment (mild to moderate)
• Difficulties with writing, math, and spatial visualization ability (e.g., solving puzzles and drawing)
• Strengths in language and rote memorization

Behavioral features

• “Cocktail party” type personality: sociable, outgoing, and engaging 
• High verbal intelligence quotient (IQ), but a low IQ and a lack of depth and understanding 
• Excessive talkers
• Attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment deficit disorder (ADD)
• Non-social anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder and phobias Phobias Neurological Examination
• Affinity for music

Cardiovascular features

Congenital Congenital Chorioretinitis heart disease is present in 80%–90% of WS cases and is a major cause of morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status and mortality Mortality All deaths reported in a given population. Measures of Health Status in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with WS. The risk of sudden cardiac death Sudden cardiac death Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest is 25–100 times greater in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with WS.

• Supravalvular aortic stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) (SVAS):
  • Most common cardiac anomaly in WS, present in 35%–65% of cases
  • Narrowing of aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy occurs just above the aortic valve Aortic valve The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. Heart: Anatomy. 
  • Least common type of aortic stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)
  • Occurs due to the loss of the ELN gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Approximately 25% of children with SVAS have WS.
  • Without treatment, SVAS can cause heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR).
• Branch or peripheral pulmonary artery Pulmonary artery The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. Lungs: Anatomy stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS): typically mild and/or spontaneously improves
• Supravalvular pulmonary stenosis Supravalvular Pulmonary Stenosis Pulmonary Stenosis: spontaneously improves and/or resolves
• Stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) in other vascular structures:
  • Thoracic or abdominal aorta Abdominal Aorta The aorta from the diaphragm to the bifurcation into the right and left common iliac arteries. Posterior Abdominal Wall: Anatomy
  • Renal arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology
  • Intracranial arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology
  • Vessels in other sites such as the neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess and limbs
• Additional structural cardiac defects:
  • Septal defects
  • Mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy prolapse + regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)
  • Bicuspid aortic valve Aortic valve The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. Heart: Anatomy
  • Valvular aortic stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) or aortic insufficiency
• Congenital Congenital Chorioretinitis long QTc syndrome ( LQTS LQTS Long qt syndrome (LQTS) is a disorder of ventricular myocardial repolarization that produces qt prolongation on electrocardiogram (ECG). Long qt syndrome is associated with an increased risk of developing life-threatening cardiac arrhythmias, specifically torsades de pointes. Long QT Syndrome): seen in approximately 15% of cases
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension: develops in childhood in almost 50% of those with WS

Endocrine features

• Transient neonatal hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia:
  • Typically mild-to-moderate ↑ serum Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)⁺ 
  • Symptomatic hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia, if present, typically occurs in the 1st 2 years of life:
    • Clinically presents with irritability, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, muscle cramps Cramps Ion Channel Myopathy, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Mostly resolves spontaneously during childhood
• Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism or subclinical hypothyroidism Subclinical Hypothyroidism Hypothyroidism:
  • 5%–10% with overt hypothyroidism Overt Hypothyroidism Hypothyroidism
  • Approximately 33% with subclinical hypothyroidism Subclinical Hypothyroidism Hypothyroidism
• Early onset of puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty may be seen in up to 20% of girls with WS.
• ↑ Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus in adults with WS

Renal and urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy features

• Congenital Congenital Chorioretinitis renal and urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy anomalies are seen in up to 30% of cases:
  • Ectopic or horseshoe kidney Horseshoe Kidney Congenital Renal Abnormalities
  • Renal aplasia Aplasia Cranial Nerve Palsies or hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) (missing or smaller than usual)
  • Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess diverticula (outpouching of the bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess lining through a weakened bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess wall)
• ↑ Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of dysfunctional voiding such as ↑ urinary frequency and nocturnal enuresis Nocturnal enuresis Involuntary discharge of urine during sleep at night after expected age of completed development of urinary control. Elimination Disorders (bed wetting) 
• ↑ Risk and frequency of urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (UTIs)
• May also have ↑ urinary calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes and nephrocalcinosis Nephrocalcinosis A condition characterized by calcification of the renal tissue itself. It is usually seen in distal renal tubular acidosis with calcium deposition in the distal kidney tubules and the surrounding interstitium. Nephrocalcinosis causes renal insufficiency. X-linked Hypophosphatemic Rickets ( Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)⁺ deposits in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy)
• Renal function is typically maintained except in rare cases.

Gastrointestinal features

• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• Feeding difficulties
• Umbilical and inguinal hernias Inguinal Hernias An abdominal hernia with an external bulge in the groin region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the abdominal wall (transversalis fascia) in Hesselbach’s triangle. The former type is commonly seen in children and young adults; the latter in adults. Inguinal Canal: Anatomy and Hernias
• Diverticula

Otologic/auditory features

• Mild-to-moderate sensorineural hearing loss Sensorineural hearing loss Hearing loss resulting from damage to the cochlea and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the auditory nerve and its connections in the brainstem. Hearing Loss
• Hyperacusis Hyperacusis An abnormally disproportionate increase in the sensation of loudness in response to auditory stimuli of normal volume. Cochlear disease, vestibulocochlear nerve diseases, facial nerve diseases, stapes surgery, and other disorders may be associated with this condition. Cranial Nerve Palsies (intense sensitivity to sounds) 
• Recurrent otitis media

Ocular features

• Hyperopia Hyperopia Refractive Errors (far-sightedness)
• Nasolacrimal duct Nasolacrimal Duct Nasolacrimal duct. Dacryocystitis obstruction

Musculoskeletal features

• Joint laxity/hypermobility in childhood
• Joint limitations Limitations Conflict of Interest and contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing as an adult
• Abnormal curvature of the spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy (e.g., kyphosis Kyphosis Deformities of the spine characterized by an exaggerated convexity of the vertebral column. The forward bending of the thoracic region usually is more than 40 degrees. This deformity sometimes is called round back or hunchback. Osteoporosis)
• Gait ataxia Gait ataxia Impairment of the ability to coordinate the movements required for normal ambulation (walking) which may result from impairments of motor function or sensory feedback. This condition may be associated with brain diseases (including cerebellar diseases and basal ganglia diseases); spinal cord diseases; or peripheral nervous system diseases. Friedreich Ataxia (difficulty walking)

Diagnosis

• History and clinical examination
• Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis.
• Labs:
  • Serum and urinary calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes levels: checked at birth (↑) and closely followed during the 1st few months of life
  • Thyroid function tests Thyroid Function Tests Blood tests used to evaluate the functioning of the thyroid gland. Ion Channel Myopathy:
    • ↑ Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH), ↓ triiodothyronine Triiodothyronine A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones ( T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones) and thyroxine Thyroxine The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroid Hormones ( T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones) in hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
    • ↑ Thyroid-stimulating hormone Thyroid-stimulating hormone A glycoprotein hormone secreted by the adenohypophysis. Thyrotropin stimulates thyroid gland by increasing the iodide transport, synthesis and release of thyroid hormones (thyroxine and triiodothyronine). Thyroid Hormones (TSH) with normal T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones and T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones levels in subclinical hypothyroidism Subclinical Hypothyroidism Hypothyroidism
  • Renal function tests
  • Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children
• Additional screening Screening Preoperative Care tests once the diagnosis is confirmed:
  • Pediatric cardiology evaluation with electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG)) and echocardiogram Echocardiogram Transposition of the Great Vessels (ECHO) to evaluate for cardiac anomalies
  • Renal and bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess ultrasounds to evaluate for anomalies
  • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy ultrasound to evaluate for possible hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS)
  • Nutritional/feeding evaluation
  • Ophthalmology evaluation
  • Auditory exam 
  • Neuropsychologic, developmental, educational, and behavioral assessments/screenings

Management

Treatment is based on the clinical manifestations present and is aimed at improving the quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life and treating associated conditions.

Cardiovascular

• Approximately 20% require surgical or catheter-based intervention in the 1st few years of life.
• Annual cardiology follow-up
• Pre-operative assessment by a pediatric cardiologist and anesthesiology Anesthesiology Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts before any procedures requiring sedation or anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts due to ↑ risk of sudden cardiac death Sudden cardiac death Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest
• Routine blood pressure check in all extremities:
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension treated with calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers or beta blockers
  • Renal ultrasound with Doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure studies to evaluate for renal artery Renal artery A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. Glomerular Filtration stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) as a cause for hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension

Endocrine

• Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia:
  • Monitor monthly with laboratory tests until resolved.
  • Avoid vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies supplementation.
• Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: treated with levothyroxine Levothyroxine Thyroid Replacement Therapy
• Oral glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance tolerance Tolerance Pharmacokinetics and Pharmacodynamics testing starting at 20 years of age
• Early puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty in girls: treated with a gonadotropin-releasing hormone Gonadotropin-releasing hormone A decapeptide that stimulates the synthesis and secretion of both pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. Gnrh is produced by neurons in the septum preoptic area of the hypothalamus and released into the pituitary portal blood, leading to stimulation of gonadotrophs in the anterior pituitary gland. Puberty agonist

Nutritional and gastrointestinal

• Regular Regular Insulin monitoring of caloric intake and any feeding difficulties
• Feeding tube may be needed.
• Routine constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation evaluations with aggressive treatment, if needed, to avoid diverticulosis Diverticulosis A pathological condition characterized by the presence of a number of colonic diverticula in the colon. Its pathogenesis is multifactorial, including colon aging, motor dysfunction, increases in intraluminal pressure, and lack of dietary fibers. Diverticular Disease, hemorrhoids Hemorrhoids Hemorrhoids are normal vascular cushions in the anal canal composed of dilated vascular tissue, smooth muscle, and connective tissue. They do not cause issues unless they are enlarged, inflamed, thrombosed, or prolapsed. Patients often present with rectal bleeding of bright red blood, or they may have pain, perianal pruritus, or a palpable mass. Hemorrhoids, and rectal prolapse Rectal prolapse Rectal prolapse, also known as rectal procidentia, is the protrusion of rectal tissue through the anus. The tissue may include just the mucosa or the full thickness of the rectal wall. Common risk factors include chronic straining, constipation, bowel motility disorders, and weakening of the pelvic floor muscles. Rectal Prolapse

Otologic

• Hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
• Tympanostomy tubes Tympanostomy Tubes Acute Otitis Media for recurrent otitis media

Ocular

• Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus correction
• Corrective lenses for hyperopia Hyperopia Refractive Errors

Other

• Physical therapy Physical Therapy Becker Muscular Dystrophy
• Speech and language therapy
• Behavioral therapy
• Educational interventions
• Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies

Differential Diagnosis

• Smith-Magenis syndrome: a non-inherited genetic condition due to a deleted region of genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 17. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship also have short stature, cardiac anomalies, hyperacusis Hyperacusis An abnormally disproportionate increase in the sensation of loudness in response to auditory stimuli of normal volume. Cochlear disease, vestibulocochlear nerve diseases, facial nerve diseases, stapes surgery, and other disorders may be associated with this condition. Cranial Nerve Palsies, and intellectual disabilities. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with Smith-Magenis syndrome additionally show self-injurious behavior patterns. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. Treatment is tailored to the clinical manifestations present. 
• Noonan’s syndrome: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic condition caused by several potential gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations. Men and women can be affected. Clinical presentation includes short stature, developmental delay, and congenital Congenital Chorioretinitis heart defects. Noonan’s syndrome patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship also have abnormal bruising and bleeding. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. Treatment is tailored to the symptoms present.