Diseases » Prader-Willi syndrome » Diagnosis

Diagnosis of Prader-Willi syndrome

Prader-Willi syndrome Diagnosis: Book Excerpts

• Ask the Following Questions - MENTAL RETARDATION
• Ask the Following Questions - OBESITY, PATHOLOGIC
• Ask the following questions - CRAMPS, MUSCULAR
• Differential Diagnosis - Short Stature
• Differential Diagnosis - Hypotonia
• Differential Diagnosis - Obesity
• Approach to the Diagnosis - OBESITY
• Approach to the Diagnosis - MUSCULAR CRAMPS
• Diagnosis - Hypogonadism
• Diagnosis - Mental retardation
• Diagnosis - Obesity
• History - Shortness of Breath
• Differential Overview - Obesity
• Clinical Features and Diagnosis - Hypotonia and Weakness
• Clinical Features and Diagnosis - Obesity
• Approach to the Diagnosis - OBESITY
• Approach to the Diagnosis - MUSCULAR CRAMPS

Diagnosis of Prader-Willi syndrome: medical news summaries:

The following medical news items are relevant to diagnosis and misdiagnosis issues for Prader-Willi syndrome:

• Rare overeating disease
• More news »

Diagnostic Tests for Prader-Willi syndrome: Online Medical Books

16 MEDICAL BOOKS ONLINE! Review excerpts from medical books online, free, without registration, for more information about diagnostis of Prader-Willi syndrome.

MENTAL RETARDATION: Ask the Following Questions:
(Algorithmic Diagnosis of Symptoms and Signs)

1. Is there decreased hair and skin pigment? These findings would suggest phenylketonuria.
2. Are there abnormal secondary sex characteristics? These findings would suggest Klinefelter's syndrome, Turner's syndrome, and Laurence-Moon-Bardet-Biedl syndrome.
3. Are there abnormalities of the skull present? Findings of deformities or enlargement of the skull should suggest rickets, microcephaly, hypertelorism, oxycephaly, and hydrocephalus, among other things.
4. Is there hepatosplenomegaly? The findings of hepatosplenomegaly suggest galactosemia, Hurler's disease, and Gaucher's disease, among other diagnostic possibilities.
5. Are there skin changes? Sturge-Weber syndrome, tuberous sclerosis, neurofibromatosis, and cretinism may present with skin changes. Kernicterus is associated with jaundice.
6. Are there other neurologic signs? Tay-Sachs disease, congenital syphilis, Arnold-Chiari malformation, and cerebral diplegia are just a few of the causes of mental retardation that may present with other neurologic signs.

DIAGNOSTIC WORKUP

Routine laboratory tests include a CBC, sedimentation rate, chemistry panel, serum galactose level, VDRL test, thyroid profile, and urine screen for carbohydrates, amino acids, and organic acids. Chromosomal analysis may detect Klinefelter's syndrome, Turner's syndrome, mongolism, and other disorders. If there are deformities of the skull present, a skull x-ray should be done.

An EEG, CT scan of the brain, and psychometric testing will often need to be done, but a referral to a neurologist should be made before ordering these expensive tests.

 

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Source: Algorithmic Diagnosis of Symptoms and Signs, 2003

OBESITY, PATHOLOGIC: Ask the Following Questions:
(Algorithmic Diagnosis of Symptoms and Signs)

1. Is there associated hyperphagia? If the patient recognizes that he or she has a ravenous appetite or eats more than is necessary, the possibility of an insulinoma or Fröhlich's syndrome should be considered.
2. Is the obesity centripetal? The presence of centripetal obesity, especially with moon facies, should suggest Cushing's syndrome.
3. Is the obesity mainly of the lower extremities? This finding would suggest lipodystrophy.
4. Is there mental retardation? The presence of mental retardation should suggest Laurence-Moon-Bardet-Biedl syndrome.
5. What is the sex of the patient? In male patients one should consider Klinefelter's syndrome, and in female patients one should consider polycystic ovary.

DIAGNOSTIC WORKUP

Routine laboratory tests include a CBC, urinalysis, chemistry panel, 2-hr postprandial blood sugar, and thyroid profile. If an insulinoma is strongly suspected, a 24- to 36-hr fast, a 5-hr glucose tolerance test, and tolbutamide tolerance test may be done. If Cushing's syndrome is suspected, a serum cortisol and cortisol suppression test should be done. Pelvic ultrasound will help diagnose polycystic ovaries. Chromosomal analysis will help diagnose Klinefelter's syndrome. Perhaps a psychiatrist should be consulted.

 

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Source: Algorithmic Diagnosis of Symptoms and Signs, 2003

CRAMPS, MUSCULAR: Ask the following questions:
(Algorithmic Diagnosis of Symptoms and Signs)

1. Is there a history of drug ingestion? Many drugs produce muscular cramps. The most notable are the diuretics.
2. Are there absent or diminished peripheral pulses? Absent or diminished peripheral pulses suggest the cramps are due to ischemia from peripheral arteriosclerosis or arterial embolism.
3. Are the femoral pulses diminished? Diminished femoral pulses suggest a Leriche syndrome or saddle embolism of the terminal aorta.
4. Is there hypertension? Hypertension suggests aldosteronism and chronic glomerulonephritis.
5. Are the cramps limited to one extremity? Limitation of the cramps to one extremity suggests an occupational neurosis (professional cramps).
6. Is there a positive Chvostek's and/or Trousseau's sign? These are signs of tetany, as might be associated with hypoparathyroidism, uremia, alkalosis, and other causes.
7. Is there fever? Fever is associated with dehydration, heat stroke, and many infectious diseases that cause cramps.

DIAGNOSTIC WORKUP

All patients should have a CBC, sedimentation rate, chemistry panel, electrolytes, and urinalysis. If there is associated diminished or absent peripheral pulses, then Doppler studies and arteriography should be done. If the cramps are acute in onset, time should not be wasted in performing these studies. Magnetic resonance angiography is an excellent alternative to invasive angiography, but it is expensive. If there is associated hypertension, then 24-hr urine aldosterone and plasma renin studies should be done. If there are positive Trousseau's and/or Chvostek's signs, a thorough investigation for hypoparathyroidism should be done. A single serum calcium and phosphorus and alkaline phosphatase is not enough, but repeated studies should be done. In addition, 24-hr urine collection for calcium and serum parathyroid hormones should be done. An endocrinologist should probably be consulted if there is any doubt about the existence of hypoparathyroidism or any of the other causes of hypocalcemia.

 

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Source: Algorithmic Diagnosis of Symptoms and Signs, 2003

Short Stature: Differential Diagnosis
(In A Page: Pediatric Signs and Symptoms)

• Familial short stature
• Constitutional delay of growth and puberty
• Hypothyroidism
• Growth hormone deficiency (GHD)
• GH resistance (Laron syndrome)
• Congenital hypopituitarism
  –Secondary to brain tumors
• Acquired hypopituitarism
  –After irradiation, surgery, and chemotherapy for neoplasms
  –Infectious
  –Infiltrative
  –Vascular
• Cushing syndrome
• Precocious puberty
  –Tall initially
  –Final height compromised
• Pseudohypoparathyroidism
• Rickets
• Genetic syndromes
  –Turner syndrome
  –Down syndrome
  –Noonan syndrome
  –Prader-Willi syndrome
• Intrauterine growth retardation
  –Silver-Russell syndrome
• Disorders of bone development
  –Achondroplasia/hypochondroplasia
  –Chondrodystrophies
• Psychosocial deprivation
• Malnutrition
• Chronic drug intake
  –Glucocorticoids
  –Methylphenidate
• Infectious
  –HIV
  –Tuberculosis
• Congenital heart disease
• Gastrointestinal
  –Celiac disease
  –Inflammatory bowel disease
  –Chronic liver disease
• Pulmonary
  –Cystic fibrosis
• Chronic renal disease
  –RTA
  –Renal failure
• Skeletal disorders

Workup and Diagnosis

• History
  –Neonatal hypoglycemia or jaundice, brain tumor or other malignancy and treatment, central nervous system infection, nutrition status, chronic illness
• Family history
  –Parents’ heights and puberty ages to judge child's growth relative to genetic potential (midparental target height), family history of chronic disease or endocrinopathy
• Physical exam
  –Anthropometrics (height, weight, sitting height), dysmorphic features, craniofacial midline abnormalities (pituitary disease), dentition maturation (delayed in hypothyroidism), chronic illness, Tanner staging for pubertal assessment, micropenis in boys (growth hormone deficiency)
• Bone age X-ray to evaluate skeletal maturation
• Labs
  –CBC with differential cell count, LFT, BUN, Cr, electrolytes
  –ESR, TSH, T4
  –Growth factors (IGF-I, IGFBP-3)
  –Celiac antibody panel (anti-tissue transglutaminase)
  –Karyotype in girls to rule out Turner syndrome
• If IGF-I and/or IGFBP-3 low, provocative growth hormone test to confirm GHD (must fail two tests)
• MRI of the brain with special cuts of the pituitary in any child diagnosed as having GHD

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Source: In A Page: Pediatric Signs and Symptoms, 2007

Hypotonia: Differential Diagnosis
(In A Page: Pediatric Signs and Symptoms)

• Benign congenital hypotonia
• Chromosome abnormalities: Trisomy 21, trisomy 13, Prader-Willi, cri-du-chat
• Hypoxic ischemic encephalopathy
• Spinal muscular atrophy (SMA)
• Infantile botulism
• Hypothyroidism
• Spinal cord injury
• Cerebral malformations
• Toxins: Organophosphates, aminoglycosides, antineoplastic agents, chloroquine, glue-sniffing
• Myasthenia gravis
  –Transient neonatal myasthenia
  –Congenital myasthenia
  –Familial infantile myasthenia
• Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP)
• Muscular dystrophy: Duchenne, Becker, facioscapulohumeral, Fuluyama, merosindeficient congenital muscular dystrophy
• Congenital myotonic dystrophy
• Hereditary motor-sensory neuropathy
• Metachromatic leukodystrophy
• Globoid cell leukodystrophy
• Congenital myopathies: Central core disease, myotubular, nemaline (rod), congenital fiber-type disproportion
• Peroxisomal disorders
  –Neonatal adrenoleukodystrophy, Zellweger
• Hypermagnesimia
• Myositis
• Lipid storage muscular disorders
• Mitochondrial encephalomyopathy
• Pompe disease (glycogen storage disease type II, acid maltase deficiency)
• McArdle disease
• Walker-Warburg syndrome
• Lowe syndrome (oculocerebrorenal)
• Werdnig-Hoffman Disease
• Familial dysautonomia
• Tick paralysis
• Poliomyelitis

Workup and Diagnosis

• History
  –Birth history, fetal motion, oligo-polyhydramnios
  –Feeding, head control, gross/fine motor milestones
  –Seizures, family history, constipation, tick bite

• Physical exam
  –Deformities, dermatoglyphics, contractures, scoliosis, spinal dimple, hernias, corneal opacities, high or cleft palate, muscle mass
  –Cardiac size, hip dislocation, flat occiput
  –Muscle mass, strength and tone, facial movements, fasiculations, DTRs, sensory responses
  –Newborns: Posture, spontaneous movements, plantar response, primary neonatal reflexes (Moro, palmar grasp, tonic neck response)
  –Older child: Gowers sign, mental status, eye movements, stance and gait

• Labs
  –Muscle enzymes (CPK, aldolase)
  –Electrolytes, TSH, lactate, pyruvate
  –Carnitine, acylcarnitine, very long chain fatty acids
  –Stool botulinum toxin
  –LP for GBS
• Studies
  –EMG/nerve conduction studies
  –Muscle biopsy for metabolic, congenital myopathies
  –MRI for cerebral malformations, spinal cord lesions
  –Specific genetic testing
  –SMA, muscular dystrophy, myotonic dystrophy

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Source: In A Page: Pediatric Signs and Symptoms, 2007

Obesity: Differential Diagnosis
(In A Page: Pediatric Signs and Symptoms)

• Exogenous obesity (most common)
  –No demonstrable disease as the cause
  –Excessive weight gain from imbalance between caloric intake and energy expenditure
  –Linear growth is robust and frequently accelerated

• Hormonal causes
  –Associated with poor linear growth
  –Hypercortisolism: Cushing syndrome is any type of glucocorticoid excess (endogenous or exogenous); Cushing disease describes pituitary ACTH overproduction
  –Hypothyroidism
  –Growth hormone deficiency

• Insulinoma
• Hypothalamic obesity
  –Tumors (e.g., craniopharyngiomas)
  –Following neurosurgery or irradiation
  –Head trauma
  –Infiltrative/inflammatory
• Genetic syndromes
  –Prader-Willi syndrome
  –Laurence-Moon-Bardet-Biedl syndrome
  –Alström syndrome
  –Cohen syndrome
  –Down syndrome
  –Carpenter syndrome
  –Grebe syndrome
  –Beckwith-Wiedemann syndrome
• Defects in metabolic/eating regulatory pathways is an area of intense investigation; multiple mutations are theoretically possible, but only a few have actually been discovered in humans
  –Congenital leptin deficiency (extremely rare)
  –Leptin resistance (more common than deficiency)
• Drugs
  –Chronic glucocorticoids
  –Neuropsychotropic medications
• Adiposogenital dystrophy syndrome

Workup and Diagnosis

• History: Age and course of onset; linear growth progression; birth and neonatal history (tone, failure to thrive); polydipsia, polyuria, polyphagia; dietary intake, physical activity; cold intolerance, constipation, dry skin, headaches; abdominal pain, onset of puberty if pubertal; developmental delay (genetic syndromes); family history of obesity and genetic disorders
• Physical exam: Vital signs (blood pressure); growth parameters (height, weight, BMI); distribution of fat, moon or coarse facies, pallor, buffalo hump, striae (Cushingoid appearance); acanthosis nigricans (dark velvety areas in skin folds; cutaneous marker of insulin resistance); abdominal masses, micropenis, hypogonadism; depressed deep tendon reflexes; in infants skin “puddling,” midline defects
• Diagnostic workup
  –24-hour urine free cortisol/creatinine ratio (best screen for Cushing syndrome)
  –MRI (hypothalamic/pituitary mass)
  –Adrenal ultrasound (if suspect adrenal mass)
  –Thyroid function tests (T4, TSH)
  –IGF-I and IGFBP-3; possibly provocative growth hormone testing (if suspect GH deficiency)
  –Genetic (FISH) testing for genetic syndromes
  –Serum leptin
• Labs: Urinalysis for glucose, serum glucose, fasting serum insulin, hemoglobin A1c
  –Fasting lipid profile, urine microalbumin

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Source: In A Page: Pediatric Signs and Symptoms, 2007

OBESITY: Approach to the Diagnosis
(Differential Diagnosis in Primary Care)

It would be ridiculous to do a complete endocrine workup on every case of obesity, but thyroid function studies may be worthwhile. Patients who fail to lose weight on a strict diet may require hospitalization with observation. If they still fail to lose weight, a complete endocrine workup would seem to be indicated.

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Source: Differential Diagnosis in Primary Care, 2007

MUSCULAR CRAMPS: Approach to the Diagnosis
(Differential Diagnosis in Primary Care)

Clinically, one should look for absent or diminished pulses in the extremity involved, Chvostek and Trousseau signs of tetany, and neurologic signs of an upper motor neuron lesion. An occupational history may disclose that the patient is a miner or iron-worker or is exposed to excessive heat on the job. Occupations such as painters, writers, seamstresses and compositors suggest the so-called professional cramps. Adson signs are positive in thoracic outlet syndrome. Cramps in the legs produced by walking a certain distance suggest peripheral arteriosclerosis and Leriche syndrome. The initial laboratory workup involves a CBC, urinalysis, chemistry panel, and electrolytes. If a vascular cause is suspected, ultrasonography and perhaps venography or angiography may be indicated

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Source: Differential Diagnosis in Primary Care, 2007

Hypogonadism: Diagnosis
(Professional Guide to Diseases (Eighth Edition))

Accurate diagnosis necessitates a detailed patient history, physical examination, and hormonal studies. Serum and urinary gonadotropin levels increase in primary (hypergonadotropic) hypogonadism but decrease in secondary (hypogonadotropic) hypogonadism. Other relevant hormonal studies include assessment of neuroendocrine functions, such as thyrotropin, corticotropin, growth hormone, and vasopressin levels. Chromosomal analysis may determine the specific causative syndrome. Testicular biopsy and semen analysis determine sperm production, identify impaired spermatogenesis, and assess low levels of testosterone.

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Source: Professional Guide to Diseases (Eighth Edition), 2005

Mental retardation: Diagnosis
(Professional Guide to Diseases (Eighth Edition))

CONFIRMING DIAGNOSIS A score of less than 70 on a standardized IQ test confirms the diagnosis of mental retardation.

The IQ test primarily predicts school performance and must be supplemented by other diagnostic evaluations.

For example, the Adaptive Behavior Scale deals with behaviors important to activities of daily living. This test evaluates self-help skills (toileting and eating), physical and social development, language, socialization, and time and number concepts. It also examines inappropriate behaviors, such as violent or destructive acts, withdrawal, and self-abusive or sexually aberrant behavior.

Age-appropriate adaptive behaviors are assessed by using developmental screening tests such as the Denver Developmental Screening test. These tests compare the subject’s functional level with the normal level for the same chronologic age. The greater the discrepancy between chronologic and developmental age, the more severe the retardation. In most European and North American cultures, the Vineland Social Maturity Scale, a tool used to determine social competence, is recommended for use when appropriate.

In children, the functional level is based on sensorimotor skills, self-help skills, and socialization. In adolescents and adults, it’s based on academic skills, reasoning and judgment skills, and social skills.

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Source: Professional Guide to Diseases (Eighth Edition), 2005

Obesity: Diagnosis
(Professional Guide to Diseases (Eighth Edition))

Observation and comparison of height and weight to a standard table indicate obesity. Measurement of the thickness of subcutaneous fat folds with calipers provides an approximation of total body fat. Although this measurement is reliable and isn’t subject to daily fluctuations, it has little meaning for the patient in monitoring subsequent weight loss. Obesity may lead to serious complications, such as respiratory difficulties, hypertension, cardiovascular disease, diabetes mellitus, renal disease, gallbladder disease, psychosocial difficulties, and premature death.

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Source: Professional Guide to Diseases (Eighth Edition), 2005

Shortness of Breath: History
(The 10-Minute Diagnosis Manual: Symptoms and Signs in the Time-Limited Encounter)

Are historical features helpful? Historical findings are neither sensitive nor specific; however, some symptoms are associated with specific diseases. Regardless of the cause, people associate shortness of breath with words that describe a sense of “work” or “effort” to breathe. Asthma is associated with words that denote a sense of “tightness.” Patients with interstitial lung disease choose terms emphasizing the sense of “rapid” breathing. Did the patient select terms indicating difficulty with both inhalation and exhalation? This is often reported by patients with CHF (Chapter 7.5). Patients who are deconditioned select rapid, breathing more, or heavy to describe their dyspnea. Patients suffering from neuromuscular disorders select terms denoting rapid breathing or difficulty with inhalation. Is the patient aged less than 40 years? Are the patient’s symptoms episodic? Reactive airway disease and hyperventilation are associated with these terms (2).

Physical examination

In the physical examination, focus on signs of respiratory or cardiac disease. For the respiratory system, this means a careful examination starting at the nose. Specifically, on head, eyes, ear, nose, and throat examination look for evidence of obstruction, infection, or postnasal drip. Exclude obstruction, subcutaneous emphysema, or tracheal deviation. On cardiac examination, look for evidence of cardiomegaly, S₃ gallop, or hepatojugular reflux (HJR). In this setting, HJR is very specific for CHF (1). Assess the lungs for abnormal breath sound intensity, rales, wheezing, rhonchi, or tachypnea. Examine the chest for abnormal movements or deformities. Exclude abdominal masses, ascites, pregnancy, or abdominal distention. Evaluate the extremities for edema, tenderness, or asymmetry. Do a complete neurologic examination, and screen for weakness atrophy, sensory loss, and fasciculations.

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Source: The 10-Minute Diagnosis Manual: Symptoms and Signs in the Time-Limited Encounter, 2000

Obesity: Differential Overview
(Field Guide to Bedside Diagnosis)

❑ Caloric excess

❑ Depression

❑ Drugs

❑ Hypothyroidism

❑ Hypogonadism

❑ Cushing syndrome

❑ Polycystic ovary syndrome

❑ Hypothalamic

❑ Insulinoma

Diagnostic Approach

Body mass index (BMI) 5 mass (kilograms)/height (meters)². Overweight is
a BMI 25 to 30 kg/m² and obesity is a BMI .30 kg/m². A body mass index .30 correlates with increased risk of type 2 diabetes, sleep apnea syndrome, fatty liver, gallstones, gout, degenerative joint disease, and accelerated atherogenesis. Abdominal obesity (waist–hip ratio .0.95 in men and .0.85 in women) with excess visceral (intra-abdominal) fat is associated with elevated trigylceride, insulin and glucose levels, and confers an especially increased incidence of adverse outcomes.

Less than 1% of patients with obesity have an endocrine or other secon-dary cause.

Rapid weight gain is usually due to fluid accumulation, seen with congestive heart failure, renal failure or chronic liver disease. Ascites with the latter can
produce a prominent abdomen, which can be mistaken for obesity by the patient.

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Source: Field Guide to Bedside Diagnosis, 2007

Hypotonia and Weakness: Clinical Features and Diagnosis
(The Diagnostic Approach to Symptoms and Signs in Pediatrics)

Brain Disorders

Cerebral Malformations

Lissencephaly(smooth brain) causes marked hypotonia in neonatal period followed byseizures and global developmental delay. MRI is procedure of choiceto demonstrate malformations (see Chap.40, Microcephaly).

Zellweger syndrome, a peroxisomal disorder,is characterized by pachygyria, polymicrogyria, severe hypotonia,neonatal seizures, hepatomegaly, leukodystrophy, renal cysts, andstippled calcification of patellae (see Chap. 13, Developmental Delay).

Dandy-Walker malformation, which consistsof posterior fossa cyst contiguous with fourth ventricle, partialor complete absence of cerebellar vermis, and hydrocephalus maybe associated with hypotonia in early infancy.

Chromosomal Abnormalities

Hypotoniaand delayed motor development are constant features of trisomy 21.Other chromosomal abnormalities that may be associated with hypotoniainclude trisomy 20p, 4p–, 9p–, and 18q– syndromes.Chromosomal karyotype confirms diagnosis.

Severe hypotonia, poor feeding, weakcry, and diminished deep tendon reflexes may occur in neonatal periodwith Prader Willi syndrome. Clinical manifestations that appearin childhood include hyperphagia, obesity, impaired linear growth,and diminished cognitive function (see Chap. 44, Obesity).

Hypoxic-Ischemic Encephalopathy

Most common cause of hypotonia in newborns.May also occur after severe head trauma, intracranial hemorrhage,strangulation, suffocation, and near drowning.

Hypotonic Cerebral Palsy

May be suspected in children with historyof perinatal asphyxia or birth trauma. In many cases, cause is unknown.Clinical findings include hypotonia, delayed motor development,and sometimes athetosis and ataxia.

Intracranial Infection

Hypotonia may occur following bacterial meningitisor viral encephalitis (see Chap.3, Alteration in Consciousness).

Trauma

Head traumamay cause cerebral contusion and intracranial hemorrhage, whichcan produce focal neurologic deficits, including seizures and hemiparesis.

CT or MRI can confirm diagnosis.

Metabolic Disorders

A numberof metabolic disorders can cause hypotonia without significant weakness, includingamino acid (nonketotic hyperglycinemia), organic acid (propionic,isovaleric, and methylmalonic acidemias), and lysosomal storage(mucopolysaccharidoses, lipidoses) disorders (see Chap. 3, Alteration in Consciousness,and Chap. 13, Developmental Delay).

Screening tests include serum electrolytes,glucose, ammonia, amino acids, lactate, pyruvate, carnitine; andurinary ketones, organic acids, and mucopolysaccharides.

Neurodegenerative Disorders

Degenerativedisorders of CNS that cause hypotonia include

Gray matter diseases (Tay-Sachs disease,Alpers disease, Menkes disease, GM-1 gangliosidosis, GM-2 gangliosidosis)

White matter diseases (Canavan disease,Pelizaeus-Merzbacher disease)

Diseases of gray and white matter (Zellwegersyndrome, neonatal adrenoleukodystrophy, Leigh syndrome)

See Chap.13, Developmental Delay.

Nonspecific Mental Retardation

Hypotonia may be associated with nonspecificmental retardation. Other findings may include impaired or delayedmotor and language development.

Spinal Cord Disorders

Trauma

Spinal cordinjury secondary to trauma may cause hypotonia and weakness in acute phase.

Flaccid weakness occurs in lower extremitiesand sometimes upper extremities, depending on level of lesion. Deeptendon reflexes may be normal or hypoactive. Subsequently, hypotoniagives way to spasticity and tendon reflexes become hyperactive.

MRI is useful in defining locationand extent of injury.

Spinal Dysraphism

May be associatedwith hypotonia and weakness, usually of lower extremities.

Cutaneous dimples or tracts, subcutaneousmass, or abnormal collections of hair in spinal area should raisesuspicion of disorder of caudal neural tube formation. Sensory abnormalitiesof legs and feet and sphincter abnormalities also may be noted.

U/S may be performed initially.Combination of CT and MRI may be necessary for definitive diagnosis(see Chap. 69, Urinary Incontinence).

Neoplasm

Tumors affecting spinal cord may cause spinalpain with radiation to specific dermatome, extremity weakness, impairedsensation, and lack of bowel and bladder control (see Chap. 5, Back Pain).

Anterior Horn Cell Disorders

Spinal Muscular Atrophies

Affect anteriorhorn cells of spinal cord and lower motor nuclei of brainstem. Genetic transmissionmay be autosomal recessive (most common), autosomal dominant, orX-linked.

3 types of autosomal-recessive formshave been described. Genetic defect in these types involves q13region of chromosome 5.

Most severe is type I, with onset priorto 6 mos of age, failure to develop ability to sit, and death usuallyby 2 yrs of age. In type II, onset is before 18 mos of age, withfailure to develop ability to stand. Death occurs after 2 yrs ofage. Type III is defined by onset after 18 mos of age, with abilityto stand and usually walk, and death occurs in adulthood.

In type I, severe hypotonia and weaknessoccur, with legs more affected than arms, and proximal musculatureaffected more than distal.

Absence of deep tendon reflexes is almost alwaysfound.

Involvement of CN nuclei results indifficulty swallowing and weak cry.

Sensory and sphincter functions arenormal.

Muscle fasciculations may be seen,especially involving tongue.

Intelligence and language developmentare normal until regression begins to occur by about 1 yr of age.

Creatine phosphokinase (CPK) concentrationis normal.

U/S shows characteristic increasein intensity of echoes from muscle.

Fibrillation potentials may be seenwith electromyography. Motor nerve conduction velocities are normal.

Muscle biopsy shows characteristicdenervation pattern that helps confirm diagnosis. Molecular geneticanalysis is definitive.

Enteroviral Infection

Infectionwith enteroviruses can produce asymmetric weakness of limbs.

Prototype disease is poliomyelitis,but now only a few cases occur each year in the Western hemisphere,which are result of oral polio vaccine and not wild-type virus.Polioviruses (types 1, 2, 3) have predilection for anterior horncells of spinal cord and cranial nerve nuclei of brainstem.

Transmission is by fecal-oral route,with incubation period of 1–5 wks.

>90% of infectedchildren are asymptomatic or have mild nonparalytic disease.

Illness begins with URI or gastroenteritisfollowed within 1 wk by fever, headache, and muscle pain. Asymmetricextremity weakness (usually legs more than arms) and absence ofdeep tendon reflexes along with weakness of facial and pharyngealmuscles may occur.

Some children develop meningoencephalitiswith spinal fluid pleocytosis and increased protein concentration.

In most severe form, paralysis spreadsfrom legs to involve abdominal and thoracic musculature and arms.

Viral isolation from pharynx, stool,or spinal fluid is diagnostic. Specific polymerase chain reactiontests or paired serologic tests are also diagnostic.

Peripheral Nerve Disorders

Acute Inflammatory Demyelinating Polyradiculopathy (Guillain-Barré Syndrome)

Prototypedisorder for acute diffuse peripheral neuropathy. Thought to haveautoimmune basis, perhaps triggered by viral infection.

In typical cases, symmetric weaknessascends from legs to trunk to arms and finally to bulbar muscles.In mild cases, only legs may be affected.

Weakness may evolve over a few daysto a few weeks. Sensory symptoms and signs are mild with pain andloss of vibratory or position sense in some patients.

Loss of pain and touch sensation areless common.

Involvement of cranial motor nerves,most commonly facial nerve, may produce difficulty with swallowingand speech.

Respiratory impairment with decreasedvital capacity and hypercarbia or frank respiratory failure arecommon complications.

Involvement of autonomic nerves cancause life-threatening cardiac arrhythmias or fluctuations in BP.

CSF is often normal in first few daysof illness; however, CSF protein increases during first 2 wks andpeaks by 4–5 wks into illness. CSF WBC count is usually <10cells/mm³ but may be up to 50cells/mm³.

Electromyographic findings are consistentwith neurogenic abnormalities. Motor nerve conduction velocity isusually decreased.

Diagnosis is based on above findings.

Chronic Inflammatory Demyelinating Polyneuropathy

Thoughtto be immune mediated, but inciting stimulus is unknown.

Duration is >2 mos.

Clinical features include distal extremityweakness and sensory loss leading to gait disturbance. Deep tendonreflexes are hypoactive or absent. Cranial nerve involvement andpain are uncommon.

CSF protein concentration is increased,but CSF WBC count is normal.

Motor nerve conduction velocity isslow.

Sural nerve biopsy may show demyelinization.

Chronic Motor-Sensory Polyneuropathy

Chronicmotor-sensory neuropathies may be inherited or acquired.

Hereditary motor-sensory neuropathiestypes I and II are characterized by extremity weakness, foot deformities(pes cavus and hammer toes), and variable loss of sensation. Onsetis usually in first or second decade.

Type III is characterized by onsetduring first year of life, with hypotonia and delay in developmentalmilestones. Muscle weakness (proximal and distal) and absence ofdeep tendon reflexes occur in childhood.

Many other hereditary motor-sensoryneuropathies also have been described (Swaiman and Ashwal, 1999).All may be distinguished by clinical, electromyographic, nerve biopsy,and molecular genetic analysis findings.

Peripheral neuropathy is also a featureof other genetic disorders, including metachromatic leukodystrophy,globoid cell leukodystrophy, and Friedreich ataxia (see Chap. 4, Ataxia, and Chap. 13, Developmental Delay).

Toxic neuropathies include lead poisoningand use of the chemotherapeutic agent vincristine.

Sensory Neuropathies

Includecongenital sensory neuropathy and familial dysautonomia and maypresent in infancy or childhood.

Characterized by hypotonia, impairedor absence of deep tendon reflexes, occasional limb weakness, andautonomic phenomena (e.g., decreased lacrimation). Impaired pain,touch, and temperature sensation also occur.

Motor nerve conduction velocities arenormal, whereas sensory nerve responses are impaired.

Sural nerve biopsy helps distinguishcongenital sensory neuropathy from familial dysautonomia (see Chap. 66, Sweating).

Neuromuscular Junction Disorders

Myasthenia

Muscle weaknessstimulated by activity and relieved by rest characterizes myasthenia.

3 types are neonatal transient myastheniagravis, congenital myasthenic syndromes, and juvenile myastheniagravis.

Neonatal Transient Myasthenia Gravis

Autoimmunedisorder that occurs in small number of infants born to motherswith myasthenia gravis.

Thought that passive transfer of antibodydirected against fetal acetylcholine receptor protein from motherleads to decrease in available acetylcholine receptors at postsynapticmembrane.

Onset in most infants is within 24hrs of birth.

Clinical manifestations include generalizedhypotonia and weakness, feeding and respiratory difficulty, facialweakness, and occasionally ptosis.

Administration of anticholinesteraseagent (e.g., edrophonium chloride, which results in decreased ptosis)is diagnostic. Finding increased serum concentration of acetylcholinereceptor binding antibody is also diagnostic.

Congenital Myasthenic Syndromes

Caused bygenetic defects affecting neuromuscular junction and not by autoimmune process.Mothers do not have myasthenia gravis.

Most common of these disorders wasformerly called congenital myasthenia but now is referred to asend-plate acetylcholine receptor deficiency.

Onset is usually in first weeks oflife with ptosis.

Ophthalmoplegia appears in ensuingmonths. Only after significant activity do hypotonia and weaknessoccur.

Diagnosis may be made by observingresponse to anticholinesterase drugs. Electrophysiologic and alpha-bungarotoxinbinding studies confirm deficiency in number or function of acetylcholine receptors.

Juvenile Myasthenia Gravis

Classicor juvenile form of myasthenia gravis occurs in children >2yrs of age; however, onset is usually in adolescence.

Most cases are caused by decrease innumber of available acetylcholine receptors secondary to circulatingreceptor-binding antibodies.

Usual finding at any age is weaknessthat worsens with exercise or repetitive use of muscles.

Diagnosis can be confirmed by detectionof antibodies against acetylcholine receptor protein or by pharmacologicor electrophysiologic means. Repetitive stimulation of motor nerveproduces progressive decrease in amplitude of action potential (decrementalconduction).

Botulism

Neurotoxinproduced by C. botulinum impairs release of acetylcholine from cholinergicnerve terminals.

Illness may be acquired by ingestionof food that was contaminated with toxin or improperly preserved(food borne), contamination of wound by clostridium organisms (woundbotulism), or production of C. botulinum toxin in intestine afterexposure to spores (infant botulism).

Infant botulism is much more commonthan foodborne or wound botulism.

Onset is usually at 2–4 mos of age,although it can occur in neonatal period.

Initially poor feeding, constipation,hypotonia, and weakness occur. Illness progresses with impairedsucking and swallowing and more severe weakness during next fewdays. Ptosis is common finding, but extraocular function is usuallyintact. Pupillary reactions to light are impaired or absent.

Characteristic electromyogram showsincremental response of muscle action potential with repetitivenerve stimulation and frequent, brief-duration, small-amplitudemotor unit potentials.

Diagnosis is confirmed by isolationof organism or detection of toxin in stool.

Tick Paralysis

Neurotoxinsproduced by dog tick (D. variabilis), which is found primarily insoutheastern U.S., and by wood tick (D. andersoni), which is foundprimarily in Rocky Mountain states, prevent release of acetylcholineat neuromuscular junction.

Tick exposure usually begins 5–10days before onset of illness, which is characterized by acute ascendingflaccid paralysis similar to that seen with Guillain-Barré syndrome.

Deep tendon reflexes are decreasedor absent, and sensation is intact.

Finding tick, which is often on scalp,is diagnostic. Removal results in dramatic improvement.

Muscle Disorders

Primary clinical manifestation of muscledisease is weakness. Clinical presentation and course, mode of inheritance,muscle biopsy, and molecular genetic analysis help distinguish variousdisorders.

Congenital Myopathies

Central Core Disease

Onset ofthis autosomal-dominant disorder is in infancy or early childhood.

Gene locus has been mapped to chromosome19q13.1.

Usual presentation is hypotonia andweakness of proximal extremities (arms more than legs). Mild facialweakness also may occur.

Serum CPK is normal, and electromyographyusually shows myopathic pattern.

Muscle biopsy shows presence of coresof myofibrils undergoing degeneration in center of type I fibers.

Nemaline Rod Myopathy

2 formshave been described.

In more common autosomal-dominant form,gene locus has been mapped to chromosome 1, and in autosomal-recessiveform, to chromosome 2.

Onset of autosomal-dominant form isin childhood, with slowly progressive generalized weakness, whereasonset of autosomal-recessive form is in neonatal period with respiratoryinsufficiency or in infancy with hypotonia and delayed motor development.

Muscle biopsy shows distinctive rodlikebodies in muscle fibers.

Myotubular Myopathy

Genetictransmission is usually X-linked; however, milder autosomal-dominantand -recessive forms also exist.

Onset is usually in infancy, with generalizedhypotonia and weakness. Other findings include facial weakness,ptosis, and impaired extraocular movements.

Distinctive muscle biopsy shows musclefibers that resemble fetal myotubes.

Congenital Myopathy with Fiber-Type Disproportion

Genetictransmission may be autosomal dominant or autosomal recessive.

Onset is in infancy, with hypotoniaand weakness (proximal more than distal muscles). Facial weakness,congenital hip dislocation, and joint contractures also may occur.

Muscle biopsy shows predominance ofsmall type I fibers and compensatory hypertrophy of type II fibers.

Other

Several unusual congenital myopathies havebeen described with distinctive morphologic changes on muscle biopsy:fingerprint bodies, spheroid bodies, cytoplasmic bodies, sarcoplasmicbodies, zebra bodies, minicores, and Mallory body–likeinclusions.

Metabolic Myopathies

Glycogenoses

Glycogen Storage Disease Type II

Autosomal-recessivedisorder caused by deficiency of acid alpha-1,4-glucosidase (acidmaltase). Gene locus has been mapped to chromosome 17q25.2-q25.3.

Classic form (Pompe disease) presentsin infancy with severe hypotonia and weakness as well as difficultyin sucking and swallowing. Tongue is usually enlarged and may havefasciculations. Enlarged liver and cardiomyopathy are other usualfindings. Death usually occurs before 2 yrs of age.

Milder form may present in older childrenwith primarily skeletal muscle involvement.

Diagnosis may be confirmed by enzymeassay of muscle, or cultured fibroblasts, or by molecular geneticanalysis.

Glycogen Storage Disease Type III

Deficiencyof glycogen debrancher enzyme occurs in this autosomal-recessivedisorder. Gene locus has been mapped to chromosome 1p21. Involvementof both liver and muscle (type IIIa) is found in most affected individuals,whereas some have only liver involvement (type IIIb).

Characteristic findings include hypotonia,weakness, hepatomegaly, poor growth, hypoglycemia, and hyperlipidemia.

Enzyme assay of liver and muscle tissueconfirms diagnosis.

Carnitine Deficiency

Carnitine, produced almost exclusively inliver, is indispensable carrier of fatty acids into mitochondria,where they undergo beta oxidation. Most cases have been shown tobe due to defects in fatty acid oxidation; most common is medium-chainacyl-CoA dehydrogenase deficiency. 2 other disorders of carnitinemetabolism have been associated with decrease in carnitine concentrationin muscle: primary carnitine deficiency (carnitine transporter deficiency)and muscle carnitine deficiency.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Autosomal-recessivedisorder caused by mutations in medium-chain acyl-CoA dehydrogenasegene, whose locus has been mapped to chromosome 1p31.

Presenting features are poor feeding,respiratory distress, hypotonia, and alteration in consciousness.

Lab findings include hypoglycemia withoutketones, metabolic acidosis, hyperammonemia, low serum carnitine,and dicarboxylic aciduria.

Assay of plasma acylcarnitines is diagnostic.Demonstration of enzyme defect in leukocytes or fibroblasts is definitive.

Primary Carnitine Deficiency (Carnitine Transporter Deficiency)

Caused bymutations in SLC22A5 gene on chromosome 5. This gene encodes sodium ion-dependentcarnitine transporter OCTN2.

Onset is usually in infancy or earlychildhood, with hypotonia and weakness. These individuals tend todevelop hypoglycemic coma precipitated by prolonged fasting.

Serum, muscle, and liver carnitineconcentrations are low.

Muscle Carnitine Deficiency

Autosomal-recessivedisorder that involves deficient transport of carnitine across intestinalmucosa.

Onset is usually in late childhoodor adolescence with generalized proximal muscle weakness.

Muscle biopsy reveals lipid storagemainly in type I fibers and low carnitine concentration in muscle.Serum carnitine concentration is normal.

Respiratory Chain Disorders

Includedefects in complex I, complex III, complex IV, and multiple enzymesof respiratory chain (mitochondrial DNA depletion).

Marked hypotonia and weakness may occurin neonatal period. Hepatomegaly and cardiomyopathy also may occur.Defects in complexes I, III, and IV also can present primarily asencephalopathy.

Abnormal serum lactate/pyruvateratio (>20) suggests respiratory chain disorder.

Muscle biopsy including electron microscopyand respiratory chain enzyme analysis is diagnostic.

Periodic Paralysis

3 typesof familial (genetic) periodic paralysis are hypokalemic, hyperkalemic,and normokalemic. Genetic transmission of each disorder is autosomal-dominant.

Hypokalemic periodic paralysis usuallypresents in childhood or adolescence with episodic weakness andlow serum potassium levels. Episodes may be precipitated by restafter exercise, meal high in carbohydrate content, exposure to cold,and physical or emotional stress. Gene locus has been mapped tochromosome 1q31-32.

Hyperkalemic periodic paralysis ismore likely to occur in infancy and childhood. Onset of episodicweakness usually occurs after exercise. Serum potassium concentrationis increased during an episode. Gene locus has been mapped to chromosome17q23.1-q25.3.

Normokalemic periodic paralysis isclinically similar to hyperkalemic form, but serum potassium concentrationis normal during an episode.

Endocrine Myopathies

Proximal extremity weakness (legs more thanarms) that is progressive can be caused by hyperthyroidism, hypothyroidism,hyperadrenalism, hypoadrenalism, hyperparathyroidism, and hypoparathyroidism.See other chapters for discussion of some of these disorders.

Dystrophies

Group of genetically transmitted muscle disorderscharacterized by progressive degeneration of skeletal muscle.

Congenital Muscular Dystrophy

Encompassesseveral disorders that are characterized by generalized hypotoniaand weakness and early joint contractures. Disorders can be classifiedaccording to presence of muscle involvement (merosin-positive congenitalmuscular dystrophy) or both muscle and CNS involvement [congenitalmuscular dystrophy with white matter abnormality (merosin-deficienttype), Fukuyama congenital muscular dystrophy, muscle-eye-braindisease, and Walker-Warburg syndrome].

Lab tests usually reveal increasedserum CPK, nonspecific myopathic pattern with electromyography,and dystrophic changes on muscle biopsy.

MRI demonstrates brain abnormalities.

Duchenne Muscular Dystrophy

This X-linkeddisorder is most common type of muscular dystrophy in childhood.

Caused by mutations in gene that encodesprotein dystrophin.

Onset is usually at 2–4 yrsof age with progressive muscle weakness, lumbar lordosis, calf musclepseudohypertrophy, and positive Gower sign. Cardiomyopathy and impairedintellectual ability also may occur.

Lab tests reveal very high serum CPK,increase in echoes of involved muscle on U/S, myopathicchanges on electromyography, and myofiber degeneration and connectivetissue proliferation on muscle biopsy.

Molecular genetic analysis is now standardfor diagnosis.

Becker Muscular Dystrophy

Same geneis defective in Becker muscular dystrophy as in Duchenne musculardystrophy, but in Becker muscular dystrophy onset is later in childhood(after 5 yrs of age), clinical course is milder, and progressionis slower.

Dystrophin analysis of muscle can distinguishDuchenne muscular dystrophy from Becker muscular dystrophy. In theformer, dystrophin content is <3% of normal, whereasin the latter, it is 3–20% of normal.

Emery-Dreifuss Muscular Dystrophy

2 typeshave been described. Type 1 is X-linked and caused by mutationsin gene that encodes the protein emerin, while type 2 is autosomal-dominantwith mutations in gene on chromosome 1q21.2 that encodes the proteinlamin A/C.

Both types have same clinical phenotypewith onset at 5–15 yrs of age.

Characteristic features include weakness,primarily in legs and shoulder girdle, cardiomyopathy, and normalintellectual function.

Serum CPK is mildly increased.

Molecular genetic analysis is definitive.

Limb-Girdle Muscular Dystrophy

Onset isin childhood or adolescence, with weakness of hip and shoulder girdlemuscles.

Later in the course, distal musclesbecome weak. Facial weakness may or may not occur.

Autosomal-dominant, autosomal-recessive,and X-linked transmission may occur depending on specific disorder.

Molecular genetic analysis is definitive.

Facioscapulohumeral Muscular Dystrophy

Autosomal-dominantdisorder associated with deletion at chromosome 4q35 locus.

Onset is variable but typically occursin second decade of life with weakness of facial, shoulder, andupper arm muscles. Foot extensor and pelvic girdle muscle weaknessmay also occur.

Serum CPK may be normal or increased.

Molecular genetic analysis is confirmatory.

Myotonic Syndromes: Myotonic Dystrophy

Autosomal-dominantdisorder almost always transmitted by affected mother. Abnormalgene has been mapped to chromosome 19q13 in most common form.

Mother usually has signs of myotonicdystrophy—long immobile face due to atrophy of temporalisand masseter muscles, ptosis, and myotonia (inability to open eyesfor a few seconds after closing them tightly and failure of immediateextension of fingers after forming clenched fist).

Usual findings in affected infant duringfirst days of life are hypotonia, bilateral facial weakness, poorfeeding, and respiratory difficulty.

Clinical findings of infant and motherand characteristic electromyogram in mother (motor unit potentialsthat wax and wane in amplitude and frequency indicative of myotonia)confirm diagnosis.

Beyond neonatal period, onset is usuallyduring adolescence or later.

Characterized by distal muscle weakness, especiallyof intrinsic muscles of hands, facial weakness with muscle atrophy,and myotonia (usually present after 5 yrs of age). Weakness is slowly progressiveand eventually involves proximal musculature.

Serum CPK is normal or mildly increased.Clinical features, family history, and characteristic electromyogramare diagnostic.

Molecular genetic analysis is definitive.

Inflammatory Myopathies

Dermatomyositis

This formof connective tissue disease has 3 main features: muscle weakness,skin lesions, and systemic symptoms (e.g., malaise and fatigue).

Usually occurs in school age children.

Weakness is usually proximal and symmetricand begins in legs, but some children have generalized weakness.Erythematous discoloration may be found over upper eyelids, nose,cheek, and joints (metacarpophalangeal, interphalangeal, elbow,knee). Gottron nodules also may be seen over finger joints. Othermanifestations include fever, swallowing difficulty, hepatosplenomegaly,lymphadenopathy, and calcinosis of muscle or skin.

Muscle biopsy helps confirm diagnosis.

Polymyositis

Producessymmetric weakness of proximal limb and trunk muscles without skinlesions but is uncommon in children.

Onset is usually insidious but progressiveover weeks or months.

Febrile illness occasionally precedesmuscle weakness.

Serum concentrations of muscle enzymes(creatine phosphokinase, aldolase, aspartate aminotransferase) areusually increased.

Muscle biopsy confirms diagnosis.

Connective Tissue Disorders

Congenital Laxity of Ligaments

Individualshave hypotonia and increased joint mobility but normal muscle strength andpreserved deep tendon reflexes.

Criteria of joint laxity and hypermobilityare hyperextension of knees and elbows beyond 180 degrees, increasedhip abduction (usually to 90 degrees), hyperextension of metacarpophalangeal jointsof fingers with extension of wrist to 90 degrees, approximationof thumb to anterior aspect of forearm, and dorsiflexion of anklesbeyond 45 degrees from neutral position.

Congenital dislocation of hip and scoliosismay be associated findings.

Ehlers-Danlos Syndrome

Primary manifestations are fragile, easilybruised, stretched skin, and hyperextensible joints. See Chap. 52, Purpura and Bleeding.

Marfan Syndrome

Easily stretched skin, hypermobile joints,long thin extremities and fingers, dislocated lens, and aortic incompetencecharacterize Marfan syndrome, an autosomal-dominant disorder. See Chap. 68, Tall Stature.

Metabolic Disorders

Hypotonia also may occur with hypopituitarism,renal tubular acidosis, rickets, and hypercalcemia. See discussionof some of these disorders in other chapters.

Diagnostic Approach

First stepis to determine whether disorder involves nervous system includingneuromuscular system. This can usually be accomplished by historyand physical exam.

If disorder involves nervous system,next step is to define anatomic level of abnormality—brain,spinal cord, anterior horn cell, peripheral nerve, neuromuscularjunction, or muscle. This can usually be accomplished by consideringdistinguishing features (e.g., pattern of weakness, deep tendonreflexes, presence of sensory loss or fasciculations, serum muscleenzyme levels, CSF findings, electromyographic pattern, nerve conductionvelocities, and muscle biopsy).

Final step is to make specific diagnosis,which usually can be done by analysis of the above findings, otherclinical findings, and other investigations.

Brain

Characteristicfindings with brain disorders include weakness of extremities (proximalas much as or more than distal), normal or increased deep tendonreflexes, seizures, developmental delay, and cognitive change.

Degree of weakness is usually lessstriking than degree of hypotonia. Cranial nerve nuclei also maybe involved.

Serum muscle enzymes, electromyography,and muscle biopsy are normal, except for particular disorders (e.g.,congenital muscle dystrophies) in which muscle and brain may beabnormal.

Neuroimaging is useful in diagnosisof many of these disorders.

Spinal Cord

Disordersaffecting spinal cord may produce flaccid weakness of all extremitiesif injury involves cervical region; usually normal or hypoactivedeep tendon reflexes, which can become hyperactive in next few weeksor months; sphincter abnormalities; and sensory level on trunk.

Cranial nerve function is normal.

MRI is useful in defining locationand extent of spinal cord lesion.

Anterior Horn Cell

Characteristicfindings of spinal muscular atrophies include severe hypotonia and weakness(proximal as much as or more than distal), muscle fasciculations,and absence of deep tendon reflexes. Facial weakness also may occur.Sensory function, spinal fluid analysis, and serum muscle enzymelevels are normal.

Fibrillations can be demonstrated byelectromyography.

Muscle biopsy shows denervation patternin which hallmark is atrophy of group of muscle fibers. Enteroviralinfection affecting anterior horn cells commonly produces asymmetricweakness and abnormal spinal fluid.

Peripheral Nerve

Characterizedby marked weakness (usually distal more than proximal), decreasedor absent deep tendon reflexes, abnormal sensory examination, increasedcerebrospinal fluid protein concentration, and decreased nerve conductionvelocities.

Muscle biopsy shows denervation pattern,and nerve biopsy is usually abnormal.

Neuromuscular Junction

Disordersof neuromuscular junction produce generalized weakness (proximalas much as distal). Facial weakness is usual finding, and extraocularmuscles may be involved. Deep tendon reflexes are usually normal.Sensory function, spinal fluid analysis, serum muscle enzyme levels,and muscle biopsy are normal.

Electromyography shows characteristicdecremental response to repetitive stimulation with myasthenia gravis.There is usually positive response to neostigmine or edrophonium.

Typical electromyographic findingsin botulism are incremental response with repetitive stimulationand frequent, brief duration, small amplitude motor unit potentials.Pupillary responses to light are impaired or absent with botulism.

Muscle

Muscle disordersproduce weakness, with proximal weakness often more pronounced thandistal weakness. Facial weakness is variable but may occur withseveral muscle disorders. These include central core disease, myotubularmyopathy, nemaline myopathy, congenital fiber disproportion, congenitalmuscular dystrophy, facioscapulohumeral dystrophy, and myotonicdystrophy. Deep tendon reflexes are usually decreased in proportionto weakness.

Sensory function and spinal fluid analysisare normal. Increased serum concentration of muscle enzymes is variable.

Electromyography shows small-amplitude,short-duration motor unit potentials and myopathic polyphasic potentials.

Muscle biopsy shows myopathic pattern,and nongrouped atrophy is essential feature.

Various studies of muscle (histologic,histochemical, biochemical, immunocytochemical, electron microscopic)are often needed for diagnosis.

Molecular genetic analysis can nowbe performed for definitive diagnosis of many muscle disorders.

>>

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Source: The Diagnostic Approach to Symptoms and Signs in Pediatrics, 2006

Obesity: Clinical Features and Diagnosis
(The Diagnostic Approach to Symptoms and Signs in Pediatrics)

Genetic Influences and Environmental Factors

In >99% ofobese children, the cause is a complex interaction between geneticinfluences and environmental factors leading to caloric intake inexcess of caloric expenditure. In general these children have normalphysical exam with normal intelligence, normal genital development,and normal or above average height for age. No further diagnosticinvestigation is necessary.

Whitaker et al. (1997) showed thatobesity in 1 or both parents can help predict a child'srisk of obesity in adulthood. In the past few years, 5 single-genedisorders resulting in early-onset obesity have been reported (Farooqiand O'Rahilly, 2000).

Endocrine Disorders

Endocrine causes of obesity are unusual exceptfor chronic corticosteroid therapy. Attenuation of growth velocityis characteristic of glucocorticoid excess, hypothyroidism, andgrowth hormone deficiency.

Glucocorticoid Excess

The term "Cushingsyndrome" is used to describe any type of glucocorticoidexcess. Most common cause of glucocorticoid excess in childhoodis chronic corticosteroid therapy. Other causes include adrenalhyperplasia and adrenal tumors (adenoma, carcinoma).

Cushing disease refers to pituitaryoverproduction of ACTH, which occurs with pituitary adenoma. EctopicACTH syndrome is production of excessive amount of ACTH from nonadrenalsource (neuroblastoma, Wilms tumor, thymoma, carcinoid).

Clinical features of glucocorticoidexcess include round facies, buffalo hump, hypertension, increasedweight gain, and decreased linear growth. Normally, serum cortisolconcentration tends to be higher in morning and lower in evening.Loss of this normal diurnal variation is screening test for Cushing syndrome.

Low-dose dexamethasone suppressiontest helps distinguish whether glucocorticoid excess is due to adrenalor pituitary cause. In low-dose test in normal individuals, plasmacortisol is decreased to <5 μg/dL. Individualswith Cushing disease usually fail to suppress cortisol with low-dosetest, but suppress with high-dose test. MRI should be performedwith suspected pituitary disease, although some tumors secretingACTH may be invisible with current techniques.

Failure to suppress cortisol secretionwith high-dose dexamethasone test usually indicates adrenal tumoror ectopic ACTH syndrome. Serum cortisol is high and ACTH is lowwith adrenal hyperplasia and adrenal tumors. ACTH stimulation testwith measurement of serum cortisol may help distinguish adrenaladenoma from adrenal carcinoma. Serum cortisol concentration usuallyincreases with adrenal adenoma, whereas no response occurs withadrenal carcinoma. With suspected adrenal tumor, CT of abdomen shouldbe performed. Both serum cortisol and ACTH concentrations are veryhigh with ectopic ACTH syndrome. Further investigation includingimaging is necessary to determine location and extent of tumor.

Hypothyroidism

Characteristic features of hypothyroidism,which may be congenital or acquired, are slow linear growth, dryhair and skin, constipation, cold intolerance, and sometimes enlargedthyroid gland. Thyroid hormone serum level [thyroxine (T₄)or free T₄] is low, whereas TSHlevel is high.

Growth Hormone Deficiency

Most striking feature of growth hormone deficiencyis severe decrease in postnatal linear growth (see Chap. 23, Growth Deficiency: Weight and Height).

Hypothalamic Dysfunction

Hypothalamiclesions associated with increased weight gain include neoplasm,trauma, and inflammatory disorders, but mechanism remains elusive.

Continuous food intake results in massiveweight gain.

CT and MRI help locate and define extentof lesion.

Polycystic Ovary Syndrome

Usuallyoccurs at puberty and is characterized by obesity, hirsutism, secondaryamenorrhea, and bilateral enlarged polycystic ovaries.

Ovaries may be palpable on exam andcan be demonstrated by pelvic U/S.

Hyperinsulinemia with insulin resistanceand acanthosis nigricans also may occur, especially in overweightindividuals. Measurement of fasting blood glucose and insulin levelsscreen for insulin resistance.

Cause of this disorder remains to bedetermined.

Syndromes

Alstrom Syndrome

This autosomal-recessive disorder, whosegene locus has been mapped to chromosome 2p13, is characterizedby obesity, usually occurring at 2–10 yrs, retinitis pigmentosawith visual loss, sensorineural hearing loss, acanthosis nigricans,chronic renal disease, diabetes mellitus with insulin resistance,and normal intelligence.

Bardet-Biedl Syndrome

Characterized by obesity, polydactyly, hypogonadism,pigmentary retinopathy with progressive decrease in visual acuity,and mental retardation. It has been linked to several genetic loci.

Carpenter Syndrome

Besides increased weight gain, characteristicfindings include flat nasal bridge, low-set ears, high-arched palate,lateral displacement of inner canthi, brachycephaly with craniosynostosis,polydactyly and partial syndactyly of feet, brachydactyly and partialsyndactyly of hands, and mental retardation.

Cohen Syndrome

In thisautosomal-recessive disorder, whose gene locus has been mapped tochromosome 8q22-q23, onset of obesity is in middle of childhood.

Clinical features include typical facieswith high nasal bridge, malar hypoplasia, short philtrum, prominentmaxillary central incisors and lips, and mild down-slanting palpebralfissures; narrow hands and feet with elongated fingers and toes;retinal degeneration with decreased vision; hypotonia; seizures;and mild mental retardation.

Prader-Willi Syndrome

Althoughthis disorder can occur in families, most instances are sporadic.

Clinical criteria for diagnosis havebeen described by Holm et al. (1993). These individuals have narrowface, almond-shaped eyes, small mouth with thin lips; developmentaldelay; mild to moderate mental retardation; and hyperphagia withobsessive food-seeking behavior. Obesity develops before 6 yrs ofage.

Deletions on proximal long arm of chromosome15 account for 70–80% of cases. The remainderare due to chromosome translocations and maternal uniparental disomy15. Fluorescence in situ hybridization (FISH) can detect the deletions.

Diagnostic Approach

If physicalexam and linear growth are normal, combination of genetic influencesand environmental factors is almost always the cause of obesity.

If decreased linear growth occurs,glucocorticoid excess, hypothyroidism, and growth hormone deficiencyshould be considered.

Many unusual syndromes associated withobesity may be distinguished by their clinical findings and moleculargenetic analysis.

>

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Source: The Diagnostic Approach to Symptoms and Signs in Pediatrics, 2006

OBESITY: Approach to the Diagnosis
(Differential Diagnosis in Primary Care)

It would be ridiculous to do a complete endocrine workup on every case of obesity, but thyroid function studies may be worthwhile. Patients who fail to lose weight on a strict diet may require hospitalization with observation. If they still fail to lose weight, a complete endocrine workup would seem to be indicated.

» READ BOOK EXCERPT ONLINE »

Source: Differential Diagnosis in Primary Care, 2007

MUSCULAR CRAMPS: Approach to the Diagnosis
(Differential Diagnosis in Primary Care)

Clinically, one should look for absent or diminished pulses in the extremity involved, Chvostek and Trousseau signs of tetany, and neurologic signs of an upper motor neuron lesion. An occupational history may disclose that the patient is a miner or iron-worker or is exposed to excessive heat on the job. Occupations such as painters, writers, seamstresses, and compositors suggest the so-called professional cramps. Adson signs are positive in thoracic outlet syndrome. Cramps in the legs produced by walking a certain distance suggest peripheral arteriosclerosis and Leriche syndrome. This is also a sign of spinal stenosis. The initial laboratory workup involves a CBC, urinalysis, chemistry panel, and electrolytes. If a vascular cause is suspected, ultrasonography and perhaps venography or angiography may be indicated.

» READ BOOK EXCERPT ONLINE »

Source: Differential Diagnosis in Primary Care, 2007

 » Next page: Signs of Prader-Willi syndrome

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