Genetic and inherited disorders include thousands of different genetic, metabolic, neurological, blood, connective-tissue, immune, and endocrine conditions. Not all genetic conditions are inherited. Individually these disorders are uncommon, but recognizing an unusual pattern of symptoms, physical findings, or family history can sometimes lead to earlier diagnosis.

When May an Inherited Disorder Be Considered?
 

• Multiple family members with the same unusual condition

• Disease occurring at an unusually young age

• Multiple relatives with sudden or unexplained deaths

• Recurrent miscarriages or infant deaths in the family

• Developmental delay or intellectual disability without a known cause

• Developmental regression — loss of previously acquired abilities

• Unusual combinations of symptoms affecting several organ systems

• Abnormal growth, body proportions, or physical development

• Unexplained muscle weakness or exercise intolerance

• Recurrent unexplained metabolic abnormalities

• Recurrent severe infections

• Unexplained anemia, bleeding, blood clots, or abnormal blood counts

• Unexplained enlargement of the liver or spleen

• Unusual skin, hair, eye, skeletal, or facial findings

• Very abnormal laboratory values without an obvious explanation

• A known genetic disorder in a biological relative

• Consanguinity (biological parents who are closely related)

Growth and Development
 

Genetic and metabolic disorders may first become apparent because a child is not growing or developing as expected.
 

Important findings include:
 

• Poor growth or failure to thrive

• Unusually short or tall stature

• Abnormal head size

• Delayed walking or talking

• Intellectual or learning difficulties

• Delayed puberty

• Abnormal sexual development

• Muscle weakness or low muscle tone

• Feeding difficulties

• Developmental regression

*Developmental regression is particularly important. A child who loses previously acquired language, movement, social, or cognitive abilities should be medically evaluated. Possible causes include genetic and metabolic disorders, neurological disease, seizures, and other medical conditions.

Unusual Physical Features
 

Some genetic syndromes produce recognizable combinations of physical characteristics.

Examples may include:
 

• Unusual facial features

• Widely or closely spaced eyes

• Unusual ear shape or position

• Abnormal jaw development

• Cleft lip or palate

• Webbed neck

• Extra fingers or toes

• Fused fingers or toes

• Unusual limb proportions

• Chest-wall abnormalities

• Significant scoliosis

• Abnormal joint flexibility

• Congenital heart abnormalities

• Multiple birth defects

A single unusual physical feature generally does not indicate a genetic syndrome. The overall pattern is more important.

Inherited Connective-Tissue Disorders
 

Inherited connective-tissue disorders affect tissues that support the skin, joints, blood vessels, bones, eyes, and internal organs.

Marfan Syndrome
 

Possible findings include:
 

• Unusually tall, slender build

• Long arms, legs, fingers, or toes

• Arm span greater than expected for height

• Chest-wall abnormalities

• Scoliosis

• Flat feet

• Joint laxity

• Severe or early nearsightedness

• Dislocation of the eye lens

• Heart murmur

• Enlargement of the aortic root

The major concern is progressive aortic enlargement, which can lead to aortic dissection.

A family history of aortic aneurysm, aortic dissection, or unexplained sudden death at a young age is important.
 

Ehlers-Danlos Syndromes
 

Depending on the type, findings may include:

• Joint hypermobility

• Recurrent joint dislocations

• Unusually stretchy skin

• Easy bruising

• Poor wound healing

• Abnormal scars

• Chronic musculoskeletal problems
   

Certain rare forms, particularly vascular Ehlers-Danlos syndrome, can cause fragile arteries and internal organs.

Genetic Heart and Blood-Vessel Disorders
 

Some genetic cardiovascular disorders may produce few symptoms until a serious event occurs.
 

Warning signs include:
 

• Fainting during exercise

• Chest pain during exercise

• Unexplained palpitations

• Unexplained seizures or fainting

• Known cardiomyopathy

• Unexplained enlarged heart

• Aortic aneurysm at a young age

• Sudden unexplained death in a young relative

Possible genetic conditions include:
 

• Hypertrophic cardiomyopathy

• Arrhythmogenic cardiomyopathy

• Dilated cardiomyopathy

• Long QT syndrome

• Brugada syndrome

• Catecholaminergic polymorphic ventricular tachycardia (CPVT)

• Familial aortopathy

Exercise-related fainting deserves particular attention and should not automatically be assumed to be simple dehydration or vasovagal fainting.

Familial Hypercholesterolemia
 

Familial hypercholesterolemia causes extremely elevated LDL cholesterol beginning early in life.

Possible clues include:
 

• Very high LDL cholesterol

• Heart attack or coronary disease at an unusually young age

• Multiple relatives with premature cardiovascular disease

• Tendon cholesterol deposits (xanthomas)

• Cholesterol deposits around the eyes

• Corneal arcus occurring unusually early in life

Because patients may otherwise feel completely healthy, cholesterol testing and family history are particularly important.

Neuromuscular Disorders
 

Genetic muscle and nerve disorders may cause:
 

• Progressive muscle weakness

• Difficulty running or climbing stairs

• Frequent falls

• Difficulty rising from the floor

• Abnormal gait

• Enlarged-appearing calf muscles

• Muscle wasting

• Muscle cramps

• Exercise intolerance

• Drooping eyelids

• Difficulty swallowing

• Breathing weakness

Examples include:
 

• Duchenne and Becker muscular dystrophy

• Spinal muscular atrophy

• Myotonic dystrophy

• Various hereditary neuropathies

Metabolic and Mitochondrial Disorders
 

Genetic metabolic disorders interfere with the body's ability to process nutrients or produce energy.
 

Symptoms vary greatly but may include:
 

• Poor feeding

• Vomiting

• Failure to thrive

• Extreme sleepiness

• Developmental delay

• Developmental regression

• Muscle weakness

• Exercise intolerance

• Seizures

• Episodes of confusion

• Low blood sugar

• Abnormal blood acidity

• Unusual body or urine odor

• Enlarged liver or spleen

• Symptoms triggered by fasting, illness, or strenuous exercise

Many severe metabolic diseases are included in newborn screening, although newborn screening does not detect every genetic or metabolic disorder.

Lysosomal Storage Disorders
 

These genetic disorders cause substances to accumulate abnormally inside cells. Examples include Gaucher disease, Fabry disease, Pompe disease, and Tay-Sachs disease.

Depending on the disorder, findings may include:
 

• Enlarged liver or spleen

• Bone abnormalities or unexplained bone pain

• Neurological deterioration

• Developmental regression

• Muscle weakness

• Vision or hearing abnormalities

• Distinctive facial features

• Heart disease

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Inherited Blood Disorders
 

Sickle Cell Disease
 

Possible symptoms include:
 

• Chronic anemia

• Fatigue

• Episodes of severe pain

• Jaundice

• Swelling of the hands or feet in infants

• Frequent or severe infections

• Delayed growth

Sickle cell disease is routinely included in U.S. newborn screening.
 

Thalassemia
 

Possible findings include:

• Anemia

• Fatigue

• Pallor

• Jaundice

• Enlarged spleen

• Poor growth in severe disease
   

Mild inherited forms may be discovered after a routine blood count shows persistently small red blood cells.
 

Hereditary Hemochromatosis
 

This disorder can cause excessive iron accumulation over many years.
 

Possible manifestations include:
 

• Fatigue

• Joint pain

• Abnormal liver tests

• Liver disease

• Diabetes

• Heart abnormalities

• Skin darkening

Symptoms generally develop in adulthood and may be absent during early disease.
 

Genetic Bleeding and Clotting Disorders

Examples include von Willebrand disease and hemophilia.

Possible warning signs include:
 

• Frequent unexplained bruising

• Prolonged bleeding

• Recurrent nosebleeds

• Excessive bleeding after dental work or surgery

• Very heavy menstrual bleeding

• Bleeding into joints

• Family history of unusual bleeding

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Conversely, some inherited disorders increase the tendency to form blood clots. Suspicion may increase with recurrent or unusually young venous blood clots, particularly when accompanied by an appropriate family history.
 

Primary Immunodeficiency Disorders
 

Genetic immune disorders can make it difficult to fight infections.
 

Warning signs may include:
 

• Recurrent severe infections

• Unusually persistent infections

• Infections with unusual organisms

• Recurrent pneumonia

• Deep abscesses

• Poor growth

• Persistent thrush

• Need for repeated intravenous antibiotics

• Family history of an immune deficiency

• Severe infection beginning during infancy

Frequent uncomplicated childhood colds alone usually do not indicate an immune deficiency.
 

Genetic Kidney Disorders
 

Genetic kidney disease may produce:
 

• Blood in the urine

• Persistent protein in the urine

• High blood pressure at a young age

• Kidney cysts

• Recurrent kidney stones

• Progressive kidney dysfunction

• Hearing abnormalities combined with kidney disease

• Strong family history of kidney failure

Examples include:
 

• Autosomal dominant polycystic kidney disease

• Alport syndrome

• Certain inherited stone disorders

Genetic Endocrine Disorders

Possible findings include:
 

• Abnormal growth

• Unusual puberty timing

• Ambiguous or atypical genital development

• Recurrent abnormal sodium or potassium levels

• Unexplained low blood sugar

• Abnormal calcium levels

• Multiple endocrine tumors in a family

Examples include congenital adrenal hyperplasia and hereditary endocrine-tumor syndromes such as multiple endocrine neoplasia (MEN).

Genetic Cancer Syndromes
 

Most cancers are not caused by a strongly inherited cancer syndrome. However, genetic evaluation may be considered when there is:
 

• Cancer at an unusually young age

• Several close relatives with the same or related cancers

• Multiple different cancers in one person

• Bilateral cancers in paired organs

• Male breast cancer

• Certain rare tumor types

• A known cancer-predisposition mutation in the family

Examples include:
 

• Hereditary breast and ovarian cancer associated with BRCA1/BRCA2

• Lynch syndrome

• Familial adenomatous polyposis (FAP)

• Li-Fraumeni syndrome

• Multiple endocrine neoplasia

A detailed family history is one of the most useful screening tools for hereditary cancer risk.
 

Skin Findings That May Provide Genetic Clues
 

Certain skin findings can occasionally be associated with genetic disorders, particularly when numerous or accompanied by other abnormalities.
 

Examples include:

• Numerous café-au-lait spots

• Multiple neurofibromas

• Unusual areas of absent pigmentation

• Multiple unusual vascular lesions

• Extreme skin elasticity

• Numerous xanthomas

• Multiple unusual tumors or growths

These findings are not diagnostic by themselves.

Family History Matters
 

Tell your healthcare provider about significant medical problems affecting your biological relatives, particularly:
 

• Sudden unexplained death

• Heart attack or stroke at a young age

• Cardiomyopathy

• Dangerous heart rhythm disorders

• Aortic aneurysm or dissection

• Extremely high cholesterol

• Blood-clotting disorders

• Kidney failure

• Neuromuscular disease

• Developmental or intellectual disabilities

• Recurrent unexplained infant deaths

• Known genetic disorders

• Cancer occurring unusually early or repeatedly within the family

When possible, knowing the specific diagnosis and the age at which it occurred is much more useful than simply knowing that a relative had "heart problems" or "cancer."

How Are Genetic Disorders Diagnosed?
 

Evaluation depends on the suspected condition and may include:
 

• Detailed personal and family history

• Physical examination

• Routine laboratory testing

• Specialized metabolic testing

• EKG or cardiac imaging

• Other diagnostic imaging

• Chromosome testing

• Single-gene testing

• Multi-gene panels

• Exome or genome sequencing

• Referral to a genetic counselor or medical geneticist

Genetic testing is most useful when it is selected based on the patient's clinical findings and family history, rather than ordering broad genetic testing without a specific clinical question.

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