Genetic Diseases

Dustin Baldridge

Dorothy Grange

DYSMORPHIC FEATURES AND MALFORMATIONS

Definitions and Epidemiology

A dysmorphic feature is any alteration in the physical structure (morphology) of a person’s anatomy.
A malformation is a specific type of structural abnormality caused by an intrinsic (genetic) factor.
- Major malformations either require surgical intervention or have a significant impact on the patient’s health.
  - Examples include craniosynostosis, cleft lip and/or palate, congenital heart disease, and omphalocele.
  - They occur in up to 3% of all live births.
- Minor malformations do not have a significant impact on the patient’s health.
  - Examples include hypertelorism, ear pit or tag, smooth philtrum, transverse palmar crease, and mild soft tissue syndactyly.
  - They are not rare in the general population.
A deformation is an abnormal structure caused by an external force during intrauterine development that resulted in abnormal growth or formation.
A dysplasia results from a failure to maintain the intrinsic cellular architecture of a tissue throughout growth and development.

Etiology

The pattern of dysmorphic features in a single individual may suggest a named genetic condition (see Table 16-1), such as up-slanting palpebral fissures, epicanthal folds, and a single palmar crease in individuals with Down syndrome.
There are also nongenetic causes for dysmorphic features. For example, the teratogenic effects of valproic acid can cause a specific constellation of facial features.

Diagnosis and Evaluation

If a patient has at least two major or one major and two minor malformations, a chromosomal microarray analysis (CMA) is indicated. If the CMA is normal, then reflex karyotype analysis should be performed to detect translocations, inversions, and other rearrangements.
Other indications for CMA include apparently nonsyndromic developmental delay or intellectual disability, and autism spectrum disorders.
If there is strong suspicion for a genetic etiology of the malformations, then specific single gene tests, gene sequencing panels, or whole exome sequence analysis could be considered.
In a patient with multiple malformations, it is also necessary to consider the following studies to detect other occult anomalies:
- Echocardiogram, abdominal ultrasound (with renal imaging), and neuroimaging study (magnetic resonance imaging [MRI])
- Ophthalmologic examination and hearing screen (federally mandated newborn screening is sufficient in neonates or infants if there is no clinical concern for hearing loss)
- Skeletal survey, especially if a patient has short stature or observable bony changes

TABLE 16-1 Frequently Encountered Genetic Disorders

Disorder	Selected features	Tests
22q11.2 deletion syndrome (also known as DiGeorge or velocardiofacial syndrome)	Congenital heart disease, abnormal palate, dysmorphic facial features, intellectual disability, immune deficiency, hypocalcemia	FISH/CMA for 22q11.2 deletion
Alagille syndrome	Characteristic facies, posterior embryotoxon and retinal pigmentary changes on ophthalmologic examination, butterfly vertebrae, tetralogy of Fallot	JAG1 sequence analysis FISH/CMA for 20p12 microdeletion
Angelman syndrome	Inappropriate laughter, ataxia, absent speech, intellectual disability, dysmorphic facial features, microcephaly, hypopigmentation	15q 11-13 methylation analysis (abnormal in ˜80% of cases) UBE3A sequence analysis (abnormal in additional 10% of cases) FISH/CMA for microdeletion; detects about 70% of cases
Beckwith-Wiedemann syndrome	Increased growth, hemihyperplasia, abdominal wall defects, macroglossia, neonatal hypoglycemia, tumor predisposition	Methylation studies at imprinting center 1 and 2 CDKN1C sequence analysis in familial cases
Congenital disorders of glycosylation (CDG)	Type Ia (classic symptoms): pontocerebellar atrophy, lipodystrophy, failure to gain weight, strabismus, coagulopathy, transaminase elevations, and intellectual disability Type Ib: chronic diarrhea, failure to thrive, protein-losing enteropathy, hypotonia, bleeding tendency	Transferrin electrophoresis Gene sequencing panels
Cri-du-chat syndrome (also known as 5p minus syndrome)	High-pitched cry, microcephaly, intellectual disability, hypotonia, dysmorphic facial features	FISH/CMA for 5p microdeletion
Down syndrome	Characteristic dysmorphic features, congenital heart disease Can be difficult to detect in premature infants and neonates	Karyotype Aneuploidy screen
Fragile X syndrome	Facial dysmorphism, postpubertal macroorchidism, autism, X-linked inheritance (females may be affected)	Fragile X mutation analysis (detects expansions and methylation status)
Marfan syndrome	Dilation of aorta, myopia, ectopia lentis, long bones, joint laxity, characteristic facial features	Clinical diagnosis based on revised Ghent criteria FBN1 mutations
Noonan syndrome	Short stature, congenital heart disease, broad neck, characteristic facial features, broad or webbed neck	Sequential or multi-gene panel testing can include testing for mutations in PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, and MAP2K1
Prader-Willi syndrome	Neonates: feeding difficulty, profound hypotonia Children: aggressive food-seeking behavior leading to obesity, behavioral abnormalities, short stature, hypogonadism	15q11-13 methylation analysis (abnormal in >99%) FISH/CMA for microdeletion; detects about 70% of cases
Rett syndrome	Acquired microcephaly, developmental regression, hand wringing, autism, intermittent hyperventilation Affected males are rare	MECP2 gene sequencing Consider gene sequencing panel if MECP2 mutation analysis normal
Smith-Lemli-Opitz syndrome	Dysmorphic facial features, 2-3 toe syndactyly, polydactyly, heart defects, hypoplastic lungs, liver disease, genitourinary malformations, intellectual disability, seizures	7-dehydrocholesterol (total cholesterol is not always low) DHCR7 mutation analysis
Sotos syndrome	Overgrowth (>97th percentile), dysmorphic facial features; possible seizures, kidney anomalies, scoliosis, slightly increased risk of malignancy	NSD1 sequence analysis FISH/CMA for chromosome 5 microdeletion NFIX sequence analysis
Turner syndrome	Short stature, webbed neck, coarctation of aorta, premature ovarian failure and infertility	Karyotype Aneuploidy screen
Trisomy 13 (Patau syndrome)	Cleft lip or palate, clenched hands, polydactyly, congenital heart disease, hernias, coloboma, microcephaly, microphthalmia, micrognathia	Karyotype Aneuploidy screen
Trisomy 18 (Edwards syndrome)	IUGR, clenched hands, rocker-bottom feet, congenital heart disease, microcephaly, micrognathia	Karyotype Aneuploidy screen
Williams syndrome	Typical dysmorphic facies, supravalvular aortic stenosis, “cocktail party personality,” hypercalcemia	FISH/CMA for deletion of 7q11.2
Wilson disease	Progressive neurologic findings, psychiatric disturbance, renal tubular dysfunction, mild or acute hemolysis, and Kayser-Fleischer ring in cornea	Ceruloplasmin Serum copper ATP7B mutation analysis
Wolf-Hirschhorn syndrome	Microcephaly, dysmorphic facial features, poor growth, psychomotor retardation, hypotonia, hearing loss, seizures, intellectual disability	FISH/CMA for 4p microdeletion
CMA, chromosomal microarray analysis; FISH, fluorescent in situ hybridization.

NEWBORN SCREENING

The state mandated newborn screening test evaluates for many disorders; information on which disorders are screened in each state is available at www.newbornscreening.info.
For some disorders, the sensitivity relies on the infant eating protein, either breast milk or formula, before testing.
If an infant is receiving total parenteral nutrition (TPN) at the time of testing, the amino acid analysis is uninterpretable and invalidates testing for certain disorders.
If an infant has received a packed red blood cell transfusion before obtaining the newborn screening sample, the galactosemia, biotinidase deficiency, and hemoglobinopathy assays are invalid.
For some disorders, a history of a normal newborn screening result should not preclude sending definitive testing if a specific disorder is clinically suspected.

Disorders of Fatty acid oxidation

This is a group of autosomal recessive inherited conditions, with reduced activity of enzymes necessary for fatty acid metabolism.
Infants are especially susceptible to a fasting state, with resulting hypoglycemia and/or acidosis. Symptoms include lethargy, vomiting, seizures, or coma. If untreated, patients can develop liver, heart, kidney, and muscle failure.
Specific conditions are diagnosed by analyzing the acylcarnitine composition. Newborn screening allows early intervention, including dietary management, which can prevent serious complications.

Amino Acid and Urea Cycle Disorders

These metabolic disorders are caused by an inability to metabolize certain amino acids, or by the inability to complete the urea cycle to detoxify ammonia, which is a by-product of amino acid metabolism. The buildup of amino acids and/or byproducts of amino acid metabolism can cause severe complications.
Examples of conditions on the newborn screen include phenylketonuria (PKU), maple syrup urine disease, tyrosinemia, homocystinuria, and citrullinemia. Ornithine transcarbamylase (OTC) deficiency is not detected by newborn screening.

Organic Acidemias

This group of conditions is due to defective downstream metabolism of amino acids or odd chain organic acids, resulting in specific toxic metabolites that can be found in the blood or urine. The classic presentation is a toxic encephalopathy, but milder forms also exist. Early dietary intervention can prevent serious complications.
Examples include methylmalonic acidemia, glutaric acidemia type I, and propionic acidemia.

METABOLIC DECOMPENSATION AS A PRESENTATION OF INBORN ERRORS OF METABOLISM

Clinical Presentation

Children with an acute decompensation from an inborn metabolic disease may present with variable and nonspecific symptoms, such as mental status changes that range from fussiness to coma, poor feeding, vomiting, changes in breathing, abnormal movements, seizures, strokes, or liver failure. They may also have chronic conditions, including low tone, global developmental delay, intellectual disability, autism, or cardiomyopathy.
Children with an underlying metabolic disease and a superimposed acute metabolic stress, such as an infection or trauma, may present with more severe symptoms than expected from the acute stressor alone.
Patients with an underlying metabolic disease may also experience difficulty recovering from surgery.
Infants with bacterial sepsis may have an inborn metabolic illness as a predisposing factor, such as the increased incidence of Escherichia coli

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