Genetic Diseases



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

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Jun 5, 2016 | Posted by in PEDIATRICS | Comments Off on Genetic Diseases

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