I. Metabolism

Section references: ^{1, 2, 3, 4, 5, 6, 7, 8}

A. Clinical Presentation of Metabolic Disease (Box 13.1)

1. 1. Metabolic disease can be conceptualized into broad categories (Table 13.1).
2. 2. When a particular diagnosis is considered, a complete patient history, including details of conception, pregnancy, prenatal screening and diagnostic studies, delivery, postnatal growth, development, and a three-generation family history in the form of a pedigree (eFig. 13.1) should accompany a comprehensive physical examination. The family history may be remarkable for close relatives who died of similar presentations (may be mistaken for “sepsis” or “SIDS”).
3. 3. A high index of suspicion is required, as routine investigations may be unrevealing. Be especially vigilant in a full-term baby presenting with “sepsis” who has no risk factors.
4. 4. Routine newborn screening (see Section II) is meant to detect many metabolic disorders before onset of clinical symptoms, but the conditions screened vary by state and not all countries screen, so clinical suspicion should remain high if clinical picture is concerning.

1. 1. Initial laboratory tests: Comprehensive metabolic panel, blood glucose, venous blood gas (VBG), ammonia (beware false-positives from prolonged tourniquet time, struggling children, lack of ice, or sample delay), complete blood cell count with differential, urinalysis
2. 2. Subsequent evaluation for metabolic disease:
   1. a. Consult a geneticist.
   2. b. A basic metabolic workup includes plasma amino acids (PAA), urine organic acids (UOA), acylcarnitine profile, quantitative (free and total) plasma carnitine, lactate/pyruvate ratio. Further specialized biochemical testing is available.
3. 3. Additional labs given specific circumstances:
   1. a. Metabolic acidosis: Ammonia, lactate, β-hydroxybutyrate, acetoacetate, UOA, urinalysis with urine pH, acylcarnitine profile, quantitative (free and total) plasma carnitine (Fig. 13.1)
   2. b. Hyperammonemia: VBG, UOA, PAA, acylcarnitine profile, urine orotic acid (Fig. 13.2)
   3. c. Hypoglycemia: Samples at time of hypoglycemia—glucose, insulin, growth hormone, cortisol, free fatty acids, β-hydroxybutyrate (see Chapter 10). Cortisol, fasting and postprandial lactate, urine ketones, creatine kinase, acylcarnitine profile, PAA, UOA (Fig. 13.3)
   4. d. Neonatal seizures: Cerebrospinal fluid (CSF) amino acids and PAA, CSF/serum glucose ratio, serum and CSF neurotransmitters, CSF and plasma lactate, plasma very-long-chain fatty acids, UOA, serum uric acid, urine sulfites. Consider trial of pyridoxine.

1. 1. Intoxication disorders (Table 13.2)
2. 2. Disorders of reduced fasting tolerance (Table 13.3)
3. 3. Disorders of complex molecules (Table 13.4)
4. 4. Mitochondrial disorders (Table 13.5)
5. 5. Neurotransmitter disorders (Table 13.6)

D. Management of Metabolic Crisis

1. 1. Specific acute management available in Tables 13.2–13.6
2. 2. A general guiding principle is to provide hydration and enough glucose to meet the patient’s caloric needs to stop catabolism.
   1. a. Use D10% + electrolytes for age at 1.5 to 2 times maintenance rate.
   2. b. Use caution in mitochondrial disorders (and do not use D10 in pyruvate dehydrogenase deficiency), because this may enhance lactic acidosis. If uncertain, measure lactate and acid-base status regularly.
3. 3. For unknown/suspected metabolic disease, treatment should not be delayed during workup.

E. Commonly Used Medications

1. 1. Carnitine 50 mg/kg/dose intravenous (IV) every 6 hours when ill, or 100 mg/kg/day orally (PO) divided every 8 hours when well. For dosing in primary carnitine deficiency, see Formulary.
2. 2. Sodium phenylacetate (10%) + sodium benzoate (10%) (Ammonul) should be combined with arginine HCl in a 25 to 35 mL/kg 10% dextrose solution and administered through a central venous catheter to treat acute hyperammonemia in a urea cycle patient. Administration through a central venous catheter is preferred, however this medication can be administered peripherally.
   1. a. For a child less than 20 kg, the dose is 250 mg/kg sodium phenylacetate and 250 mg/kg sodium benzoate.
   2. b. For a child greater than 20 kg, the dose is 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate.
   3. c. The dose of arginine HCl is 200 to 600 mg/kg for a child <20 kg, or 4–12 g/m² for a child or adult >20 kg, depending on the diagnosis.
      1. (1) 200 mg/kg or 4 g/m² for carbamylphosphate synthase (CPS) deficiency and ornithine transcarbamylase (OTC) deficiency.
      2. (2) 600 mg/kg or 12 g/m² for citrullinemia and argininosuccinate lyase (ASL) deficiency.
   4. d. Administer as a loading dose over 90 to 120 minutes, followed by an equivalent dose as a maintenance infusion over 24 hours.
3. 3. Arginine HCl for MELAS stroke-like episode: Treatment for MELAS is generally supportive. During the acute stroke-like episode, a bolus of intravenous arginine (500 mg/kg for children or 10 g/m² body surface area for adults) within three hours of symptom onset is recommended followed by the administration of a similar dosage of intravenous arginine as a continuous infusion over 24 hours for the next three to five days.¹⁰(MELAS: mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)
4. 4. Sodium benzoate for nonketotic hyperglycinemia (NKH): Patients with attenuated NKH require a lower dose (200–550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m² BSA). Patients with severe NKH require a higher dose (550–750 mg/kg/day); for adults, maximum 16.5 g/m²/day¹⁰

II. Newborn Metabolic Screening

Section references: 7

A. Timing

1. 1. First screen should be performed within the first 48 to 72 hours of life (at least 24 hours after initiation of feeding).
2. 2. Second screen (requested in some states) should be performed after 7 days of age.
3. 3. Preterm infants: Perform initial screen at birth (to collect sample before transfusions), another at age 48 to 72 hours, a third at age 7 days, and a final at age 28 days or before discharge (whichever comes first).

B. Abnormal Result

1. 1. Requires immediate follow-up and confirmatory testing; consult a geneticist
2. 2. ACT Sheets and Confirmatory Algorithms are available for more information on how to proceed with specific abnormalities: https://www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_a... (search ACT sheets).

C. Results Affected by Transfusion
NOTE: Repeat newborn metabolic screen 3 months after last transfusion.

1. 1. Biotinidase enzyme activity
2. 2. Galactose-1-phosphate uridyltransferase (GALT) activity
3. 3. Hemoglobinopathy evaluation

III. Dysmorphology

Section references: 7 Section references: ^{11, 12, 13, 14}

A. History
Pertinent history includes pregnancy course, prenatal exposures, type of conception (natural or assisted), perinatal history, developmental milestones, and review of systems.

B. Family History

1. 1. Three-generation pedigree focused on both medical and developmental histories (see eFig. 13.1).
2. 2. Helpful mnemonics include:
   1. a. SIDE mnemonic¹⁵: Anything SIMILAR in the family? Anything INHERITED through the family? Any premature, unexplained DEATHS? Any EXTRAORDINARY events?
   2. b. SCREEN mnemonic¹⁶: SOME CONCERNS about conditions running in the family? REPRODUCTION—any issues with pregnancy infertility, or birth defects? EARLY disease, death, or disability? ETHNICITY? NONGENETIC—any other risk factors?
   3. c. Rule of Too/Two¹³:
      1. (1) Too: tall? short? many? few? early? young? different?
      2. (2) Two: cancers? generations? in the family? birth defects?
3. 3. Patterns of inheritance: See Online Content for discussion of different patterns of inheritance.

C. Physical Examination

1. 1. Major anomalies: Structural anomalies that are found in less than 5% of the population and may cause significant cosmetic or functional impairment, often requiring medical or surgical management.
2. 2. Minor anomalies ^{11, 12, 14, 17} : Structural anomalies that are found in greater than 5% of the population with little or no cosmetic or functional significance to the patient.
3. 3. Examples of major and minor anomalies (Table 13.7). Three or more minor anomalies may be a nonspecific indicator of occult or major anomaly.

D. Workup: Tailor to individual patient and existing information, including effective chart review, prior genetic testing, and genetic testing in the family

1. 1. Imaging to evaluate for major anomalies
   1. a. Head ultrasound (US) or brain magnetic resonance imaging (MRI)
   2. b. Echocardiogram
   3. c. Complete abdominal US
   4. d. Skeletal survey with radiographs composed of: AP views of skull, chest/ribs, upper extremities and hands, lower extremities and feet; lateral views of skull, complete spine, chest, and odontoid view
2. 2. Dilated eye exam
3. 3. Hearing evaluation
4. 4. Genetic testing: See Fig. 13.4 and Table 13.8. The patient should be referred to genetics for a dysmorphology evaluation and appropriate testing.

IV. Patterns of Genetic Conditions with Distinctive Appearance

Section references: 11,14
This section is not comprehensive; it covers some common reasons to seek a genetics consult. These conditions will often be managed by a multidisciplinary team.

A. Cardiac Conditions

1. 1. Congenital heart disease: Investigation for co-occurring anomalies with abdominal US. Chromosome microarray testing indicated, including for 22q11 deletion syndrome (Table 13.9).
2. 2. Cardiomyopathy: Can be from inborn errors of metabolism, channelopathies, mutations in genes important for sarcomere and desmosome production/function, or other single gene disorders.
3. 3. Long QT disorders: Many single gene disorders

B. Ciliopathies

1. 1. Nonmotile ciliopathies: Defects in primary (nonmotile) ciliary function. Cystic renal disease, brain malformations (molar tooth sign), retinal degeneration, congenital hepatic fibrosis, polydactyly, skeletal dysplasia, obesity. Examples: Cystic kidneys as a result of heritable polycystic kidney disease; neurodevelopmental ciliopathies such as Joubert syndrome or Bardet-Biedl syndrome
2. 2. Primary ciliary dyskinesias: Defects in motile cilia. Recurrent respiratory infections (chronic sinopulmonary disease), infertility, situs inversus. Examples: More than 45 genes known to cause primary ciliary dyskinesia. When situs inversus is present, it is referred to as Kartagener syndrome.
3. 3. Evaluation: Evaluation for potentially affected organ systems, including abdominal US, echocardiogram, brain MRI, and complete retinal evaluation with ophthalmology. Skeletal survey if limb defects. CMP to evaluate kidney and liver function. Unless a specific disorder is suspected, broad genetic testing is appropriate.

C. Cleft Lip and Palate (CLP)

1. 1. Can be isolated or part of a syndrome
2. 2. Risk factors: Maternal smoking, heavy alcohol use, systemic corticosteroid use, folic acid and cobalamin deficiency¹⁸
3. 3. Submucosal clefts may be indicated by a bifid uvula.
4. 4. Evaluation: Children can have difficulties with feeding, speech, and hearing (chronic otitis or hearing loss as part of a syndrome). If not an isolated anomaly, may need further workup with ophthalmology and echocardiogram.
5. 5. Examples: Autosomal dominant inheritance seen in Van der Woude syndrome (associated with lip pits) and Stickler syndrome (can have retinal detachment, hearing loss)

D. Connective Tissue Disorders

1. 1. Consider when a patient has velvety skin, hyperextensible joints, abnormal scarring, poor healing, striae, pectus deformities, tall stature, myopia, lens dislocations, arachnodactyly
2. 2. Evaluation: Some connective tissue disorders are associated with dilated aorta (echocardiogram), dysplastic vessels, or fragility of lens/retina (ophthalmology evaluation).
3. 3. Examples: Dilated aorta with characteristic physical features in Marfan syndrome; vascular fragility in vascular Ehlers-Danlos (type IV); isolated hyperextensibility of joints in hypermobile Ehlers-Danlos (type III)

E. Developmental Delay, Intellectual Disability

1. 1. All children should be offered genetic evaluation.
2. 2. See Chapter 9 for information on evaluation.

Examples: Microarray is first tier test because it can detect microdeletion and microduplication syndromes, such as 1p36 deletion syndrome. FMR1 repeat testing can detect fragile X syndrome and heterozygous females, who can also have developmental delays. The American College of Medical Genetics (ACMG) is currently reviewing the possibility of starting with whole exome sequencing (WES). If whole genome sequencing becomes the clinical standard, then chromosome microarray and even fragile X testing will no longer be indicated.

F. Deafness, Hard of Hearing

1. 1. Approximately 60% of hearing loss is genetic. It can be syndromic or nonsyndromic.
2. 2. Consider perinatal infectious causes (e.g., cytomegalovirus).
3. 3. Evaluation: Consider connexin 26 and 30 gene testing as first step if nonsyndromic and/or broad gene panel testing. Individualize inner ear/brain imaging. Ophthalmology assessment, ECG, and renal US should be considered for those with negative connexin testing.
4. 4. Examples: Approximately half of nonsyndromic hearing loss is from GJB2 (encodes connexin 26) gene mutations. Syndromic causes include Usher syndrome, which can also have gradual vision loss.

G. Hypotonia

1. 1. Central: Abnormalities of brain function, normal strength or axial weakness, preserved/persistent newborn reflexes, normal CK, normal muscle bulk
   1. a. Evaluation: CK to differentiate. Evaluate for causes such as hypothyroidism (TSH); evaluate brain structure and function with MRI and EEG.
   2. b. Examples: Prader-Willi syndrome, peroxisomal disorders, many others
2. 2. Peripheral: Alert, profound weakness that is often appendicular, absent reflexes, feeding difficulties, normal or increased CK
   1. a. Evaluation: Evaluate for causes such as hypothyroidism (TSH) or mitochondrial disease (lactate/pyruvate). Electromyography (EMG) to determine if muscle or nerve affected. Consider that cardiac muscle could be affected (echocardiogram).
   2. b. Examples: Spinal muscular atrophy (now included in newborn screening), myotonic dystrophy, muscular dystrophies

H. Limb and Stature Conditions

1. 1. Can be defects in collagen formation, bone formation, or remodeling
2. 2. Evaluation: Radiographic skeletal survey of all bones to localize dysplasia. Some conditions, including achondroplasia, can have narrowing at the foramen magnum or cervical instability (flexion/extension C-spine films). There can be a risk of central or peripheral sleep apneas (sleep study). Karyotype for females with short stature to evaluate for Turner syndrome. Unless a specific condition is suspected, broad genetic testing is appropriate.
3. 3. Examples: Rhizomelic limb shortening and narrow foramen magnum seen in achondroplasia. Cervical instability seen in COL2A1 gene mutations (spondyloepiphyseal dysplasia congenita, Stickler syndrome). The presence of multiple congenital joint contractures is called arthrogryposis, which is seen in many conditions. Fractures can be seen in osteogenesis imperfecta and hypophosphatasia.

I. Liver Disease

1. 1. Liver failure and/or direct and indirect hyperbilirubinemia can be a manifestation of a metabolic condition or the result of a genetic syndrome.
2. 2. Evaluation: Metabolic workup, including PAA, UOA, urine succinylacetone, very-long-chain fatty acids, urine-reducing substances. Some syndromes have ocular features (ophthalmology evaluation). Unless a specific condition is suspected, broad genetic testing is appropriate.
3. 3. Examples: Cholestasis found in progressive familial intrahepatic cholestasis (type 1, 2, and 3). Liver dysfunction can be seen in tyrosinemia. Indirect/unconjugated hyperbilirubinemia can be seen in Gilbert and Crigler-Najjar syndromes.

J. Oncologic Conditions¹⁹

1. 1. Approximately 10% of pediatric oncology patients have a heritable cancer predisposition syndrome or germline mutation. This puts them and affected family members at risk for certain cancers and may affect their individualized treatments.
2. 2. Obtain a thorough family history with specific cancer diagnoses and age of diagnosis.
3. 3. Evaluation: Many cancers warrant referral. Genetic testing is tailored to each specific diagnosis. Examples include myelodysplastic syndrome, medulloblastoma, atypical teratoid rhabdoid tumor, sarcomas, pituitary blastoma, and many more.
4. 4. Examples: Early onset of cancers in Li-Fraumeni syndrome (especially sarcoma) and von Hippel-Lindau syndrome (especially hemangioblastoma)

K. Overgrowth

1. 1. Generalized overgrowth can result in macrosomia at birth or height and/or head circumference greater than the 98th percentile.
2. 2. Hemihypertrophy may be the result of mosaicism from somatic changes.
3. 3. Be aware that certain overgrowth syndromes have associated cancer risks and may require routine monitoring (e.g., abdominal US screening in Beckwith-Wiedemann syndrome).
4. 4. Evaluation: Condition-specific genetic testing based on exam findings; may require skin biopsy. In some conditions, internal organs can be affected (echocardiogram, ECG, renal US).
5. 5. Examples: Generalized overgrowth with developmental delays can be the result of Sotos syndrome, Beckwith-Wiedemann syndrome, or others. Segmental overgrowth/hemihypertrophy can result from somatic PIK3CA mutations affecting the brain (MCAP syndrome) or a limb (Klippel-Trénaunay syndrome).

L. Conditions Associated With Seizures

1. 1. Consider genetics, especially with positive family history, intractable epilepsy, infantile onset, developmental regression, intellectual disability, dysmorphic features, autism, or brain malformations.
2. 2. Can be the result of metabolic conditions or syndromic conditions
3. 3. Increased recurrence risk in families even if no genetic cause identified
4. 4. Evaluation: Consideration of microarray, epilepsy panels, or whole exome sequencing (particularly if dysmorphic features present); consider biochemical testing for inborn errors of metabolism; physical exam with Wood’s lamp for cutaneous manifestations (e.g., hypopigmented macules).
5. 5. Examples: Sodium channel defects (SCN1A mutations) can lead to a broad spectrum of seizures. Accompanying dermatologic findings can be characteristic for neurocutaneous conditions, including neurofibromatosis type 1 and tuberous sclerosis.

M. Skin Pigmentation Alterations

1. 1. Can be the result of post-zygotic mosaicism. As a result, genetic variants may only be detectable in affected skin and not in blood.
2. 2. Skin and the central nervous system are derived from the same neural crest lineage; many skin pigmentation anomalies have associated central nervous system abnormalities, including malformations or seizures. Often referred to as neurocutaneous conditions.
3. 3. Evaluation: Examination with a Wood’s lamp, ophthalmology evaluation
4. 4. Examples: Multiple café-au-lait macules seen in neurofibromatosis type 1 and Legius syndrome. Genetic mosaicism in skin can lead to a pigmentation pattern called hypomelanosis of Ito.

N. Vascular Anomalies

1. 1. Can involve arterial, vascular, and lymphatic systems. Can be caused by germline pathogenic variants or postzygotic somatic mutations (mosaicism). Some are associated with segmental overgrowth.
2. 2. Vascular syndromes can cause clinically significant arteriovenous malformations and arteriovenous fistulas in the skin, internal organs, and brain/spine.
3. 3. Evaluation: Examine mucosal membranes. Some conditions require evaluation for intraorgan arteriovenous malformations with abdominal US and/or MRI/magnetic resonance angiography (MRA) of brain and spine. Several conditions are autosomal dominant—obtain family history for vascular lesions.
4. 4. Examples: Autosomal dominant history of multiple capillary malformations could be from RASA1 mutations. Port-wine stains seen in Sturge-Weber syndrome. Telangiectasias on lips, nose, and hands seen in hereditary hemorrhagic telangiectasia

V. Etiologies of Dysmorphic Features

FIG. 13.4 Section references: 11,14,29

A. Aneuploidy
Abnormal number of chromosomes

1. 1. Aneuploidy syndromes are most commonly due to maternal nondisjunction and more rarely due to chromosomal translocation or mosaicism. Risk increases with maternal age.
2. 2. The evaluation for aneuploidy often begins prenatally with a first trimester screen (nuchal translucency, nasal bone, free β-human chorionic gonadotropin [β-hCG], PAPP-A) or circulating cell-free fetal DNA analysis showing increased risk.
3. 3. Prenatal diagnostic testing options include chorionic villus sampling in the first trimester or amniocentesis during or after the second trimester.
4. 4. Fluorescence in situ hybridization (FISH) may be performed in the first 24 to 48 hours of life to indicate number of chromosomes but will not determine the morphology of the chromosomes (e.g., if a translocation is present). Therefore karyotype analysis is still indicated in aneuploidy syndromes, both to provide a diagnosis and to provide accurate genetic counseling.
5. 5. Specific aneuploidy syndromes:
   1. a. Down syndrome (Trisomy 21):
      1. (1) Features: Hypotonia and characteristic facial features (brachycephaly, epicanthal folds, flat nasal bridge, upward-slanting palpebral fissures, Brushfield spots, small mouth and ears), excess skin at the nape of the neck, single transverse palmar crease, short fifth finger with clinodactyly, wide gap between the first and second toes. Intellectual disability present in all, but severity is variable.
      2. (2) Full health supervision guidelines from the American Academy of Pediatrics (AAP) are available (see Section VII).
      3. (3) In brief: In addition to karyotype, neonates should have echocardiogram to assess for congenital heart disease, ophthalmologic evaluation to assess for cataracts, hearing screen, complete blood count (CBC) to assess for transient myeloproliferative disease, thyroid studies to assess for hypothyroidism, and referral to early intervention services. Annual thyroid studies, CBC (add ferritin and CRP for any child at risk of iron deficiency), hearing and vision assessments. Cervical spine x-ray at age 3 years if asymptomatic (sooner imaging with immediate neurosurgical referral if symptomatic). Monitor for signs of obstructive sleep apnea and neurologic dysfunction.
   2. b. Edwards syndrome (Trisomy 18):
      1. (1) Features: Intrauterine growth restriction and polyhydramnios, small for gestational age at birth, clenched hands with overlapping fingers, hypoplastic nails, short sternum, prominent occiput, low-set and structurally abnormal ears, micrognathia, rocker-bottom feet, congenital heart disease, cystic and horseshoe kidneys, seizures, hypertonia, significant developmental and cognitive impairments
      2. (2) Ninety percent die before 1 year of life.
   3. c. Patau syndrome (Trisomy 13):
      1. (1) Features: Defects of forebrain development (holoprosencephaly), severe developmental disability, low-set malformed ears, cleft lip and palate (CLP), microphthalmia, aplasia cutis congenita, polydactyly (most frequently of the postaxial type), narrow hyperconvex nails, apneic spells, cryptorchidism, congenital heart defects
      2. (2) Ninety-five percent die before 6 months of life.
   4. d. Turner syndrome (45, X):
      1. (1) Features: Short stature, gonadal dysgenesis with amenorrhea and lack of a pubertal growth spurt, broad chest with hypoplastic or inverted nipples, webbed neck. The diagnosis should be considered prenatally in a female fetus with hydrops, increased nuchal translucency, cystic hygroma, or lymphedema. Intelligence is usually normal, but patients are at risk for cognitive, behavioral, and social disabilities.
      2. (2) Full health supervision guidelines from the AAP are available (see Section VII).
      3. (3) In brief: Obtain baseline echocardiogram, renal US, ophthalmology and audiology evaluations. Routine thyroid testing, biochemical liver tests, Hemoglobin A_1c, vitamin D, TTG and immunoglobulin A (IgA), audiology, skin examinations, bone mineral density, and skeletal assessments.
   5. e. Klinefelter syndrome (47, XXY; 48, XXYY; 48, XXXY; and 49, XXXXY):
      1. (1) Features: Primary hypogonadism, which may present in infancy with hypospadias or cryptorchidism or in adolescence/adulthood with infertility, gynecomastia, and small testes. Children may have expressive language delay.
      2. (2) There is an increased risk of breast carcinoma in 47, XXY.
      3. (3) Testosterone therapy is indicated at puberty for hypergonadotropic hypogonadism.

B. Copy Number Variation (Deletions and Duplications)
Partial loss or additional copies of genetic material on part of a chromosome

1. 1. 22q11 Deletion syndrome (velocardiofacial syndrome, DiGeorge syndrome)
   1. a. Features: Congenital heart disease (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect [VSD], and truncus arteriosus most common), palatal abnormalities (velopharyngeal incompetence, cleft palate), characteristic facial features in approximately two-thirds, developmental delays, learning disabilities, immunodeficiency, hypocalcemia, feeding problems, renal anomalies, hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures (with or without hypocalcemia), and psychiatric disorders
   2. b. Diagnostic evaluation: Microarray; FISH is no longer recommended. Assessments should include serum calcium, absolute lymphocyte count, B- and T-cell subsets, renal US, chest x-ray, cardiac examination, and echocardiogram
   3. c. Health supervision: Hold live vaccines until immune function is assessed.
2. 2. 5p– syndrome (cri-du-chat syndrome)
   1. a. Features: High-pitched cry, delayed development, intellectual disability, microcephaly, low birth weight, hypotonia, hypertelorism, low-set ears, small jaw, round face, congenital heart disease (VSD, atrial septal defect [ASD], PDA)
   2. b. Diagnostic evaluation: Can be detected on karyotype or microarray
3. 3. 1p36 Deletion syndrome
   1. a. Features: Developmental delay, intellectual disability, delayed growth, hypotonia, seizures, speech delay, hearing and vision impairment, microcephaly, low ears with thick helices, congenital heart disease (structural defects or cardiomyopathy)
   2. b. Diagnostic evaluation: Microarray

C. Disorders of Methylation/Epigenetics
Heritable changes that affect gene activity and expression

1. 1. Prader-Willi syndrome
   1. a. Features: Severe hypotonia and feeding difficulties in infancy, followed by an insatiable appetite in later infancy or early childhood. Developmental delays in motor and language abilities. All affected individuals have some degree of intellectual/learning disability. Short stature is common; males and females have hypogonadism, and in most, infertility.
   2. b. Diagnostic evaluation: Results from missing paternally contributed region. Methylation testing can detect almost all individuals—whether due to abnormal paternal-specific imprinting, a paternal deletion, or maternal uniparental disomy within the Prader-Willi/Angelman critical region of 15q. Follow up with further molecular testing.
   3. c. Health supervision: Full health supervision guidelines from the AAP are available (see Section VII). Monitor for feeding difficulties in infancy and close supervision beginning in childhood to prevent obesity. Evaluate for and treat hypothyroidism, sleep apnea (central and obstructive), central adrenal insufficiency,²¹ and cryptorchidism.
   4. d. Treatment: Growth hormone can be beneficial, and hormone replacement therapy can aid in sexual development.
2. 2. Angelman syndrome
   1. a. Features: Happy demeanor, hand-flapping, and fascination with water. Severe developmental delay, intellectual disability, severe speech impairment, gait ataxia, tremulous limbs, hypotonia, microcephaly, and seizures
   2. b. Diagnostic evaluation: Results from missing maternally contributed region. Methylation testing can detect almost all individuals—whether due to abnormal maternal-specific imprinting, a maternal deletion, or paternal uniparental disomy within the Prader-Willi/Angelman critical region of 15q. Some individuals can be detected through UBE3A sequence analysis.
   3. c. Health supervision: Monitor for seizures, behavior problems, feeding issues, sleep disturbance, scoliosis, strabismus, constipation, and gastroesophageal reflux disease.
   4. d. Treatment: Antiepileptic drugs for seizures; be careful not to overtreat, because Angelman syndrome also associated with movement abnormalities (avoid carbamazepine, vigabatrin, and tiagabine).²² Speech therapy with a focus on nonverbal communication. Sedatives for nighttime wakefulness.
3. 3. Classic Rett syndrome: X-linked condition present only in females because pathogenic MECP2 variants are most often lethal in males who have only one X chromosome. Males who do survive with MECP2 mutations have presentation different from Rett syndrome that often incudes neonatal encephalopathy.
   1. a. Features: Neurodevelopmental syndrome that presents after 6 to 18 months of typical development with acquired microcephaly, then developmental stagnation, followed by rapid regression. Gait ataxia or inability to ambulate; repetitive, stereotypical handwringing; fits of screaming or inconsolable crying; episodic breathing abnormalities (sighing, apnea, or hyperpnea); tremors; and generalized tonic-clonic seizures
   2. b. Diagnostic evaluation: Molecular testing of MECP2
   3. c. Health supervision: Regular ECG to evaluate QT interval,²³ monitor for scoliosis

D. Repeat Expansion
Pathogenic expansion of trinucleotide repeats during DNA replication

1. 1. Fragile X syndrome
   1. a. Most common cause of inherited intellectual disability
   2. b. Features: Males have relative macrocephaly and prominent ears. Postpubertal macroorchidism and tall stature that slows in adolescence. Females have a range of intellectual disability due to the degree of inactivation of the affected X chromosome. Female premutation carriers (55 to 200 repeats) can develop primary ovarian insufficiency; males with 55 to 200 repeats can develop a tremor/ataxia phenotype.
   3. c. Diagnostic evaluation: Repeat expansion testing of FMR1 gene to assess number of CGG trinucleotide repeats (typically >200 in fragile X syndrome).
   4. d. Health supervision: Full health supervision guidelines from the AAP are available (see Section VII). Symptom and supportive psychopharmacologic medications
2. 2. Other examples include Huntington disease (CAG repeats), myotonic dystrophy (CTG repeats), and Friedrich ataxia (GAA repeats).

E. Mendelian/Single Gene Disorders
Mutation in a single gene causing a disorder

1. 1. Marfan syndrome
   1. a. Features: Myopia, ectopia lentis, aortic dilatation with predisposition to rupture, mitral valve prolapse, pneumothorax, bone overgrowth and joint laxity, pectus carinatum or excavatum, scoliosis, pes planus
   2. b. Diagnostic evaluation: Clinical diagnosis based on the revised Ghent criteria (a “systemic score” system based on clinical features that can support a diagnosis if score is greater than or equal to 7). Sequencing of FBN1 gene
   3. c. Health supervision: Annual ophthalmologic examination; annual echocardiography; intermittent surveillance of the entire aorta with computed tomography (CT) or MRA scans beginning in young adulthood. Avoid contact sports, competitive sports, isometric exercise. Full health supervision guidelines from the AAP are available (see Section VII).
   4. d. Treatment: β-blocker (atenolol) and/or an angiotensin-II type 1 receptor blocker (losartan) is current standard of care. Valve-sparing surgery to replace aortic root when diameter exceeds ∼4.5 cm in adults (or if rates of aortic dilation exceed ∼0.5 cm/year) and significant aortic regurgitation is present.²⁴
2. 2. Ehlers-Danlos syndrome (EDS)
   1. a. Features: Smooth, velvety, hyperextensible skin, widened scars, poor healing, easy bruising, joint hypermobility with recurrent dislocations, chronic joint or limb pain, and a positive family history. The vascular-type EDS is distinct and involves translucent skin, characteristic facies (pinched nose), as well as risk for arterial, intestinal, and uterine fragility or rupture.
   2. b. Diagnostic evaluation: Clinical evaluation and family history. There are more than thirteen types; for classical and vascular types, echocardiogram and DNA testing. Vascular type additionally needs CTA/MRA imaging of head to pelvis. Joint hypermobility can be scored with Beighton criteria. No known genetic cause of hypermobile type, which is most common
   3. c. Treatment: Physical therapy to improve joint stability, low-resistance exercise, and pain medications as needed; treat gastroesophageal reflux. Vascular EDS requires management in a clinic specializing in connective tissue disorders.
3. 3. Achondroplasia
   1. a. Features: Short arms and legs (due to rhizomelia or shortening of the most proximal extremity segments: humerus and femur); bowing of the lower legs; large head with characteristic facial features including frontal bossing and midface retrusion. Infantile hypotonia is typical, followed by delayed motor development. Gibbus deformity of the thoracolumbar spine leads to exaggerated lumbar lordosis. Rarely, children have hydrocephalus and restrictive pulmonary disease. Stenosis at the foramen magnum in infancy increases the risk of death; lumbar spinal stenosis may present in childhood but is more common in adulthood. Intelligence and life span are usually normal. Average adult height for males and females is approximately 4 feet.
   2. b. Diagnostic evaluation: Clinical diagnosis based on characteristic physical exam. FGFR3 mutation testing available if diagnostic uncertainty
   3. c. Health supervision: Full health supervision guidelines from the AAP are available (see Section VII). In brief: Use standard growth charts for achondroplasia. Baseline head CT including cervicomedullary junction in infancy, and precautions against uncontrolled head movement or neck manipulation. Monitor for signs of obstructive sleep apnea, middle ear complications (e.g., otitis media), or spinal stenosis (more common in adults). New treatments available and in clinical trials

F. Teratogen Exposure (Table 13.10)

G. In utero Forces ²⁵

1. 1. Uterine compression:
   1. a. Can be intrinsic (oligohydramnios, multiple fetuses, uterine deformities) or extrinsic (small pelvis)
   2. b. Results in deformations, including craniofacial (plagiocephaly, flattened facies, crumpled ear, craniosynostosis), extremities (dislocated hips, equinovarus or calcaneovalgus feet, tibial bowing, contractures), torticollis, lung hypoplasia, scoliosis
2. 2. Abnormal fetal muscular tone or posture can result in hyperextended knees, dislocated hips, contractures.
3. 3. Placental compromise
4. 4. Amniotic bands

VI. Consent and Disclosure of Genetic Testing

A. Ethics of Genetic Testing in Pediatrics
Genetic testing in pediatric patients poses unique challenges given that children require proxies (most often parents) to give consent for testing. Several publications and statements have been released about genetic testing in children, including the “Ethical Issues with Genetic Testing in Pediatrics” statement made by the AAP.²⁶ Important considerations include:

1. 1. Testing and screening of a pediatric patient should be in his/her best interest and provide clear benefits.
2. 2. If testing is performed for the interests of parents or other family members, it should not be to the detriment of the child.
3. 3. Treatment and/or follow-up must be available after testing is sent.
4. 4. Carrier testing or screening in children and adolescents is not broadly supported.
5. 5. Predictive testing for late-onset disorders is discouraged until a patient is able to make an autonomous decision; in these cases, extensive pre-test counseling is recommended.

B. Informed Consent
Pretest counseling and informed consent are important prior to sending any genome-wide testing, and documentation of informed consent is recommended. Possible results from genetic testing include:

1. 1. Positive: A causative/related variant is found.
2. 2. Negative: Either no causative/related variant is present, or the available technology or scope of the test methodology was unable to detect the causative/related variant. A negative result does not guarantee the condition does not have a genetic etiology.
3. 3. Variant(s) of uncertain significance: Variants for which the meaning is uncertain (could be variants without clinical significance or related to the patient’s presentation but not previously reported)
4. 4. Incidental or secondary finding(s): Variants anticipated to affect the patient’s health that are unrelated to the indication for sending the test (and may be an adult-onset condition)
5. 5. Discovery that parents are blood relatives and/or nonmaternity/nonpaternity

C. Professional Disclosure of Familial Genetic Information
Pretest counseling should include the discussion that genetic testing may have implications for family members. With regard to disclosure of genetic testing results to at-risk family members when a patient or family member chooses not to disclose, the provider must weigh the duty to respect privacy and autonomy of the patient with the duty to prevent harm in another identifiable person. The ethical and legal duties of the physician are not well defined. The American Society of Human Genetics released a statement on professional disclosure of familial genetic information, which outlines “exceptional circumstances,” which if all are present, disclosure may be permissible: (1) attempts to encourage disclosure by the patient have failed, (2) harm is “highly likely” to occur, (3) the harm is “serious and foreseeable,” (4) either the disease is preventable/treatable or early monitoring will reduce risks, (5) the at-risk relative(s) are identifiable, and (6) the harm of failure to disclose outweighs the harm that may result from disclosure.²⁷

D. Disclosure of Incidental Findings
Patients are sometimes given the option to be informed of any incidental or secondary findings when they pursue genetic testing, but in general, it is recommended that incidental findings should be reported when there is strong evidence of benefit to the patient. The minimal list of reportable incidental findings may be found in the ACMG March 2013 statement and related updates.²⁸

VII. Web Resources

A. Specific Genetic Disorders

• Genetics Home Reference: https://ghr.nlm.nih.gov/ (patient-friendly information)
• GeneReviews: https://www.genereviews.org (expert-authored clinical descriptions including diagnosis and management recommendations)
• National Organization for Rare Disorders: https://www.rarediseases.org
• Online Mendelian Inheritance in Man (OMIM): https://omim.org (curated primary literature, can be used to search for clinical features to build a differential)

B. Guidelines for Genetic Conditions

• Newborn screening ACT Sheets and Confirmatory Algorithms: https://www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/ACT_Sheets_a...

C. Molecular Testing Resources

• Concert Genetics: https://www.concertgenetics.com
• Genetics Testing Registry: https://www.ncbi.nlm.nih.gov/gtr

D. Teratogen Evaluation

• LactMed: Drugs and lactation database available through the U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK501922/...
• Patient-oriented information on exposures during pregnancy: https://www.mothertobaby.org³¹

VIII. Online Content

A. Patterns of Inheritance

1. 1. Autosomal dominant:
   1. a. Disease manifestation with a variant in one allele of a gene; the other allele is normal.
   2. b. It can appear in multiple generations.
   3. c. An affected individual has a 50% risk of passing on the variant with each pregnancy.
2. 2. Autosomal recessive:
   1. a. Disease manifestation requiring variants in both alleles of the gene
   2. b. There can be multiple affected individuals in the same generation.
   3. c. An affected couple (each being a carrier) has a 25% chance of having an affected child, a 25% chance of having an unaffected child, and a 50% chance of producing a carrier of the condition with each pregnancy.
3. 3. X-linked:
   1. a. Because females have two X chromosomes and males have only one X chromosome, males are more commonly and more severely affected by X-linked conditions. Females can be unaffected or have a spectrum of manifestations. In carrier females, lyonization is the process of silencing one X chromosome in each cell and “unfavorable lionization” can result in a large proportion of cells that inactivated the normal X chromosome, and as a result clinical features are present.
   2. b. Females have a 50% chance of passing on an affected X to each male or female child. Males will pass on the affected X to all female children and will have unaffected sons.
4. 4. Mitochondrial:
   1. a. Classically a matrilineal inheritance pattern, caused by mitochondrial DNA inherited from one’s mother that contributes to mitochondrial function. Sons will be affected but cannot pass the condition on to their offspring.
   2. b. There may be significant phenotypic variability due to “heteroplasmy,” in which the relative proportion of affected and unaffected mitochondria may change as cells divide.
   3. c. Mitochondrial disease is currently known to be caused either by variants in mitochondrial DNA or by recessive variants in nuclear genes that code for proteins that function in the mitochondria.
5. 5. Genomic imprinting and uniparental disomy:
   1. a. The two alleles of a gene may be functionally equivalent but may be expressed or silenced depending on the parent of origin of the chromosome. This is due to the presence of epigenetic machinery influencing the expression of genes and resulting in different methylation patterns.
   2. b. Uniparental disomy is a rare occurrence in which offspring have inherited both copies of a chromosome from one parent. There are two types: (1) Uniparental isodisomy is an error in meiosis II, in which the offspring receives two identical copies of a chromosome from one parent. This can result in autosomal recessive disorders because any variant on one parental allele could be present on both alleles of their offspring. (2) Uniparental heterodisomy is an error in meiosis I, in which the offspring receives both copies of a single parent’s chromosome. This can result in disorders of imprinting because only one parent contributed to the epigenetic pattern of that chromosome.

Author(s)

Jacqueline Wood, MD, MA

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