Genetic Flashcards
(235 cards)
1
Q
What is the genetic basis of Down Syndrome?
A
Down Syndrome is most commonly caused by trisomy of chromosome 21, resulting from nondisjunction during meiosis (especially maternal meiosis I). Other mechanisms include Robertsonian translocation (~4%) and mosaicism (~1%).
2
Q
What is the karyotype of a typical Down Syndrome case caused by nondisjunction?
A
47,XX,+21 or 47,XY,+21 — indicating an extra chromosome 21.
3
Q
Describe the Robertsonian translocation in Down Syndrome.
A
Involves fusion of long arm of chromosome 21 with another acrocentric chromosome (often chromosome 14). Balanced in a carrier parent, unbalanced in the affected child.
4
Q
How does mosaic Down Syndrome arise and what are its implications?
A
Post-zygotic nondisjunction results in a mixture of normal and trisomy 21 cells. Clinical features are typically milder, with less cognitive and physical impairment.
5
Q
What are the most common craniofacial features seen in Down Syndrome?
A
Brachycephaly, flat facial profile, upslanting palpebral fissures, epicanthic folds, Brushfield spots (on iris), small nose with flat nasal bridge, and low-set small ears.
6
Q
List musculoskeletal findings typical in Down Syndrome.
A
Generalized hypotonia, joint hyperlaxity, short stature, brachydactyly, single palmar crease, clinodactyly of the 5th digit, and sandal gap between 1st and 2nd toes.
7
Q
What are common congenital cardiac anomalies in Down Syndrome?
A
Atrioventricular septal defect (AVSD) is most common, followed by VSD, ASD, and Tetralogy of Fallot.
8
Q
What gastrointestinal abnormalities are associated with Down Syndrome?
A
Duodenal atresia (“double bubble” sign), Hirschsprung disease, annular pancreas, esophageal atresia, and imperforate anus.
9
Q
Name three hematological conditions seen in Down Syndrome.
A
Transient abnormal myelopoiesis (TAM) in neonates, acute myeloid leukemia (especially AMKL subtype, M7), acute lymphoblastic leukemia (increased risk).
10
Q
What endocrine disorders are commonly associated with Down Syndrome?
A
Congenital hypothyroidism, acquired autoimmune hypothyroidism (Hashimoto’s), Type 1 diabetes mellitus.
11
Q
Describe the neurodevelopmental profile of Down Syndrome.
A
Global developmental delay, intellectual disability (mild to moderate), delayed speech and motor skills, and increased risk of early-onset Alzheimer’s disease.
12
Q
What ophthalmologic and hearing issues are common in Down Syndrome?
A
Ophthalmologic: strabismus, cataracts, refractive errors, Brushfield spots. Hearing: conductive hearing loss from recurrent otitis media, sensorineural loss.
13
Q
Which immune-related issues are common in Down Syndrome?
A
Increased susceptibility to infections (especially respiratory and otitis media), increased risk of autoimmune diseases (e.g., thyroiditis, celiac disease).
14
Q
How does Down Syndrome affect growth parameters?
A
Children have their own growth charts; generally smaller in height, weight, and head circumference. Growth hormone deficiency may be present in some.
15
Q
What cervical spine anomaly should be screened for in Down Syndrome?
A
Atlantoaxial instability — risk of spinal cord compression, especially during anesthesia or sports.
16
Q
What prenatal screening markers suggest Down Syndrome?
A
1st trimester: low PAPP-A, high β-hCG. 2nd trimester (Quad screen): ↓AFP, ↓uE3, ↑hCG, ↑inhibin A. Increased nuchal translucency on ultrasound.
17
Q
What definitive prenatal diagnostic tests can confirm Down Syndrome?
A
Chorionic villus sampling (CVS) at 10–13 weeks, amniocentesis at 15–20 weeks, fetal karyotyping or microarray.
18
Q
What are key recommendations for newborn evaluation of a baby with Down Syndrome?
A
Echocardiogram, hearing screen (ABR), TSH and T4, vision screen, CBC (to detect TAM), karyotype to determine cause.
19
Q
Outline the long-term follow-up plan for a child with Down Syndrome.
A
Annual thyroid screening, regular hearing and vision assessments, growth and developmental surveillance, monitor for sleep apnea and behavioral issues.
20
Q
What genetic counseling should be offered to parents after a diagnosis of Down Syndrome?
A
Karyotyping the child to identify translocation. If Robertsonian translocation: test both parents. Counseling on recurrence risk and psychosocial support.
21
Q
What is the genetic basis of Turner Syndrome?
A
Turner Syndrome results from complete or partial monosomy of the X chromosome, most commonly 45,X. Other variants include mosaicism (e.g., 45,X/46,XX) and structural abnormalities like isochromosomes or ring chromosomes.
22
Q
What is the karyotype of classical Turner Syndrome?
A
45,X — complete monosomy of one X chromosome.
23
Q
List key physical features of Turner Syndrome.
A
Short stature, webbed neck, low posterior hairline, shield chest with widely spaced nipples, lymphedema of hands and feet (especially at birth), and cubitus valgus.
24
Q
What are the main cardiac anomalies seen in Turner Syndrome?
A
Bicuspid aortic valve, coarctation of the aorta, aortic root dilation, and increased risk of aortic dissection.
25
What renal abnormalities are seen in Turner Syndrome?
Horseshoe kidney, duplicated collecting system, and other congenital anomalies predisposing to urinary tract infections.
26
What endocrine dysfunctions are common in Turner Syndrome?
Primary ovarian insufficiency (streak ovaries), delayed puberty, infertility, hypothyroidism (Hashimoto’s thyroiditis), and increased risk of Type 2 diabetes.
27
How does Turner Syndrome affect puberty and fertility?
Girls often have delayed or absent puberty due to gonadal dysgenesis and are usually infertile without assisted reproduction.
28
What are typical growth patterns and bone issues in Turner Syndrome?
Short stature (even before puberty), delayed bone age, and osteoporosis due to estrogen deficiency.
29
What cognitive profile is associated with Turner Syndrome?
Normal intelligence with specific deficits in visuospatial, executive, and mathematical skills; often good verbal ability.
30
What autoimmune diseases are Turner patients at risk for?
Autoimmune thyroiditis, Type 1 diabetes, celiac disease, and inflammatory bowel disease.
31
What is the role of growth hormone in Turner Syndrome?
Recombinant growth hormone is started early in childhood to improve adult height.
32
When is estrogen therapy initiated in Turner Syndrome and why?
Estrogen is usually started around age 11–12 to induce secondary sexual characteristics and continued for bone and cardiovascular health.
33
What is the typical finding on pelvic ultrasound in Turner Syndrome?
Streak ovaries (fibrous, non-functional), hypoplastic uterus.
34
What are common ENT complications in Turner Syndrome?
Recurrent otitis media, hearing loss (both conductive and sensorineural), high-arched palate.
35
What screening is essential at diagnosis of Turner Syndrome?
Echocardiogram, renal ultrasound, thyroid function tests, audiometry, baseline growth parameters, and karyotype confirmation.
36
What are the key prenatal ultrasound findings suggestive of Turner Syndrome?
Cystic hygroma, generalized fetal edema (hydrops fetalis), left-sided heart defects, and oligohydramnios.
37
What is the recurrence risk of Turner Syndrome?
Turner Syndrome is typically sporadic with a low recurrence risk; parental karyotyping is not routinely indicated unless mosaicism or structural abnormalities are present.
38
How is mosaic Turner Syndrome different from classical 45,X?
Patients with mosaicism (e.g., 45,X/46,XX or 45,X/46,XY) may have milder features, spontaneous puberty, menstruation, or ambiguous genitalia depending on Y material.
39
Why is screening for Y chromosome material important in Turner Syndrome?
Presence of Y material (e.g., 45,X/46,XY) increases risk of gonadoblastoma; prophylactic gonadectomy is recommended.
40
What are long-term health monitoring recommendations in Turner Syndrome?
Regular cardiac imaging, bone mineral density assessments, hearing evaluations, thyroid function, metabolic screening, and psychological support.
41
What is the genetic basis of Klinefelter Syndrome?
Klinefelter Syndrome results from the presence of one or more extra X chromosomes in males, most commonly 47,XXY. Other variants include 48,XXXY and mosaic 46,XY/47,XXY.
42
What is the most common karyotype in Klinefelter Syndrome?
47,XXY — a male with an extra X chromosome.
43
Describe the pathophysiology behind the clinical features in Klinefelter Syndrome.
Extra X chromosome leads to primary testicular failure due to seminiferous tubule dysgenesis, resulting in decreased testosterone and elevated gonadotropins (hypergonadotropic hypogonadism).
44
What are the typical physical features of Klinefelter Syndrome in adolescents?
Tall stature, long limbs, small firm testes, gynecomastia, sparse facial/body hair, and underdeveloped secondary sexual characteristics.
45
What are the fertility implications of Klinefelter Syndrome?
Most patients are infertile due to azoospermia or oligospermia; however, assisted reproductive techniques may be possible in mosaic cases.
46
How does Klinefelter Syndrome present in early childhood?
Often subtle or asymptomatic. May present with speech/language delays, motor incoordination, learning difficulties, or behavioral problems.
47
What neurodevelopmental and cognitive problems are associated with Klinefelter Syndrome?
Verbal processing deficits, language delay, learning disabilities, and executive function impairment, with relatively preserved visual-spatial skills.
48
Which endocrine abnormalities may be seen in Klinefelter Syndrome?
Low testosterone, elevated LH and FSH, insulin resistance, increased risk of metabolic syndrome and Type 2 diabetes.
49
What are the psychosocial challenges commonly encountered in Klinefelter Syndrome?
Low self-esteem, depression, social difficulties, and anxiety, especially in adolescence.
50
What are the risks of malignancy in Klinefelter Syndrome?
Increased risk of breast cancer (similar to females), mediastinal germ cell tumors, and extragonadal germ cell tumors.
51
What are common skeletal findings in Klinefelter Syndrome?
Increased arm span, reduced upper/lower segment ratio, osteopenia or osteoporosis due to androgen deficiency.
52
How is Klinefelter Syndrome diagnosed?
Confirmed by karyotype analysis showing an extra X chromosome (e.g., 47,XXY). May be incidentally discovered during fertility workup or developmental evaluation.
53
What is the role of hormone levels in the evaluation of Klinefelter Syndrome?
Elevated FSH and LH with low testosterone (hypergonadotropic hypogonadism) support the diagnosis and guide timing for testosterone replacement.
54
When should testosterone therapy be initiated in Klinefelter Syndrome?
Usually started at puberty (around 12–14 years) to promote secondary sexual development, muscle mass, bone density, and psychosocial functioning.
55
What is the role of fertility preservation in Klinefelter Syndrome?
Early referral to reproductive endocrinology may allow sperm retrieval in some mosaic or non-mosaic patients via testicular sperm extraction.
56
How does mosaic Klinefelter Syndrome (46,XY/47,XXY) differ from classic 47,XXY?
Milder phenotype with possible spontaneous puberty and fertility. Clinical variability is greater.
57
What additional X chromosome abnormalities can resemble Klinefelter Syndrome?
Variants include 48,XXXY and 49,XXXXY syndromes, which have more severe intellectual and physical disability.
58
What are the prenatal diagnostic options for Klinefelter Syndrome?
Can be detected via chorionic villus sampling or amniocentesis as part of chromosomal screening.
59
What supportive therapies are beneficial for boys with Klinefelter Syndrome?
Speech therapy, physical and occupational therapy, educational support, psychological counseling, and social skills training.
60
What long-term monitoring is needed for individuals with Klinefelter Syndrome?
Regular follow-up for endocrine, bone health, cardiovascular risks, psychosocial support, and malignancy screening (breast exams in adults).
61
What is the genetic basis of DiGeorge Syndrome?
DiGeorge Syndrome is caused by a microdeletion at chromosome 22q11.2, affecting TBX1 and other genes. It results in abnormal development of the pharyngeal pouches.
62
What are alternative names for DiGeorge Syndrome?
Velocardiofacial syndrome, 22q11.2 deletion syndrome, and conotruncal anomaly face syndrome.
63
What are the most common cardiac anomalies seen in DiGeorge Syndrome?
Conotruncal defects including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, and VSD.
64
Which immune system abnormality is characteristic of DiGeorge Syndrome?
Thymic hypoplasia or aplasia, leading to T-cell immunodeficiency. Severity ranges from partial to complete DiGeorge Syndrome.
65
What endocrine abnormality is typically found in DiGeorge Syndrome?
Hypocalcemia due to hypoplasia or aplasia of the parathyroid glands.
66
What craniofacial features are associated with DiGeorge Syndrome?
Micrognathia, low-set and posteriorly rotated ears, hypertelorism, cleft palate or bifid uvula, and short philtrum.
67
What renal anomalies are seen in DiGeorge Syndrome?
Renal agenesis, dysplastic kidneys, or other structural anomalies leading to functional impairment.
68
What neurodevelopmental issues are associated with DiGeorge Syndrome?
Learning disabilities, developmental delays, intellectual disability, speech delays, and increased risk of ADHD and autism.
69
Which psychiatric disorders are more common in DiGeorge Syndrome?
Schizophrenia-like psychosis, anxiety disorders, and depression, especially during adolescence and adulthood.
70
How is DiGeorge Syndrome diagnosed genetically?
Confirmed by FISH (fluorescence in situ hybridization), MLPA, or chromosomal microarray identifying a 22q11.2 deletion.
71
What infections are common in DiGeorge Syndrome?
Recurrent viral, fungal, and bacterial infections due to T-cell deficiency, especially in complete DiGeorge Syndrome.
72
What is the difference between partial and complete DiGeorge Syndrome?
Partial: some thymic function preserved; Complete: absent thymus, severe immunodeficiency (SCID-like presentation).
73
What hematological findings can occur in DiGeorge Syndrome?
Lymphopenia (especially low CD3+ T cells), poor response to vaccines, and absent thymic shadow on chest X-ray.
74
What imaging findings suggest DiGeorge Syndrome in newborns?
Absent thymic shadow on chest X-ray, conotruncal heart defects on echocardiogram.
75
What prenatal ultrasound features may raise suspicion for DiGeorge Syndrome?
Conotruncal heart defects, polyhydramnios, renal anomalies, and increased nuchal translucency.
76
What multidisciplinary follow-up is recommended in DiGeorge Syndrome?
Cardiology, immunology, endocrinology, ENT, speech therapy, developmental pediatrics, psychiatry, and genetics.
77
What are treatment options for hypocalcemia in DiGeorge Syndrome?
Calcium supplementation and activated vitamin D analogs (e.g., calcitriol).
78
How is T-cell deficiency managed in DiGeorge Syndrome?
Avoid live vaccines if T-cell counts are low, prophylactic antibiotics, and in severe cases, thymic or hematopoietic stem cell transplantation.
79
What is the long-term prognosis of DiGeorge Syndrome?
Highly variable; depends on severity of cardiac and immune defects. Many patients lead functional lives with early multidisciplinary intervention.
80
What is the genetic basis of Fragile X Syndrome?
Fragile X Syndrome is caused by a CGG trinucleotide repeat expansion (>200 repeats) in the FMR1 gene on the X chromosome, leading to methylation and silencing of the gene.
81
What is the mode of inheritance of Fragile X Syndrome?
X-linked dominant with variable expression; affects males more severely than females due to lack of a second normal X chromosome.
82
What protein is deficient in Fragile X Syndrome and what is its function?
FMRP (Fragile X Mental Retardation Protein), involved in synaptic plasticity and regulation of mRNA translation in neurons.
83
What are the typical physical features in males with Fragile X Syndrome?
Long narrow face, prominent ears, macroorchidism (especially after puberty), high-arched palate, and joint hypermobility.
84
What neurodevelopmental disorders are associated with Fragile X Syndrome?
Intellectual disability (moderate to severe in males), autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and speech delays.
85
What behavioral characteristics are typical of Fragile X Syndrome?
Social anxiety, hand flapping, gaze aversion, tactile defensiveness, hyperactivity, and repetitive behaviors.
86
What are the features of Fragile X Syndrome in females?
Milder cognitive impairment, subtle behavioral issues, anxiety, or even normal intelligence due to X-inactivation of the mutated gene.
87
What is Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)?
Late-onset neurodegenerative disorder affecting premutation carrier males, characterized by intention tremor, gait ataxia, and cognitive decline.
88
What is Fragile X-associated Primary Ovarian Insufficiency (FXPOI)?
Condition in female premutation carriers causing irregular menses, early menopause, and infertility.
89
How is Fragile X Syndrome diagnosed?
Molecular genetic testing using PCR and Southern blot to assess CGG repeat size and methylation status of FMR1.
90
What brain imaging abnormalities may be seen in Fragile X Syndrome?
Enlarged caudate nucleus, increased brain volume in childhood, and reduced cerebellar vermis volume.
91
What genetic counseling points are important for Fragile X Syndrome?
Risk of expansion increases in maternal transmission. Premutation carriers can have affected offspring and health issues themselves.
92
What are the prenatal diagnostic options for Fragile X Syndrome?
Chorionic villus sampling or amniocentesis with FMR1 repeat analysis in known carriers.
93
What treatments are available for Fragile X Syndrome?
No cure; management includes behavioral therapy, special education, speech therapy, and medications for ADHD, anxiety, and aggression.
94
How does Fragile X differ from other causes of X-linked intellectual disability?
It is the most common inherited cause and often coexists with autism, making it a leading genetic diagnosis in ASD evaluations.
95
What percentage of males with Fragile X have autism spectrum disorder?
Approximately 50–60% meet criteria for autism or show significant autistic traits.
96
Why is carrier screening important in Fragile X Syndrome?
Identifies women with premutation who are at risk of FXPOI and of having children with Fragile X Syndrome.
97
What supportive services are essential for Fragile X Syndrome patients?
Early intervention, individualized education plans (IEPs), behavioral therapy, family support, and genetic counseling.
98
What is the genetic cause of Prader-Willi Syndrome (PWS)?
Loss of paternally expressed genes on chromosome 15q11-q13, most commonly due to paternal deletion (~70%), maternal uniparental disomy (~25%), or imprinting defects (~5%).
99
What is the inheritance pattern of Prader-Willi Syndrome?
It is not inherited in a Mendelian pattern; it results from abnormal genomic imprinting involving chromosome 15q11-q13.
100
What are the two main phases of clinical presentation in Prader-Willi Syndrome?
1) Infancy: hypotonia, poor feeding, failure to thrive; 2) Early childhood: hyperphagia, obesity, developmental delay, and behavioral issues.
101
How is Prader-Willi Syndrome diagnosed?
DNA methylation analysis of chromosome 15q11-q13 confirms the absence of paternal alleles. Further tests (FISH or microarray) may identify deletions or UPD.
102
What are common sleep disorders in Prader-Willi Syndrome?
Obstructive sleep apnea, excessive daytime sleepiness, and abnormal sleep architecture. Polysomnography is often recommended.
103
What dental issues are common in Prader-Willi Syndrome?
Thick, sticky saliva leading to dental caries, enamel erosion, and increased risk of periodontal disease.
104
What is the long-term prognosis of individuals with Prader-Willi Syndrome?
With early diagnosis and multidisciplinary management, many individuals can achieve functional independence, though obesity-related complications are a major concern.
105
What is the genetic cause of Angelman Syndrome?
Loss of function of the maternally inherited UBE3A gene on chromosome 15q11-q13, most commonly due to maternal deletion (~70%), paternal uniparental disomy (~5%), imprinting defects (~5%), or UBE3A mutation (~10%).
106
What is the inheritance pattern of Angelman Syndrome?
It is due to genomic imprinting; the maternal allele is normally active in neurons while the paternal allele is imprinted (silenced).
107
What is the role of UBE3A in Angelman Syndrome?
UBE3A encodes a ubiquitin ligase critical for synaptic development and function; its expression is exclusively maternal in the brain.
108
What are hallmark clinical features of Angelman Syndrome?
Severe intellectual disability, absence or minimal speech, gait ataxia, seizures, frequent laughter or smiling, hand-flapping, and hyperexcitability.
109
How is Angelman Syndrome different from Prader-Willi Syndrome genetically?
Both involve 15q11-q13; Angelman results from maternal loss of UBE3A, while Prader-Willi results from paternal gene loss.
110
What are common facial features seen in Angelman Syndrome?
Prominent chin, wide mouth, protruding tongue, deep-set eyes, and flat occiput.
111
What is the typical age of clinical presentation in Angelman Syndrome?
Symptoms often begin before age 1 (delayed milestones, hypotonia), but classic features become more apparent by 2–3 years.
112
What are the characteristic behavioral features of Angelman Syndrome?
Happy demeanor with frequent laughter, excitability, fascination with water, and hypermotoric behavior.
113
What type of seizures are seen in Angelman Syndrome?
Multiple seizure types, including myoclonic, atypical absence, and generalized tonic-clonic seizures; onset typically by age 3.
114
What EEG findings are typical in Angelman Syndrome?
High-amplitude slow-spike waves, especially in anterior leads, even without clinical seizures.
115
How is Angelman Syndrome diagnosed?
Methylation analysis of 15q11-q13 followed by UBE3A gene sequencing if needed.
116
What are differential diagnoses for Angelman Syndrome?
Rett syndrome, Lennox-Gastaut syndrome, cerebral palsy, and severe autism with intellectual disability.
117
What is the recurrence risk for Angelman Syndrome?
Low for deletions or UPD (<1%), but up to 50% if caused by UBE3A mutation or imprinting center defect with a familial component.
118
What motor abnormalities are seen in Angelman Syndrome?
Gait ataxia, tremulous movements, hypotonia in infancy progressing to increased tone later.
119
What language impairments are typical in Angelman Syndrome?
Minimal to absent speech; receptive language is better than expressive.
120
What gastrointestinal issues are common in Angelman Syndrome?
Feeding difficulties in infancy, constipation, and gastroesophageal reflux.
121
What are some common sleep disturbances in Angelman Syndrome?
Difficulty falling asleep, frequent awakenings, and reduced need for sleep.
122
What supportive therapies are essential in Angelman Syndrome?
Physical, occupational, and speech therapy; seizure management; behavioral and sleep interventions.
123
What pharmacologic treatments are used in Angelman Syndrome?
Antiepileptic drugs for seizure control; melatonin or clonidine for sleep disturbances.
124
What is the long-term prognosis in Angelman Syndrome?
Lifelong intellectual disability and motor impairment, but many individuals live into adulthood with structured support and interventions.
125
What is the genetic cause of Williams Syndrome?
A microdeletion on chromosome 7q11.23, which includes the elastin (ELN) gene.
126
Which gene's deletion is primarily responsible for the cardiovascular features in Williams Syndrome?
The elastin (ELN) gene deletion leads to arterial abnormalities, especially supravalvular aortic stenosis.
127
What is the inheritance pattern of Williams Syndrome?
Typically sporadic due to de novo deletion, but autosomal dominant inheritance can occur.
128
What are the characteristic facial features of Williams Syndrome?
Broad forehead, periorbital fullness, short nose with broad tip, full cheeks, wide mouth, small chin, and 'elfin facies'.
129
What cardiovascular anomalies are associated with Williams Syndrome?
Supravalvular aortic stenosis (SVAS), peripheral pulmonary stenosis, and systemic hypertension.
130
What are the hallmark neurodevelopmental features of Williams Syndrome?
Mild to moderate intellectual disability, strong verbal abilities, poor visuospatial skills, and learning disabilities.
131
What behavioral profile is typical of Williams Syndrome?
Overfriendliness, high sociability, empathy, anxiety, and poor social judgment.
132
What are common musculoskeletal findings in Williams Syndrome?
Joint laxity in early childhood followed by joint stiffness and contractures later in life.
133
What endocrine abnormalities are common in Williams Syndrome?
Hypercalcemia (especially in infancy), hypothyroidism, early puberty, and impaired glucose tolerance.
134
What gastrointestinal issues may occur in Williams Syndrome?
Feeding difficulties in infancy, constipation, and abdominal pain.
135
What renal anomalies may be present in Williams Syndrome?
Structural anomalies such as renal artery stenosis or small kidneys, which can contribute to hypertension.
136
What are common ocular features in Williams Syndrome?
Strabismus, stellate pattern of the iris, and refractive errors.
137
What audiologic findings are associated with Williams Syndrome?
Sensorineural hearing loss, typically developing in adolescence or adulthood.
138
How is Williams Syndrome diagnosed?
FISH or microarray testing confirms deletion at 7q11.23.
139
What is the prevalence of hypercalcemia in Williams Syndrome?
About 15% of infants with Williams Syndrome experience hypercalcemia, often transient.
140
What neurological features may be seen in Williams Syndrome?
Seizures (rare), hyperreflexia, and coordination difficulties.
141
What psychiatric disorders are more common in Williams Syndrome?
Generalized anxiety disorder, specific phobias, and attention deficit hyperactivity disorder (ADHD).
142
What is the management for cardiovascular complications in Williams Syndrome?
Echocardiographic surveillance, beta-blockers or surgery for SVAS, and treatment of hypertension.
143
What is the importance of calcium monitoring in infancy in Williams Syndrome?
To detect and manage hypercalcemia, which may cause irritability, vomiting, and failure to thrive.
144
What supportive therapies are essential in Williams Syndrome?
Multidisciplinary approach with developmental pediatrics, speech and occupational therapy, educational support, and cardiology/endocrinology follow-up.
145
What is the genetic cause of Noonan Syndrome?
Mutations in genes involved in the RAS-MAPK signaling pathway, most commonly PTPN11 (50%), followed by SOS1, RAF1, KRAS, NRAS, and others.
146
What is the inheritance pattern of Noonan Syndrome?
Autosomal dominant, although many cases are de novo mutations.
147
What are the characteristic facial features of Noonan Syndrome?
Hypertelorism, downslanting palpebral fissures, ptosis, low-set posteriorly rotated ears, and deeply grooved philtrum.
148
What are common cardiovascular anomalies in Noonan Syndrome?
Pulmonary valve stenosis (most common), hypertrophic cardiomyopathy, atrial septal defect, and other structural defects.
149
What growth abnormalities are seen in Noonan Syndrome?
Short stature is common, often due to growth hormone insensitivity or deficiency.
150
What are typical chest wall and musculoskeletal features in Noonan Syndrome?
Pectus excavatum or pectus carinatum, scoliosis, joint hypermobility, and cubitus valgus.
151
What are the typical ocular findings in Noonan Syndrome?
Strabismus, refractive errors, ptosis, and nystagmus.
152
What hematologic abnormalities can occur in Noonan Syndrome?
Coagulation defects (e.g., factor XI deficiency), platelet dysfunction, and easy bruising.
153
What are the developmental and cognitive outcomes in Noonan Syndrome?
Variable intellectual development; some have mild learning disabilities or developmental delays, but many have normal intelligence.
154
What genitourinary anomalies may be seen in Noonan Syndrome?
Cryptorchidism in males, renal anomalies (rare), and delayed puberty.
155
What are the skin and hair findings in Noonan Syndrome?
Curly or sparse hair, café-au-lait spots, keratosis pilaris, and easy bruising.
156
How is Noonan Syndrome diagnosed?
Clinical features supported by genetic testing identifying mutations in RAS-MAPK pathway genes.
157
What are differential diagnoses for Noonan Syndrome?
Turner Syndrome (especially in females), Costello Syndrome, Cardiofaciocutaneous Syndrome, and LEOPARD Syndrome.
158
What prenatal findings may suggest Noonan Syndrome?
Increased nuchal translucency, cystic hygroma, polyhydramnios, and cardiac defects on fetal ultrasound.
159
What is the role of growth hormone therapy in Noonan Syndrome?
Used in patients with short stature; response varies, and baseline GH testing is often performed first.
160
How are coagulation abnormalities managed in Noonan Syndrome?
Screening before surgery; avoid aspirin/NSAIDs; hematology input for significant bleeding disorders.
161
What is hypertrophic cardiomyopathy's significance in Noonan Syndrome?
Seen in ~20% of cases; associated with RAF1 mutations and can cause heart failure or arrhythmias.
162
What are the genetic counseling considerations in Noonan Syndrome?
50% recurrence risk if a parent is affected; de novo mutations are common, and testing of parents is advised.
163
What supportive services are essential in Noonan Syndrome management?
Multidisciplinary care: cardiology, endocrinology, hematology, genetics, developmental pediatrics, and early intervention.
164
What is the long-term prognosis in Noonan Syndrome?
Generally good with supportive care, but depends on severity of cardiac and bleeding abnormalities.
165
What is the genetic cause of Tuberous Sclerosis Complex (TSC)?
Mutations in either the TSC1 gene (chromosome 9q34, encoding hamartin) or the TSC2 gene (chromosome 16p13.3, encoding tuberin).
166
What is the genetic cause of Neurofibromatosis Type 1 (NF1)?
Mutations in the NF1 gene on chromosome 17q11.2, which encodes neurofibromin, a tumor suppressor that negatively regulates the Ras pathway.
167
What are the three genetic causes of Down Syndrome?
Trisomy 21 due to nondisjunction (~95%), Robertsonian translocation (~4%), and mosaicism (~1%).
168
Which congenital heart defect is most characteristic of Down Syndrome?
Complete atrioventricular septal defect (AVSD).
169
What gastrointestinal malformations are common in Down Syndrome?
Duodenal atresia, Hirschsprung disease, and annular pancreas.
170
What karyotypes are associated with Turner Syndrome?
45,X (classic), 45,X/46,XX (mosaic), or structural X abnormalities (e.g., isochromosome Xq).
171
Which cardiovascular defects are associated with Turner Syndrome?
Coarctation of the aorta and bicuspid aortic valve.
172
What are the reproductive consequences of Turner Syndrome?
Primary amenorrhea and infertility due to streak ovaries.
173
What is the typical personality seen in Williams Syndrome?
Overfriendliness, high empathy, and talkativeness.
174
What is the typical cardiovascular finding in Williams Syndrome?
Supravalvular aortic stenosis.
175
What cognitive profile is common in Williams Syndrome?
Strength in verbal abilities with weakness in visuospatial tasks.
176
What is the key distinguishing feature between Angelman and Prader-Willi Syndromes?
Angelman results from loss of maternal 15q11-q13 expression; Prader-Willi from loss of paternal expression.
177
What are the hallmark features of Angelman Syndrome?
Severe intellectual disability, ataxia, frequent laughter, seizures, and minimal to absent speech.
178
What causes Fragile X Syndrome?
CGG repeat expansion in the FMR1 gene on the X chromosome.
179
What are key features of Fragile X Syndrome in boys?
Macroorchidism, long face, intellectual disability, autism traits, and hyperactivity.
180
What behavioral traits are characteristic of Williams Syndrome?
Overfriendliness, empathy, and hypersocial behavior.
181
What congenital heart defect is most associated with Noonan Syndrome?
Pulmonary valve stenosis.
182
What genetic pathway is disrupted in Noonan Syndrome?
RAS-MAPK signaling pathway.
183
What is the genetic cause of Achondroplasia?
A gain-of-function mutation in the FGFR3 gene on chromosome 4p16.3.
184
What is the inheritance pattern of Achondroplasia?
Autosomal dominant; most cases are de novo.
185
What are the hallmark clinical features of Achondroplasia?
Rhizomelic limb shortening, frontal bossing, midface hypoplasia, and trident hands.
186
What are the major complications of Achondroplasia?
Foramen magnum stenosis, hydrocephalus, obstructive sleep apnea, spinal stenosis, and recurrent ear infections.
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What is the genetic basis of Duchenne Muscular Dystrophy (DMD)?
Mutations (usually deletions) in the DMD gene on Xp21, leading to absent dystrophin protein.
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What is the inheritance pattern of DMD?
X-linked recessive.
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What are the hallmark features of DMD?
Progressive proximal muscle weakness, Gower sign, calf pseudohypertrophy, and loss of ambulation by adolescence.
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What are common complications of DMD?
Dilated cardiomyopathy, respiratory failure, scoliosis, and learning difficulties.
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What immune defect occurs in DiGeorge Syndrome?
T-cell deficiency due to thymic hypoplasia.
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What are the most common heart defects in DiGeorge Syndrome?
Conotruncal anomalies: tetralogy of Fallot, truncus arteriosus, interrupted aortic arch.
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What facial features are seen in DiGeorge Syndrome?
Micrognathia, low-set ears, hypertelorism, and cleft palate or velopharyngeal insufficiency.
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What is the genetic cause of Spinal Muscular Atrophy (SMA)?
Homozygous deletion or mutation in the SMN1 gene on chromosome 5q13.
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What is the inheritance pattern of SMA?
Autosomal recessive.
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What are the clinical features of SMA type 1 (Werdnig-Hoffmann disease)?
Severe hypotonia, tongue fasciculations, absent reflexes, respiratory failure, and poor feeding in infancy.
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What are current treatments for SMA?
Nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam.
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What is the most common cause of CAH?
21-hydroxylase deficiency due to mutations in CYP21A2.
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What is the inheritance pattern of CAH?
Autosomal recessive.
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What are the classic features of salt-wasting CAH?
Vomiting, dehydration, hyponatremia, hyperkalemia, and ambiguous genitalia in females.
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What is the treatment of CAH?
Lifelong glucocorticoid and mineralocorticoid replacement therapy.
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What is the genetic cause of McCune-Albright Syndrome?
Somatic activating mutation in the GNAS gene.
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What are the triad features of McCune-Albright Syndrome?
Polyostotic fibrous dysplasia, café-au-lait spots with irregular borders, and precocious puberty (or other endocrinopathies).
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Is McCune-Albright Syndrome inherited?
No, it results from postzygotic somatic mosaicism and is not inherited.
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What is the genetic cause of Marfan Syndrome?
Mutations in the FBN1 gene on chromosome 15q21.1 encoding fibrillin-1.
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What is the inheritance pattern of Marfan Syndrome?
Autosomal dominant.
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What are the major clinical features of Marfan Syndrome?
Tall stature, long limbs (arachnodactyly), ectopia lentis, aortic root dilation, and pectus deformities.
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What is the most serious complication in Marfan Syndrome?
Aortic aneurysm or dissection.
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What is the general genetic basis of Ehlers-Danlos Syndrome (EDS)?
Mutations affecting collagen synthesis or structure; classic type often due to COL5A1/COL5A2 mutations.
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What is the inheritance pattern of EDS?
Autosomal dominant for classic and hypermobile types.
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What are the hallmark features of EDS?
Hyperextensible skin, joint hypermobility, easy bruising, and poor wound healing.
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What complications can occur in vascular EDS?
Arterial or organ rupture, often life-threatening.
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What is the genetic cause of Rett Syndrome?
Mutations in the MECP2 gene on the X chromosome.
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Who is typically affected by Rett Syndrome?
Females; the mutation is usually lethal in hemizygous males.
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What are the key features of Rett Syndrome?
Regression after 6–18 months, loss of purposeful hand use, hand-wringing, seizures, and severe intellectual disability.
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What is the genetic cause of classic galactosemia?
Deficiency of galactose-1-phosphate uridyltransferase (GALT) due to mutations in the GALT gene.
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What is the inheritance pattern of galactosemia?
Autosomal recessive.
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What are the clinical features of classic galactosemia in neonates?
Vomiting, jaundice, hepatomegaly, cataracts, failure to thrive, and E. coli sepsis.
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What is the treatment of galactosemia?
Elimination of galactose from the diet (lactose-free formula).
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What is the genetic cause of hereditary fructose intolerance?
Deficiency of aldolase B due to mutations in the ALDOB gene.
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What is the inheritance pattern of HFI?
Autosomal recessive.
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What are the clinical features of HFI?
Hypoglycemia, vomiting, lethargy, hepatomegaly, jaundice, and failure to thrive after ingesting fructose or sucrose.
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What is the treatment for HFI?
Strict avoidance of fructose, sucrose, and sorbitol in the diet.
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What is the genetic cause of Cystic Fibrosis?
Mutations in the CFTR gene on chromosome 7q31.2, most commonly ΔF508.
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What is the inheritance pattern of Cystic Fibrosis?
Autosomal recessive.
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What are hallmark features of Cystic Fibrosis?
Chronic lung disease, recurrent respiratory infections, pancreatic insufficiency, meconium ileus, and infertility in males.
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What diagnostic tests are used for CF?
Sweat chloride test (>60 mmol/L), CFTR gene mutation analysis, and newborn screening.
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What is the genetic cause of Hemophilia A?
Deficiency or dysfunction of coagulation factor VIII due to F8 gene mutations on the X chromosome.
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What is the inheritance pattern of Hemophilia A?
X-linked recessive.
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What are common clinical features of Hemophilia A?
Spontaneous hemarthroses, muscle hematomas, and prolonged bleeding after trauma or surgery.
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What is the treatment for Hemophilia A?
Recombinant factor VIII replacement and desmopressin (DDAVP) in mild cases.
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What is the genetic cause of Beta Thalassemia Major?
Mutations in the HBB gene leading to absent or reduced beta-globin chain production.
233
What is the inheritance pattern of Beta Thalassemia?
Autosomal recessive.
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What are the key features of Beta Thalassemia Major?
Severe anemia in infancy, hepatosplenomegaly, bone deformities, and growth retardation.
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What is the mainstay of treatment for Beta Thalassemia Major?
Regular blood transfusions and iron chelation therapy.
