16 Genetic disorder

MNJ16-001
MNJ-P-OSCE 16. Genetic disorder_page_5_Figure_4.jpeg

Identify the genetic inheritance pattern of pedigrees A, B, C, and D, and give 2 examples of each:

Answer

A. Autosomal Recessive (AR): Cystic fibrosis, Thalassemia major, Wilson disease, Sickle cell anemia.
B. Autosomal Dominant (AD) with Incomplete Penetrance: Familial retinoblastoma, Familial adenomatous polyposis (FAP), Hereditary non-polyposis colorectal cancer (HNPCC).
C. X-Linked Dominant (XLD): Incontinentia pigmenti, Hypophosphatemic (Vitamin D-resistant) rickets, Rett syndrome, Ornithine transcarbamylase (OTC) deficiency.
D. Y-Linked (Holandric): SRY gene defects / Hypertrichosis pinnae, Langer mesomelic dysplasia / Léri-Weill dyschondrosteosis (SHOX on PAR region).

MNJ16-002
MNJ-P-OSCE 16. Genetic disorder_page_5_Figure_8.jpeg

Identify the pattern of inheritance shown in the pedigree.
Name 3 conditions with a similar inheritance pattern.
What is the risk/degree of transmission to offspring of an affected individual?
Which sex is affected?

Answer

Inheritance pattern: Autosomal Dominant (AD) (vertical transmission, present in every generation without skipping, equal sex distribution).
Examples:
- Marfan syndrome
- Achondroplasia
- Neurofibromatosis type 1 (NF-1)
- Tuberous sclerosis
- Hereditary spherocytosis
- Osteogenesis imperfecta
Transmission risk: 50% (1 in 2) chance of transmission to each offspring in each pregnancy.
Sex predilection: Both males and females are equally affected and equally capable of transmitting the disease.

MNJ16-003
MNJ-P-OSCE 16. Genetic disorder_page_6_Picture_5.jpeg

Identify this genetic inheritance pattern and give 4 examples:

Answer

Inheritance pattern: Mitochondrial (Maternal) Inheritance (affected mother transmits the condition to all of her children [100% of sons and daughters]; affected father transmits to none [0%]).
Examples:
1. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes)
2. MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
3. Leber Hereditary Optic Neuropathy (LHON)
4. Kearns-Sayre Syndrome (KSS)
5. Pearson syndrome
6. NARP (Neuropathy, Ataxia, Retinitis Pigmentosa)

MNJ16-004
A 39-year-old female Ritu, 10 weeks pregnant, is concerned about Down syndrome:

Which invasive antenatal diagnostic tests will you advise, along with their gestational timing?
Name the serum screening markers used in antenatal screening.
If the mother is a Robertsonian translocation carrier $t (14; 21)$ , what is the recurrence risk to the offspring?
Name the chromosomes most commonly involved in Robertsonian translocations in Down syndrome.
The recurrence risk is highest ( $100 %$ ) with which translocation?

Answer

Invasive diagnostic tests:
- Chorionic Villus Sampling (CVS): 10–12 weeks of gestation
- Amniocentesis: 15–20 weeks of gestation
- Cordocentesis (Percutaneous Umbilical Blood Sampling): $\geq 18 - 20 weeks$
Screening markers:
- First Trimester Combined Screen: Free $β -hCG$ (elevated), PAPP-A (low), plus Fetal USG Nuchal Translucency (NT $\geq 3 mm$ ).
- Second Trimester Quadruple Screen: Maternal serum AFP (low), unconjugated estriol ( ${uE}_{3}$ - low), $hCG$ (high), and Inhibin-A (high).
- Cell-free fetal DNA (NIPT): High-accuracy non-invasive screening after 10 weeks.
Recurrence risk for maternal $t (14; 21)$ carrier: 10–15% (risk is only ~1–2% if father is carrier).
Chromosomes involved: Chromosomes 14, 21, 13, 15, 22 (acrocentric chromosomes).
Highest risk translocation: $t (21 q; 21 q)$ / 21q21q isochromosome translocation ( $100 %$ recurrence risk to all viable offspring).

MNJ16-005
MNJ-P-OSCE 16. Genetic disorder_page_6_Picture_19.jpeg

Images of a female child Pooja at birth (congenital pedal lymphedema) and at 6 years of age (webbed neck, short stature):

Identify the syndrome and state the chromosomal anomaly.
What is the phenotypic sex in this syndrome?
Mention 6 cardinal clinical features of this syndrome.
Name an easy outpatient bedside screening procedure for diagnosis.
Which hormone therapies will you offer during childhood and adolescence?
What is the phenotypically similar condition seen in males and females with normal karyotypes?

Answer

Syndrome & Karyotype: Turner Syndrome, 45,X (monosomy X or mosaicism 45,X/46,XX).
Phenotypic sex: Phenotypic Female.
Cardinal clinical features:
- Proportionate short stature
- Webbed neck (pterygium colli) and low posterior hairline
- Broad "shield" chest with widely spaced hypoplastic nipples
- Congenital lymphedema of hands and feet in neonates
- Cubitus valgus and short 4th metacarpals
- Ovarian dysgenesis / streak gonads (primary amenorrhea, hypergonadotropic hypogonadism, infertility)
- Cardiovascular anomalies: Bicuspid aortic valve (most common), Coarctation of the aorta
- Renal: Horseshoe kidney
Bedside screening test: Buccal smear examination for Barr body (absent / negative Barr body in 45,X).
Hormone therapies:
- Recombinant Growth Hormone (rhGH): Initiated early to optimize final adult height.
- Estrogen replacement therapy: Initiated at 11–12 years for pubertal induction and secondary sexual characteristics.
- Progesterone: Added after 2 years of estrogen or upon breakthrough bleeding to cycle endometrium.
- Thyroxine: If associated autoimmune Hashimoto thyroiditis is present.
Phenotypic analogue: Noonan Syndrome (autosomal dominant, normal 46,XX or 46,XY karyotype, commonly associated with pulmonic stenosis).

MNJ16-006
MNJ-P-OSCE 16. Genetic disorder_page_7_Picture_9.jpeg

Which syndrome is represented by this 47,XXY karyotype?
What is the phenotypic sex?
State the salient clinical features.
What investigations will you perform?
What is the main medical treatment?

Answer

Syndrome: Klinefelter Syndrome ( $47, XXY$ due to meiotic non-disjunction).
Phenotypic sex: Phenotypic Male.
Salient clinical features:
- Tall eunuchoid stature with long limbs (increased lower segment:upper segment ratio)
- Small, firm testes ( $\leq 2 ml$ ) and micropenis / hypogonadism
- Gynecomastia in adolescence
- Sparse facial and body hair
- Azoospermia and primary infertility
- Learning difficulties, delayed speech/reading skills, behavioral and executive function issues
Investigations:
- Chromosomal karyotype: Confirms $47, XXY$
- Endocrine profile: Elevated serum FSH and LH (hypergonadotropic) with low/subnormal testosterone after mid-puberty
- Semen analysis: Azoospermia
- Testicular biopsy: Hyalinization and fibrosis of seminiferous tubules with Leydig cell hyperplasia
Treatment:
- Intramuscular Testosterone replacement therapy (e.g., testosterone enanthate/cypionate depot) initiated around 11–12 years of age to promote virilization, muscle mass, bone mineral density, and prevent osteoporosis.
- Educational/psychological support and screening for metabolic syndrome and breast malignancy.

MNJ16-007
MNJ-P-OSCE 16. Genetic disorder_page_7_Picture_17.jpeg

A male child presents with developmental delay, long narrow face, large prominent ears, and intellectual disability:

Identify the syndrome and explain the structural cytogenetic term "fragile site".
What is the exact gene locus involved?
What is the molecular mechanism of mutation / inheritance?
What are the clinical, cognitive, and behavioral manifestations?
Mention 4 other triplet repeat expansion disorders with their respective trinucleotide repeats.

Answer

Syndrome & Fragile Site:
- Fragile X Syndrome (Martin-Bell syndrome).
- A fragile site is a specific, non-staining gap or constriction on a chromosome that fails to condense properly during mitosis and exhibits a propensity to break under folate-deficient culture conditions.
Gene Locus: Xq27.3 (FMR1 gene - Fragile X Messenger Ribonucleoprotein 1).
Molecular mechanism: Trinucleotide (CGG) repeat expansion in the 5' untranslated region of FMR1:
- Normal: 5–44 repeats
- Premutation: 55–200 repeats
- Full mutation: $> 200 CGG repeats$ $\to$ hypermethylation and transcriptional silencing of FMR1.
Manifestations:
- Physical: Elongated narrow facies, prominent forehead, large prominent/protruding ears, high-arched palate, macroorchidism (post-pubertal enlarged testes $> 25 ml$ ), joint hypermobility, flat feet, mitral valve prolapse.
- Cognitive / Behavioral: Moderate intellectual disability, severe speech/language delay, autistic spectrum features (hand-flapping, poor eye contact, tactile defensiveness), ADHD, hyperactivity.
Other Triplet Repeat Disorders:
- Huntington Disease: CAG expansion (Chromosome 4p)
- Myotonic Dystrophy (DM1): CTG expansion (Chromosome 19q)
- Friedreich Ataxia: GAA expansion (Chromosome 9q)
- Spinocerebellar Ataxias (SCAs): CAG expansion

MNJ16-008
MNJ-P-OSCE 16. Genetic disorder_page_8_Picture_1.jpeg

Identify the pattern of inheritance shown in this pedigree.
Name 4 conditions with this inheritance pattern.
Which sex is predominantly affected? What is the risk of transmission to offspring of a carrier mother?

Answer

Inheritance pattern: X-Linked Recessive (XLR) (males affected; carrier females transmit the condition; no male-to-male transmission).
Examples:
- Hemophilia A and Hemophilia B
- Duchenne and Becker Muscular Dystrophy (DMD/BMD)
- Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
- Wiskott-Aldrich Syndrome (WAS)
- Menkes kinky hair disease
- Hunter syndrome (MPS II)
- Chronic Granulomatous Disease (CGD - X-linked form)
Transmission risks for a carrier mother ( $X^{A} X^{a}$ ):
- Sons: 50% risk of being affected ( $X^{a} Y$ ).
- Daughters: 50% risk of being asymptomatic carriers ( $X^{A} X^{a}$ ); 0% risk of full disease.

MNJ16-009
MNJ-P-OSCE 16. Genetic disorder_page_8_Picture_7.jpeg

Identify the syndrome shown with whorled cutaneous hyperpigmentation and state its pattern of inheritance.
What are the 4 dermatological stages and which gene is affected?
Give 3 other examples of disorders with a similar mode of inheritance.
What is the risk of transmission to the offspring of an affected male?

Answer

Syndrome & Inheritance: Incontinentia Pigmenti (Bloch-Sulzberger syndrome); X-linked dominant (XLD) (typically male lethal in utero).
Stages & Gene:
- Gene: IKBKG / NEMO gene on chromosome Xq28.
- 4 Cutaneous Stages:
  - Stage 1 (Vesicular): Linear vesicles and pustules on extremities at birth/neonatal period.
  - Stage 2 (Verrucous): Warty, hyperkeratotic papules and plaques (weeks to months).
  - Stage 3 (Hyperpigmented): Swirled, marble-cake "lines of Blaschko" hyperpigmentation on trunk and thighs (infancy to childhood).
  - Stage 4 (Atrophic / Hypopigmented): Pale, hairless, atrophic streaks on lower legs (adolescence/adulthood).
Other XLD examples:
- Hypophosphatemic (X-linked) Rickets
- Ornithine Transcarbamylase (OTC) deficiency
- Rett syndrome
- Alport syndrome (XLD form)
Transmission from an affected male ( $X^{*} Y$ ):
- 100% of daughters will inherit the mutant X chromosome and be affected.
- 0% of sons will inherit the disease (receive the Y chromosome; male-to-male transmission never occurs in X-linked inheritance).

MNJ16-010
MNJ-P-OSCE 16. Genetic disorder_page_9_Picture_1.jpeg

Identify the diagnostic cytogenetic technique and state the diagnosis shown in Slide B (showing 3 fluorescent signals for chromosome 21).
Name 4 microdeletion syndromes in which this technique is used for diagnosis.

Answer

Technique & Slide B Diagnosis:
- Technique: Fluorescent In Situ Hybridization (FISH) (using locus-specific fluorochrome-labeled DNA probes).
- Slide B Diagnosis: Trisomy 21 (Down Syndrome) (interphase FISH showing 3 specific fluorescent hybridization signals for the chromosome 21 probe).
Microdeletion syndromes diagnosed by FISH / CMA:
- 22q11.2 deletion syndrome (DiGeorge / Velocardiofacial syndrome)
- Prader-Willi syndrome / Angelman syndrome (15q11-q13 deletion)
- Williams syndrome (7q11.23 deletion / elastin gene)
- Miller-Dieker lissencephaly syndrome (17p13.3 deletion)
- Cri du chat syndrome (5p15 deletion)
- Wolf-Hirschhorn syndrome (4p16.3 deletion)

MNJ16-011

State three invasive procedures for antenatal genetic diagnosis, along with the earliest gestational age at which each can be performed.
What is the procedure-related risk of fetal loss for each?
Name 4 common diseases for which antenatal diagnosis is readily available.
Name 3 viral/non-viral vectors used in gene therapy, and 3 candidate single-gene disorders for gene therapy.

Answer

& 2. Antenatal Procedures & Fetal Loss Risk:
- Chorionic Villus Sampling (CVS): 10–12 weeks; Fetal loss risk $\sim 1 - 2 %$ .
- Amniocentesis: 15–18 weeks; Fetal loss risk $\sim 0.5 - 1 %$ .
- Percutaneous Umbilical Blood Sampling (Cordocentesis): $\geq 18 - 20 weeks$ ; Fetal loss risk $\sim 1 - 2 %$ .
Conditions for antenatal diagnosis:
- Chromosomal aneuploidies (Trisomy 21, 18, 13, Turner syndrome)
- Hemoglobinopathies ( $β$ -Thalassemia major, Sickle cell anemia)
- Muscular dystrophies (Duchenne/Becker muscular dystrophy)
- Spinal Muscular Atrophy (SMA)
- Cystic Fibrosis
- Inborn errors of metabolism (Gaucher disease, MPS, CAH)
Gene Therapy Vectors & Candidate Disorders:
- Vectors: Adeno-Associated Virus (AAV), Lentivirus / Retrovirus, Adenovirus, Lipid nanoparticles (LNPs / Naked plasmid DNA).
- Candidate Disorders: Spinal Muscular Atrophy (SMN1), Severe Combined Immunodeficiency (ADA-SCID, X-SCID), $β$ -Thalassemia, Hemophilia A/B, Duchenne Muscular Dystrophy, Leber Congenital Amaurosis (RPE65).

MNJ16-012
MNJ-P-OSCE 16. Genetic disorder_page_9_Picture_14.jpeg

A 7-year-old male child presents with marked hyperphagia, truncal obesity, small hands and feet, developmental delay, neonatal hypotonia, and hypogonadism:

Identify the syndrome and the specific chromosomal region involved.
Name the genetic mechanisms of inheritance responsible for this disorder.
Which other neurodevelopmental syndrome is mapped to the same chromosomal region due to maternal vs paternal genomic imprinting?

Answer

Syndrome & Region: Prader-Willi Syndrome (PWS); Chromosome 15q11.2–q13.
Genetic mechanisms: Loss of expression of paternally inherited genes on 15q11-q13:
- Paternal 15q11-q13 deletion (~70% of cases)
- Maternal Uniparental Disomy (UPD 15) (~25–30% of cases)
- Imprinting center defect / mutation (~1–3%)
Imprinting counterpart: Angelman Syndrome ("Happy Puppet" syndrome), resulting from loss of maternal UBE3A expression on chromosome 15q11-q13 (characterized by severe speech impairment, ataxia, paroxysms of inappropriate laughter, seizures, and microcephaly).

MNJ16-013
MNJ-P-OSCE 16. Genetic disorder_page_10_Picture_1.jpeg

Identify the overgrowth syndrome shown (showing macroglossia, anterior abdominal wall defect, ear lobe creases).
Which metabolic complication must be screened and managed in the neonatal period?
Give 3 salient clinical features.
Mention the chromosomal region involved and the underlying imprinting defect.

Answer

Syndrome: Beckwith-Wiedemann Syndrome (BWS).
Metabolic complication: Severe Neonatal Hypoglycemia (due to pancreatic islet cell hyperplasia and hyperinsulinism).
Salient features:
- Macrosomia / Large for gestational age (LGA)
- Macroglossia (large protruding tongue)
- Abdominal wall defects (Omphalocele, umbilical hernia, diastasis recti)
- Anterior earlobe creases and posterior helical ear pits
- Hemi-hypertrophy / lateralized overgrowth
- Organomegaly (nephromegaly, hepatomegaly)
- Predisposition to embryonal tumors (Wilms tumor, hepatoblastoma; requiring 3-monthly abdominal USG and serum AFP screening until 8 years of age)
Genetics: Chromosome 11p15.5 imprinting region (loss of methylation at IC2/KCNQ1OT1, gain of methylation at IC1/H19, or paternal uniparental disomy 11p15).

MNJ16-014
MNJ-P-OSCE 16. Genetic disorder_page_10_Picture_8.jpeg

A newborn is suspected of having Down syndrome:

Name 3 organ systems commonly involved and state 2 specific conditions in each.
Name an essential screening test that must be performed prior to hospital discharge.
What are key radiological features of Down syndrome?
Outline a structured long-term multidisciplinary follow-up plan.

Answer

Systems & Associated Anomalies:
- Cardiovascular: Endocardial cushion defect (AV canal / AVSD - 40%), VSD, ASD, PDA.
- Gastrointestinal: Duodenal atresia ("double bubble" sign), annular pancreas, tracheoesophageal fistula, Hirschsprung disease, celiac disease.
- Ocular: Brushfield spots, congenital cataract, strabismus, severe refractive errors, nystagmus.
- Endocrine: Congenital and acquired hypothyroidism, Type 1 diabetes mellitus.
Essential screening before discharge:
- Echocardiogram (screening for congenital heart defects)
- Newborn thyroid screen (TSH / Free $T_{4}$ )
- Universal Newborn Hearing Screening (OAE / BERA)
Radiological features:
- Pelvic X-ray: Decreased acetabular and iliac angles, flaring of iliac wings.
- Chest/Neck X-ray: 11 pairs of ribs, atlantoaxial subluxation/instability (increased atlantodens interval $> 4.5 mm$ on flexion-extension views).
- Abdominal X-ray: "Double bubble" gas pattern in duodenal atresia.
- Hand X-ray: Hypoplastic middle phalanx of the 5th digit with clinodactyly.
Follow-up plan:
- Annual thyroid screening (TSH)
- Regular audiometry (6–12 monthly) and ophthalmological evaluation
- Celiac disease serology screening at 2–3 years
- Screening for hematological malignancy (CBC for transient myeloproliferative disorder / AML / ALL)
- Cervical spine radiographs for atlantoaxial instability prior to sports/anesthesia
- Early intervention, physiotherapy, and speech therapy.

MNJ16-015

Diagnose the condition characterized by facial angiofibromas (adenoma sebaceum), ash-leaf hypopigmented macules, subependymal giant cell astrocytomas (SEGA), and renal angiomyolipomas.
What is the mode of inheritance?
What is the recurrence risk for the next offspring if one parent is affected?
Which sex is involved?
Which genes and gene products are implicated in this condition?

Answer

Diagnosis: Tuberous Sclerosis Complex (Bourneville disease).
Inheritance: Autosomal Dominant with high penetrance and variable expressivity (~65–70% represent de novo mutations).
Recurrence risk: 50% (1 in 2) if a parent is affected.
Sex: Equal in males and females ( $1 : 1$ ).
Genes & Proteins:
- $T S C 1$ gene on chromosome 9q34 $\to$ encodes Hamartin.
- $T S C 2$ gene on chromosome 16p13.3 $\to$ encodes Tuberin.
  (The hamartin-tuberin complex acts as a GTPase-activating protein to inhibit the mTOR signaling pathway).

MNJ16-016

Name 4 teratogenic drugs contraindicated in pregnancy.
Name 3 drug-induced teratogenic syndromes with one characteristic anomaly for each.

Answer

Teratogenic drugs:
- Thalidomide
- Warfarin
- Valproic acid / Sodium valproate
- Phenytoin
- Isotretinoin (Retinoic acid)
- Methotrexate
- ACE inhibitors / ARBs
- Lithium
Teratogenic Syndromes & Characteristic Anomalies:
- Fetal Alcohol Spectrum Disorder (FASD): Smooth philtrum, thin upper vermilion border, short palpebral fissures, microcephaly, and CNS dysfunction.
- Fetal Hydantoin (Phenytoin) Syndrome: Distal digital hypoplasia / nail hypoplasia, cleft lip/palate, hypertelorism, growth deficiency.
- Fetal Valproate Syndrome: Neural tube defects (spina bifida aperta), characteristic facial dysmorphism (broad nasal bridge, shallow philtrum), congenital heart defects.
- Fetal Warfarin Syndrome (Conradi-Hünermann phenocopy): Nasal hypoplasia (depressed nasal bridge), stippled epiphyses (chondrodysplasia punctata), hypoplastic distal phalanges.
- Thalidomide Embryopathy: Phocomelia (severe limb reduction defects), amelia, anotia/microtia.

MNJ16-017
MNJ-P-OSCE 16. Genetic disorder_page_10_Picture_25.jpeg

Write the pattern of inheritance (AD, AR, XLR, or XLD) for each condition listed below:

Achondroplasia
Congenital adrenal hyperplasia (CAH)
Cystic fibrosis
Hemophilia A
Duchenne muscular dystrophy
Huntington's disease
Neurofibromatosis type 1
Marfan syndrome
Phenylketonuria (PKU)
Sickle cell disease
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemophilia B

Answer

Achondroplasia $\to$ Autosomal Dominant (AD)
Congenital adrenal hyperplasia $\to$ Autosomal Recessive (AR)
Cystic fibrosis $\to$ Autosomal Recessive (AR)
Hemophilia A $\to$ X-Linked Recessive (XLR)
Duchenne muscular dystrophy $\to$ X-Linked Recessive (XLR)
Huntington's disease $\to$ Autosomal Dominant (AD)
Neurofibromatosis type 1 $\to$ Autosomal Dominant (AD)
Marfan syndrome $\to$ Autosomal Dominant (AD)
Phenylketonuria (PKU) $\to$ Autosomal Recessive (AR)
Sickle cell disease $\to$ Autosomal Recessive (AR)
G6PD deficiency $\to$ X-Linked Recessive (XLR)
Hemophilia B $\to$ X-Linked Recessive (XLR)

MNJ16-018
Define the following terms used in dysmorphology and give examples of each:

Association
Sequence
Developmental Field Defect
Syndrome

Answer

Association: A non-random occurrence in individuals of multiple congenital anomalies not explained by chance, but without a known unifying genetic etiology or specific cascade.
- Examples: VACTERL association (Vertebral, Anal, Cardiac, Tracheoesophageal fistula, Renal, Limb), CHARGE association.
Sequence: A pattern of multiple secondary defects that result cascades from a single primary structural defect or mechanical disruption during development.
- Examples: Potter sequence (renal agenesis $\to$ oligohydramnios $\to$ pulmonary hypoplasia, compressed facial features, clubbed feet); Pierre Robin sequence (micrognathia $\to$ glossoptosis $\to$ cleft palate).
Developmental Field Defect: A pattern of anomalies resulting from the aberrant development of an entire morphogenetic unit or contiguous embryonic region during morphogenesis.
- Examples: Holoprosencephaly field defect, Poland sequence/anomaly, Moebius syndrome.
Syndrome: A recognizable, clinically consistent constellation of multiple congenital anomalies affecting multiple organ systems, known or presumed to have a single unifying etiology (e.g., chromosomal, single-gene mutation, or environmental teratogen).
- Examples: Down syndrome (Trisomy 21), Turner syndrome (45,X), Marfan syndrome (FBN1).

MNJ16-019
MNJ-P-OSCE 16. Genetic disorder_page_11_Picture_18.jpeg

Spot the diagnosis and give the alternate name of this condition.
What is the embryological defect causing this condition?
What is the overall prognosis and cognitive outcome?

Answer

Diagnosis: Goldenhar Syndrome (also known as Oculo-Auriculo-Vertebral [OAV] Spectrum / First and Second Branchial Arch Syndrome).
Embryological defect: Vascular disruption / abnormal morphogenesis of structures derived from the first and second branchial arches and clefts (typically unilateral, resulting in preauricular tags, microtia, hemifacial microsomia, epibulbar dermoids, and vertebral anomalies like hemivertebrae).
Prognosis: Generally favorable; normal lifespan and normal intelligence in $\geq 85 %$ of patients (mild intellectual disability in ~10–15%). Managed with hearing aids, reconstructive craniofacial surgery, and spine monitoring.

MNJ16-020
MNJ-P-OSCE 16. Genetic disorder_page_11_Picture_22.jpeg

A child presents with a tall forehead, craniosynostosis (turribrachycephaly), midface hypoplasia, and symmetric complex osseous and cutaneous syndactyly of the hands and feet ("mitten hands" and "sock feet"):

Spot the diagnosis of this child and name the causative gene.
What is the timing and role of surgical intervention for facial dysmorphism?

Answer

Diagnosis & Gene: Apert Syndrome (Acrocephalosyndactyly Type I); caused by gain-of-function mutations in the $F G F R 2$ (Fibroblast Growth Factor Receptor 2) gene on chromosome 10q26.
Surgical interventions:
- Infancy (3–12 months): Early cranial vault decompression and remodeling (fronto-orbital advancement) to relieve elevated intracranial pressure.
- Hand surgery (1–3 years): Staged syndactyly release to create functional digits and an opposable thumb.
- Midface advancement: LeFort III osteotomy / monobloc distraction osteogenesis performed in mid-childhood (6–10 years) or pre-adolescence after substantial facial growth to correct severe midface hypoplasia, proptosis, and obstructive sleep apnea.

MNJ16-021
A 6-year-old male child Panna is brought with concerns of a flat facial profile, low IQ, delayed milestones, hypotonia, and recurrent respiratory infections. On examination, he has epicanthal folds, short broad hands, brachycephaly, and a Grade 4 pansystolic murmur over the lower left sternal border:

Keeping the diagnosis in mind, which specific joint articulation must you evaluate carefully and why?
When evaluating for treatable/reversible causes of intellectual and developmental delay in this child, which endocrine test will you perform?
On regular long-term follow-up, which hematological surveillance test should be done?
Elaborate the cytogenetic nomenclature: $46, XY, t (14; 21) (q 11; q 22)$ .

Answer

Joint of concern: Atlantoaxial joint (C1-C2 articulation) for Atlantoaxial instability (AAI) (due to transverse odontoid ligament laxity). Subluxation can cause spinal cord compression, quadriparesis, gait changes, or sudden death.
Endocrine test: Serum TSH and Free $T_{4}$ (screening for congenital/acquired primary hypothyroidism, which occurs in up to 15–30% of children with Down syndrome and represents a reversible cause of cognitive and growth deterioration).
Hematological monitoring: Complete Blood Count (CBC) with peripheral smear annually to screen for acute leukemia (10- to 20-fold increased risk of ALL and Acute Megakaryoblastic Leukemia [AML-M7]).
Cytogenetic explanation:
- 46: Total number of chromosomes in the cell.
- XY: Male chromosomal complement.
- t: Translocation (Robertsonian/reciprocal translocation).
- (14;21): Involves chromosomes 14 and 21.
- (q11;q22): Breakpoint is at band q11 on the long arm of chromosome 14, and band q22 on the long arm of chromosome 21.

MNJ16-022
MNJ-P-OSCE 16. Genetic disorder_page_12_Picture_10.jpeg

Define and classify the degrees of consanguinity and genetic relationship between relatives:

Answer

First-degree relatives (Share 50% / $\frac{1}{2}$ of genes):
- Parents and children
- Full brothers and sisters (siblings)
Second-degree relatives (Share 25% / $\frac{1}{4}$ of genes):
- Grandparent and grandchild
- Uncle / Aunt and Nephew / Niece
- Half-siblings
- Double first cousins
Third-degree relatives (Share 12.5% / $\frac{1}{8}$ of genes):
- First cousins (children of siblings — most common consanguineous marriage worldwide)
- Great-grandparent and great-grandchild

MNJ16-023
MNJ-P-OSCE 16. Genetic disorder_page_12_Picture_14.jpeg

Identify the skeletal dysplasia shown in the clinical picture and chest radiograph.
State the mode of inheritance and the gene implicated.
What characteristic abnormalities are seen on the hand radiograph and skull?
What classic clinical maneuver / sign demonstrates this condition on physical examination?

Answer

Diagnosis: Cleidocranial Dysostosis (Cleidocranial Dysplasia) (radiograph showing complete absence / aplasia or hypoplasia of clavicles and bell-shaped thorax).
Inheritance & Gene: Autosomal Dominant with complete penetrance and variable expressivity; caused by heterozygous mutations in the $R U N X 2$ (CBFA1) gene on chromosome 6p21.
Radiological features:
- Clavicles: Total or partial absence of clavicles.
- Skull: Widely patent cranial fontanelles and delayed suture closure, multiple Wormian bones, frontal/parietal bossing, hypertelorism.
- Hand X-ray: Long second metacarpals, hypoplastic tapering distal phalanges, cone-shaped epiphyses, accessory ossification centers.
- Dentition: Delayed eruption of secondary teeth, supernumerary impacted teeth.
Clinical maneuver: Hypermobility of the shoulders — the patient can easily approximate both shoulders in the anterior midline of the chest.

MNJ16-024
MNJ-P-OSCE 16. Genetic disorder_page_13_Picture_8.jpeg

Identify the karyotype anomaly shown (showing terminal deletion of the short arm of chromosome 5).
What is the specific cytogenetic defect?
List 4 cardinal clinical features of this syndrome.

Answer

Karyotype & Syndrome: $46, XX, del (5 p)$ or $46, XY, del (5 p)$ — Cri du Chat (Cat Cry / 5p-minus) Syndrome.
Genetic defect: Partial deletion of the short arm of chromosome 5 (5p15.2–p15.3 critical region).
Clinical features:
- High-pitched, monochromatic monotonous cat-like cry in infancy (due to abnormal laryngeal development).
- Severe intellectual disability and developmental delay.
- Microcephaly with round "moon" face and hypertelorism.
- Low-set, dysplastic ears, epicanthal folds, downward-slanting palpebral fissures.
- Micrognathia, broad nasal bridge, hypotonia in infancy, and single palmar (simian) crease.

MNJ16-025
MNJ-P-OSCE 16. Genetic disorder_page_13_Picture_13.jpeg

A 10-year-old male child Raman presents with short stature, webbed neck, low posterior hairline, chest deformity (pectus excavatum/carinatum), hypertelorism, and cryptorchidism:

What is the diagnosis of this condition?
What chromosomal karyotype is typically expected in this condition?
What are 3 cardiac manifestations, and which one is the most common?

Answer

Diagnosis: Noonan Syndrome (autosomal dominant, RASopathy; PTPN11, SOS1, RAF1, RIT1 mutations).
Karyotype: Normal $46, XY$ (or $46, XX$ in females; normal chromosomal analysis distinguishes Noonan syndrome from Turner syndrome).
Cardiac manifestations:
- Dysplastic Pulmonic Valve Stenosis (PVS) — Most common (~50–60%).
- Hypertrophic Cardiomyopathy (HCM) (asymmetric septal hypertrophy — ~20–30%).
- Atrial Septal Defect (ASD - ostium secundum) and Ventricular Septal Defect (VSD).