# Clinical Cases: Genetic and Metabolic Disorders

## Case 1: Down Syndrome

### Patient Demographics
- **Age:** Newborn (1 day old)
- **Sex:** Female

### Chief Complaint
"The baby looks different and I'm worried something is wrong."

### History of Present Illness
A 1-day-old female infant is in the newborn nursery after an uncomplicated vaginal delivery at 39 weeks gestation. The mother is 38 years old (G2P2) and had prenatal care starting at 12 weeks. First-trimester combined screening showed increased risk for Down syndrome (1:150), but the mother declined further genetic testing. The infant was noted to have dysmorphic features at birth. She is having difficulty latching for breastfeeding and seems "floppy" according to the nursing staff.

### Physical Examination
- **Vital Signs:** Weight 3.0 kg (25th percentile), Length 48 cm (25th percentile), HC 34 cm (50th percentile), HR 145 bpm, RR 45/min, SpO2 98% on room air
- **General:** Alert infant with distinctive facial features
- **HEENT:**
  - Flat facial profile
  - Upslanting palpebral fissures
  - Epicanthal folds
  - Small ears with overfolded helices
  - Flat nasal bridge
  - Small mouth with protruding tongue
  - Flat occiput (brachycephaly)
- **Neck:** Redundant nuchal skin
- **Cardiovascular:** Regular rate, 3/6 holosystolic murmur at left lower sternal border
- **Abdomen:** Soft, no hepatosplenomegaly
- **Extremities:**
  - Single transverse palmar crease (simian crease) bilaterally
  - Wide space between first and second toes (sandal gap)
  - Fifth finger clinodactyly (curved fifth fingers)
- **Neurologic:** Marked hypotonia, decreased Moro reflex, poor suck

### Laboratory and Imaging Findings
- **Chromosome analysis (karyotype):** 47,XX,+21 (Trisomy 21)
- **Echocardiogram:** Complete atrioventricular canal defect (AVCD)
- **TSH:** 8.5 mIU/L (mildly elevated; will repeat at 2 weeks)
- **Hearing screen:** Refer bilaterally (needs formal audiology)

### Diagnosis
**Down syndrome (Trisomy 21) with complete atrioventricular canal defect**

### Clinical Reasoning
This infant has classic features of Down syndrome including: hypotonia (nearly universal), characteristic facial features (upslanting palpebral fissures, epicanthal folds, flat nasal bridge, small ears), single palmar crease, sandal gap deformity, and brachycephaly. The karyotype confirms trisomy 21. The cardiac murmur prompted echocardiography, revealing an atrioventricular canal defect, the most common congenital heart defect in Down syndrome. Approximately 40-50% of children with Down syndrome have congenital heart disease. Early identification allows appropriate health supervision and cardiac surgical planning.

### Management
1. **Genetics consultation:** Confirm diagnosis, provide counseling, discuss recurrence risk (approximately 1% for non-disjunction)
2. **Cardiology consultation:** Plan for surgical repair of AV canal defect (typically around 4-6 months of age)
3. **Health supervision per AAP guidelines:**
   - **Thyroid:** TSH at birth, 6 months, 12 months, then annually (high risk for hypothyroidism)
   - **Hearing:** Formal audiology by 3 months; ongoing monitoring (high risk for hearing loss)
   - **Vision:** Ophthalmology exam by 6 months (risk of cataracts, strabismus)
   - **Atlantoaxial instability:** Screening radiographs before sports participation or procedures
   - **Hematology:** Monitor for leukemia (10-20x increased risk)
4. **Early intervention referral:** Physical therapy, occupational therapy, speech therapy
5. **Family support:** Connect with Down syndrome support organizations
6. **Feeding support:** Lactation consultation; may need specialized nipples or feeding therapy
7. **Growth monitoring:** Use Down syndrome-specific growth charts

### Clinical Image
![Infant with Down syndrome facial features](case_01_image.jpg)

**Image Description:** Newborn with Down syndrome demonstrating characteristic facial features including upslanting palpebral fissures, epicanthal folds, and flat nasal bridge.

**Source:** Wikimedia Commons
**URL:** https://commons.wikimedia.org/wiki/File:Down_Syndrome.jpg
**License:** CC BY-SA 4.0

---

## Case 2: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

### Patient Demographics
- **Age:** 8-month-old male
- **Sex:** Male

### Chief Complaint
"He won't wake up after being sick."

### History of Present Illness
An 8-month-old previously healthy boy is brought to the emergency department after his parents found him unresponsive in his crib this morning. He has had a viral illness with decreased oral intake and vomiting for the past 2 days. Last night he ate poorly and went to bed at 7 PM. His parents checked on him at 6 AM and found him limp and difficult to arouse. He has been exclusively breastfed and is just starting solids. Family history reveals that a maternal male cousin died unexpectedly at 11 months of age during a "stomach flu."

### Physical Examination
- **Vital Signs:** Temperature 37.8C, HR 180 bpm, RR 10/min (slow), BP 75/50 mmHg, SpO2 94% on room air, Glucose by fingerstick: 22 mg/dL
- **General:** Lethargic, minimally responsive to painful stimuli
- **HEENT:** Dry mucous membranes
- **Cardiovascular:** Tachycardic, weak pulses
- **Respiratory:** Slow, shallow breathing
- **Abdomen:** Liver edge palpable 3 cm below costal margin
- **Neurologic:** GCS 8 (E2V2M4), hypotonic, sluggish pupils

### Laboratory Findings
- **Glucose:** 18 mg/dL (critically low)
- **Venous blood gas:** pH 7.28, pCO2 35, HCO3 16 (mild metabolic acidosis)
- **Urine ketones:** Trace (inappropriately low - should be elevated with hypoglycemia)
- **Ammonia:** 125 umol/L (elevated; normal <50)
- **Liver function tests:** AST 450, ALT 380 (elevated)
- **Acylcarnitine profile (newborn screen was reportedly normal, but sample was collected at 20 hours of life):** Elevated octanoylcarnitine (C8) - DIAGNOSTIC
- **Urine organic acids:** Dicarboxylic aciduria

### Diagnosis
**Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency with metabolic crisis**

### Clinical Reasoning
This infant presents with the classic MCAD deficiency crisis: hypoketotic hypoglycemia (severe hypoglycemia with inappropriately low ketones) triggered by fasting during illness. Key features include:
- **Fasting stress:** Viral illness with poor intake for >12 hours (the overnight fast)
- **Hypoketotic hypoglycemia:** Glucose 18 mg/dL with only trace ketones (in normal fatty acid oxidation, prolonged fasting produces ketones; in MCAD, medium-chain fatty acids cannot be oxidized)
- **Hepatomegaly and elevated transaminases:** From fatty acid accumulation in liver
- **Encephalopathy:** From hypoglycemia and toxic metabolite accumulation
- **Family history:** Unexplained infant death (likely undiagnosed MCAD)
- **Diagnostic:** Elevated C8 (octanoylcarnitine) on acylcarnitine profile

The newborn screen may have been falsely negative due to early collection (metabolic derangements may not be apparent at 20 hours).

### Management

**Acute Management:**
1. **IV dextrose IMMEDIATELY:**
   - D10W bolus: 2-4 mL/kg IV (target glucose >70 mg/dL)
   - Then D10W at 1.5x maintenance to maintain anabolism and prevent catabolism
2. **Goal glucose:** Maintain 70-120 mg/dL
3. **Avoid lipid infusions:** Contraindicated (cannot metabolize medium-chain fats)
4. **Monitoring:** Glucose every 1-2 hours initially
5. **Treat underlying infection:** Supportive care for viral illness

**Long-Term Management:**
1. **Avoid fasting:**
   - Infants: No longer than 4-6 hours without feeding
   - Toddlers: No longer than 8-10 hours
   - Older children: No longer than 10-12 hours
2. **Sick day protocol:**
   - Frequent high-carbohydrate feeds during illness
   - Low threshold for IV dextrose if cannot maintain oral intake
   - Emergency letter for ER visits
3. **L-carnitine supplementation:** Consider based on carnitine levels
4. **Genetics referral:** Confirm diagnosis, family counseling, sibling screening
5. **Medical alert bracelet:** Essential

### Prognosis
With early diagnosis and fasting avoidance, children with MCAD deficiency have excellent outcomes and normal development. Without diagnosis, mortality rate during crises is 20-25%.

### Clinical Image
![Acylcarnitine profile showing elevated C8](case_02_image.jpg)

**Image Description:** Tandem mass spectrometry acylcarnitine profile demonstrating elevated octanoylcarnitine (C8), the biochemical hallmark of MCAD deficiency.

**Source:** Wikimedia Commons - Metabolic Screening
**URL:** https://commons.wikimedia.org/wiki/File:Mass_spectrometry.svg
**License:** CC BY-SA 4.0

---

## Case 3: Urea Cycle Disorder - Ornithine Transcarbamylase Deficiency

### Patient Demographics
- **Age:** 3-day-old male
- **Sex:** Male

### Chief Complaint
"The baby is lethargic and not feeding."

### History of Present Illness
A 3-day-old full-term male infant is brought from home after becoming increasingly lethargic over the past 12 hours. He was born at home with a midwife and was breastfeeding well initially. Over the past day, he has become difficult to arouse, has stopped feeding, and has been breathing rapidly. His mother notes he has become "stiff" and has had some jerky movements of his arms. There is no fever. He is the first child of non-consanguineous parents. The maternal uncle died at 5 days of life from "unknown causes."

### Physical Examination
- **Vital Signs:** Temperature 36.0C (hypothermic), HR 170 bpm, RR 60/min (Kussmaul-type), BP 55/35 mmHg
- **General:** Lethargic, intermittently irritable newborn with minimal response to stimulation
- **HEENT:** Anterior fontanelle full
- **Respiratory:** Tachypneic (central hyperventilation), clear breath sounds
- **Neurologic:** Hypotonic with intermittent extensor posturing, poor suck, hyperreflexia

### Laboratory Findings
- **Glucose:** 65 mg/dL (normal)
- **ABG:** pH 7.52, pCO2 22, HCO3 18 (respiratory alkalosis)
- **Ammonia:** 1,850 umol/L (critically elevated; normal <50)
- **Lactate:** 2.5 mmol/L (mildly elevated)
- **BUN:** 2 mg/dL (low)
- **Plasma amino acids:** Elevated glutamine, low citrulline, absent argininosuccinate
- **Urine orotic acid:** Markedly elevated

### Diagnosis
**Ornithine transcarbamylase (OTC) deficiency with hyperammonemic crisis**

### Clinical Reasoning
This infant presents with hyperammonemic encephalopathy. The pattern of findings is diagnostic:
- **Severe hyperammonemia** (>1,500 umol/L) causing encephalopathy
- **Respiratory alkalosis** (from central hyperventilation - ammonia stimulates respiratory center; distinguishes from organic acidemias which cause metabolic acidosis)
- **Low BUN** (cannot synthesize urea)
- **Elevated glutamine, low citrulline** (amino acid pattern)
- **Elevated urine orotic acid** (pathognomonic for OTC deficiency - carbamoyl phosphate is shunted to pyrimidine synthesis)
- **Symptom-free interval** followed by deterioration (normal at birth, then decompensates as protein intake increases)
- **Family history** of neonatal male death (X-linked inheritance - males severely affected)

OTC deficiency is the most common urea cycle disorder, with X-linked inheritance. Male infants with complete deficiency present in the first days of life with devastating hyperammonemia.

### Management

**EMERGENCY - Hyperammonemia is neurotoxic and requires immediate treatment:**

1. **Stop all protein intake:** NPO immediately

2. **Prevent catabolism:**
   - D10W at 1.5-2x maintenance (10-12 mg/kg/min glucose)
   - Consider intralipids for calories (20% lipid at 2-3 g/kg/day)

3. **Nitrogen scavengers (Ammonul - sodium benzoate/sodium phenylacetate):**
   - Loading dose: 250 mg/kg of each IV over 90-120 minutes
   - Maintenance: 250-500 mg/kg/day continuous infusion
   - Provides alternative pathways for nitrogen excretion

4. **Arginine supplementation:**
   - Arginine HCl 200-600 mg/kg/day IV
   - Arginine becomes essential when urea cycle is blocked

5. **Hemodialysis:**
   - Indicated for ammonia >500 umol/L or rising despite medical management
   - Most effective method for rapid ammonia removal

6. **Supportive care:**
   - Correct hypothermia
   - Seizure management if needed
   - Prepare for possible intubation

7. **Genetics/Metabolic consultation:** Immediate

**Long-Term Management (if survives acute crisis):**
- Protein-restricted diet
- Chronic nitrogen scavengers (sodium phenylbutyrate or glycerol phenylbutyrate)
- Arginine or citrulline supplementation
- Consider liver transplantation (curative)

### Prognosis
Neonatal-onset OTC deficiency with severe hyperammonemia has high mortality and significant neurodevelopmental morbidity in survivors. Early hemodialysis may improve outcomes. Liver transplantation is curative but does not reverse existing brain injury.

### Clinical Image
![Urea cycle pathway showing OTC location](case_03_image.jpg)

**Image Description:** Diagram of the urea cycle showing the location of the ornithine transcarbamylase (OTC) enzyme and the biochemical consequences of its deficiency, including accumulation of carbamoyl phosphate and orotic acid.

**Source:** Wikimedia Commons
**URL:** https://commons.wikimedia.org/wiki/File:Urea_cycle.svg
**License:** CC BY-SA 4.0