Pediatrics

Pathophysiology — Aganglionosis

Failure of normal craniocaudal migration of neural crest-derived ganglion cells → a variable-length distal segment lacking ganglion cells in both the myenteric (Auerbach's) and submucosal (Meissner's) plexuses.

Clinical Presentation

• Delayed passage of meconium (beyond 24–48 hours of life) — the classic, most important early clue
• Progressive abdominal distension
• Bilious vomiting if obstruction persists/unrecognized
• Subset (shorter segment): delayed presentation with chronic, severe, refractory constipation in early infancy/childhood

Diagnostic Evaluation

Surgical Pull-Through Procedures

Resection of the aganglionic segment with “pull-through” of ganglionic proximal bowel to the anus. Technique variations: Swenson, Duhamel, Soave procedures.

Genetics — SMN1 Deletion and the Critical Role of SMN2 Copy Number

SMA results from homozygous deletion/mutation of SMN1 (chromosome 5) → progressive anterior horn motor neuron degeneration. Autosomal recessive.

Clinical Classification (Types 1–4)

Novel Targeted Therapies — Three Distinct Mechanisms

Clinical Significance

Genetics

Mutations in the dystrophin gene (largest human gene, X chromosome), X-linked recessive. Dystrophin connects intracellular cytoskeleton to extracellular matrix in muscle fibers.

Clinical Progression

Presents ages 2–5 years: delayed motor milestones, waddling gait, frequent falls, difficulty climbing stairs/rising from floor. Progresses to loss of ambulation (typically early-mid adolescence untreated), respiratory muscle weakness, and cardiomyopathy (dystrophin's role in cardiac muscle too — requires ongoing cardiac surveillance). Calf pseudohypertrophy is a classic exam finding.

Gowers’ Sign

Diagnostic Evaluation

Steroid Protocols

Prednisolone or deflazacort (increasingly favored, more favorable side-effect profile) — slows disease progression, prolongs ambulation, benefits respiratory/cardiac function. Requires monitoring for: growth impairment, weight gain, bone health (density surveillance, vitamin D/calcium), behavioral effects — given essentially lifelong therapy.

Gene Addition/Exon Skipping Advances

Pathophysiology of 21-Hydroxylase Deficiency

21-hydroxylase deficiency (CYP21A2 mutations) accounts for >90% of CAH cases — impairs conversion of progesterone→deoxycorticosterone and 17-OHP→11-deoxycortisol, blocking both aldosterone and cortisol synthesis.

Salt-Wasting versus Simple Virilizing Forms

Clinical Presentation by Sex

Antenatal Diagnosis and Treatment

For families with a known prior affected child, antenatal maternal dexamethasone has historically been used to suppress fetal adrenal androgens (reduces virilization of an affected female fetus). Requires very early initiation (before fetal sex/genetic status known) — current use is more selective given evolving risk-benefit evidence.

Newborn Screening — 17-OHP

17-hydroxyprogesterone (precursor accumulating proximal to the block) is measured on the standard heel-prick dried blood spot — identifies affected males lacking the visible genital clue, enabling treatment before unrecognized crisis.

Acute Adrenal Crisis Management

Lifelong Hormone Replacement

• Hydrocortisone — replaces cortisol deficiency AND suppresses excess ACTH drive (limiting ongoing androgen excess)
• Fludrocortisone — mineralocorticoid replacement for salt-wasting forms
• Stress-dose steroid coverage required lifelong during illness, surgery, or physiological stress

Etiology — Thyroid Dysgenesis versus Dyshormonogenesis

Newborn Screening Protocols

TSH-based screening on the standard dried blood spot — elevated TSH triggers urgent confirmatory serum testing (free T4 + TSH). Some programs use a second sample (e.g., at 2 weeks) to catch delayed postnatal TSH rise or confounding by the normal transient neonatal TSH surge if screened too early.

Clinical Features

When apparent in unscreened/undiagnosed infants: prolonged jaundice, lethargy, poor feeding, constipation, hypotonia, large/protruding tongue, umbilical hernia, hoarse cry. Bone age (delayed) can be a supportive, adjunctive assessment.

Treatment — The Critical Urgency of Immediate Levothyroxine Initiation

Neurodevelopmental Monitoring

Even with prompt treatment, ongoing structured neurodevelopmental monitoring is required (most severely affected infants retain some risk). Thyroid function requires regular monitoring/dose adjustment throughout childhood growth.

West Syndrome — Clinical Triad

Peak onset 3–7 months:

1. Infantile spasms — brief (1–2 sec), symmetric contractions, “jackknife”/“salaam” pattern, in clusters around sleep transitions
2. Hypsarrhythmia — chaotic, high-amplitude, disorganized interictal EEG
3. Developmental arrest or regression — the abnormal EEG activity itself contributes to impairment

West Syndrome — Etiology and Treatment

Diverse etiology: structural brain abnormalities, genetic syndromes (tuberous sclerosis complex — Q179 — particularly important), metabolic disorders, perinatal HIE; a proportion cryptogenic.

Dravet Syndrome — Genetics and Clinical Features

Most commonly caused by SCN1A mutations (voltage-gated sodium channel). Presents in first year with prolonged febrile seizures (modest fever; can be vaccination-triggered — vaccination does not cause it, merely unmasks the predisposition). Evolves to multiple seizure types + developmental regression, after an initial period of normal development.

Dravet Syndrome — Contraindicated Medications

Appropriate options: valproate, clobazam, stiripentol, cannabidiol, fenfluramine.

Clinical Variants

CSF Albuminocytological Dissociation

Nerve Conduction Studies

Treatment — IVIG versus Plasmapheresis

Both represent evidence-based, broadly equivalent first-line options; choice often guided by practicality (IVIG generally more available/simpler, especially in pediatrics where plasmapheresis vascular access can be more challenging). Earlier initiation is associated with more favorable outcomes.

Respiratory Monitoring Criteria

Pathophysiology — Autoimmune Beta-Cell Destruction

T-cell-mediated autoimmune destruction of pancreatic beta cells → progressive, near-complete/complete insulin deficiency. Autoantibodies (anti-GAD65, anti-islet cell, anti-insulin, anti-IA2) are diagnostic/predictive biomarkers, not primary pathogenic mediators (that role belongs to cytotoxic T-lymphocytes) — sometimes detectable years before clinical onset.

The “Honeymoon Phase”

Intensive Insulin Regimens

Continuous Glucose Monitoring (CGM)

Near-continuous, real-time interstitial glucose readings (sensors replaced every 7–14 days, minimal fingerstick calibration). Improves glycemic control, reduces hypoglycemia risk. Integrated with pumps in hybrid closed-loop/“artificial pancreas” systems with algorithmic insulin adjustment.

HbA1c Targets

Contemporary guidelines recommend target HbA1c <7.0% for most children/adolescents, individualized by hypoglycemia risk, technology access, and family capacity — more stringent than older historical targets.

Cytogenetics

Antenatal Screening

Clinical Features and Comprehensive Health Supervision

Dysmorphic features: upslanting palpebral fissures, epicanthal folds, flat facial profile, single palmar crease.

Clinical Phenotype

Complete or partial absence of one X chromosome in a phenotypic female (classic 45,X; numerous mosaic/structural variants also produce the phenotype).

• Short stature — essentially universal, often the presenting feature
• Webbed neck
• Low posterior hairline
• Broad “shield” chest with widely-spaced nipples
• Cubitus valgus
• Lymphedema of hands/feet (particularly notable in the neonatal period)

Systemic Associations

Diagnostic Confirmation

Karyotyping is the definitive test, confirming 45,X, mosaic pattern, or structural X abnormality; carries some prognostic relevance though individual variation exists.

Management