Pediatrics

Genetics — CGG Repeat Expansion in FMR1

Most common inherited cause of intellectual disability and most common single-gene cause of ASD. Expansion of a CGG repeat in FMR1 (X chromosome).

Clinical Phenotype

Long, narrow face; large, prominent ears; post-pubertal macroorchidism in affected males. Intellectual disability typically more severe in males (protective effect of second X, X-inactivation, in heterozygous females).

Behavioral Features

Hyperactivity/attention difficulties, social anxiety, gaze avoidance, substantial ASD phenotype overlap, sensory sensitivities, occasionally self-injurious/stereotyped behaviors — an important diagnosis to actively test for in unexplained developmental delay/ASD workups.

Diagnostic Testing

Genetic Counseling

Requires attention to: repeat length category in the index patient/family members, sex of the transmitting parent (maternal transmission carries the expansion risk), and testing of at-risk (particularly maternal) relatives, plus counseling regarding FXTAS/FXPOI in identified premutation carriers.

Neurofibromatosis Type 1 — NIH Diagnostic Criteria

NF1 tumor suppressor gene mutation, autosomal dominant (substantial de novo proportion). Diagnosed with ≥2 of 7 criteria:

1. ≥6 café-au-lait macules (size threshold varies by age)
2. ≥2 neurofibromas of any type, or 1 plexiform neurofibroma
3. Axillary or inguinal freckling (Crowe’s sign)
4. Optic pathway glioma
5. ≥2 Lisch nodules (iris hamartomas)
6. A distinctive osseous lesion (sphenoid wing dysplasia, long bone cortical thinning ± pseudarthrosis)
7. A first-degree relative with NF-1 meeting the above criteria

Tuberous Sclerosis Complex — TSC Diagnostic Criteria

TSC1 or TSC2 mutation, autosomal dominant, substantial de novo rate. Definite diagnosis: 2 major criteria, OR 1 major + ≥2 minor.

Genetic Basis and Multidisciplinary Surveillance

mTOR inhibitor therapy (everolimus) targets the shared TSC1/TSC2 pathway — a mechanism-targeted option for SEGA and refractory epilepsy.

Clinical Presentation

Acute, typically monophasic, immune-mediated CNS demyelinating disorder, most common in children — follows a preceding infection (or rarely vaccination) by 1–3 weeks. Presents with rapid-onset multifocal neurological deficits plus encephalopathy (altered mental status) — this combination is the key defining and distinguishing feature.

CSF Findings

Mild lymphocytic pleocytosis, mildly elevated protein. Oligoclonal bands typically absent or only transiently present (contrast with MS).

Characteristic MRI Features

Multiple, large, poorly-demarcated, bilateral (often asymmetric) white matter lesions, characteristically also involving deep grey matter (basal ganglia, thalamus) — more confluent/less well-demarcated than typical MS lesions.

Differentiation from Multiple Sclerosis

Treatment

High-dose IV methylprednisolone first-line; IVIG as alternative/adjunct for steroid-refractory cases. Prognosis generally favorable with substantial/complete recovery in most children.

Revised Chicago Consensus Classification

Stepwise Diagnostic Evaluation

1. Detailed history (family history of DSD/unexplained neonatal death; maternal medication/hormone exposure)
2. Physical examination (standardized genital assessment; palpate for gonads — palpable gonads suggest testicular tissue)
3. Karyotype (establishes chromosomal category)
4. Pelvic/abdominal ultrasound (Mullerian structures, gonadal location)
5. Hormonal evaluation (17-OHP for CAH given urgency; testosterone/androgen pathway hormones as guided by findings)

Endocrine Workup and Gender Assignment Principles

Management requires urgent, coordinated multidisciplinary involvement: pediatric endocrinology, urology/surgery, genetics, and psychology/ethics support for the family.

Etiology of Arterial Ischemic Stroke in Children

Neuroimaging

MRI/MRA is preferred first-line — superior sensitivity for acute ischemic changes vs CT, plus vascular imaging without ionizing radiation, well suited to pediatric radiation sensitivity and the vascular/structural etiological spectrum.

Acute Management

General supportive care (oxygenation, BP, glucose control). Thrombolysis (tPA) is used much more cautiously/selectively than in adults, given limited pediatric safety/efficacy evidence and the different, often non-atherosclerotic etiology. Management centers on addressing the specific underlying cause (e.g., exchange transfusion for SCD-associated stroke; antithrombotic therapy for cardioembolic/arteriopathy-related stroke).

Secondary Prevention

Differential Diagnosis — Acute versus Progressive Ataxia

Friedreich Ataxia — Genetics

Most common inherited ataxia — GAA trinucleotide repeat expansion in FXN (frataxin, essential for mitochondrial iron-sulfur cluster assembly). Autosomal recessive (no premutation/anticipation instability pattern, unlike Fragile X, Q178).

• Progressive ataxia (later childhood/adolescence onset)
• Dysarthria
• Loss of deep tendon reflexes combined with extensor plantar responses (mixed peripheral + corticospinal involvement)
• Hypertrophic cardiomyopathy — major morbidity/mortality cause, requires ongoing cardiac surveillance
• Elevated diabetes mellitus risk

Ataxia-Telangiectasia — Features

Autosomal recessive, ATM gene mutation (DNA damage response/repair).

Diagnostic Approach — Central versus Peripheral Localization

Distinguishing Features

Peripheral Category — Further Localization

Diagnostic Investigation Pathway

Classification of Epidemiological Study Designs

A. Observational Studies

The investigator observes exposures and outcomes as they naturally occur, without actively assigning or controlling the exposure/intervention.

Cohort studies may be prospective (exposure assessed at initiation, outcomes observed over follow-up) or retrospective/historical (existing records reconstruct past exposure, then the cohort is followed forward, potentially to the present, using existing outcome data).

B. Experimental Studies — Randomized Controlled Trials (RCTs)

The investigator actively assigns the exposure/intervention via randomization, distributing both known and unknown confounders evenly between groups — the gold-standard design for establishing causality.

• Advantage: Randomization controls for confounding (measured and unmeasured) that observational designs cannot fully address.
• Limitations: Ethical/practical constraints (cannot randomize harmful exposures); expensive and time-consuming; limited generalizability if trial population/setting differs from real-world practice (strict inclusion/exclusion criteria).

Advantages and Limitations — Comparative Summary

Measures of Association — Odds Ratio and Relative Risk

Core Diagnostic Test Parameters (2×2 Table Framework)

Critical Impact of Prevalence on Predictive Values

ROC Curve Construction and Interpretation

Plots Sensitivity (True Positive Rate) on the y-axis against 1 − Specificity (False Positive Rate) on the x-axis, across the full range of diagnostic thresholds for a continuous/ordinal test.

The optimal diagnostic threshold is identified as the point on the curve closest to the top-left corner, or via the Youden Index (maximizing sensitivity + specificity).

Factors Influencing Sample Size Calculation

• Expected effect size — smaller expected effects require larger samples.
• Statistical power (conventionally 80% or 90%) — higher desired power requires larger samples.
• Significance level (α) (conventionally 0.05) — more stringent α requires a larger sample.
• Expected variability/SD of the outcome measure — greater variability requires a larger sample.
• Expected baseline event rate (for studies of proportions).

Probability Sampling Methods

Non-Probability Sampling Methods

Includes convenience sampling, purposive/judgmental sampling, and snowball sampling — do not provide known selection probability, limiting statistical generalizability.