November 2025 - Page 2 of 2 - Dr Chaitanya Joshi, MD

Rett Syndrome

Definition

Rett syndrome is a neurodevelopmental disorder that primarily affects girls, characterized by normal early development followed by regression of acquired skills, especially speech and purposeful hand movements, with onset typically between 6–18 months of age.

Etiology

Genetic cause: Mutation in MECP2 gene (methyl-CpG-binding protein 2) on the X chromosome (Xq28)
Inheritance: Usually sporadic (de novo); rarely familial
Pathophysiology: Dysfunction of MECP2 protein → abnormal brain maturation and synaptic development

Epidemiology

Affects 1 in 10,000–15,000 female births
Lethal in males (most do not survive infancy unless mosaic or XXY)

Clinical Features

Phases of Disease

Early Onset (6–18 months)
- Normal development initially
- Gradual loss of interest in surroundings
- Loss of purposeful hand skills
- Deceleration of head growth (acquired microcephaly)
Rapid Destructive Phase (1–4 years)
- Loss of speech and purposeful hand use
- Stereotyped hand movements: hand-wringing, washing, clapping, or mouthing
- Gait ataxia, truncal apraxia
- Autistic-like behavior
Plateau Phase (2–10 years)
- Some improvement in social interaction and eye contact
- Persistent motor problems and seizures
Late Motor Deterioration (>10 years)
- Progressive scoliosis, muscle wasting, rigidity, dystonia
- Loss of ambulation in many cases

Other Features

Breathing abnormalities: hyperventilation, apnea during wakefulness
Seizures: common (up to 90%)
Bruxism, cold/purple extremities (autonomic dysfunction)
Sleep disturbances
Growth retardation

Investigations

Genetic testing: MECP2 mutation analysis (diagnostic)
EEG: slowing with epileptiform activity
MRI brain: may show nonspecific atrophy
Metabolic tests: normal (to rule out other causes)

Diagnosis

Clinical + confirmed MECP2 mutation
Diagnostic criteria include:
- Regression after normal early development
- Loss of purposeful hand skills and spoken language
- Gait abnormalities
- Stereotypic hand movements

Differential Diagnosis

Autism spectrum disorder
Angelman syndrome
Cerebral palsy (especially ataxic type)
Childhood disintegrative disorder

Management

No cure – supportive and multidisciplinary care
- Physiotherapy & occupational therapy: maintain mobility
- Speech therapy: communication support (eye-tracking devices)
- Antiepileptics: for seizures
- Nutritional support: adequate calories, manage feeding difficulties
- Behavioral therapy: improve interaction
- Orthopedic care: for scoliosis, contractures

Prognosis

Progressive but non-degenerative
Life expectancy: many survive into adulthood (40–50 years)
Main causes of death: sudden unexplained death, pneumonia, cardiac arrhythmias

Mnemonic (Key features) — “RETT”

R = Regression (speech, hand skills)
E = Episodic breathing abnormalities
T = Typical hand movements (wringing, washing)
T = Tiny head (acquired microcephaly)

~~Table of Contents(toc)~~

1. Definition

Hypothyroidism is a clinical state resulting from deficiency of thyroid hormone production or action, leading to a generalized slowing of metabolic processes.

It may be:

Congenital (Neonatal) – present at birth.
Acquired (Childhood) – develops later due to autoimmune, iatrogenic, or other causes.

2. Classification

A. Based on Level of Defect

Type	Site of Defect	TSH	T4/T3
Primary	Thyroid gland	↑	↓
Secondary	Pituitary	↓/N	↓
Tertiary	Hypothalamus	↓/N	↓
Peripheral (Resistance)	Target tissue	N/↑	N/↑

B. Based on Onset

Congenital hypothyroidism (CH)
Acquired hypothyroidism

3. Epidemiology

CH: ~1 in 2,000–4,000 live births.
More common in females.
Acquired form common in older children/adolescents, often autoimmune (Hashimoto’s).

thyroid gland

4. Etiology

A. Congenital Hypothyroidism

Thyroid dysgenesis (80–85%)
- Agenesis, ectopy, or hypoplasia.
- Usually sporadic.
Dyshormonogenesis (10–15%)
- Inborn errors of thyroid hormone synthesis (autosomal recessive).
- E.g. TPO, TG, Pendrin, NIS mutations.
Central hypothyroidism (rare)
- Pituitary/hypothalamic malformation, midline defects.
Transient CH
- Iodine excess/deficiency, maternal antibodies or antithyroid drugs.
Thyroid hormone resistance – extremely rare.

B. Acquired Hypothyroidism

Autoimmune thyroiditis (Hashimoto’s) – most common.
Iodine deficiency/excess.
Post-irradiation or post-surgical.
Drugs: amiodarone, lithium, interferon-α.
Secondary causes: pituitary tumors, craniopharyngioma.

5. Pathophysiology

↓ Thyroid hormone → ↓ metabolic activity → impaired CNS myelination, growth retardation, delayed bone maturation.

In neonates: irreversible neurodevelopmental impairment if untreated.
In older children: growth failure and delayed puberty predominate.

6. Clinical Features

A. Neonatal / Congenital

Often asymptomatic at birth due to transplacental maternal T4.

Typical features (develop over weeks):

Prolonged jaundice
Lethargy, hypotonia
Feeding difficulty, constipation
Large fontanelles
Macroglossia
Umbilical hernia
Cold, dry skin
Hoarse cry
Poor growth
Delayed bone age
Delayed milestones (later)

B. Childhood / Acquired

Growth retardation, short stature
Weight gain with poor height velocity
Fatigue, cold intolerance
Constipation
Dry skin, coarse hair
Bradycardia
Delayed puberty / menstrual irregularities
Pseudoprecocious puberty (rare, due to high TRH → prolactin ↑)
Goiter (especially in Hashimoto’s)

7. Investigations

A. Screening

Neonatal screening: heel-prick sample at 48–72 hr.
- Primary TSH (most programs).
- Elevated TSH → confirm with serum free T4.

B. Diagnostic Tests

Test	Interpretation
Serum TSH, Free T4	↓T4 with ↑TSH → primary hypothyroidism
T3	less reliable in neonates
Thyroglobulin	Low in agenesis, high in dyshormonogenesis
Imaging	Thyroid scan (99mTc or I-123) – ectopy, agenesis, uptake defects
Ultrasound	Gland location and size
Antibodies (TPO, Tg)	Positive in autoimmune
Bone age X-ray	Delayed
Additional: Pituitary MRI if central hypothyroidism suspected

8. Complications (if untreated)

Neurologic: irreversible intellectual disability, deaf-mutism, spasticity.
Growth: severe stunting, delayed bone age.
Metabolic: dyslipidemia.
Cardiac: bradycardia, pericardial effusion.

9. Management

A. Principles

Early, adequate, lifelong replacement.
Monitor and titrate carefully to maintain euthyroid state.

B. Drug

Levothyroxine (L-T4) – drug of choice.
- Dose:
  - Neonates: 10–15 µg/kg/day.
  - Infants: 8–10 µg/kg/day.
  - Children: 4–6 µg/kg/day.
  - Adolescents: 2–4 µg/kg/day.
- Given on empty stomach (preferably crushed with water or milk).

C. Monitoring

Age	Frequency	Parameters
0–6 mo	Every 2 wk till T4 normal, then q1–2 mo	T4, TSH
6–12 mo	q2–3 mo	〃
1–3 yr	q3–4 mo	〃
>3 yr	q6–12 mo	〃

Target: Free T4 in upper half of normal range, TSH normal.

D. Developmental Follow-up

Neurodevelopmental assessment
Hearing evaluation
Growth chart monitoring

10. Prognosis

Normal IQ if therapy started within first 2 weeks of life.
Delay in treatment → irreversible intellectual deficit.
Acquired forms usually fully reversible with treatment.

11. Key Differentials

Pituitary insufficiency
Hypothyroxinemia of prematurity
Chronic systemic illness (euthyroid sick syndrome)
Constitutional growth delay

12. Summary Table

Feature	Congenital	Acquired
Onset	Birth	Childhood/adolescence
Cause	Dysgenesis > dyshormonogenesis	Hashimoto’s most common
Presentation	Lethargy, constipation, macroglossia	Growth failure, delayed puberty
TSH	High	High
T4	Low	Low
Rx	Levothyroxine	Levothyroxine
Prognosis	Excellent if early	Excellent

References

Nelson Textbook of Pediatrics, 22nd ed.
Indian Academy of Pediatrics Guidelines (2021) — Screening and management of congenital hypothyroidism.
Endocrine Society Clinical Practice Guideline (2020) – Congenital Hypothyroidism.
Sperling MA, Pediatric Endocrinology, 5th ed.