Paediatrics Marrow Pg 71-80 (Genetic Disorders)

Scurvy

• Vitamin C deficiency leads to collagen deficiency, affecting bone, skin, and blood vessels.
• Scurvy is caused by inadequate Vitamin C intake from citrus fruits, green vegetables, and boiled/evaporated cow's milk.
• Early symptoms include irritability, decreased appetite, anemia, and bleeding gums.
• Characteristic signs include perifollicular bleeding and corkscrew hair.
• Bone manifestations include subperiosteal bleeding, pain, and pseudo-paralysis (frog leg posture).
• Diagnosis is mainly clinical; x-rays reveal subperiosteal hemorrhage and poorly formed bony trabeculae.
• Treatment involves oral Vitamin C (100-200 mg/day) until lesions subside.

Rickets & Scurvy

• Rickets is a bone disorder caused by Vitamin D deficiency, leading to soft and weak bones.
• Treatment for rickets includes phosphate supplementation (Joulie solution) and Burosumab (monoclonal antibody against FGF-23).

Vitamin D Dependent Rickets (VDDR)

• This autosomal recessive disorder is characterized by defects in vitamin D metabolism leading to hypocalcemia.
• Classic features include rickets and ectodermal defects (milia, epidermal cysts, oligodontia, alopecia).

Treatment for VDDR

• Type I VDDR is treated with calcidiol (active form of vitamin D) and calcium supplements.
• Type II VDDR is treated with high doses of Vitamin D to overcome resistance and improve symptoms.

Approach to Refractory Rickets

• Biochemical values help diagnose refractory rickets:
  • High Serum PO3−4PO_3^{−4}PO3−4​ suggests CKD associated rickets.
  • Low Serum PO3−4PO_3^{−4}PO3−4​ suggests renal tubular acidosis or PTH deficiency.
  • High response of Serum PO3−4PO_3^{−4}PO3−4​ to decreased calcium levels suggests VDDR.
  • Normal response of Serum PO3−4PO_3^{−4}PO3−4​ to decreased calcium levels suggests Familial hypophosphatemic rickets.

Angelman Syndrome

• Also known as Happy Puppet Syndrome.
• Caused by a deletion of the maternal allele or disomy of the paternal allele on chromosome 15 q 11 - 13.
• Characterized by neurological features (increased seizure incidence), hypotonia, low IQ, speech defects, and abnormal movements of hands and feet (ataxia).

Trinucleotide Repeat Disorders (TRD)

Fragile X Syndrome

• Caused by an expansion of CGG repeats in the FMR1 gene.
• Features include large ears, long face, prominent chin, macroorchidism (large testes) after puberty, and behavioral abnormalities (ADHD, autism).
• Other associations include connective tissue defects, low IQ, hyperextensive joints, high arched palate, and mitral valve prolapse.

Genomic Imprinting Disorders

Prader-Willi Syndrome

• Characterized by a deletion or disomy on chromosome 15q11-13.
• Prominent features include massive obesity, short stature, small hands and feet, small eyes, and hypogonadism.
• Other clinical features include:
  • Thin upper lip
  • Small jaw
  • Hypertelorism (widely separated eyes)
  • Low-lying notched ears
  • Elfin face
  • Hypercalcemia
  • Prominent forehead
  • Puffiness of eyes and cheeks
  • Wide mouth
  • Cardiac conotruncal defects (Tetralogy of Fallot)
  • Abnormal face
  • T-cell deficiency (due to absence of thymus)
  • Cleft lip/palate
  • Hypocalcemia (due to PTH deficiency)
  • Heart defect: Supravalvular aortic stenosis
  • Low IQ, learning disabilities

Childhood Infections

Complications of Measles

• Acute:
  • Most common: Otitis media
  • Most severe: Pneumonia (increased mortality risk) due to Giant cell/HECHT pneumonia or superimposed bacterial infection (Staphylococcus aureus/Streptococcus pneumoniae).
• Chronic:
  • SSPE (Subacute sclerosing pan encephalitis) a rare complication (1:100,000).
• Latent complications:
  • Occur 7-13 years after primary infection.
  • Characterized by myoclonic seizures, cognitive impairment, and personality changes.
  • Diagnosis involves detecting IgG anti-measles antibody in CSF.
  • Fatal condition despite immunomodulatory treatment.

Management of Measles

• Supportive treatment: adequate nutrition, antipyretics, and IV fluids.
• Vitamin A supplementation: reduces morbidity and mortality by 50% (two doses 24 hours apart).

Classification of Childhood Infections

• Arranged based on historical importance:
  • 1st - Measles
  • 2nd - Scarlet Fever
  • 3rd - Rubella
  • 4th - Erythema Infectiosum
  • 5th - Roseola infantum/exanthema subitum

Measles

• Caused by the Paramyxoviridae (ss RNA virus).
• Incubation period: 8-14 days.
• Mode of spread: respiratory droplets.
• Secondary attack rate: >90% (highly contagious).
• Infectivity period/isolation period: 4 days before to 5 days after onset of rash.

Clinical Features of Measles

• Prodromal Stage (Day 1-3):
  • Fever (intensifies after rash appears).
  • Cough.
  • Coryza.
  • Conjunctivitis.
• Exanthem (Internal Manifestation, Day 2-3):
  • Koplik spots: characteristic white spots surrounded by reddish hue usually opposite the lower molars.
• Exanthematous Phase (External Manifestation, Day 4-8):
  • Maculopapular rash: starts behind ears/face and spreads downward to the trunk and extremities.
  • Leaves behind brownish pigmentation.
  • Increased fever intensity after rash appears.

Genetic Disorders

Aneuploidies

• Abnormal number of chromosomes.
• Example: Trisomies (presence of three chromosomes instead of a pair)

Down Syndrome (Trisomy 21)

• Most common Trisomy.
• Pathogenesis:
  • Maternal meiotic non-disjunction (most common cause).
  • Translocation (+(14;21) or +(21;21)).
  • Abnormal pair of chromosome 21 with 3 others.
• Frequency:
  • Trisomy 21: 95%
  • Translocation: 4%
  • Mosaic: 1%

Chromosomal Abnormalities in Down's Syndrome

• Facies:
  • Brushfield spots.
  • Upslanting palpebral fissures/Mongoloid slant of eyes.
  • Flat face.
  • Flat occiput.
  • Flat nose.
  • Epicanthal fold.
  • Mongoloid facies.
• Skull:
  • Brachycephaly.
  • Redundant skin.
  • Open mouth with protruding tongue (due to hypoplastic mandible).
  • Low-set ears.
• Limbs:
  • Palms: Simian crease (single transverse palmar crease).
  • 5th/Little finger: Clinodactyly (curved finger due to hypoplasia of phalanx).
  • Foot: Sandal gap (increased gap between 1st and toe).
• Internal Manifestations:
  • Heart: Congenital Heart Defect (most common 40%).

Internal Manifestations of Down's Syndrome

• Heart: Bicuspid aortic valve/coarctation of aorta.
• Kidney (50%): Horseshoe kidney.
• Delayed puberty & Infertility in adulthood.

Pseudo Turner Syndrome/Noonan Syndrome

• Autosomal dominant inheritance (males and females affected).
• Gene defect: PTPN gene on chromosome 12q24.
• Features:
  • Normal IQ (Turner) vs. Low IQ (Noonan).
  • Streak ovaries (Turner) vs. both genders (Noonan).
  • Bicuspid aortic valve, Coarctation of aorta (both), Pulmonary stenosis (both), Cryptorchidism (male, Noonan).

Klinefelter Syndrome

This disorder is characterized by tall stature, reduced facial and axillary hair, breast development (gynecomastia), cryptorchidism, low testosterone, increased aromatase enzyme activity (testosterone to estrogen conversion),eunuchoid body habitus

Microdeletion Syndromes

• Deletions of tiny parts of chromosomes undetectable by karyotyping.
  • 22q11.2 deletion:
    • DiGeorge syndrome, characterized by defective development of the third and fourth pharyngeal pouches, resulting in thymus and parathyroid defects.
  • 7q11.23 deletion:
    • Williams syndrome.

Patau Syndrome (Trisomy 13)

• Characteristics:
  • Scalp defects: Aplasia cutis and microphthalmos.
  • Cleft lip and/or palate.
  • Dysplastic or malformed ears.
  • Clenched hands and polydactyly (extra fingers).
  • Undescended testes/cryptorchidism (male child).
  • Postaxial polydactyly.
  • Heart defects (80-90%): VSD > PDA > ASD.
  • CNS: Holoprosencephaly.
  • Absent/missing ribs.

Turner Syndrome

• Karyotype: 45, X0/monosomy X (57%) > mosaicism (29%) > Partial monosomy X (14%).
• Gender: Female.
• Clinical Aspects:
  • External Manifestations:
    • Short stature (< 145 cm).
    • Web neck.
    • Loose skin folds.
    • Normal IQ.
    • Lymphedema (foot, hand, neck, cystic hygroma).
  • Other Characteristics:
    • Low hairline.
    • Shield-shaped thorax.
    • Widely spaced nipples.
    • Shortened metacarpal IV.
    • Small finger nails.
    • Cubitus valgus (carrying angle > 135°).

Edward's Syndrome (Trisomy 18)

• Most frequent Trisomy.
• External Manifestations:
  • Occipital or back part of skull prominent.
  • Dysplastic or malformed ears.
  • Microphthalmos (small eyes).
  • Short palpebral fissures (eyelid).
  • Short neck.
• Internal Manifestations:
  • Congenital heart disease (CHD):
    • Ventricular septal defect (VSD).
    • Patent ductus arteriosus (PDA).
    • Atrial septal defect (ASD).
  • Horseshoe kidney.
• Rocker bottom feet.

Recurrence Risk of Down Syndrome

• General risk: 1%.
• Increased risk for mothers over 35: up to 4%.
• Higher risk in parents with Robertsonian translocation.

Translocation Types and Associated Risk

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Edwards Syndrome (Trisomy 18)

• Other characteristics:
  • Internal Manifestations:
    • Congenital heart disease (CHD) (over 90%):
      • Ventricular septal defect (VSD)
      • Patent ductus arteriosus (PDA)
      • Atrial septal defect (ASD)
    • Horseshoe kidney.
  • External Manifestations:
    • Occipital or back part of skull prominent.
    • Dysplastic or malformed ears.
    • Microphthalmos (small eyes).
    • Short palpebral fissures (eyelid).
    • Short neck.
  • Rocker bottom feet.