What are Chromatin Regulatory Disorders?

Compose genetic conditions having pathogenic variations in proteins regulating gene expression in nuclear chromatin. Frequently associated with development delay & facial dysmorphism. Common conditions include:

• Kabuki Syndrome
• Rubinstein-Taybi Syndrome
• Cornelia De Lange Syndrome
• Coffin-Siris Syndrome
• Others (e.g., CHARGE syndrome, Rarely VATER syndrome).

Kabuki Syndrome

Also called Kabuki Make-Up Syndrome

Genetic Basis: Two subtypes with different genes are described: 

• Type 1: KMT2D gene (Previously called MLL2) on Chr 12. Normally codes for a histone methyltransferase. Germline heterozygous loss of function variants are responsible. 90% of all cases, mostly de novo mutations, can show AD inheritance.
• Type 2: KDM6A gene on Chr X, normally codes for a histone demethylase. Hemizygous or heterozygous variants cause disease. X-linked Dominant inheritance.

Also read: Complex Vascular Anomalies : NEET SS Pediatrics

Clinical Features of Kabuki Syndrome

Physical Features: Long palpebral fissures, sometimes with slanting, broad arched eyebrows, eversion of lateral 1/3rd of lower eyelids, depressed nasal tip with short columella, large ears, persistent fingertip pads. Dental abnormalities include widely spaced teeth & hypodontia.

Growth Abnormalities: Short stature, feeding difficulties. May need tube feeds. Developmental Abnormalities: Global developmental delay & mild to moderate ID. Autism may occur.

Neurological: Hypotonia is common, but no structural brain differences occur. Seizures occur in 30%.

Congenital heart disease: seen in 70% cases. MC CHD: Coarctation of aorta > ASD> VSD

GIT: Anal atresia, CDH, cholestasis

Endocrine: Hypoglycemia with hyperinsulinemia; females may have premature thelarche

Eye: ↑ Tears, ptosis, cataracts, strabismus, blue sclera

ENT: Conductive deafness due to chronic OM > SNHL. Cleft lip & palate can also occur

Genitourinary: Seen in 25% cases. Comprise ectopic kidneys, renal duplication, hypospadias, and cryptorchidism. Females may have hypoplastic labia.

MSK: joint hypermobility, scoliosis, hemivertebra.

Immunology & Hematology: Recurrent sinopulmonary infections, otitis media (OM), hypogammaglobulinemia. Vitiligo, hemolytic anemia, immune thrombocytopenia, coagulopathy.

Kabuki Phenotype Scoring List

Also read: Tubercular Meningitis In Children

Rubinstein-Taybi Syndrome

Genetic Basis

Defect in the transcriptional co-activators, e.g., Histone Lysine Acetyltransferase. 

Two types:

CREB-BP gene (Chr.16)

• Classic RSTS, severe
• Mostly de novo
• Rarely autosomal dominant inheritance

EP-300 gene (Chr.22)

• Atypical RSTS, milder

Clinical Features of Rubinstein-Taybi Syndrome

• Physical Features: Downward slanting palpebral fissures, arched eyebrows, low-hanging columella, grimacing smile. Broad, enlarged thumb & great toe are characteristic
• Growth: Short stature & obesity
• Development: Global Developmental Delay (GDD), Walking at 30 months, 1st words at 25 months Speech delay in 90%; Autism & mood swings also seen
• Intellectual Disability: Moderate to severe, IQ 25-79, verbal more affected
• Neurological: Posterior fossa abnormalities like Chiari, seizure disorders
• Eye: Refractory errors, ptosis, cataract, coloboma, etc.
• Congenital Heart Disease (CHD): Seen in 30%, Sequence: ASD > VSD > PDA > CoA > PS > AS
• Respiratory: Obstructive sleep apnea
• Genitourinary: Hydronephrosis, renal duplication, cryptorchidism
• GIT: Feeding issues, GERD, constipation
• Musculoskeletal (MSK): Scoliosis, lax joints, hypotonia

Also read: Surfactant Dysfunction Disorders

Cornelia De Lange Syndrome (CdLS)

Genetic Basis

• Mutation in Cohesin Complex
• Critical for transcription & nucleosomal compaction.
• 60–70% patients will have mutations in NIPBL, which plays a role in regulation & loading of cohesin complex
• 3-10% mutations in SMC3, SMC1A/B, RAD21, HDAC-8
• Mutation: De-novo Mutation

Clinical Features of Cornelia De Lange Syndrome

• Physical Features: Synophrys, thick bushy eyebrows, thick eyelashes, short nasal bridge. Upturned nasal tip with anteverted nostrils. Long smooth philtrum, thin vermillion of the upper lip, downward turning of the mouth. High arched palate with or without cleft palate. Micrognathia, small, widely spaced teeth
• Growth Failure: Short stature with microcephaly
• Eye: Ptosis, nystagmus, myopia
• ENT: Sensorineural hearing loss (SNHL), conductive deafness
• Cardiovascular (CVS): seen in 50%. Sequence: PS > VSD > ASD > others
• GIT: Reflux in all patients, CHPS, CDH, malrotation
• Skin: Hypertrichosis, temporal hair
• Skeletal: 25% have upper limb deformities like clinodactyly, rarely complete absence of forearm bones. Radioulnar synostosis is also common
• Development Delay & Intellectual Disability: Global developmental delay, average IQ of 53. Many have severe to profound intellectual disabilities and behavioral problems

Also read: An Overview Of Genetic Skin Disorders

Coffin-Siris Syndrome (CSS)

Genetic Basis

Abnormality in the BAF (BRG1 or BRM - Associated Factor) Complex leads to CSS. Involved in chromatin packaging & transcription regulation. 

Genes:

• ARID1A
• ARID1B
• SMARCA4
• SMARCB1
• SMARCE1
• SOX-11

Clinical Features of Coffin-Siris Syndrome

• Physical Features: Facial features tend to become coarse with age. Wide mouth with thick everted upper and lower lips, broad nasal bridge & nasal tip, thick eyebrows, and long eyelashes.
• Musculoskeletal (MSK): 5th digit nail & distal phalanx hypoplasia or aplasia is the hallmark & was used as a diagnostic criterion in the pre-exome era. Brachydactyly of the same finger, joint laxity, & scoliosis are also seen.
• Growth: short stature & poor weight gain postnatally.
• Development: Global Developmental Delay (GDD), moderate to severe intellectual disability (ID), with IQ range 40-69. May show autistic features.
• Neurological: hypotonia, Dandy-Walker malformation, agenesis of the corpus callosum. Deafness & seizures may also occur.
• Eye: Ptosis, strabismus, myopia.
• GIT: Feeding issues
• Genitourinary: Horseshoe kidneys, hypospadias
• Cardiac: Congenital heart defects (CHDs) are common
• Sequence: VSD > ASD > TOF
• Skin: Hypertrichosis & hirsutism

Also read: Noonan Syndrome : Epidemiology, Genes Implicated

Hope you found this blog helpful for your NEET SS Pediatrics Genetic Disorder Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs. 

Download PrepLadder's Best App for NEET SS Preparation for Android 

Download PrepLadder's Best App for NEET SS Preparation for iOS.