Surfactant Dysfunction Disorders

Pulmonary Surfactant

A mixture of phospholipids and proteins Produced by type-2 alveolar pneumocytes Known as AEC2 cells. Alveolar epithelial cells type 2 reduces surface tension in alveoli in preterm infants

Deficiency of surfactant is present and leads to Respiratory distress syndrome. Most important component of surfactant: lecithin, also known as dipalmitoyl phosphatidylcholine (DPPC). Surfactant is also composed of proteins (10%). Host defense- produces local immunity

• Surfactant protein A (SP-A)
• Surfactant protein D (SP-D)

Supplement surface tension reduction

• Surfactant protein B (SP-B)
• Surfactant protein C (SP-C)

SP-B and SP-C are essential for monolayer formation of the surfactant in alveoli. Their function is as critical as lecithin, even if the number is less. The deficiency of SP-B and SP-C will cause:

• Inability to form a uniform layer of surfactant
• Ineffective surface tension lowering

Lamellar bodies (LBs) are also involved in proper surfactant functioning. Specialized structure in the cytoplasm of type 2 pneumocytes. Storage of surfactants: ABCA3 protein is present on the surface of lamellar bodies involved in transport of surfactant and also involved in recycling and metabolism of surfactant. ABCA3 depends on Transcription factor TTF 1 (Thyroid Transcription factor 1)

Also read: An Overview Of Genetic Skin Disorders

What is Surfactant Dysfunction Disorder? 

Inherited disorders involving SP-B, SP-C, ABCA-3, or TTF-1 are collectively called surfactant dysfunctional disorders. They share common features, including:

• AEC2 hyperplasia
• Alveolar macrophages
• Interstitial thickening
• Inflammation
• Alveolar proteinosis

Genes coding for SP-D are not associated with any disease. Genes coding for SP-A are not associated with inherited or pediatric disease, although they may have a risk of interstitial pulmonary fibrosis or lung cancer in adults.

Surfactant Protein-B (SP-B) deficiency

Gene involved: SFTP-B on Chromosome-2

Type of mutation: 121 ins2: 2 Base pair insertion in codon 133 Leading to loss of function → SP-B deficiency. Mode of inheritance: Autosomal Recessive. Age of onset: at birth or early neonatal period (first 7 days of birth)

Clinical Presentation

RDS-like illness—clinically and radiologically

• Progressive tachypnea
• Expiratory grunting
• Increased work of breathing—chest retractions
• Progressive distress → Nasal flaring
• Cyanosis
• Poor response to oxygen alone

Chest X-ray shows:

• Air bronchogram
• Reticulonodular shadows
• Ground glass opacities

RDS-like illness affects full-term infants Refractory to

• Surfactant replacement therapy
• Ventilation
• Steroids

Exogenous/animal origin surfactant has lesser SP-B Hence, there is no response after surfactant replacement therapy in RDS-like illness Some genetic variants that have partial deficiency of SP-B can survive in heterozygous patients. Normal in childhood. Smoking in adulthood leads to obstructive lung disease.

Also read: Noonan Syndrome : Epidemiology, Genes Implicated

Investigations & Diagnosis

Investigation of choice Gene sequencing for SFTP-B gene

Other investigations: Tracheal aspirate

• Absent SP-B
• Incomplete processing of SP-C

Lung biopsy – on electron microscopy:

• Disorganized LBs
• Lack of tubular myelin
• Abnormal multivesicular bodies in type -2 pneumocytes

Treatment: Lung transplantation. If a transplant is not available Compassionate care

Surfactant Protein-C (SP-C) deficiency

Gene involved: SFTP-C gene on chromosome 8

Type of mutation:

• Substitution of Isoleucine by Threonine in codon 73
• Leads to the formation of misfolded Pro-SPC will not form SP-C

Mode of inheritance: Sporadic or Autosomal dominant

Age of onset: Birth to adulthood

Also read: Image Based Questions On Genetics

Clinical Presentation

Neonatal presentation: RDS-like illness

Early infancy or childhood presentation: Failure to thrive, Poor gain of height and weight, Progressive hypoxia and cyanosis; Progressive development of interstitial lung disease (ILD)

Adult-onset manifestation: After 18 years of age It can present as late as 50–60 years of age. Present as pulmonary fibrosis

Investigation of choice: Gene sequencing for SFTP-C gene

Treatment: Lung transplantation. If a transplant is not available, compassionate care

ABCA-3 Deficiency

Gene involved: ABCA-3 on chromosome 16.

Type of mutation: Loss of function

• Null mutations—very severe
• Missense mutation (codon 292)

Mode of inheritance: Autosomal recessive

Age of onset: at birth or infancy

Clinical Presentation

Neonatal presentation / Null mutation: RDS-like illness

Infant onset / Missense mutation: Progressive ILD

Investigation: Investigation of choice: Gene sequencing

Lung biopsy: Presence of small, dense LBS with eccentrically placed dense cores on electron microscopy Indicates that LBs are filled with surfactant

Treatment: Lung transplantation; If a transplant is not available - Compassionate care.

Also read: Genetic Disorders - Basics, Multifactorial/polygenic inheritance

Thyroid Transcription Factor -1 (TTF-1) deficiency

Gene involved: NKX-2 on chromosome 14

NKX-2 codes for TTF-1

TTF-1 is expressed in:

• Lung
• Thyroid
• Brain
• Lung involvement is common, severe, and generally the cause of death. In lung, TTF-1 is involved in the expression and production of
  • ABCA-3
  • Club cell secretory protein
  • Collectin proteins: involved in defense
• Type of mutations: Loss of function (LOF)
• Mode of inheritance: Sporadic or Autosomal dominant
• Age of onset: variable

Clinical Presentations

Respiratory involvement: Lethal neonatal RDS-like presentation or Progressive chronic lung disease in childhood, Recurrent pulmonary infections due to reduced pulmonary collection

Brain involvement: Hallmark: Chorea Onset is variable

• Hypotonia
• Ataxia
• Dysarthria
• Developmental delay

Rare cause of global developmental delay. Gross and fine motor milestones are more affected

Thyroid involvement: Hypothyroidism

If the lung, brain, and thyroid are affected by BTL syndrome (Brain-Thyroid-Lung),

Investigation: Investigation of choice: Gene sequencing

Treatment

• Supportive therapy
• Levothyroxine if hypothyroid

Also read: Microdeletion Syndromes Part-3 : Williams Syndrome

Important Points to Remember

• SP-B deficiency & ABCA-3 deficiency present with Acute disease
• SP-B deficiency—the closest differential diagnosis of RDS
• SP-C deficiency often causes Chronic progressive disease
• TTF-1 deficiency causes Multi-system disease
• SP-C deficiency & ABCA-3 deficiency have no specific drug therapy
• In ILD- presenting cases
• Drugs like Fluoroquinolones, Steroids, and Macrolides have been tried but not systemically evaluated

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