Microdeletion Syndromes Part-3 : Williams Syndrome,  Rubinstein Taybi Syndrome, Smith Magenis  Syndrome

What Are Microdeletion Syndromes?

• Microdeletion syndromes arise due to deletions smaller than  5 Mbps from a gene. These diseases are not identified by conventional karyotyping. The microdeletion syndromes are best diagnosed using FISH ( Fluorescent In Situ Hybridization).

Key Microdeletion Syndromes

• DiGeorge Syndrome/Velocardiofacial Syndrome
• Williams Syndrome
• Prader-Willi Syndrome (microdeletion occurs in the long arm of chromosome 15)
• Angelman Syndrome (microdeletion occurs in the long arm of chromosome 15)
• Rubinstein-Taybi Syndrome
• Smith-Magenis Syndrome
• Miller-Dieker Syndrome (involvement of CNS)
• Wolf-Hirschhorn Syndrome
• Microdeletions can also lead to- NF-1, Rett Syndrome, Fragile X Syndrome
• NF-1 is not a microdeletion syndrome. Rarely it can be caused due to microdeletion, but the sole cause of the disease is usually something different.

Williams Syndrome

It is also called William Beuren Syndrome. It is a microdeletion syndrome involving chromosome 17q11.23. The area involves multiple genes; the ELN gene is the most important among the ones deleted. ELN gene codes for the elastin protein. Elastin protein is the key component of connective tissues, especially in the dermis, Tunica Media, and Tunica adventitia of the muscular arteries of the large vessels. It is also involved in pathophysiological processes related to calcium metabolism.  Hence the loss of the ELN gene leads to characteristic facies, CVS disease, and connective tissue abnormalities. Most cases are due to de novo mutations. Some cases may show parent-to-child transmission. In such families, an autosomal dominant pattern is most common.

Clinical Features

Facial characteristic : The characteristic facial feature in Williams Syndrome is called Elfin Facies. This refers to an elf-like face. The features of such a face are: Broad forehead, Flat nasal bridge (usually broad). Thin but long smooth philtrum. The wide oral aperture is more prominent in the upper lip. The fullness of the cheeks. Some have small mandibles. Widely spaced peg-like teeth.

Facial features in Williams syndrome. Two special ocular findings or eye characteristics are seen in these children. They are: Periorbital puffiness (without diurnal variation). The stellate pattern in the iris. The stellate pattern of the iris.

1. Neurobehavioral problems:

• These children have low IQ that usually ranges between 41 to 80. Rare patients may have severe mental retardation, and occasional patients may also have a near-normal IQ. These children may have visuospatial deficits, especially in drawing and pointing in/at complex figures.
• They have a loquacious personality (Nelson) or overtly social or cocktail personality (other textbooks). Cocktail personality means over-friendly, over-talkative behaviour with loss of inhibition. They are sometimes referred to as always happy. Relative spasticity in the limbs is seen. They may have abdominal muscle hypotonia that tends to improve with age. This is usually seen in early life.

2. Systemic features:

• 75 to 80% of patients with Williams syndrome present with cardiovascular abnormalities. The most common CVS abnormality seen in them is supravalvular aortic stenosis. Idiopathic hypercalcemia of infancy is a common endocrine dysfunction in these children which often progresses to produce nephrocalcinosis as well. They may be present with hypertension.They have an increased risk of hernias. 

A few rare but known features of Williams syndrome include:

• Increased risk of hypothyroidism.
• Joint hypermobility due to connective tissue dysfunction.
• Branch pulmonary artery stenosis. 
• Progressive pulmonary hypertension (rare). 
• Hypoplastic nails.

Also Read: Uniparental Disomy And Related Disorders ">Genomic Imprinting, Uniparental Disomy And Related Disorders 

Rubinstein Taybi Syndrome

• It is a microdeletion syndrome involving chromosome 16p13.3 (the short arm of chromosome 16 is implicated here). More than 90% of cases occur due to mutations or deletions in the CREB-BP gene (BP-binding protein). Rare cases arise due to mutations involving the EP 300 G. Most cases are due to de novo mutations. Some cases show autosomal dominant patterns of inheritance, but it is rare. Mosaicism has also been described.

Clinical Features 

• Abnormal facial features presented are: Prominent forehead, well-developed arching eyebrows. The antimongoloid slant of eyes (seen in patients of CREB-BP gene mutation and mainly in boys). Prominent nose with excessively long overhanging columella. The fullness of cheeks. The characteristic grin on opening the mouth.

Abnormal facial features are seen in Rubinstein-Taybi syndrome. 

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The limb abnormalities seen in Rubinstein Taybi syndrome are: Abnormal thickening of distal phalanges . Abnormal thick and stubby thumbs with radial deviation bilaterally. Abnormal large and squared-off great toe, bilaterally. Other features seen include: Undescended testis. Low IQ in the vast majority. Renal and cardiovascular anomalies. (CVs anomalies mostly as septal defects).

Also Read: Marfan Syndrome : Signs, Diagnosis, Management and Prognosis

Smith Magenis  Syndrome

• It is also called 17p- syndrome. This disease is a microdeletion syndrome involving chromosome 17p11.2. It leads to the loss of function of RAI-1 (Retinoic Acid Induced-1 gene). This gene plays an important role in cell-cell interaction and checking normal circadian rhythm. Most cases are due to spontaneous mutations and are not inherited.

Clinical Features

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• The abnormal facial features seen in patients with this disease are: Arching eyebrows with or without mongoloids slant of eyes. Flat nasal bridge with a prominent distal nasal segment. Short philtrum with an appearance of upper lip almost touching the columella. Thickened upper lip with a characteristic grin. 
• The neurobehavioral problems seen in these patients are: Normal to low IQ. The hallmark neurological finding here is abnormal or disturbed circadian rhythm. Hyperactivity and self-mutilating behaviour.The lick-flick phenomenon is seen as an irresistible urge.The self-embracing phenomenon is often exhibited.Rarely mentally retarded.They tend to notice particular points or fine points about people or their surroundings which normal people cannot.They usually don't have cardiovascular and other congenital malformations.

Also Read: Aneuploidies Including Turner And Klinefelter Syndrome

Miller Dieker Syndrome 

• It is a microdeletion syndrome involving Chromosome 17p13.3.The gene deleted is LIS-1, also called PAFAH1B1. A hallmark feature of this condition is a neuronal migration disorder called Lissencephaly or Agyria (the normal sulci and gyri pattern of the brain is lost, and it has an abnormally smooth brain with abnormalities of Sylvian fissure). According to Nelson 21st Ed, about 15% of Lissencephaly cases are association with underlying Miller Dieker Syndrome.

MRI of a patient with Miller Dieker syndrome. 

Clinical Features

• The features of abnormal facies are: A prominent forehead with bitemporal hollowing. Anteverted nostrils.Prominent upper lip. Micrognathia. Low set posteriorly reverted ears.

The neurological problems present in these children due to lissencephaly are:- Developmental delay and low IQ.Seizures. Feeding difficulties. Progressive spasticity. Spasticity is usually a rare feature, and most patients tend to die because of neurological causes in the first decade of life. 

Also Read: Infections of the Upper Airway- Common Cold and Sinusitis

Wolf Hirschhorn Syndrome

It is a microdeletion syndrome involving Chromosome 4p16.3. The genes deleted are WHSCR-1 and 2. Key Features: Hypertelorism, wide prominent forehead, small narrow philtrum, small jaw or micrognathia, some have low-set ears, mental retardation is absent or mild. 

Rare features include some degree of congenital heart diseases like a septal defect or short stature and scoliosis.

Also Read: KEY POINTS AND RECOMMENDATIONS IN PEDIATRIC ADVANCED LIFE SUPPORT

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.