Moderate short stature, facial +/- genital

Flashcards covering key vocabulary, characteristics, etiology, and associated conditions of Williams Syndrome and Noonan Syndrome based on the provided lecture notes.

What is Williams Syndrome (WS)?

A rare neurodevelopmental disorder characterized by a specific triad: 'elfin facies,' a unique cognitive/behavioral profile, and cardiovascular anomalies (especially Supravalvular Aortic Stenosis).

What is the genetic cause of Williams Syndrome?

Williams Syndrome is caused by a heterozygous microdeletion on chromosome 7q11.23, typically spanning 1.55-1.8 Mb and affecting 25-27 genes, including ELN (elastin).

What is the prevalence and diagnostic method for Williams Syndrome?

WS has a prevalence of 1 in 10,000 to 1 in 20,000 live births. Diagnosis relies on molecular genetic testing (e.g., FISH or chromosomal microarray) to confirm the 7q11.23 deletion.

What is Supravalvular Aortic Stenosis (SVAS)?

SVAS is a congenital narrowing of the ascending aorta just above the aortic valve. It is the most common and clinically significant cardiovascular anomaly in Williams Syndrome, occurring in ~75% of affected individuals.

What causes SVAS in Williams Syndrome?

SVAS is directly caused by haploinsufficiency of the elastin gene (ELN) at 7q11.23. Reduced elastin leads to disorganized and thickened arterial walls.

What are the clinical implications of SVAS?

SVAS can lead to left ventricular hypertrophy, aortic insufficiency, and myocardial ischemia. It requires close cardiological monitoring with echocardiograms and often surgical repair to prevent progressive cardiac dysfunction.

What are the ocular facial features typical of Williams Syndrome?

Ocular features include periorbital fullness, deep-set eyes, blue irises with stellate or 'lacy' patterns, medial eyebrow flare, and epicanthal folds.

Describe the nasal and midface features in Williams Syndrome.

Typical nasal features include a depressed nasal bridge and anteverted nares (upturned nostrils). Midface features often show a long, smooth philtrum and full cheeks.

What are the oral facial features characteristic of Williams Syndrome?

Oral features include full, prominent lips with a wide, often open mouth, along with potential microdontia or other dental abnormalities.

How is the cognitive profile described in Williams Syndrome?

The cognitive profile is 'spiky,' meaning there are significant strengths and weaknesses. The average full-scale IQ typically falls between 50 and 70 (around 60).

What are the behavioral and language strengths in Williams Syndrome?

Strengths include a highly gregarious and empathetic personality ('cocktail party personality'), strong social drive, excellent facial recognition, and exceptional expressive language skills with rich vocabulary and good rote memory.

What are the key cognitive and sensory weaknesses in Williams Syndrome?

Weaknesses include profound visuospatial constructional deficits, impaired numerical cognition (difficulty with math), and auditory hypersensitivity (hyperacusis).

What behavioral challenges are common in Williams Syndrome?

Common behavioral challenges include generalized anxiety, specific phobias (e.g., to loud noises or heights), and attention-deficit/hyperactivity disorder (ADHD).

How is the behavioral phenotype of Williams Syndrome managed?

Management requires a multidisciplinary approach, including behavioral therapy, psychiatric support for anxiety, and targeted educational strategies to address specific cognitive difficulties.

What is the primary genetic event causing Williams Syndrome?

WS results from a de novo heterozygous microdeletion at chromosome 7q11.23 in about ~95% of cases, arising from non-allelic homologous recombination (NAHR) during meiosis. ~5% are inherited in an autosomal dominant manner.

What is the role of the ELN gene in Williams Syndrome?

Haploinsufficiency of the ELN (elastin) gene is responsible for connective tissue abnormalities and vascular stenoses, most notably Supravalvular Aortic Stenosis (SVAS).

What are the roles of other genes in the Williams Syndrome deletion?

Other deleted genes include LIMK1 (implicated in visuospatial deficits), GTF2I and GTF2IRD1 (contribute to cognitive/behavioral features), and NCF1 (may modulate blood pressure when deleted).

What does 'elastin gene hemizygosity' mean in WS?

It means individuals with Williams Syndrome have only one functional copy of the ELN gene due to the microdeletion, resulting in ~50% of normal elastin protein levels. Elastin is crucial for arterial elasticity and tissue resilience.

How does ELN hemizygosity impact the vascular system?

It causes vascular stenoses, including SVAS and peripheral pulmonary stenosis, as well as narrowing in renal, cerebrovascular, and coronary arteries. Arterial walls become thickened, stiff, and prone to narrowing.

What other clinical impacts result from ELN hemizygosity?

It contributes to distinctive facial features, a hoarse voice, and sometimes joint laxity. It can also contribute to hypertension, especially with renal arterial stenosis. Regular cardiovascular monitoring is essential.

What is 7q11.23 Microduplication Syndrome?

This is the reciprocal genetic disorder to Williams Syndrome, caused by a duplication (three copies) of the same ~1.55-1.8 Mb region on chromosome 7q11.23. It involves increased gene dosage.

Describe the neurodevelopmental and language phenotype of 7q11.23 Microduplication Syndrome.

Patients exhibit global developmental delay and intellectual disability (often severe). A striking feature is severe expressive language delay, which contrasts with WS language strengths.

What are the behavioral and neurological features of 7q11.23 Microduplication Syndrome?

Common features include a high prevalence of autism spectrum disorder (ASD), ADHD, anxiety, seizures, and hypotonia. Dysmorphic features are often subtle and non-specific.

What is Noonan Syndrome (NS)?

Noonan Syndrome is an autosomal dominant neurodevelopmental disorder (a Rasopathy) caused by gain-of-function mutations in RAS-MAPK pathway genes. It features characteristic facial appearance, congenital heart defects, and short stature.

What is the genetic basis of Noonan Syndrome?

NS is part of the 'Rasopathies,' a group of disorders caused by germline gain-of-function mutations in genes of the RAS-MAPK signaling pathway, leading to constitutive pathway activation.

What are Rasopathies?

Rasopathies are genetically heterogeneous Mendelian disorders caused by germline mutations in genes encoding components of the RAS-MAPK signaling pathway. This pathway controls cell proliferation, differentiation, and survival.

Name some common conditions within the Rasopathies spectrum.

Common Rasopathies include Noonan Syndrome, Noonan Syndrome with Multiple Lentigines (LEOPARD syndrome), Costello syndrome, cardiofaciocutaneous (CFC) syndrome, and neurofibromatosis type 1 (NF1).

What are the shared clinical features across Rasopathies?

They share overlapping phenotypes: craniofacial dysmorphism, congenital heart defects, cutaneous abnormalities, developmental delays, intellectual disability, and increased risk for certain malignancies like Juvenile Myelomonocytic Leukemia (JMML).

Describe short stature in Noonan Syndrome.

Short stature affects 50-70% of individuals with NS, with postnatal onset. Final adult height is typically significantly below average ($-2.0$ to $-4.0$ SDS).

What causes short stature in Noonan Syndrome?

It's due to multifactorial dysregulation of the growth hormone (GH) / insulin-like growth factor-1 (IGF-I) axis, including relative GH resistance and sometimes impaired GH secretion. Feeding difficulties in infancy also contribute.

How is short stature managed in Noonan Syndrome?

Management involves monitoring with NS-specific growth charts and baseline GH/IGF-I evaluation. Growth hormone therapy is approved for NS and can improve adult height, with variable response.

How prevalent and impactful are cardiac defects in Noonan Syndrome?

Congenital heart defects affect 80-90% of NS patients and are the primary cause of morbidity and mortality. Lifelong cardiological surveillance is required.

What is the most common cardiac defect in Noonan Syndrome?

Pulmonary Valve Stenosis (PVS) occurs in ~50-60% of cases. It's characterized by a dysplastic, thickened valve causing right ventricular outflow obstruction. PTPN11 mutations are strongly associated with PVS.

Describe Hypertrophic Cardiomyopathy (HCM) in Noonan Syndrome.

HCM occurs in ~20-30% of cases, involving asymmetrical ventricular wall thickening leading to outflow obstruction and diastolic dysfunction. It carries a risk of arrhythmias and sudden cardiac death. RAF1 and RIT1 mutations are commonly associated.

What other cardiac defects occur in Noonan Syndrome, and how are they managed?

Other defects include atrial septal defect (ASD) (~10-15%), ventricular septal defect (VSD), and tetralogy of Fallot. Management may involve pharmacological treatment, interventional procedures (e.g., balloon valvuloplasty), or surgical repair. Genotype-phenotype correlations guide strategies.

What is the inheritance pattern and genetic cause of Noonan Syndrome?

NS is an autosomal dominant disorder, with ~50% inherited and ~50% de novo mutations. It's caused by gain-of-function variants in RAS-MAPK signaling pathway genes, leading to constitutive pathway hyperactivation.

What is the most common gene mutation in Noonan Syndrome?

Gain-of-function mutations in the PTPN11 gene account for 40-50% of NS cases. PTPN11 encodes SHP2, a positive regulator of RAS-MAPK signaling.

Name other key genes mutated in Noonan Syndrome.

Other significant causative genes include SOS1 (10-15% of cases), RAF1 (5-10%, often linked to HCM), RIT1 (~5%), and less commonly LZTR1, NRAS, KRAS, MAP2K1, and BRAF. Each mutation can influence specific phenotypic variations.

What is the role of PTPN11 mutations in NS?

Mutations in the PTPN11 gene, which encodes SHP2 protein, lead to its constitutive activation or reduced autoinhibition. This causes aberrant, prolonged activation of the RAS-MAPK pathway, contributing to developmental anomalies.

What is the mechanism of PTPN11 mutations in NS?

They are typically missense variants (often in exon 3 or 8) that induce a conformational change in SHP2, leading to its constant activation and thus sustained RAS-MAPK signaling.

What are the clinical impacts associated with PTPN11 mutations?

PTPN11 mutations are strongly associated with Pulmonary Valve Stenosis (PVS) and an increased risk of Juvenile Myelomonocytic Leukemia (JMML), particularly mutations at codons Asp61 or Asp63.

What is Juvenile Myelomonocytic Leukemia (JMML)?

JMML is a rare, aggressive, and often fatal myeloproliferative disorder affecting young children. It is a severe complication in Noonan Syndrome and other Rasopathies.

What is the genetic association of JMML with NS/Rasopathies?

JMML arises from germline gain-of-function mutations in RAS-MAPK pathway genes, most notably PTPN11 (especially at Asp61/Asp63), NRAS, and less commonly CBL.

What are the clinical characteristics and prognosis of JMML?

JMML is characterized by uncontrolled proliferation of myeloid/monocytic cells, leading to splenomegaly, hepatomegaly, and lymphadenopathy. Symptoms include fever, rash, bleeding. It has a poor prognosis with conventional chemotherapy.

How is JMML managed and surveilled in NS patients?

Definitive treatment often requires allogeneic hematopoietic stem cell transplantation (HSCT). Due to high risk, patients with associated PTPN11, NRAS, or CBL mutations require careful hematological surveillance during early childhood.

What are the common ocular facial features in Noonan Syndrome?

Ocular features include epicanthal folds, bilateral ptosis (droopy eyelids), hypertelorism (widely spaced eyes), and downslanting palpebral fissures.

Describe the nasal and auricular features in Noonan Syndrome.

Nasal features include a low nasal bridge and broad base. Auricular (ear) anomalies often show low-set, posteriorly rotated, or abnormally shaped auricles with thickened helices and prominent antihelices.

What are the oral and neck features typical of Noonan Syndrome?

Oral features include a prominent upper lip with a 'Cupid's bow' shape, a deep philtrum, and moderate retrognathia (receding chin). Neck features often include a short neck, sometimes with webbing (pterygium colli) and a low posterior hairline.