What syndromes are associated with both cognitive or developmental delay and hypertelorism?

Syndromes Associated with Cognitive Delays and Hypertelorism

The most common syndromes presenting with both cognitive/developmental delay and hypertelorism are Noonan syndrome, 22q11.2 deletion syndrome (DiGeorge/Shprintzen), cardio-facio-cutaneous (CFC) syndrome, ICF syndrome, and CHARGE association, with Noonan syndrome being the most prevalent at 1:1,000-2,500 live births. 1

Primary Syndromes to Consider

Noonan Syndrome

• Hypertelorism with down-slanting palpebral fissures and ptosis are hallmark facial features, occurring in 68% and 56% of patients respectively 2
• Cognitive impairment ranges from mild intellectual deficit to borderline intelligence, with learning disabilities being common 1, 3
• Caused by PTPN11 gene mutations in >50% of cases, with additional mutations in SOS1, RAF1, or KRAS genes 1
• Incidence is 1:1,000-2,500 live births, making it the most common syndromal cause of congenital heart disease after Down syndrome 3, 4
• Associated features include short stature, webbed neck, pulmonary stenosis, and hypertrophic cardiomyopathy 1

22q11.2 Deletion Syndrome (DiGeorge/Shprintzen/CATCH-22)

• Characterized by partial deletion of chromosome 22q11.2, affecting approximately 1:2,000-4,000 live births 1, 5
• Cognitive profile shows borderline intellectual functioning (IQ 70-84) in the majority, with one-third having mild to moderate intellectual disability 5
• Facial features include malar flatness, upslanting palpebral fissures, and hooded eyelids, though hypertelorism is less prominent than in other syndromes 1
• Motor delays, speech/language deficits, and learning difficulties are commonly observed from infancy onward 5
• Associated with velopharyngeal incompetence, congenital heart disease (particularly conotruncal anomalies), and immunodeficiency 1, 6

Cardio-Facio-Cutaneous (CFC) Syndrome

• Hypertelorism, downslanting palpebral fissures, ptosis, and epicanthal folds are characteristic ocular features 1
• Marked cognitive delay and intellectual disability are more severe and frequent compared to Noonan syndrome 1
• Distinctive features include coarse facial features, sparse curly/friable hair, and follicular hyperkeratosis (ulerythema ophryogenes) 1
• Caused by mutations in BRAF, MEK1, MEK2, or KRAS genes 1
• Prenatal findings include increased nuchal lucency, cystic hygroma, and polyhydramnios in 77% of cases 1

ICF Syndrome (Immunodeficiency, Centromeric Instability, Facial Anomalies)

• Hypertelorism, epicanthal folds, low-set ears, and flat nasal bridge occur in approximately 90% of patients 1
• Developmental delay or cognitive impairment is present in about two-thirds of patients 1
• Hypogammaglobulinemia occurs in most patients (39/44 in one series), with frequent bacterial respiratory infections 1
• Caused by mutations in DNMT3B gene (ICF1) in 60% of cases or ZBTB24 gene (ICF2) 1
• Growth retardation occurs in approximately half of patients 1

CHARGE Association

• Growth and developmental delay are core features, along with coloboma of the eye, heart defects, and choanal atresia 1
• Caused by autosomal dominant mutations in the CHD7 gene 1
• The acronym CHARGE represents: Coloboma, Heart defects, Atresia choanae, Growth/developmental delay, Genital abnormalities, and Ear abnormalities 1

Additional Syndromes with Overlapping Features

Noonan Syndrome with Multiple Lentigines (formerly LEOPARD syndrome)

• Shares hypertelorism, short stature, pulmonary stenosis, and hypertrophic cardiomyopathy with classic Noonan syndrome 1
• Some patients have cognitive delay, though less frequently than in CFC syndrome 1
• Distinguished by multiple skin lentigines, frequent sensorineural deafness, and cardiac conduction abnormalities 1

Baraitser-Winter Syndrome

• Features hypertelorism, ptosis, short stature, and cognitive delay 1
• Distinguished from CFC by iris coloboma, lissencephaly, pachygyria, and aortic valve anomalies 1

Nijmegen Breakage Syndrome (NBS)

• Characterized by microcephaly, characteristic facies, growth retardation, and cognitive impairment 1
• Caused by mutations in NBS1 gene, with prominent immunodeficiency as a distinguishing feature 1
• Part of the chromosomal repair disorders with increased cancer predisposition 1

Clinical Approach and Diagnostic Pitfalls

Key Distinguishing Features

• Noonan syndrome typically has less severe cognitive impairment and fewer cutaneous features compared to CFC syndrome 1
• CFC syndrome shows more pronounced follicular hyperkeratosis, sparse eyebrows, and marked cognitive delay 1
• ICF syndrome is distinguished by prominent immunodeficiency with hypogammaglobulinemia and recurrent infections 1
• 22q11.2 deletion syndrome has characteristic cardiac (conotruncal) and immunologic (thymic hypoplasia) features 1

Important Caveats

• Facial features in many of these syndromes become less pronounced with age, making early recognition critical 1
• Genetic testing is essential for definitive diagnosis, as clinical overlap between RASopathies (Noonan, CFC, Costello syndromes) is substantial 1
• Chromosome microarray analysis should be considered if initial gene-specific testing is negative 1
• Whole exome or genome sequencing may be warranted when standard genetic testing is unrevealing 1