IllnessCornelia-de Lange syndrome, differential diagnosis

NGS +

Cornelia de Lange syndrome (CdL) is a developmental disorder that affects multiple organ systems or areas of the body. The symptoms vary widely and range from relatively mild to severe. CdL patients grow slowly before and after birth and exhibit moderate to severe intellectual disability in addition to short stature. The bones in the arms, hands and fingers are abnormally shaped. Most people with CdL have characteristic facial features with strongly arched eyebrows and synophrys, long eyelashes, low-set ears, small and spaced teeth including a small snub nose. Behavioral abnormalities are common and resembe autism. Hypertrichosis, microcephaly, hearing loss and digestive malfunctions occur, as do cleft palate, seizures, heart defects and eye problems. CdL is likely underdiagnosed because affected individuals with mild or unusual features may never be recognized. The syndrome can result from mutations in at least five genes: NIPBL, SMC1A, HDAC8, RAD21 and SMC3, with mutations in the NIPBL gene occurring in more than half of all patients. SMC1A, RAD21 and SMC3 mutations cause milder symptoms. HDAC8 mutations cause delayed closure of the anterior fontanel, hypertelorism, dental abnormalities and significant intellectual disability. Thus CdL features vary widely, and severity can be markedly different even among individuals with the same gene mutation. CdL is caused by autosomal or X-linked dominant acting mutations. In approximately 30% of cases, the cause of CdL remains unknown, so a negative DNA test result does not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1104/

• CDLS: Facial dysmorphism, low anterior hairline, arched eyebrows, synophrys, anteverted nares
• CDLS: Maxillary prognathism, long philtrum, thin lips/carp mouth, pre-/postnatal growth retardation
• Alazami-Yuan syndrome (TAF6)
• Alias: Brachmann-de Lange-Syndrom
• Alias: Cornelia de Lange like syndrome 2 AFF4)
• Alias: Mental retardation + upper limb anomalies
• Allelic: Dystonia-Parkinsonism, XL (TAF1)
• Allelic: Epileptic encephalopathy, infantile, 85, midline brain defects (SMC1A)
• Allelic: Mungan s.: Pseudoobstruction, chronic intest., Barrett esophagus, cardiac abnorm. (RAD21)
• Allelic: Myelodysplastic syndrome, somatic (ASXL1)
• Bohring-Opitz syndrome [malformations, severe intrauterine growth retardation] (ASXL1)
• CHOPS [Cognitive, Coarse face, Heart, Obesity, Pulmonary, Short, Skeletal ] syndrome (AFF4)
• Cornelia de Lange syndrome 1 (NIPBL)
• Cornelia de Lange syndrome 2 (SMC1A)
• Cornelia de Lange syndrome 3 (SMC3)
• Cornelia de Lange syndrome 4 / Cohesinopathy (RAD21)
• Cornelia de Lange syndrome 5 (HDAC8)
• Cornelia de Lange-like syndrome [MONDO:0016033] (BRD4)
• KBG syndrome [Short stat.-facial + skeletal anomalies-intellectual disability-macrodontia] (ANKRD11)
• Menke-Hennekam syndrome 2 (EP300)
• Mental retardation, XL, syndromic 33 [dysmorphism, intell. disab., neurological signs] (TAF1)
• Multiple congenital anomalies-hypotonia-seizures syndrome 1 (PIGN)
• Rubinstein-Taybi syndrome 2 (EP300)