CHEDDA syndrome

Last revised by Tania Mercado Avendaño on 19 Jul 2020

CHEDDA syndrome stands for congenital hypotonia, epilepsy, developmental delay and digital anomalies. Is a newly discovered neurodevelopmental syndrome associated with mutations in a conserved histidine-rich motif within Atrophin-1 (ATN-1).1

CHEDDA syndrome is very rare, with only eight cases reported since its identification in 2007 making any sensible estimate of prevalence or demographic predilection difficulty. Typically, presentation is within the first three months of life. 

CHEDDA syndrome's clinical presentation includes:

  • global developmental delay
  • truncal hypotonia
  • feeding difficulties
  • intellectual disability
  • epilepsy
  • facial dysmorphisms: a relative lack of lateral forehead hair, a tall forehead with bitemporal narrowing, down-slanting and small palpebral fissures with inferior epicanthic folds and deeply set eyes, low-set and malformed ears, flat nose, prominent columella, bulbous nasal tip, cleft palate, thin upper lip, long philtrum, and retrognathism 1-3
  • short neck
  • stenosis of the craniocervical junction
  • digital abnormalities: camptodactyly, palmar creases, bulbous endings to the fingers and toes, and overlapping toes 3
  •  global motor disability
  • minimal verbal communication

Genetic analysis of patients diagnosed with CHEDDA syndrome demonstrates various missense and insertion mutations in a conserved histidine-rich motif within Atrophin-1 (ATN-1) resulting in a toxic gain-of-function mutation in the Atrophin1 protein, leading to neurotoxicity. ATN-1  is known to have a role as a critical nuclear transcriptional regulator involved in the regulation of organ development, including the development of the brain and heart, lungs, kidneys and the reproductive organs. It interacts with other important transcription factors which regulate gene expression, including proto-oncogenes involved in acute myeloid leukaemias. ATN-1 also interacts with other suppressors and co-repressors implicated in neuronal migration, development, and patterning.1,3

  • the presence of a mutation in ATN-1 suggests that CHEDDA may be related to dentatorubral-pallidoluysian atrophy (DRPLA), which is also associated with mutations in ATN-1.
  • Pierre–Robin anamaloid association has been reported.1

Antenatal ultrasound may show polyhydramnios or/and a combination of some of the above clinical features.1

Cerebral atrophy with markedly prominent supratentorial and infratentorial subarachnoid spaces and third ventricles, dysplastic tectum, thinning of the corpus callosum, small brainstem and hypoplasia of the cerebellum including the vermis, absence of the falx cerebri and polymicrogyria that appear more severe in the perisylvian regions.1,2

CHEDDA syndrome has an uncertain but probably poor prognosis.

Smith–Lemli–Opitz syndrome: presents with low serum cholesterol, slow growth, microcephaly, facial dysmorphisms, cleft palate, heart defects, polydactyly, and underdeveloped genitalia in males. In contrast, cholesterol levels in CHEDDA syndrome are normal.1

Pallister-Killian syndrome has a very similar presentation to CHEDDA syndrome (severe cognitive impairment, congenital anomalies including cleft palate, polymicrogyria, limb abnormalities, and cardiac defects).1

NEDBEH, or neurodevelopmental disorder with or without anomalies of the brain, eye, or heart. its main features include  intellectual disability, delayed development, optic abnormalities (colobomas or optic nerve hypoplasia), and cardiac abnormalities (ventral septal defects).1

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