CHEDDA syndrome stands for congenital hypotonia, epilepsy, developmental delay and digital anomalies, and is a neurodevelopmental syndrome associated with mutations in a conserved histidine-rich motif within atrophin-1 (ATN1) ¹.

Epidemiology

CHEDDA syndrome is very rare, with only a handful of 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. 

Clinical presentation

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

Autopsy findings

• patent foramen ovale with persistent left superior vena cava

• left renal hypoplasia

• microphthalmia ² 

Pathology

Genetic analysis of patients diagnosed with CHEDDA syndrome demonstrate various missense or insertion mutations in a conserved histidine-rich motif within atrophin-1 (ATN1), resulting in a toxic gain-of-function mutation in the atrophin-1 protein, leading to neurotoxicity. ATN1 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. ATN1 also interacts with other suppressors and co-repressors implicated in neuronal migration, development, and patterning ^1,3.

Associations

• the presence of a mutation in ATN1 suggests that CHEDDA syndrome may be related to dentatorubral-pallidoluysian atrophy (DRPLA), which is also associated with mutations in ATN1

• Pierre-Robin anamaloid association has been reported ¹

Radiographic features

Ultrasound

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

CT and MRI

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.

Treatment and prognosis

There is no disease-modifying treatment. CHEDDA syndrome has an uncertain but probably poor prognosis.

Differential diagnosis

• 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 (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