PEHO syndrome (ORPHA:2836)
A rare early childhood onset progressive encephalopathy characterized by extreme cerebellar atrophy, infantile-onset hypotonia, infantile spasms with hypsarrhythmia, profound intellectual disability, and optic atrophy. PEHO stands for the main features of the syndrome: Progressive encephalopathy with Edema, Hypsarrhythmia and Optic atrophy.
Epidemiology
PEHO syndrome is enriched in the Finnish population, where the minimum incidence is estimated at 1 in 74,000. A few patients have been described from other countries including Estonia, The Netherlands, and Spain, but mainly before the molecular genetic analysis or neuroimaging techniques were available.
Clinical description
Onset occurs during the first few weeks or months of life with hypotonia, poor feeding, drowsiness and abnormal movements. Infantile spasms, hypsarrhythmia and seizures appear during the first year of life. Visual loss, abnormal eye movements and optic atrophy also occur during infancy. Other features include early arrest of psychomotor development, severe intellectual deficit, microcephaly, edema (particularly of the extremities), tapered fingers and facial dysmorphism (including a 'Pear-shaped' face with a narrow forehead and full cheeks, receding chin, epicanthic folds, an open mouth with a curved upper lip, protruding ear lobes and a short nose with anteverted nostrils).
Etiology
PEHO syndrome is an autosomal recessive disorder caused by mutations in the ZNHIT3 gene. ZNHIT3 encodes an evolutionarily conserved nuclear protein implicated in transcription regulation and chromatin remodeling.
Diagnostic methods
Diagnosis is based on molecular genetic testing. The clinical diagnostic criteria include: early-onset severe hypotonia; the occurrence of seizures, infantile spasms and hypsarrhythmia after the first two weeks of life; onset of optic atrophy before two years of age; and failure to obtain any of the milestones for motor, visual and language development. An additional criterion is demonstration of cerebellar and brainstem atrophy by MRI.
Differential diagnosis
A significant number of patients have been described as displaying most of the diagnostic criteria and features of PEHO syndrome, but without the typical changes in neuroimaging studies, or without ophthalmologic signs. This group of patients was diagnosed with PEHO-like syndrome. NESCAV syndrome also presents with PEHO-like features. The differential diagnosis should also include Aicardi syndrome, mevalonic aciduria, the carbohydrate-deficient glycoprotein (CDG) syndromes, autosomal recessive cerebellar hypoplasia, Joubert syndrome and olivo-pontine cerebellar atrophies.
Antenatal diagnosis
Prenatal diagnosis is available for the families with identified pathogenic variants.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic only. The infantile spasms are refractory to antiepileptic drugs or adrenocorticotropic hormone (ACTH) therapy.
Prognosis
The prognosis is poor and most patients die before 15 years of age, mainly as a result of pneumonia or aspiration.

                            Last update: 
                            April 2024


                            - Expert reviewer(s): 
                            Dr Anna-Kaisa ANTTONEN | ITHACA*


                                * European Reference Network