Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease (ORPHA:163746)
Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease (PCWH) is a systemic disease characterized by the association of the features of Waardenburg-Shah syndrome (WSS) with neurological features of variable severity.
Epidemiology
Prevalence is unknown. Less than 50 cases have been reported in the literature so far.
Clinical description
PCWH occurs in the neonatal and infancy period, and includes features of WSS (sensorineural hearing loss, iris heterochromia, skin hypopigmentation associated with Hirschsprung disease) and neurological features (neonatal hypotonia, intellectual disability of variable severity, nystagmus, progressive spasticity, ataxia and epilepsy). These signs are not fully penetrant (PCWH without Hirschsprung disease is sometimes referred as PCW), the depigmentation may not be obvious, and there is a broad range of severity for the neurologic features. Autonomic dysfunction (asialia, alacrima and hypohidrosis, bradycardia and arrhythmia) may also be present. Delayed white matter myelination is observed on brain magnetic resonance imaging (MRI), and may also be responsible for neuropathy at the peripheral level. MRI often shows defects of the semi-circular canals and agenesis of the olfactory bulbs. Kallmann syndrome can be associated.
Etiology
Most of the cases are caused by mutations involving the SOX10 gene (22q13.1, coding for the SOX10 transcription factor). Most frequently truncating mutations of the last coding exon induce escape from NMD (non-sense mediated mRNA decay), although a few gene deletions and missense mutations have also been described.
Diagnostic methods
Diagnosis is suspected on recognition of the clinical picture and should be confirmed by genetic molecular analysis.
Differential diagnosis
The disease overlaps with central or peripheral neuropathies/dysmyelination, and the diagnosis may be difficult in absence of the typical Waardenburg syndrome depigmentation.
Antenatal diagnosis
Prenatal diagnosis is possible by fetal DNA mutation analysis if a causal mutation is identified in a member of the family (either in case of an affected parent (a rare situation) or due to the risk of germline mosaicism).
Genetic counseling
The inheritance pattern of PCWH is autosomal dominant (parents of an affected individual have a probability of 50% to transmit the causal mutation to the offspring). Most cases are sporadic but a few patients with an affected sibling have been reported and are associated with germinal mosaicism in one of the parents. Genetic counseling should be offered to affected families in order to provide more information about this genetic condition, its risk of recurrence and the availability of prenatal diagnosis.
Management and treatment
Management is only symptomatic, consisting in the management of WS (protection from exposure to ultraviolet light, avoidance of sunburn, management of hearing loss), Hirschprung disease (surgical treatment) and the neurologic manifestations.
Prognosis
The prognosis and disease course may be severe with onset of deafness, intellectual disability and sometimes motor impairment. In rare cases, the disease is fatal shortly after birth. Long-term evolution in adulthood is not well established.

                            Last update: 
                            March 2018


                            - Expert reviewer(s): 
                            Dr Véronique PINGAULT