Peripheral Demyelinating Neuropathy, Central Dysmyelination, Waardenburg Syndrome, And Hirschsprung Disease

A number sign (#) is used with this entry because of evidence that peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH) is caused by heterozygous mutation in the SOX10 gene (602229) on chromosome 22q13.

Allelic disorders include Waardenburg syndrome type 2E (WS2E; 611584) and Waardenburg syndrome type 4C (WS4C; 613266).

Description

PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see 118200), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see 142623) (Inoue et al., 2004). Inoue et al. (2004) proposed the acronym PCWH for this disorder.

Clinical Features

Inoue et al. (1999) reported an 11-year-old Japanese girl with Waardenburg-Shah syndrome and neurologic abnormalities, including severe leukodystrophy suggestive of Pelizaeus-Merzbacher disease (312080) and peripheral neuropathy consistent with Charcot-Marie-Tooth disease type I (see 118200). The patient was born at near term, weighing 2.1 kg, and presenting with neonatal asphyxia with an Apgar score of 4 at 5 minutes. Soon after birth, a series of operations were performed to correct her long-segment Hirschsprung disease. She also had heterochromia iridis, profound neurosensory deafness, a broad nasal root, and dystopia canthorum. She had severe developmental delay and never held her head upright or crawled or sat alone. She had been bedridden since birth with spastic quadriplegia. Loss of deep tendon reflexes and sensory dullness suggested peripheral neuropathy. Electrophysiologic studies showed reduced motor nerve conduction velocities in all nerves tested. The muscles in all limbs were severely atrophic. Protein in the cerebrospinal fluid was elevated to 62 mg/dl. She had no auditory brainstem response bilaterally. Head MRI scanning showed prominent deficiency of myelination in the entire brain.

Touraine et al. (2000) reported 3 unrelated patients from Europe with a neurologic variant of Waardenburg-Shah syndrome. The first patient had early delayed developmental milestones, nystagmus, myopia, reduced tear production, hypotonia, and growth deficiency. In addition to extensive intestinal aganglionosis, deafness, iris heterochromia, and hypomelanic skin patches consistent with Waardenburg-Shah syndrome, the patient developed cerebellar ataxia, spasticity, and severe mental retardation. Evidence of autonomic dysregulation was also found. There was almost no local reaction to the histamine test. He developed hepatosplenomegaly and portal hypertension of unknown origin. Three other boys who were members of his family had died during the first week of life; they had intestinal obstruction and it was likely that they had Waardenburg syndrome, since the third child had patchy depigmentation of the scalp and white hair. Neither the mother nor any other family member had any signs of WS or Hirschsprung disease. The second patient was initially diagnosed with short-segment aganglionosis; he then presented with myoclonus at age 2 weeks. He later developed nystagmus, head bobbing, and paroxysmal movement of the upper limbs. On the basis of a later occurrence of torticollis and the benign course of the nystagmus, head bobbing, and paroxysmal movement, a putative diagnosis of spasmus nutans was made. Ataxia, spasticity, and reduced production of tears, saliva, and sweat developed progressively. Growth failure was noted by age 8 years. He had neither hypomelanic lesions nor hepatosplenomegaly. Neither of his parents or any other family member had signs of WS or Hirschsprung disease. The third patient had severe neonatal distress that required immediate resuscitation and admission to an intensive care unit. He presented with coma, arthrogryposis, meconium ileus, and a white forelock, but did not have heterochromia iridis. Severe aganglionosis extending to the jejunum was identified. Neither auditory brainstem-evoked responses nor electromyographic reactivity could be found. Electroencephalogram was abnormal, showing immaturity and discontinuity of the tracing, but paroxysmal discharges were not present. Analysis of muscle biopsy showed no specific lesions. The child died on day 11 of life.

Vinuela et al. (2009) reported an 11-year-old Spanish boy with Hirschsprung disease since birth and progressive sensorineural hearing loss associated with hypoplasia of the cochlea. He had blue eyes, but no pigmentary anomalies of the skin or white forelock. Neurologic findings included congenital nystagmus and delayed motor development due to hypotonia and spasticity. Brain MRI showed central dysmyelinization.

Elmaleh-Berges et al. (2013) retrospectively reviewed imaging studies from 14 Waardenburg probands who all had different mutations in the SOX10 gene, including 2 patients with WS2E; 6 with WS4C, 1 of whom was previously reported by Pingault et al. (2002); and 6 with PCWH, 2 of whom were previously reported by Pingault et al. (2002) and 1 by Bondurand et al. (2007). The patients, who had imaging for cochlear implant evaluation, a diagnosis of hearing loss, and/or evaluation of neurologic impairment, all had bilateral temporal bone abnormalities; the most frequent pattern consisted of agenesis or hypoplasia of one or more semicircular canals, an enlarged vestibule, and a cochlea with a reduced size and sometimes abnormal shape, but with normal partition. Three patients lacked a cochlear nerve, bilaterally in 2 patients with PCWH. Associated abnormalities observed when adequate MRI sequences were available included agenesis of the olfactory bulbs in 7 (88%) of 8 patients, hypoplastic or absent lacrimal glands in 11 (79%) of 14 patients, hypoplastic parotid glands in 12 (86%) of 14 patients, and white matter signal anomalies in 7 (54%) of 13 patients. These associated abnormalities were variably present in patients with all 3 SOX10-related Waardenburg diagnoses, except for the 2 patients with WS2E, who had normal lacrimal and parotid glands.

Clinical Variability

Pingault et al. (2000) described a patient with peripheral neuropathy with hypomyelination, deafness, and chronic intestinal pseudoobstruction, but not Hirschsprung disease or pigmentary abnormalities. Chronic intestinal pseudoobstruction is defined by repetitive episodes or continuous symptoms of bowel obstruction in the absence of a mechanical occluding lesion. It differs from Hirschsprung disease by the persistence of ganglionic cells and nervous plexus in the submucosal compartments of the bowel. Genetic analysis identified a de novo heterozygous deletion in the SOX10 gene (602229.0019).

Molecular Genetics

In 3 patients with the neurologic variant of Waardenburg-Shah syndrome, Touraine et al. (2000) identified heterozygosity for 1 of 2 truncating mutations in the SOX10 gene: tyr313 to ter (Y313X; 602229.0006) or ser251 to ter (S251X; 602229.0007). The extended spectrum of the Waardenburg-Shah syndrome phenotype was considered relevant to the brain expression of SOX10 during human embryonic and fetal development.

In a patient with Waardenburg-Shah syndrome and neurologic abnormalities, Inoue et al. (1999) identified a mutation in the SOX10 gene (602229.0008) that did not disrupt the coding region but extended the peptide and hence was thought to act as a dominant-negative allele. The healthy parents and sibs did not have the mutation, indicating that it was de novo.

Pingault et al. (2000) and Inoue et al. (2002) also identified SOX10 mutations in patients with Waardenburg-Shah syndrome and neurologic abnormalities.

In 2 patients with PCWH, one of whom had previously been reported by Jacobs and Wilson (1992), Inoue et al. (2004) found the Y313X mutation in the SOX10 gene. Both patients had muscle wasting/atrophy, pes cavus, and areflexia/hyporeflexia, indicating peripheral neuropathy. Both had developmental delay and hypotonia, indicative of central dysmyelination, with nystagmus and spastic diplegia also present in the younger patient. Both patients had hypopigmentation and neurosensory deafness, indicating dysmyelinating Waardenburg syndrome, and both had long segment Hirschsprung disease. In another patient with PCWH, Inoue et al. (2004) identified a gln250-to-ter (Q250X; 602229.0011) mutation in the SOX10 gene.

In a Spanish boy with a PCWH, Vinuela et al. (2009) identified a de novo heterozygous mutation in the SOX10 gene (915delG; 602229.0020). Vinuela et al. (2009) noted that the location of this mutation would cause an escape from nonsense-mediated decay and generate a dominant-negative effect resulting in neurologic features, consistent with the findings of Inoue et al. (2004).

Genotype/Phenotype Correlations

In addition to causing the neurologic variant of Waardenburg-Shah syndrome, mutations in the SOX10 gene also cause Waardenburg-Shah syndrome (277580), which has a more restricted phenotype. Inoue et al. (2004) reported that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype (the neurologic variant) is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. They observed similar results for truncating mutations of MPZ (159440), which convey a number of distinct myelinopathies. These observations indicated that triggering NMD and escaping NMD may be critical factors in the resulting neurologic phenotype.