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CASE REPORT Table of Contents  
Ahead of print publication
Developmental delay and assessment in an infant with PCWH syndrome: A case report

1 Department of Pediatrics, Neurology Division, Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India
2 Department of Medical Genetics, Kasturba Medical College, Manipal, Karnataka, India
3 Department of Neuroimaging and Intervention Radiology, STAR Institute of Neurosciences, STAR Hospitals, Hyderabad, Telangana, India
4 Department of Neurology, Safdarjung Hospital, New Delhi, India

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Date of Submission24-Jul-2022
Date of Decision27-Aug-2022
Date of Acceptance12-Oct-2022
Date of Web Publication31-Jan-2023


Peripheral demyelinating polyneuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung’s disease is a rare genetic disorder caused by de novo variants in the SOX10 gene. The SOX10 gene is expressed in the neural crest cells during early embryonic development and in the glial cells of the peripheral and central nervous systems during late embryonic development, as well as in adults. Here, we describe our findings in a 9-month-old male infant presenting with failure to thrive, global developmental delay, seizures, hypotonia, heterochromia iridis, hypopigmented skin macules, pendular nystagmus, Hirschsprung’s disease, and hearing impairment. Nerve conduction studies were suggestive of sensorimotor demyelinating polyneuropathy. Brain magnetic resonance imaging showed diffuse hypomyelination. Targeted genetic testing revealed a novel stop-loss variant in the SOX10 gene (NM_006941.4). This case highlights the importance of clinical phenotyping that can aid in targeted genetic testing.

Keywords: Hirschsprung’s disease, hypomyelination, pendular nystagmus, Waardenburg syndrome

How to cite this URL:
Kumar A, Rosario Md, Siddiqui S, Garg D, Shukla A, Sharma S. Developmental delay and assessment in an infant with PCWH syndrome: A case report. Ann Mov Disord [Epub ahead of print] [cited 2023 Mar 23]. Available from: https://www.aomd.in/preprintarticle.asp?id=368619

  Introduction Top

Shah–Waardenburg syndrome (Waardenburg syndrome type 4) is a rare genetic disorder with an incidence of one in 50,000.[1] It occurs due to variants in any one of three implicated genes: EDN, EDNRB, and SOX10. Among these, the SOX10 gene is known to cause a distinct and severe phenotype, characterized by peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung’s disease, also known as PCWH syndrome.[2],[3] The protein encoded by the SOX10 gene is a transcriptional activator, which functions as a nucleocytoplasmic shuttle for development of the neural crest and peripheral nervous system during the embryonic period. Here, we describe an infant presenting with PCWH, resulting from a novel de novo stop-loss variant in the SOX10 gene.

  Case Report Top

A 9-month-old male infant, born to non-consanguineous parents, presented with progressive abnormal movements since the age of 2.5 months. These movements included turning of head to either side with deviation of eyes to the same side, jerky limb movements, drooling, and episodes of urinary incontinence. In addition, he had abnormal movements of the eyeballs that were noted since the age of 1 month.

The infant was born via vaginal delivery to a 33-year-old fifth gravida mother with an uneventful antenatal period. He cried immediately after birth but failed to pass meconium within 24 hours after birth. He developed progressive abdominal distension in the newborn period, for which he was examined, and a probable diagnosis of Hirschsprung’s disease was made. A loop colostomy and resection of the involved segment was performed. The diagnosis was confirmed by histopathological examination of the resected segment.

Developmental history revealed that the infant had not attained social smile, neck holding, or visual fixation, and he appeared unresponsive to sound.

On examination, the infant was malnourished; his weight-for-age was at a z-score of -3.50, length-for-age was at a z-score of -3.52, and his head circumference was at a z-score of -0.77. A hypopigmented patch was noted over the anterior aspect of his left forearm. He had heterochromia iridis and nystagmus with no gaze fixation (Supplemental video) [Additional file 1]. He was alert but had poor environmental interaction, with lack of engagement on stimuli. Motor examination showed that he was hypotonic, he had reduced antigravity movements, and he was areflexic with mute plantars and choreoathetotic movements of bilateral toes. The infant responded to touch and pain sensation, and his spine examination was normal.

The findings of heterochromia iridis, hypopigmented macule on forearm, abnormal hearing, Hirschsprung’s disease, pendular nystagmus, and neurological involvement prompted us toward a possible diagnosis of Waardenburg syndrome type 4. Brain magnetic resonance imaging revealed diffuse hypomyelination ([Figure 1]). Electroencephalogram showed slow background with multifocal spike wave abnormalities. Brainstem-evoked response audiometry
Figure 1: Axial T2-weighted brain magnetic resonance images (A) and (C) at the level of the basal ganglia and posterior fossa, respectively, reveal presence of T2-hyperintense diffusely unmyelinated white matter involving the posterior limb of the internal capsule, pons, middle cerebellar peduncle, and peridentate white matter in the cerebellum. Corresponding T1-weighted images reveal hypointensities in the same regions
Supplemental video: The video shows the presence of heterochromia iridis and pendular nystagmus with no gaze fixation

Click here to view
demonstrated absent waveforms at 105 decibels. Nerve conduction studies were suggestive of sensorimotor demyelinating polyneuropathy in all four limbs.

After the initial clinical evaluation, peripheral blood samples were collected from the proband, his unaffected siblings, and parents. DNA was extracted using the QIAgen, Manchester, United Kingdom. All cases of PCWH reported to date are noted to be caused by de novo variants in the last exon of the SOX10 gene; therefore, only exon 4 of the SOX10 gene was Sanger sequenced in the proband and his parents. Sanger sequencing of the SOX10 gene rendered a novel heterozygous stop-loss variant, c.1400A>T, in exon 4 in the proband. Segregation of the variant in the family confirmed the de novo status of the variant in the proband. This variant is not observed in the heterozygous and homozygous state in population databases such as gnomAD as well as in our customized exome sequencing data of 1189 individuals in the homozygous state. Furthermore, the in silico analysis tool, FATHMM-MKL, predicted that the variant caused damage to the function of the SOX10 protein. This variant was submitted to Clinvar (SUB9585180) as “likely pathogenic” using the American College of Medical Genetics and Genomics guidelines for the interpretation of sequence variants.

  Discussion Top

PCWH syndrome was first described by Inoue et al. in 2004 to include the neurological manifestations in patients presenting with the Shah–Waardenburg-like phenotype.[4] It is a rare phenotype comprising four components: peripheral demyelinating polyneuropathy, central hypomyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung’s disease. It is a neurocristopathy, which usually manifests in infancy with varying combinations of delayed development of milestones, nystagmus, sensorineural hearing loss, heterochromia iridis, peripheral neuropathy, spasticity, mental retardation, central hypotonia, ataxia, and autonomic dysfunction.[2] In addition, hypomelanotic skin lesions and intestinal aganglionosis are present. Neuroimaging usually reveals dysmyelinating leukodystrophy. Furthermore, temporal bone abnormalities, including hypoplasia of the semicircular canal, enlarged vestibule, and reduced cochlea may be observed.[1] Our patient presented with the classical clinical phenotype, with onset in early infancy, with intestinal obstruction, delayed development of milestones, integumentary and eye changes, and peripheral neuropathy. His magnetic resonance imaging showed dysmyelination.

Almost all cases of PCWH reported to date are due to variants in the SOX10 gene, which can be detected by targeted sequencing. The SOX10 gene is located on chromosome 22, which is inherited as an autosomal dominant gene and encodes for a member of the SOX (SRY-related HMG box) family of transcription factors involved in the regulation of embryonic development. In addition, variants in this gene have been implicated in Waardenburg syndrome 4 (WS4).[5] Most variants that cause PCWH are de novo frameshift or nonsense variants in the final exon of the SOX10 gene.[3] These variants result in the formation of a truncated protein. The truncated protein still possesses its DNA binding site, which is present upstream in the protein; therefore, it is able bind to the target sequences. However, they are transcriptionally inactive since they lack the C-terminal activation site. Furthermore, stop-loss variants in the last exon have been reported with a more severe PCWH phenotype.[6] These variants lead to the formation of aberrant proteins that are longer than wild-type proteins due to translation of the extra sequences, which possess functional toxicity, from the 3′ untranslated region. Therefore, these variants are implicated to have a probable gain-of-function mechanism. On the other hand, variants in the initial exons of the SOX10 gene undergo nonsense-mediated mRNA decay, resulting in haploinsufficiency; they are often noted to cause WS4. Therefore, WS4 is caused by haploinsufficiency, whereas two different molecular pathologies, dominant inhibition and gain-of-function, are involved in PCWH.

Targeted genetic testing in the present proband rendered a novel de novo stop-loss mutation in exon 4 of the SOX10 gene. This variant is predicted to result in the loss of the normal stop codon. As a result, it generates a mutant protein longer than the wild-type protein with probable functional toxicity. Furthermore, the stop-loss variants, c.1399T>A, c.1400_*10del, and c.1401A>C have been previously reported to cause PCWH syndrome.[5],[7]

  Conclusion Top

Skin and eye abnormalities provide useful etiological pointers in inherited neurological disorders. Pendular nystagmus is one such abnormality that points toward underlying hypomyelination. A targeted genetic testing can be a useful test for confirmation of diagnosis. Our case highlights the importance of clinical phenotyping, which can help in targeted genetic testing.


We thank the patient and the patient’s family for their cooperation.

Author contribution

AK: conception, organization, execution, Manuscript preparation: writing of the first draft, review, and critique. MdR, ShS, DG, AS, SS contributed to research project: conception, organization, execution; Manuscript preparation: writing of the first draft, review, and critique.

Ethical approval

The genetic testing was performed in the project entitled ‘Genetic Diagnosis of Neurodevelopmental Disorders in India’ Grant ID - 1R01HD093570-01A1, which was approved by the Institutional Ethics committee. Informed consent was taken from the parents for the publication of this case report.

Financial support and sponsorship

This work was funded by National Institutes of Health, USA under the project titled ‘Genetic Diagnosis of Neurodevelopmental Disorders in India’ Grant ID - 1R01HD093570-01A1.

Conflicts of interest

There are no conflicts of interest.

  References Top

Wadhwani M, Gupta YK, Gangwani K. Waardenburg Shah syndrome: A rare case from India. Oman J Ophthalmol 2015;8: 74-5.  Back to cited text no. 1
[PUBMED]  [Full text]  
Verheji JB, Sival DA, vab der Hoeven JH, Vos YJ, Meiners LC, Brouwer OF, van Essen AJ. Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: A case report and review of literature. Eur J Paediatr Neurol 2006; 10:11-7.  Back to cited text no. 2
Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease: Clinical and nosological study. J Child Neurol 1986;1:233-9.  Back to cited text no. 3
Inoue K, Shilo K, Boerkoel CF, Crowe C, Sawady J, Lupski JR, et al. Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: Phenotypes linked by SOX10 mutation. Ann Neurol 2002;52:836-42.  Back to cited text no. 4
Pingault V, Faubert E, Baral V, Gherbi S, Loundon N, Couloigner V, et al. SOX10 mutations mimic isolated hearing loss. Clin Genet 2015;88:352-9.  Back to cited text no. 5
Mohan SLNC. Case of Waardenburg Shah syndrome in a family with review of literature. J Otol 2018:13; 105-10.  Back to cited text no. 6
Sham MH, Lui VC, Chen BL, Fu M, Tam PK. Novel mutations of SOX10 suggest a dominant negative role in Waardenburg-Shah syndrome. J Med Genet 2001;38:E30.  Back to cited text no. 7

Correspondence Address:
Suvasini Sharma,
Department of Pediatrics, Neurology Division, Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None


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