Brief clinical and laboratory observation

White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: Possible variant of Waardenburg syndrome

Waardenburg Syndrome (WS) type IV or Waardenburg-Shah Syndrome (WSS) is a genetic disorder characterized by sensorineural hearing loss, pigmentary defects of the hair and skin, heterochromia of the eyes, and Hirschsprung Disease (HD). There are three other forms of WS, none of which include HD.

A 7-year-old female born to non-consanguineous parents presented to our clinic with a history of chronic constipation. She had a white forelock on the frontal aspect of the head and multiple depigmented macules on the chest and lower extremities. She also had sensorineural hearing loss. On the physical exam, her abdomen was distended but soft and non-tender. The digital rectal exam was unremarkable. Plain film of the abdomen showed dilated bowel loops. She underwent a contrast enema that showed a narrow rectum and a dilated sigmoid colon. She subsequently underwent a rectal biopsy, which confirmed the diagnosis of HD. The combination of all the features confirmed the diagnosis of WSS. She underwent a laparotomy-assisted trans-anal pull-through, from which she recovered uneventfully.

The possibility of WSS must be considered when a patient with HD presents depigmented lesions in the body and hearing loss.

SOX10 is one of the master transcription factors in neural crest development. Human SOX10 mutations are associated with Waardenburg syndrome type 4 (Waardenburg-Shah, WS4), which can be inherited in both autosomal dominant and recessive patterns. Here, the human embryonic stem cell (hESC) line, H9, was used to generate a heterozygous SOX10 knockout cell line as the in vitro model of WS4 by CRISPR/Cas9-mediated gene targeting. This cell line may represent a valuable tool for uncovering the pathogenesis of WS4.

Waardenburg syndrome is a rare disease characterized by sensorineural deafness in association with pigmentary defects. Depending on additional symptoms, WS have been classified into four types. Waardenburg syndrome type 4, also called as Waardenburg Shah Syndrome is a very rare congenital disorder with astounding variable clinical expression, characterized by pigmentary abnormalities of the hair (A white forelock of hair, premature graying) and pigmentary changes of the iris such as heterochromia or homochromia irides, sensorineural deafness and Hirschsprung disease. Three genes have been bestowed so far in consociation with EDNRB, EDN3, and SOX10 genes. The pattern of inheritance is multifarious with the SOX10 mutation affiliation with autosomal dominant inheritance whereas the EDNRB and EDN3 genes are passed down in an autosomally recessive pattern.

Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1–WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3. Therefore, the mutant cannot transactivate the MITF promoter effectively, inhibiting melanin synthesis and leading to WS2. Our study confirmed haploinsufficiency as the underlying pathogenesis for WS2.

Waardenburg syndrome is a rare genetic disorder, characterized by the association of sensorineural hearing loss and pigmentation abnormalities. Four subtypes have been classified. The present study aimed to analyze the clinical feature and investigate the genetic cause for a Chinese case of Waardenburg type IV (WS4).

The patient and his family members were subjected to mutation detection in the candidate gene SOX10 by Sanger sequencing.

The patient has the clinical features of WS4, including sensorineural hearing loss, bright blue irides, premature graying of the hair and Hirschsprung disease. A novel heterozygous frameshift mutation, c.752_753ins7 (p.Gly252Alafs*31) in the exon 5 of SOX10 was detected in the patient, but not found in the unaffected family members and 100 normal controls. This mutation results in a premature stop codon 31 amino acid downstream.

The novel mutation c.752_753ins7 (p.Gly252Alafs*31) arose de novo and was considered as the cause of WS4 in the proband. This study further characterized the molecular complexity of WS4 and provided a clinical case for genotype-phenotype correlation studies of different phenotypes caused by SOX10 mutations.

We present a new case of Skip segment Hirschsprung's disease (SSHD) associated to Waardenburg's syndrome, in a patient with total colonic aganglionosis (TCA). Even though there are more than 30 cases reported in the literature, SSHD's existence is controversial, due to the fact that there is not clear embriological theory to explain this phenomenon.

20 months-old male patient, that at four days-old had a temporary ileostomy because of an episode of intestinal obstruction. A microileum and right microcolon was observed at the moment of surgery. Biopsies of the ileum and microcolon confirmed the aganglionism. At four months-old definitive surgery was performed according to Boley's procedure. Hystopathological study of the surgical piece showed absence of ganglion cells in cecum and ascending colon (SSHD). The postoperatory has been favorable. A mutation in SOX10 gen was objectified in the molecular study, that confirmed the Shah Waardenburg syndrome.

Most of cases of SSHD were observed in patients with TCA, as in our case. These patients usually need a temporary stoma before the definitive surgery. We think that the only way to discover SSHD cases is to make extended biopsies in left, transverse and right colon, and in ileum, while performing the ileostomy or in the definitve surgery.

SSHD must be included as a new phenotype in Hirschsprung spectrum. Preservation of these intestinal segments can improve intestinal function, specially in patients with TCA.