Vein of Galen malformations
Vein of Galen malformations are congenital arteriovenous malformations involving the deep venous system of the brain that were first described in 1895
Sep. 24, 2021
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Waardenburg syndrome was first reported by van der Hoeve in 1916. In 1951, Waardenburg defined 6 main features: (1) dystopia canthorum, (2) prominent broad nasal root, (3) synophrys, (4) white forelock, (5) heterochromia iridis, and (6) congenital deaf-mutism. Four types of Waardenburg syndrome have now been delineated on the basis of clinical and genetic criteria. The molecular defective gene has been identified in all 4 forms. Patients with Waardenburg syndrome (WS) 1 have a characteristic pleasant feline appearance. In WS2, dystopia canthorum is absent. Deafness and all the facial and hypopigmentation features are due to a disturbance in the neural crest, the origin of melanocytes. The congenital anomalies plus neurosensorial deafness, neural tube defects, and other neurologic manifestations observed in Waardenburg syndrome justify its inclusion as a neurocutaneous syndrome. SOX10 mutations in WS4 are associated with a more severe neurologic phenotype: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease (PCWH). It has been demonstrated that the same deletions at the SOX10 gene locus also may cause WS2. Additional systemic findings have also subsequently been described.
Waardenburg syndrome is a hereditary neurocristopathy that occurs in all ethnic groups, affecting mainly skin, hair, and audition.
There are 4 clinical presentations of this syndrome. Waardenburg first described the syndrome. Type I is the most frequent and benign form.
The 4 presentations manifest pigmentary and auditory deficits that can be identified at birth, but require specific investigations and confirmation to enable early intervention and prevent further complications.
Genetic defects have been identified in this hereditary condition in all 4 phenotypes. Consanguinity is frequent.
In some instances early abdominal surgery is required, as in Waardenburg syndrome type IV with aganglionic megacolon.
Waardenburg syndrome was first reported by the Dutch ophthalmologist Jan van der Hoeve in 1916 in 2 deaf twin girls with a special type of blepharophimosis (125). In December 1947, Dr. Petrus J Waardenburg, a Dutch ophthalmologist and geneticist, presented a deaf-mute man with "dystopia punctorum lacrimarum, blepharophimosis, and partial iris atrophy" to a meeting of the Dutch Ophthalmological Society (131). He acknowledged the report of the van der Hoeve twins with the same eye abnormalities who were “coincidentally” also deaf-mute. In August 1947, David Klein presented a 10-year-old girl with a severe auditory-pigmentary syndrome and dystopia canthorum to the Swiss Society of Genetics in Geneva (62). In addition, Klein’s patient had a severe musculoskeletal involvement. In 1948, Klein showed this patient to Waardenburg, who later did a search among 1050 patients of 5 Dutch institutions for the deaf. Other ophthalmologists who studied this ocular anomaly and confirmed its dominant inheritance were Halbertsma in 1929, cited by Waardenburg and Klein, and Gualdi in 1930 (63).
In 1951, Waardenburg published the first comprehensive review of this new syndrome (132) in which he fully acknowledged Van der Hoeve’s initial description and subsequent publications about this syndrome. Waardenburg defined 6 main features: (1) lateral displacement of the medial canthi combined with dystopia of the lacrimal punctum and blepharophimosis, (2) prominent broad nasal root, (3) hypertrichosis of the medial part of the eyebrows, (4) white forelock, (5) heterochromia iridis, and (6) deaf-mutism. Waardenburg characterized the syndrome as autosomal dominant with high penetrance of dystopia (159/161) but reduced penetrance of all other features.
Waardenburg observed several patients with heterochromia or isochromic hypoplastic irides but without canthus dystopia, but he did not investigate them further (100). In 1971, Arias drew attention to these patients as a separate division of the syndrome, which he named Waardenburg syndrome type II (05). Two of Waardenburg's original families had this variant, but both were small, and Waardenburg overlooked the familial "nonpenetrance" of dystopia. In 1981, Shah and colleagues described 12 infants with several characteristics of Waardenburg syndrome associated with Hirschsprung disease (103). For the congenital cutaneous lesions and the neurosensory deafness (plus other nervous system abnormalities), Waardenburg syndrome should now be included in the group of primary neurocutaneous syndromes (101). Waardenburg syndrome can be considered a disease because the etiology is known; however, it also represents a syndrome due to the constellation of clinical findings.
Four main types of Waardenburg syndrome have been delineated based on clinical and genetic criteria.
Waardenburg syndrome type I (WS1). This is the most frequent type; as a general rule, families characteristically are large.
The 5 cardinal features in WS1, an autosomal dominant disease, are as follows:
• dystopia canthorum
The first 4 are distinctive developmental abnormalities of this syndrome, whereas synophrys (confluent eyebrows), is a feature that may be found in normal people.
Waardenburg syndrome type I is the most benign of the 4 types. In the absence of deafness, these individuals are basically normal. In contrast to most genetic syndromes that cause cosmetic disadvantages, patients with WS1 usually have a pleasant physical appearance.
Dystopia canthorum (canthus dystopia, telecanthus). This was first described by van der Hoeve in 1916 in association with blepharophimosis (125). It refers to the lateral displacement of the medial canthus (internal canthus) and inferior lachrymal ducts with the punctate opposite the cornea, toward the limbus. This leads to increased distance between the inferior lacrimal points. Shortness of the nasal palpebral fissures with the appearance of blepharophimosis and fusion of the inner lids results in reduction of the medial sclerae.
The interpupillary distance usually is normal; however, in some patients the interpupillary and outer canthal distances are greater than normal, indicating a degree of hypertelorism. Dystopia canthorum is the most penetrant feature of WS1, present in 99% of patients (06); it affects both eyes. Since van der Hoeve, different interocular distances have been used for determining the presence of canthal dystopia. A biometric index measuring the inner canthal, interpupillary, and outer canthal distances is used presently. Arias and Mota developed the W index for the diagnosis of lateral displacement of the inner canthi (06). A W index of more than 2.07 determines dystopia, whereas an index of less than 1.87 is normal. Other authors consider 1.95 or more to be indicative of a WS1 diagnosis (Newton 1989; 100). Resetting the threshold of W index or novel index formulated with ethnicity-matched samples is necessary for clinical classification, which, in turn, is consistent with genetic classification for Waardenburg patients with distinct ethnicity (80).
Hypopigmentation. This abnormality is 1 of the cardinal signs observed in all 4 forms of Waardenburg syndrome. It affects the eyes, hair, and skin.
Eyes. Hypopigmentation of the iris results in a brilliant blue color that may be bilateral or unilateral (heterochromia, different color) and complete or partial.
Partial heterochromia of the iris may be seen in the affected eye with a blue segment sharply demarcated from the rest of the iris. It is more common in WS2 than in WS1 (71). Bilateral congenital cataracts are an infrequent presentation (128).
Hair. Poliosis, typically in the form of a white forelock, may be present in 20% to 40% of Waardenburg syndrome patients.
Less commonly, the forelock may be red or black (05). Hypopigmentation also may affect eyelashes and eyebrows. Poliosis may be present at birth then disappear and reappear later. Premature graying of the hair is frequent; it can be seen as early as 7 years of age (26). Complete depigmentation of the hair may occur in the teens (37). According to the Waardenburg Consortium, depigmentation occurs before 30 years, with the white hairs appearing in the midline (33).
Skin. Patchy hypopigmentation of the skin (leukoderma) is congenital and may be found on the face, trunk, or limbs.
It is present in 8.3% to 50% of patients (27). Arias noted that hypopigmented areas frequently had hyperpigmented borders (05). Histological studies show absent or severely reduced melanocytes in the hypopigmented areas (27).
Deafness. Congenital deaf-mutism is frequent in patients with Waardenburg syndrome. The hearing loss may be unilateral or bilateral and varies in degree from slight to profound. Profound bilateral loss of hearing is the most common in both WS1 and WS2. The auditory deficit is sensorineural and usually nonprogressive. Hageman and Delleman reported that 25% of subjects with WS1 and 50% of those with WS2 had a bilateral sensorineural hearing loss (43; 25). Newton found that the penetrance of sensorineural hearing loss varied from 69% in WS1 to 87% in WS2 (89). Variation between families was high, particularly in WS1. Unusual audiogram shapes include low frequency and U-shaped losses, bilateral or unilateral, and sometimes a combination of a low frequency sensorineural hearing loss in 1 ear and a profound loss in the other (100). Unilateral sensorineural hearing loss is observed with less frequency (61).
Tubular nose. Patients with WS1 have a characteristic nose with a hypertrophic, broad, high nasal bridge usually with lack of frontonasal angle associated with hypoplasia of alae nasi, giving the nose a tubular appearance.
Tubular nose is present in 80% of patients.
Synophrys. Joining of the eyebrows in the midline with hypertrichosis of the medial eyebrows is reported in 63.3% of patients with WS1 but only in 6% of those with WS2 (71). The later frequency is similar to that in the general population. In some patients, synophrys can be prominent (45).
Other facial features such as patent metopic suture and square jaw have been described (35). Together, the peculiar development of the facial bones with the high nasal root, hyperplasia of the eyebrows, a small, narrow nose, the dystopia canthorum, and the color of the eyes give most patients with WS1 a pleasant feline appearance. All these facial features can be explained by a disturbance in the neural crest. In a family of 29 members evaluated for Waardenburg syndrome, 16 showed features of WS1. Dental abnormalities were identified in 3 members, including conical teeth, taurodontism, and especially dental agenesis. WS1 was transmitted in this family in an autosomal dominant pattern with variable expressivity and high penetrance. Dental manifestations resulted in considerable functional and aesthetic impact on affected individuals (107).
Neurologic complications are uncommon in WS1 and include neural tube defects such as spina bifida (95; 27; 72); a familial occurrence of this association is rare (86; 17). A report of a patient with WS1 was associated with meningomyelocele, Chiari malformation, and hydrocephalus at birth (44). These authors reviewed 32 cases of a variety of neural tube defects associated with Waardenburg syndrome, in particular meningomyelocele, but did not find any cases of meningocele. Epilepsy is infrequent. A report of a 5-month-old infant who presented multiple generalized seizures that responded to pharmacological treatment showed he had delayed myelination that later normalized (111).
Several associated abnormalities have been reported in WS1 (23), including high arched or cleft palate (40), blepharophimosis (type 3), glaucoma, hydrophthalmos, true esotropia (20% of the cases), unilateral or bilateral renal and urinary system anomalies (30) and rarely, anal atresia. Homozygous patients have more severe systemic complications (11; 138). The association of WS1 and laryngomalacia in a neonate had not been previously described (121).
Waardenburg syndrome type II (WS2). WS2 is less well defined than WS1; it covers any auditory-pigmentary syndrome that does not clearly belong elsewhere. These patients have a normal face without midline anomalies. Dystopia canthorum is absent, and the nose is indistinct. However, the same pigmentation defects observed in WS1 are present in WS2 but with different frequency (71). In general, WS2 occurs sporadically. However, several familial cases have been reported (67; 84; 20). Heterochromia irides is present in 47%, which is more common than in WS1; partial heterochromia is also common, in as many as 27.5% (100).
A unique pattern of non-uniform pigmentation in the ocular fundi has been reported (84). The hearing loss also is more frequent than in WS1, observed in up to 77% of these patients (27). A white forelock and hypopigmented skin patches are more frequent in WS1 than in WS2 (71). As in WS1, systemic and neurologic abnormalities are uncommon; however, Dr. Flores-Sarnat has seen 2 children with WS2 with intellectual disability and autistic features without other neurologic or systemic manifestations. In 2007, 2 other patients with WS2 and intellectual disability were described (15); 1 patient also presented severe congenital heart disease. Another child was reported with autistic-like behavior; he has more severe intellectual disability as well as hypotonia, unilateral cryptorchidism, and patchy depigmented areas at the thighs and in the abdomen (106). A 3‑year‑old girl with congenital bilateral sensory neural hearing loss and asymmetrical partial heterochromia of iris and fundus, showed normal development (65). Infrequently, sensorimotor polyneuropathy with distal demyelination has been reported (01). Unilateral congenital ptosis was reported in 1 member of a family with WS2 (18). Mandibular asymmetry and malocclusion were reported in a 14-year-old Romanian boy with a family history of Waardenburg syndrome in the mother and Usher syndrome in the father (109). An infant examined for speech delay was found to have a profound hearing deficit, WS2, and overt cerebellar asymmetry due to right hemispheric hypoplasia (58). A report of a 6-year-old boy with bilateral anophthalmia, brain anomalies, and epilepsy also showed some overlapping features of WS2, including neurosensorial deafness and multiple white lesions in the lower extremities (38).
Waardenburg syndrome type III (WS3, Klein-Waardenburg syndrome). This form is the least frequent of the 4. It usually presents as a sporadic disorder; only occasional familial cases have been reported (120; 135). WS3 patients have the same features observed in WS1 (dystopia canthorum, depigmentation, and deafness) plus a musculoskeletal syndrome. Usually, the hypopigmentation anomalies are more severe than in WS1 (138). After Klein’s first report, a small number of other patients have been described who show musculoskeletal abnormalities similar to Klein's patient but in milder form (104). There are bilateral defects of the upper limbs, including hypoplasia, contractures, carpal fusion, syndactyly, and upper limb-pectoral girdle arthromyodysplasia. Other neurologic abnormalities such as microcephaly and cognitive impairment may be observed in these patients (27), but intelligence is generally normal. Meningomyelocele also has been reported in these patients (92). A rare presentation in a patient with cognitive deficit and multiple congenital malformations, including anophthalmia, low-set ears, and dental and leg anomalies, included self-mutilation, particularly in the oral region (76). Extensive scars on the tongue, lips, and hands were a consequence.
Waardenburg syndrome type IV (WS4, Waardenburg-Shah syndrome, Waardenburg-Hirschsprung disease). WS4 also is characterized by the association of WS1 features with congenital aganglionic megacolon or Hirschsprung disease. WS4 is rare, the less frequent type with an incidence of approximately 1 in 40,000 to 50,000 live births; it occurs in all races (21). The prevalence is less than 1 in 1,000,000 (16). This is also the most severe form of Waardenburg syndrome, with risk of mortality in early infancy. Mortality due to the abdominal complications and sepsis in the neonatal period and early infancy is high in WS4 (130; 56; 02; 74; 42). It was described by Shah and colleagues in 1981 in 12 newborns from 5 families in Bombay who had Hirschsprung disease, white forelocks, and white eyelashes (103). Canthus dystopia was absent, hearing was not tested because all babies died in the neonatal period, and the description of the pigmentary disorder of the irides was nonspecific. The first report of the association between Waardenburg syndrome and Hirschsprung disease, suggesting that a neural crest defect was the common pathogenesis, appeared earlier (78). This is the only form of Waardenburg syndrome that may be transmitted as either an autosomal dominant or autosomal recessive trait, depending on the gene mutated. In a family with WS4 distinct phenotypes among 3 different generations, hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband were observed (34). Neurologic involvement such as severe global developmental delay has been described since the early reports of this association (24). Dandy-Walker syndrome, congenital hypomyelinating neuropathy (52), and neonatal hypotonia and arthrogryposis (122) have been reported. A 4-year-old girl with the PCWH phenotype (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease) showed also intellectual deficit, deafness, distal arthrogryposis, white hairlock, and growth retardation (127). The association of polydactyly, lumbosacral myelomeningocele, and agenesis of the corpus callosum reported in a female infant with WS4 is an unusual presentation (102). A severe form in a child with deafness, bilateral complete agenesis of the semicircular canals, and mental retardation without Hirschsprung disease has been reported (112). Hirschsprung disease has a high prevalence in Kuwait, with an estimated consanguinity rate of 54%, and a strong male predominance; 2% of cases are associated with Waardenburg syndrome (137). The defective segment can be short, long, ultra-short, or total colonic aganglionosis (137). The clinical presentation is intestinal obstruction within 48 hours after birth; at times emergent surgery is required (56). WS4 with total intestinal aganglionosis is rare. A neonate from Pakistan presented with bilious vomiting, refusal to feed, and failure to pass meconium, requiring several surgeries (60). Children with Shah-Waardenburg syndrome may develop short bowel syndrome and malabsorption that occurs after extensive intestinal resection (69). They present abdominal pain, diarrhea, and food intolerance because the decreased intestinal absorptive area leads to weight loss and malnutrition. Food allergy due to specific foods and eosinophilic infiltration of parts of the gastrointestinal system also can occur (69). Chronic constipation from the neonatal period was reported in a girl with heterochromia iridis, profound bilateral sensorineural hearing loss, inner ear malformations, and hypopigmentation of the hair without dystopia canthorum. She had a SOX10 mutation and was considered a clinical phenotype intermediate between type II and type IV syndromes (07). A female neonate with WS4 presented a rare anomaly consisting of bilateral agenesis of the external ears (29). In a nonconsanguineous family from India, a 6-year-old boy was diagnosed with WS4 after investigation for bilateral hypoacusis and the finding of brilliant blue eyes (16). He had a history of severe constipation at 6 months of age that required surgery and confirmed aganglionic megacolon. His 8-year-old sister and father were later diagnosed with WS1.
• Congenital sensorineural hearing loss
- Two eyes of different color
• Hair hypopigmentation:
- White forelock
• Dystopia canthorum:
- W > 2.07 (Read and Newton suggest 1.95)
• First degree relative with diagnosis of Waardenburg syndrome
• Congenital leucoderma
From: Waardenburg Consortium. Summarized from: (33)
At least 2 of the following criteria must be present:
• Congenital sensorineural hearing loss
- Complete or partial heterochromia of the iris
• Pigmentary disturbances of the hair
- White forelock from birth or in teens
• A first or second degree relative with 2 or more of criteria 1-3
Modified from (71)
* Criterion 2c of Farrer and colleagues, corresponds to hypopigmented iris (33); however, it has been changed to hypoplastic eyes by Liu and colleagues (71) and Read and Newton (100). Patients with WS1 and WS2 do not have hypoplasia of the eyes; therefore, the correct description is hypopigmented iris as cited in the original reference.
When deafness is absent, WS1 is a benign, nonprogressive condition that requires no treatment. Affected individuals have normal intelligence and they may have a normal life with normal life expectancy. Deafness is the most common associated complication; the impact of the disability depends on the severity of the auditory deficit. WS2 has a similar prognosis; however, deafness is more common in WS2 than in WS1. The prognosis in WS3 and WS4 is less favorable due to the associated anomalies, which also show different grades of severity.
A 15-year-old Mexican boy with Waardenburg syndrome type I had a negative family history and Mexican parents with brown eyes. He was the product of normal pregnancy and was delivered at term. He had a history of normal development except for lack of speech that lead to medical consultation in infancy. Audiometry revealed a profound bilateral deafness. Subsequent examination showed an alert, cooperative, teenager. He could not speak but understood and followed commands by signs or reading.
His skin was uniformly brown without areas of hypopigmentation. He had a median white forelock, present since birth; bilateral blue eyes with dystopia canthorum; synophrys; a tubular nose with a high, broad nasal bridge and hypoplasia of alae nasi; and a square jaw. Neurologic examination was normal with the exception of bilateral impairment of V3 auditory nerve without vestibular involvement. Repeat audiometry and auditory evoked potentials confirmed a profound bilateral neurosensorial deafness. His intelligence was normal. He attended special education for the deaf, had good support from his family, and was well adapted to his disability.
The mutations of primarily 6 different genes responsible for Waardenburg syndrome have been identified (98):
Waardenburg syndrome type I. WS1 has been mapped to the distal part of chromosome 2q35, and the gene identified is PAX3 (paired homeobox) (36; 123). A different phenotype with mutations of PAX3 has been reported depending on whether homozygous or heterozygous inheritance occurs (135). Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects. Mutations in the murine homologue, Pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for neural tube defects (72). A novel missense c.788T>G mutation in PAX3 in a Turkish family with Waardenburg syndrome with intrafamilial phenotypic heterogeneity was identified (45). Previously unreported digenic mutations in PAX3/GJB2 Waardenburg syndrome type I were observed in 2 Chinese siblings (19). A novel truncating mutation in exon 3 of SOX10 that is associated with neurologic symptoms was demonstrated in a 5-month-old infant boy with WS1 who had multiple generalized seizures (111). An autosomal recessive mutation in EDNRB was described as the cause of WS1 in a 5-year-old patient (81). In another study, single-nucleotide variants and copy number variation detection was applied to investigate the genotype spectrum of Waardenburg syndrome in a large Chinese population (70). Five EDNRB variants were associated with WS1 in the heterozygous state, with a detection rate of 22.2%.
Waardenburg syndrome type II. WS2 has been mapped to chromosome 3p12.3-p14.1, and the causal gene is MITF (microphthalmia transcription factor, human microphthalmia) (49; 114; 117). Only 10% to 15% of patients with WS2 show the mutation in MITF gene (84; 20). The finding of SOX10 deletions in patients with WS2 confirmed a new gene of WS2 (15). Theses authors also reported neurologic phenotypes that have been observed in WS4 (intellectual impairment, abnormal myelination) in some WS2-affected patients with SOX10 deletions. In a boy with a neurologic variant of WS2, a 725 kb deletion at the 22q13.1 chromosomal region, including SOX10 gene, was found (106). A novel Waardenburg syndrome-associated mutation was reported in a 19-year-old Chinese girl with WS2 at the stop codon of MITF (p.X420Y). This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively (110). In a screening of a WS2 cohort, 6 heterozygous EDNRB variations were disclosed; these variations are now estimated to be responsible for 5% to 6% of WS2 cases (53). A novel mutation (Lys344Ter) in exon 9 of the MITF gene has been reported in a 3-year-old girl that was pathogenic for WS2A (65). The diagnosis of a subtype of WS2 relies on identifying the genetic cause. For some subtypes, the general location (locus) of the responsible gene is known, but the specific responsible gene has not yet been identified.
Waardenburg syndrome type III. WS3 (Klein-Waardenburg) is also associated to PAX3 gene (48). An infant born to consanguineous parents with WS1 presented the typical picture of WS3. The 3 of them had mutations of PAX3 gene with a novel missense mutation. However, only the child presented a homozygous PAX3 mutation (135). A spontaneous mutant mouse line, Rwa, has been identified, which displays white spots on bellies and tail and white digits; spina bifida was also observed with lower penetrance (93). The defective allele of Pax3 was named Pax3 Rwa.
Waardenburg syndrome type IV. WS4 (Waardenburg-Shah syndrome) is caused by mutations of 3 genes: the endothelin receptor B gene (EDNRB) on chromosome 20q13 (124), the endothelin-3 gene (EDN3) on chromosome 20q13 (09; 28; 47), and the SOX10 gene, also on chromosome 20q13 (113). When EDN3 or EDNRB genes are responsible for WS4, it is inherited as an autosomal recessive trait. If SOX10 mutations are involved, WS4 is inherited as an autosomal dominant condition (122). The expression of SOX10 in the human embryo is not restricted to neural crest-derived cells but also involves fetal brain cells, most likely of glial lineage (122). Heterozygotes are usually unaffected or have isolated Hirschsprung disease (04; 10; 66). SOX10 mutations are specifically associated with a more severe phenotype called PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (127). SOX10 mutations, inherited in autosomal dominant way, are found in 45% to 55% of WS4 patients (34). These mutations are usually associated with a more severe phenotype, as in the case of a patient with congenital deafness, iris heterochromia, Hirschsprung disease, foot deformity, peripheral demyelinating sensorimotor neuropathy, and central dysmyelinating leukodystrophy with a novel heterozygous missense variant in the SOX10 gene (14).
The zebrafish, lacking functional SOX10, is considered a good animal model for human WS4 (32). Peripheral neuropathy and lack of Hirschsprung disease has been reported in WS4 with a SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). (112). The first characterization of SOX10 deletions in patients with WS4 was reported in 2007 (15). The SOX10 gene, encoding a transcription factor, is essential for neural crest development and myelin formation both in the central and peripheral nervous systems (134). Mutations in this gene are associated with 2 distinct “neurocristopathies.” A milder, more restricted spectrum trait, Waardenburg-Hirschsprung disease (WS4, OMIM: 277580), combines Waardenburg syndrome and Hirschsprung disease (97). A more severe and complex neurologic trait, “peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease” (PCWH, OMIM: 609136) reveals additional de- and dysmyelinating phenotypes in the peripheral and central nervous systems (99; 122; 52; 50). The report of a WS4 family, carrying an insertion of 19 nucleotides in exon 5 of SOX10, showed distinct phenotypes among 3 different generations (34). The vast majority of disease-associated SOX10 mutations result in premature termination codons (PTCs), causing either WS4 or PCWH depending on the position of the mutations. Failure to properly terminate SOX10 translation causes the generation of a deleterious functional domain that occurs because of translation of the normal 30-UTR; the mutant fusion protein causes a severe neurologic disease (51). Bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and cochlear deformity, strongly suggest a diagnosis of Waardenburg syndrome linked to a SOX10 mutation (31).
Waardenburg syndrome results from a defect in the migration and differentiation of neural crest cells. Three derivatives of the neural crest are related to Waardenburg syndrome: melanocytes, ganglion cells and membranous bones of the face (particularly the forehead, the orbits, and the nasal bones). Waardenburg syndrome has been recognized as a neurocristopathy since 1959 (35).
Physical absence of melanocytes from the skin, hair, eyes (choroid and iris) and the stria vascularis of the cochlea cause the auditory-pigmentary manifestations of Waardenburg syndrome. The absence of the plexuses of Meissner and Auerbach that derive from the neural crest result in aganglionic megacolon or Hirschsprung disease. The cartilages of the larynx (thyroid, cricoid, and arytenoids) and the intrinsic muscles also derive from neural crest, which might explain the rare association of Waardenburg syndrome and laryngomalacia (121). Microtia and severe micrognathia were observed in a neonate with Waardenburg syndrome and multiple malformations, also due to defective neural crest (136). Several mechanisms may contribute. Motor trigeminal nerve sheaths derive from neural crest; if they are defective, innervation of the mandibular muscles is impaired and the muscular stimulation of bone growth is deficient during the period of most rapid growth in the late 2nd and 3rd trimesters. Neural crest forms the membranous bone of the mandible itself. Microtia can occur if neural crest cells that differentiate in the mesenchyme of branchial arches are defective. The rare finding of bilateral agenesis of external ears is also the result of defective neural crest (29).
Melanocytes originating in the neural crest produce all the melanin that pigments the skin, hair, and eyes, with the exception of the retinal melanocytes that are derived from neural ectoderm. In addition, melanocytes are required for the development of auditory structures such as the stria vascularis of the cochlea (108). In the absence of melanocytes, the stria is abnormally thin, no endocochlear potential is generated, and later in development Reissner membrane collapses, leading to destruction of the organ of Corti (108). Absence of melanocytes could be caused by a failure in differentiation of the neural crest, a migration failure of melanoblasts, or a failure in survival at their final destination (100). In WS2, both skin and retinal melanocytes are affected; therefore, this is a melanocyte-specific disorder, whereas WS1, WS3, and WS4 are neurocristopathies involving neural crest derivatives such as the frontal bone, limb muscles, and enteric ganglia (100). The PAX3 gene is involved in neural crest development; it is expressed in the developing somites, dorsal spinal cord, mesencephalon, and neural crest derivatives (41; 118; 119; 39). This gene controls some aspects of the development of the face and inner ear and is expressed in the mesenchyme of the limb buds, explaining the phenotype of WS3 (12). Malformations include a lack of muscle in the limb, a failure of neural tube closure, and dysgenesis of numerous neural crest derivatives (75). At present, over 50 PAX3 mutations have been identified in patients with WS1 or WS3 (119; 116; Farrer et al 1994; 100).
The MITF gene is the human homologue of the mouse microphthalmia (mi) gene (08; 46) and is an important factor for differentiation, function, and survival of melanocytes (129). It is expressed in adult skin and in embryonic retina, otic vesicle, and hair follicles. It has been suggested that in dominant families with WS2, haploinsufficiency is the most likely cause (90).
The SOX10 gene is expressed during human embryonic and fetal development and has an important role in early development of neural crest-derived tissues related to Waardenburg syndrome, such as melanocytes and the enteric nervous system.
The ligand-receptor interaction between EDN3 and EDNRB is important for the development of epidermal melanocytes and enteric neurons.
Pathologic findings. Inner ear histological studies in patients with Waardenburg syndrome have revealed cochleosaccular degeneration (35). Absent organs of Corti, atrophy of the spiral ganglion, and reduction of the nerve fibers have been reported. A computed tomographic study in patients with WS1 and WS2 presenting profound, bilateral deafness showed several abnormalities in the temporal bone (73). They included narrowing of the internal auditory canal porus and hypoplasia of the modiolus. A third case of WS4, which did not have myenteric ganglion cells in the sigmoid colon and rectum, was reported (133).
Autopsy reports of individuals with Waardenburg syndrome are rare. A male infant born at 29 weeks’ gestation with Waardenburg syndrome (type not confirmed) had gross tetraphocomelia and multiple organ malformations (lungs, cardiac, renal, liver) and died 10 minutes after birth. His brain showed hydrocephalus and malformation of the temporal lobes (136). Cochleosaccular degeneration and a complete absence of pigmentation was reported at necropsy in a 3-year-old child with WS4 (85). Another case, a 2.5-year-old boy with congenital deafness, patchy cutaneous hypopigmentation, bilateral blue irides, patchy white eyelashes and eyebrows, a broad nasal root, and Hirschsprung disease also showed Dandy-Walker malformation, which was confirmed by autopsy (130). The colon was absent and the small intestine showed an absence of ganglia. Bilateral complete semicircular canal agenesis was reported in a child with WS4 (112). An unusual demyelinating peripheral neuropathy characterized by excessive focal folding of myelin sheaths was described in a patient with Hirschsprung disease and a diagnosis of Waardenburg syndrome type II (probably corresponded to WS4) (55). An infant boy with lethal congenital hypomyelinating neuropathy and WS4 who had a heterozygous SOX10 mutation (Q250X) showed in the histopathological studies an absence of peripheral nerve myelin despite normal numbers of Schwann cells and profound dysmyelination in the central nervous system (52).
Waardenburg syndrome is observed at all ages, from newborns to elderly people. Both sexes are affected equally. It occurs in all ethnic groups without any predominance. The estimated prevalence in the Netherlands in the Waardenburg review (132) was 1/42,000 of the general population and 1.43% in the congenitally deaf. Fraser studied 2355 deaf children and estimated a prevalence of 1.44 to 2.05/100,000 in the general population (37). The most common types are WS1 and WS2, and according to the diagnostic criteria, they are about equally common. Waardenburg estimated a mutation rate of 0.4/100,000 gametes (132). A high incidence in Africans from Kenya has been reported (27). A computerized literature review found sporadic cases of the syndrome in many ethnic groups, including Japanese, Taiwanese, and Middle Eastern families (87). The first reports of WS1 and WS2 in China with novel mutations in PAX3, MITF and SOX10 genes have appeared (18). The authors identified, for the first time, SOX10 mutations in cases of WS2 with an estimated frequency similar to that of MITF mutations. A screening program for Waardenburg syndrome in Colombia disclosed 95 affected individuals belonging to 95 families, giving a frequency of 5.38% of Waardenburg syndrome among the institutionalized deaf population and 45 noninstitutionalized affected relatives. They classified 62.1% of the propositi as WS2 and 37.9% as WS1 (115).
Folic acid has been recommended in high-risk pregnancies for Waardenburg syndrome (57; 29; 42). Rare patients with Waardenburg syndrome who present hyperpigmented regions in their fundi should be monitored closely for the development of choroidal malignant melanoma (54).
The differential diagnoses for Waardenburg syndrome include piebaldism, dominant partial albinism of the Tietz-Smith type, Fisch syndrome, Rozycki syndrome, and Woolf syndrome.
Identification of the clinical picture and categorization of the type of Waardenburg syndrome is the first step for confirming the diagnosis. Conventional audiometry and the use of otoacoustic emissions are recommended in order to provide optimum fitting of hearing aids, especially in children (94). Early detection of hearing deficits, as early as the newborn period, may be established with auditory evoked potentials. In children with unilateral sensorineural hearing loss, a rigorous screen for pigmentary abnormalities is recommended (61). Computed tomographic scanning of the temporal bone may disclose abnormalities of the inner ear, such as malformation or absence of the semicircular canals and cochlea (88). The rare report of a young infant with WS1 and seizures revealed bilateral hypoplasia of the semicircular canals and cochlea by CT (111). His brain MRI demonstrated delayed myelination, which showed recovery to normal myelination on his follow-up MRI. Molecular genetic tests are important to determine the specific genes involved and may be essential in some patients without a classical picture. The biometric index based on 3 measurements is particularly helpful in distinguishing WS1 and WS2 and may be used as a guide to look for a PAX3 mutation (100). A W index of 1.95 or more is diagnostic of dystopia canthorum and, therefore, of WS1. It is important to pay attention to the characteristic dysmorphology of Waardenburg syndrome; otherwise, it could be misdiagnosed as nonsyndromic deafness (105). Molecular analysis is necessary in doubtful cases (55) and essential to define the most severe cases in WS4 (122; 52; 127). The detection of both partial and whole gene deletions of PAX3/MITF increases the mutation detection yield by at least 6% and supports integrating MLPA into clinical molecular testing primarily for patients with WS1 and WS3 (79). Analysis of the 3-dimensional (3D) structure of PAX3 helps verify the pathogenicity of a missense mutation. Multiple ligation-dependent probe amplification (MLPA) analysis of PAX3 has increased the sensitivity of genetic diagnosis in patients with WS1, particularly in those patients with isolated, mild, or nonspecific symptoms (77). In those cases presenting with neuropathy, electrodiagnostic studies and nerve biopsy are required (01). In patients with the PCWH phenotype, MRI is essential to investigate central hypomyelination (127). Studies in large samples, including familial and isolated probands, have the advantage of finding novel causative mutations in different types of Waardenburg syndrom. In a large Brazilian sample of patients with WS1 and WS2, 10 novel causative mutations were found (13). In special cases, prenatal diagnosis of spina bifida can lead to the diagnosis of WS1 in the mother and other members of her family (64). Neonates and young infants with difficult breathing and inspiratory stridor require direct laryngoscopic examination to rule out laryngomalacia (121). Bilateral temporal bone abnormalities associated with agenesis or hypoplasia of greater than 1 semicircular canal, an enlarged vestibule, cochlear hypoplasia, or agenesis of cochlear nerve have been demonstrated with MRI (31). In addition, agenesis of the olfactory bulbs, hypoplastic or absent lacrimal glands, hypoplastic parotid glands, and white matter signal anomalies were found by the same authors (31). A scoring system designed to predict the severity of Hirschsprung disease, isolated or associated with Waardenburg syndrome, was applied at the time of diagnosis (91). The authors’ goal was to evaluate a possible clinical-genetic correlation. In the severe group, most mutations were located in the RET proto-oncogene.
Management is directed to the treatment of associated complications. The hearing deficit is the most common impairment; therefore, early diagnosis and intervention to improve this problem are important steps for the psychological development of these children and help to reduce their sense of isolation (27). Special education is essential to enhance normal development in children with hearing deficits. Cochlear implants are indicated in these patients. In 1 study, the average age at implantation was 37 months (range, 18 to 64 months) and children accepted and regularly used their devices. In general, patients with Waardenburg syndrome have above-average performance after cochlear implantation (22) and their cognitive development gradually improves to a normal level (133).
In another study, cochlear implantation at the age of 2 years or younger had similar good results, but the presence of additional disabilities requires special counseling (126). Surgical correction of congenital megacolon should be performed early; in many cases it is successful. Understanding of the syndrome and tolerance of associated disabilities are important for the integration of these patients into society (27). In Waardenburg-Shah syndrome patients, the Ziegler operation is recommended when there is inadequate ganglionic bowel length to gain time for the child to grow and to decrease total parenteral nutrition complications (56). Patients with Shah-Waardenburg syndrome who develop food allergy and eosinophilic gastrointestinal diseases with abdominal pain, nausea, vomiting, and chronic diarrhea after intestinal resection might benefit from a trial of strict dietary avoidance of suspect allergenic foods (69). In a female infant with WS4 who underwent 14 surgical interventions from birth to 3 years of age, including a skin grafting of a nonhealing ulcer from malnutrition, parenteral nutrition was required for more than 20 months due to recurrent enterocolitis and poor oral intake (83). Self-evacuation improves with daily glycerin enemas; probiotics are also recommended (133).
No complications have been reported during pregnancy on WS1. Fertility is normal in WS1 and WS2. A reduction of fetal movement was noted during the last month of pregnancy; the proband had WS4, arthrogryposis, and meconial ileus and died on day 11 of life (122). In the case that both parents are affected by Waardenburg syndrome, complications in the pregnancy including polyhydramnios, intrauterine growth restriction, and decreased fetal movements associated with multiple anomalies in the fetus also affected by Waardenburg syndrome were reported (68). Folic acid has been recommended in women with pregnancies at risk of Waardenburg syndrome (57; 29). Patients with Waardenburg syndrome requiring obstetrical anesthesia have not been reported in the literature, suggesting that there is no increased risk of obstetrical complications (03). Two cases of WS3 were diagnosed in the first trimester of pregnancy, due to a homozygous mutation in PAX3. The ultrasound revealed increased nuchal translucency and lack of active movements, with bilateral wrist contractures and club feet (82).
Patients with Waardenburg syndrome may require surgical treatment, particularly in types 3 and 4, but very little has been published about the anesthetic implications (02). Characteristic facial features, muscle contractures, and difficult airway may cause difficulties in both direct laryngoscopy and tracheal intubation, often require cochlear implant at an early age, and require anticipation and special equipment (96). The anesthetic management of a child with WS4 undergoing multiple surgical procedures was complicated by perioperative problems, such as malnutrition, electrolyte imbalance, and communication difficulties due to congenital deafness and blindness (83). In a report of 2 neonates with WS4 who presented with constipation since birth, the second neonate was lost to follow-up (02). Pudendal nerve block was applied in a child with Waardenburg syndrome who required surgery for cleft palate and spina bifida (59). Meticulous attention is required with preoperative evaluation, coexistence of other system abnormalities, airway management, and perioperative nutrition strategies (risk of malnutrition increasing with the extended aganglionic segment of the intestine).
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