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The case of the young lady with pretty blue eyes and hearing loss

Accreditation Number: ODO 002/001/02/2019

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A 12 Year old African female presented at a school screening. She attends a school for learners with special educative needs (LSEN). She has hearing aids in both her ears, but communicates normally. She previously wore spectacles but lost them. She struggles to see both at distance and near. Furthermore, it was noted the young lady has brilliant blue eyes, and she is the only one in her family who has blue eyes. Telecanthus and a small patch of white hair were noted at the back of her head.

Inner ocular inter-cantal distance (a) = 43 mm
Inter-pupillary distance (b) = 61 mm
Outer ocular inter-cantal distances (c) = 99 mm
VA (R) = 6/24     VA (L) = 6/24
Colour vision: Normal
Stereopsis: Normal
Motilities: Normal
NPC: 3cm, maintains and repeats easily
Cover test: Exophoria at distance and near
Ophthalmoscopy showed clear crystalline lenses with peripapillary atrophy in both eyes.

Figure 1: The Auto refraction reading of her eyes.

Waardenburg syndrome was first reported in 1916 by Dutch Ophthalmologist Jan van der Hoeve. Van der Hoeve described twin girls who were deaf and presented with a type of blepharophimosis syndrome. Nearly 30 years later similar physical features were described by Dr Petrus J Waardenburg in a male patient who also was deaf and mute. Waardenburg initially found it coincidental that both the twins and the older gentleman presented with auditory abnormalities, but it was not until 1951 when David Klein presented a similar case of blepharophimosis with hearing impairments to Waardenburg that the condition was classified as Waardenburg Syndrome (WS) (Read and Newton, 1997).

Waardenburg described the condition as a hereditary autosomal dominant condition with six main clinical features. These included lateral displacement if the medial canthi combined with dystopia of the lacrimal punctum and blepharophimosis, prominent broad nasal root, hypertrichosis of the medial part of the eyebrows, white forelock, heterochromia iridis and deaf-mutism (Flores-Sarnat, 2003). Later the condition was further classified into four types, Waardenburg syndrome I (WS I), Waardenburg syndrome II (WS II), Waardenburg syndrome III or Klein-Waardenburg syndrome (WS III) and Waardenburg syndrome IV or Waardenburg-Shah syndrome (WS IV).

Characteristics

Individuals affected with the condition may present with several different physical features based on the type and severity of the syndrome (Table 1). Most often, affected individuals have brilliant blue eyes and a patch of silver or grey hair. The other most common feature is hearing deficiencies.

It is estimated that about 1 in 40 000 individuals are affected by WS (Read and Newton, 1997, Zaman et al., 2015) and is caused by several gene mutations such as the PAX3, MITF, SOX10, EDN3 or EDNRB, EDN3, PCWH genes (Zaman et al., 2015, Pingault et al., 2010).

Mutations in the above-mentioned genes affect the development of several cells, most importantly for WS the development of melanocytes.

Melanocytes are derived from the neural crest and play a major role in the skin’s pigmentation system. Each melanocyte makes contact with 30-40 keratinocytes; this connection allows melanin to be transferred to the keratinocytes and determines skin colour providing protection against Ultraviolet radiation.  Skin colour is not determined by the amount of melanocytes, but rather their level of activity (Tsatmali et al., 2002). This also explains the brilliant blue eyes individuals with WS present with. The colour of the iris is dependent on the amount of melanin present. Lighter eye colours occur because there is less melanin pigment present.

Characteristic WS I WS II WS III WS IV
Hearing abnormalities x x x x
Dystopia canthorum x   x x
White forelock / poliosis x x x x
Synophrys x x    
Hypopigmentation of Iris/Heterochromia x x x x
Neurological abnormalities*   x   x
Camptodactyly     x  
Hirchsprung disease       x
Peripheral neuropathy       x
Gene involvement PAX3 MITF; SOX 10; SNAI 2 PAX3 SOX 10; EDNRB; EDN3

*Neurological abnormalities may include mental retardation and Cerebellar Ataxia/ Spastically

Table 1: A summary of different physical features which may be present in the four different types of WS. 

Hearing abnormalities

Melanocytes are not only melanin-producing cells but have many physiological functions in the body. A correlation between pigmentation and hearing was first hypothesised by Darwin in 1859. Darwin noted in a batch of kittens born, the white kittens were all deaf and the kittens with normal pigment had normal hearing. Furthermore, he noted all young kittens have blue eyes which later may change color. He also noted one kitten, which appeared deaf with blue eyes, later developed hearing and pigmentation (Ghiselin, 2003) (Read and Newton, 1997). All types of WS and their symptoms confirm Darwin’s observations.

The optimal functioning of the cochlea is not dependent on melanin, but rather the presence of melanocytes. In the development of the ear, different cell types are derived from the neural crest; most importantly for WS, there is a deficiency in the development of melanocytes of the cochlea and a portion of the otic capsule of the ear leading to hearing deficiencies (Sandell, 2014).  This explains why individuals with albinism do not have hearing loss as they have a normal amount of melanocytes, but have a deficiency in the production and/ or distribution of melanin (Grønskov et al., 2007).

In 70% of WS cases the hearing loss is progressive, may be unilateral, and may be asymmetrical (Pingault et al., 2010).

Dystopia canthorum

Dystopia canthorum occurs when the nose bridge appears underdeveloped due to lateral displacement of the inner cantus. Not only the inner canthal distance, but also the inter-pupillary distance and the outer canthal distance are larger than normal. This feature is the most reliable diagnostic criterion for WS I and is present in 99% of WS I cases (Read and Newton, 1997); it may also present in WS III and WS IV (Pingault et al., 2010).

White forelock or poliosis

A white forelock can be expected in 20-40% of WS patients. Often these patients experience poliosis, and complete graying of hair before the age of 30 years (Flores-Sarnat, 2003).

Synophrys

Synophrys is the medical term for a unibrow or monobrow, often seen in patients with WS I (Pardono et al., 2003) (Flores-Sarnat, 2003).

Hypopigmentation of the Iris / Heterochromia

Hypopigmentation of the iris is one of the easiest signs to identify in patients of African descent.  Most often patients with WS present with brilliant blue eyes. The hypopigmentation may be complete or partial. Heterochromia can also occur (Flores-Sarnat, 2003).

Neurological abnormalities

Neurological abnormalities are rare in WS types I & II, but a few cases have been observed. In type III abnormalities such as microcephaly and mental retardation may be present, but intelligence is generally normal. Type IV has the highest risk of neurological abnormalities, which include peripheral neuropathy, mental retardation, cerebellar ataxia and spasticity (Pingault et al., 2010). These children rarely survive infancy (Flores-Sarnat, 2003).

Camptodactyly

Camptodactyly refers to one or more of the fingers being permanently bent, and is usually only present in WS III (Faivre and Vekemans, 2005b).

Hirchsprung disease

This condition affects the large intestine, leading to constipation.

Peripheral neuropathy

This refers to weakness or numbness in the hand and the feet due to nerve damage and is most often noticed in WS IV.

Classification

Identifying the type of WS your patient presents with is best done through genetic mapping, but several diagnostic criteria have been proposed to help the clinician.

Zaman et al, (2015) suggested making use of Table 2 to classify the type.

WS I is diagnosed in the presence of two major criteria, or 1 major and 2 minor criteria.

WS II is diagnosed when two major criteria are present, but excludes dystopia canthorum.

WS III is diagnosed when the patient has the same criteria as WS I, but also has musculoskeletal abnormalities.

WS IV is diagnosed when the patient has the same criteria as WS I, but also suffers from Hirchsprung disease.

Major criteria Minor criteria
Congenital sensorineural hearing loss Congenital hypopigmentation of the skin
Pigment disturbance of the iris
Partial/segmental heterochromia
Hypoplastic blue eyes
Complete heterochromia
Synophrys
White forelock Broad high nasal root
Dystopia canthorum Hypoplasia of alae nasi
Affected first degree relative Premature greying of hair

Table 2: Diagnostic criteria as suggested by Zaman et al, (2015).

Read and Newton (1997) used a similar criteria, but included the W index, derived in 1978 by Arias and Motta (Pardono et al., 2003), and is used to determine the presence of dystopia canthorum. This numerical value is determined by making use of indices such as inner canthal (label a, figure 2), inter-pupillary (label b, figure 2) and outer canthal distances (label c, figure 2). If the average W-value for all affected members is ≥1.95 it suggests that WS I is present.

Pardono et al. (2003) concluded that using only the W-index to classify WS, 93% of WS II patients are accurately classified, but only 60% of WS I patients are correctly classified.

Figure 2: Label a is the inner intercanthal distance. Label b is the inter-pupillary distance. Label c is the Outer ocular inter-cantal distances. These values can be measured with a PD ruler, and used to determine the w-value.

To calculate the w-value one can either make use of the following formulae (Formula 1 – 3), or download the w-index Waardenburg calculator at http://utysotabilin.ml/w-index-waardenburg-calculator-download.html.

So, what about our case?

It is easy to conclude the young lady has Waardenburg syndrome. By making use of the diagnostic criteria one can attempt to classify the type, but it can only be confirmed by identifying whether there is a modification in one of the genes previously discussed.

By making use of the above-mentioned formulae her w-index is calculated as 2.42. Because she is the only individual in her family with the condition, she certainly has dystopia canthorum.

By placing her signs and symptoms into Table 3 (Figure 4), it is not yet possible to conclude what type she may have.

Table 3: A modified version of table 1, the red crosses indicate the features this patient presented with.

By applying her signs and symptoms to the criteria explained by Zaman et al, (2015), it can be concluded that she certainly has WS I as she has more than two major criteria.

Table 4: A modified version of table 2, the red writing indicates the features the patient presented with.

Even though this young lady has poor vision which can be attributed to hyperopic astigmatism, which may be due to keratoconus (Pentacam® or corneal topography scans need to be done to confirm this), there is little evidence to support that the condition has an effect on vision. However, Flores-Sarnat ( 2003) stated there might be a connection between Glaucoma and WS. In this young lady’s case her vison would probably have been the same even in the absence of WS.

Conclusion

WS is a rare condition affecting 1 in 40 000 individuals, and contributing to 2-3% of congenital hearing loss (Faivre and Vekemans, 2005a). Abnormal cases like these are rare to come across, but certainly keeps the profession interesting.

References

FAIVRE, L. & VEKEMANS, M. 2005a. Waardenburg syndrome type I. April Available: https://www.orpha.net/data/patho/GB/uk-WS1(05).pdf [Accessed 17/01/2019].

FAIVRE, L. & VEKEMANS, M. 2005b. Waardenburg syndrome type III. April. Available: https://www.orpha.net/data/patho/GB/uk-WS3(05).pdf [Accessed 17/01/2019].

FLORES-SARNAT, L. 2003. Waardenburg syndrome [Online]. MedLink Neurology. Available: http://www.medlink.com/article/waardenburg_syndrome.

GHISELIN, M. T. 2003. The Triumph of the Darwinian Method, Dover Publications.

GRØNSKOV, K., EK, J. & BRONDUM-NIELSEN, K. 2007. Oculocutaneous albinism. Orphanet journal of rare diseases, 2, 43-43.

PARDONO, E., BEVER, Y., ENDE, J., C HAVRENNE, P., IUGHETTI, P., MAESTRELLI, S., COSTA F, O., RICHIERI-COSTA, A., FROTA-PESSOA, O. & OTTO, P. 2003. Waardenburg syndrome: Clinical differentiation between types I and II.

PINGAULT, V., ENTE, D., DASTOT-LE MOAL, F., GOOSSENS, M., MARLIN, S. & BONDURAND, N. 2010. Review and update of mutations causing Waardenburg syndrome. Human Mutation, 31, 391-406.

READ, A. P. & NEWTON, V. E. 1997. Waardenburg syndrome. Journal of Medical Genetics, 34, 656-665.

SANDELL, L. 2014. Neural Crest Cells in Ear Development.

TSATMALI, M., ANCANS, J. & THODY, A. J. 2002. Melanocyte Function and Its Control by Melanocortin Peptides. Journal of Histochemistry & Cytochemistry, 50, 125-133.

ZAMAN, A., CAPPER, R. & BADDOO, W. 2015. Waardenburg syndrome: more common than you think! Clinical Otolaryngology, 40, 44-48.

 

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