Marshall syndrome in a Nigerian teenager presenting with refractive error

Olufunmilola Abimbola Ogun; Olusegun Adetomiwa Adediran; Adeyinka Olusola Ashaye; Onyekwere George Benjamin Nwaorgu

doi:10.4103/njo.njo_33_20

CASE REPORT

Year : 2021 | Volume : 29 | Issue : 1 | Page : 52-57

Marshall syndrome in a Nigerian teenager presenting with refractive error

Olufunmilola Abimbola Ogun¹, Olusegun Adetomiwa Adediran¹, Adeyinka Olusola Ashaye¹, Onyekwere George Benjamin Nwaorgu²
¹ College of Medicine, University of Ibadan, Ibadan; Department of Ophthalmology, University College Hospital, Ibadan, Oyo State, Nigeria
² College of Medicine, University of Ibadan, Ibadan; Department of Otorhinolaryngology, University College Hospital, Ibadan, Oyo State, Nigeria

Date of Submission	04-Sep-2020
Date of Decision	08-Oct-2020
Date of Acceptance	23-Oct-2020
Date of Web Publication	16-Jul-2021

Correspondence Address:
Olufunmilola Abimbola Ogun
Department of Ophthalmology, University College Hospital, Ibadan, Oyo State, Nigeria. and College of Medicine University of Ibadan, Ibadan
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/njo.njo_33_20

Abstract

A 14-year-old girl, presented to our eye clinic, with poor distance vision since childhood. High myopia with degenerative retina was found. However, craniofacial disproportion and skeletal dysmorphism, as well as hearing impairment, drew clinical suspicion for a single multisystemic disorder prompting a literature review, which supported a clinical diagnosis of Marshall syndrome (MS). This case report and review of literature describes MS, worthy of note for its rarity, genetic basis and distinctive phenotypic features, but yet easily overlooked in routine clinical practice. This is the second case of MS reported in West Africa and the first in a Nigerian female. This extremely rare, systemic disorder may present unexpectedly, as a seemingly common condition as a refractive error and can be easily overlooked, without a high index of suspicion. Accurate diagnosis, however, is important because MS requires collaborative management by a multidisciplinary team and not the ophthalmologist alone, to ensure a good quality of life.

Keywords: Female teen, Marshall syndrome, myopia, Nigeria

How to cite this article:
Ogun OA, Adediran OA, Ashaye AO, Nwaorgu OG. Marshall syndrome in a Nigerian teenager presenting with refractive error. Niger J Ophthalmol 2021;29:52-7

How to cite this URL:
Ogun OA, Adediran OA, Ashaye AO, Nwaorgu OG. Marshall syndrome in a Nigerian teenager presenting with refractive error. Niger J Ophthalmol [serial online] 2021 [cited 2023 Jun 5];29:52-7. Available from: http://www.nigerianjournalofophthalmology.com/text.asp?2021/29/1/52/321645

Introduction

Myopia is a common refractive condition that may be associated with several other ocular and systemic disorders.^[1],[2] Any tendency to focus on the magnitude of the refractive error alone can lead to failure to recognize the potentially wide range of ocular and systemic associations of high myopia. This potentially serious oversight can lead to a missed diagnosis, misdiagnosis or diagnostic delay, with consequent impact on the patient’s health-related quality of life. This case illustrates the need to focus on the bigger picture, even in an apparently routine patient–doctor encounter in a busy clinic. Only few cases of Marshall syndrome ^{More Details} (MS) have been reported in literature, worldwide and in Africa in particular.^{[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16]}

This case is reported to describe the features of MS, in a Nigerian female teenager, as it may present to an ophthalmologist. We also highlight the fact that, although MS is very rare, it can present with a seemingly common condition, such as refractive error, and may be overlooked, if not considered in the systemic evaluation.

Case Description

A 14-year-old female student presented with a history of poor distance vision since childhood. She had developed partial hearing loss at approximately 7 years of age. Her mother mentioned, in passing, that she also had difficulty pronouncing words and poor academic performance, which she had attributed to her poor eyesight and hearing impairment. She was the product of a full term uneventful pregnancy and delivery and the only child of her mother, in a polygamous setting. Her father is bilaterally blind from unknown aetiology. She had been seen in consultation at the Otorhinolaryngology clinic, where a hearing aid was prescribed for sensorineural hearing impairment [Figure 1]. However, this was not obtained due to financial constraints. The remainder of her history and systemic review was unremarkable. She had been seen at a rural/ primary eye care centre and was referred to our clinic for low vision services. On examination, she had a short stature, measuring only 1.43 m in height (<2 SD below expected height-for-age), with underdeveloped pubertal features, frontal bossing and craniofacial dysmorphism. She, however, had long, thick, naturally curly hair on her head. She also had a small upturned nose (anteverted nares) with a flattened nasal bridge, hypertelorism, maxillary hypoplasia, low set ears [Figure 2] and a high-arched palate. Ocular examination revealed unaided Snellen visual acuity of 6/60 in the right eye, and 6/36 on the left, respectively, with a 15° exotropia in primary position. With refraction and correction of −15.00 DS–2.00 DC × 35° in the right eye and −16.00 DS–2.00 DC × 160° in the left eye, her vision improved to 6/18⁻² and 6/18 in the right and left eye, respectively. The ocular adnexa, conjunctiva and cornea were normal. Her pupils were equal, regular and reactive to light and accommodation. There were no cataracts. Binocular indirect ophthalmoscopy revealed clear, liquefied degenerate vitreous with vitreous strands, pink optic discs with large physiologic cups, tessellated fundus [Figure 3] with peripheral areas of lattice degeneration. Colour vision, intraocular pressure and gonioscopy were also normal. Examination of her other systems was unremarkable except for moderately severe sensorineural hearing loss in the right ear and near profound deafness in the left ear confirmed with pure tone audiometry [Figure 1] and thickened calvarium seen on her skull radiographs [Figure 4]. Venereal disease laboratory test was negative, but genetic testing was not available.

Figure 1 Pure tone audiometry showing bilateral sensorineural deafness; profound deafness in right ear and of moderate severity in left ear.

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Figure 2 Fourteen-year-old female with Marshall syndrome showing hypertelorism (left), a short anteverted nose (right) with malar hypoplasia producing a flattened mid facial appearance (right) with relatively low set ears and frontal bossing.

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Figure 3 Fundus photograph of same patient, showing very thin retina with atrophic retinal pigment epithelium and baring of underlyng choroidal vessels consistent with high myopia.

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Figure 4 Skull radiographs of same patient showing thickening of the calvarium (yellow arrows).

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Based on the above ocular and systemic findings, a clinical diagnosis of MS was made. Although she obtained a spectacle prescription, she is still unable to afford low vision services or the hearing aid.

Discussion

MS, was first described by Don Marshall in 1958, in a multigenerational family with seven affected individuals.^[13] It is a rare autosomal dominant condition characterized by anomalous formation of the ectoderm and its accessory structures. It is thought that the genetic basis of MS involves splicing mutations of 54-bp exons in the c-terminal region of the collagen gene, COL11A1.^[5] Mutations in COL2A1 collagen gene have also been reported in association with both Marshall and Stickler syndrome phenotypes.^[8] Because of similarities in their phenotypic features, some authors believe that Marshall and Stickler syndromes exist in a composite spectrum with overlaps.^[8],[17] Recent knowledge, however, suggests that the two syndromes are distinct entities.^[6] The presence of short stature is a key feature of MS, although it is rarely seen in Stickler syndrome.^[6],[18] There is some confusion in literature between the syndrome of ectodermal dysplasia associated with specific ocular features and sensorineural deafness, described by ophthalmologist, Don Marshall in 1958^[13] and a more recent eponymous syndrome described in paediatric medicine by Gary Marshall in 1987.^[19] However, Gary MS, which is characterised by recurrent fever, associated with pharyngitis, cervical adenitis and aphthous stomatitis, can be differentiated from Don Marshall syndrome of ectodermal dysplasia because the former is an acquired disorder, while the latter is inherited. Moreover, the paediatric MS occurs more frequently and has an autoimmune aetiology,^[16],[19] while the latter results from splicing genetic mutations and is very rare.^[5]

MS as described by Don Marshall, is characterized by a distinctive facies with a flattened nasal bridge, upward tilted nostrils (anteverted nares), widely spaced eyes (hypertelorism), near-sightedness (myopia), cataracts and hearing loss. Stature in males is average and normal, while females tend to be small and of short stature. While personality is normal, intellect is somewhat subnormal in a few. Females have ample and normal hair, normal secondary sexual characteristics although it is not mentioned whether these may be delayed, as it appears to have been in our case. Onset of menstruation is however not delayed. Skin is soft, smooth and dry with normal nails. Teeth are also normal.^[13] Ocular findings described by Don Marshall include basic (rather than index) myopia, fluid vitreous, pigmented retina with bearing of choroidal vessels and normal intraocular pressures,^[13] all of which were present in our case.

Moreover, our patient demonstrated moderately severe hearing loss as described in all of Marshall’s cases. Our patient represents only the second case of MS to be described in West Africa and the first female and the only case to have detailed documentation of the ocular findings. The first case diagnosed and described in West Africa was diagnosed in our institution in a 14-year-old boy suspected to have congenital syphilis because of saddle nose deformity, bilateral cataracts, optic atrophy and hearing loss.^[14] He was diagnosed as a case of ectodermal dysplasia based on negative screening for syphilis, sparse hair, scaly skin and loss of dentition (two upper incisors) in addition to the previously described findings. Our patient demonstrates numerous similarities and a few striking differences, characteristic of female cases of Marshall such as the short stature, with ample hair.^[13]

Poor distance vision, particularly high myopia, associated with hearing deficit, short stature and poor intellectual ability should prompt a consideration of MS. Hearing impairment is suggested to be present in up to 80% of cases and should be actively sought because patients may require hearing aids.^[7] [Table 1] summarizes various clinical features of MS that have been reported in literature. Of these features, our patient had short stature, large prominent myopic eyes with tessellated fundus, flattened nasal bridge with upturned nostrils, high-arched palate, poor intellectual ability, sensorineural hearing impairment and a thickened calvarium [Figure 1],[Figure 2],[Figure 3],[Figure 4].

Table 1 Ocular and systemic features that have been reported in association with Marshall syndrome

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Craniofacial features are detectable via ultrasonography as early as the second trimester of gestation, and are present at birth.^[12] Prenatal diagnosis may be indicated where there is a known family history, based on clinical features or via genetic studies. As seen in our patient, associated features are often noticed as the affected individual advances in age. Life expectancy is not diminished in MS. The phenotypic expression of MS is more classical in males, while females tend to express phenotypic features to a lesser degree, being carriers. Differential diagnoses include Stickler syndrome and congenital syphilis. Stickler syndrome is more frequently associated with tall stature, retinal detachments and arthropathy, than MS.^[6],[18] The overlap of features between Stickler syndrome and MS was a point of discussion in a recent case of Stickler syndrome, reported in a Nigerian boy from Northern Nigeria, presenting with cataracts, deafness and ventricular septal defect.^[3] Furthermore, the Pierre-Robin anomalad of cleft palate, mandibular hypoplasia (small jaw) and glossoptosis, are more frequently associated with Stickler syndrome.^[8],[18] Congenital syphilis can be differentiated from MS using a serological test (venereal disease research laboratory, VDRL test) for screening, and the fluorescent treponemal antibody test for confirmatory diagnosis. These tests can be repeated within a 1 month interval, if in doubt.^[14]

It is unfortunate, however, that our patient, despite obtaining an accurate diagnosis, of such a rare multisystem disorder, was unable to benefit from full rehabilitation due to the high cost of low vision devices and hearing aids in our environment. Low vision devices are useful in high myopes, with degenerative myopia, to enhance their magnification at near distance, increase brightness or contrast and to generally improve their reading ability.^[22] Patients with degenerative myopia, such as our patient, could benefit from “high-addition” reading spectacles, the use of handheld, foldable or stand magnifiers with or without in-built illumination and dome or bar magnifiers, for reading. Many young high myopes also accept the use of hand-held monocular telescopes to improve their distance vision, although this is less well tolerated by adults and the elderly.^[23] Some high myopes with more advanced chorioretinal degeneration, with thin retinal pigment epithelium, may have photophobia and may benefit from special ultraviolet A filters, such as a yellow or red tinted lenses to improve their visual performance.^[24] However, low vision services and prescription of low vision devices are highly individualized and therefore time and cost intensive.^[24]

Despite the highly publicised National Health Insurance Scheme in Nigeria, less than 5% of the population have been enrolled^[25],[26] and the scheme does not provide coverage for any form of vision or hearing rehabilitation at any age.^[27],[28] Majority of patients who access the healthcare system must pay out-of-pocket for all their investigations and treatment.^{[25],[26],[28]} In an event that the financial burden becomes unbearable, they simply abscond and abandon further care, sometimes with fatal consequences.^[29] Cases such as this patient’s report should therefore not only elicit an increase in clinical awareness for rare clinical disorders but also generate awareness of existing healthcare inequalities in the 21^st century and its impact on health-related quality of life.

Conclusion

MS is a multisystem disorder, affecting the eyes, ears, musculoskeletal, maxillofacial and central nervous systems, resulting in various complications and manifestations that develop throughout life. Management of the different manifestations of MS requires a multidisciplinary team, which may include paediatricians, ophthalmologists, maxillofacial surgeons, orthopaedics, otorhinolaryngology, geneticists, social workers and even intervention of special educationists, speech or physical therapists. Therefore, failure to recognise or diagnose this condition leaves affected individuals, vulnerable to unattended complications, which impact upon their quality of life. Therefore, ophthalmologists need to maintain a high index of suspicion for potential underlying inherited systemic disorders in cases of myopia with hearing loss.

Finally, there is a need to review the financing of public healthcare systems in low–middle income countries with a high poverty index, to facilitate equitable access to basic rehabilitation services, especially in patients with multisystem disorders.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms and the patient gave consent that their images and other clinical information be reported in the journal.

Acknowledgements

Authors thank the Consortium for Advanced Research and Training in Africa (CARTA) for their support. Authors also wish to thank Dr. Tunji S. Oluleye, Retina Unit, Department of Ophthalmology for his assistance in the clinical review of this patient.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors report no conflicts of interest.

References

1.	Flitcroft DI, Loughman J, Wildsoet CF, Williams C, Guggenheim JA. Novel myopia genes and pathways identified from syndromic forms of myopia. Invest Ophlhalmol Vis Sci 2018;59:338-48.
2.	Tekin M, Chioza BA, Matsumoto Y et al. SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest 2013;123:2094-102.
3.	Ibrahim A. Marshall-Stickler spectrum. J Mahatma Gandhi Inst Med Sci 2016;21:56-8. [Full text]
4.	Al Kaissi A, Ganger R, Klaushofer K, Grill F. Significant ophthalmoarthropathy associated with ectodermal dysplasia in a child with Marshall-Stickler overlap: a case report. Cases J 2008;1:270.
5.	Annunen S, Körkkö J, Czarny M et al. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. Am J Hum Genet 1999;65:974-83.
6.	Ayme S, Preus M. The Marshall and Stickler syndromes: objective rejection of lumping. J Med Genet 1984;21:34-8.
7.	Bacciu A, Di Lella F, Iaccarino I et al. Audiologic manifestations of Marshall syndrome. Otol Neurotol 2018;39:e691–8.
8.	Baraitser M. Marshall/Stickler syndrome. J Med Genet 1982;19:139-40.
9.	Çalışkan E, Açıkgöz G, Yeniay Y et al. A case of Marshall’s syndrome and review of the literature. Int J Dermatol 2015;54:e217–21.
10.	Demikova NS, Blinnikova OE, Kozlova VM. Description of a case of Marshall’s syndrome. Pediatriia 1987;10:98-100.
11.	Iafusco F, D’Avanzo M, Ansanelli V. A case of accelerated skeletal maturation (Marshall’s syndrome). Pediatria 1977;85:487-96.
12.	Iacoboni D, Karpel BM, Shanske AL, Marion RW, Gross SJ. Prenatal diagnosis of Marshall syndrome by targeted sonography. J Ultrasound Med 2005;24:1735-7.
13.	Marshall D. Ectodermal dysplasia report of kindred with ocular abnormalities and hearing defect. Am J Ophthalmol 1958; 45(Part 2):143-56.
14.	Onile BA, Rotowa A, Osoba AO, Alausa OK. Marshall syndrome: a condition resembling congenital syphilis. Br J Vener Dis 1981;57:100-2.
15.	Taillard F, Desbois JC, Delepine N, Allaneau C, Wyart D. Marshall’s syndrome or Stickler’s syndrome? Discussion apropos of a family. Ann Pediatr 1987;34:279-84.
16.	Trandafir LM, Chiriac MI, Diaconescu S, Ioniuc I, Miron I, Rusu D. Marshall syndrome in a young child, a reality: case report. Medicine 2016;95:e5065.
17.	Snead MP, Payne SJ, Barton DE et al. Stickler syndrome: correlation between vitreoretinal phenotypes and linkage to COL 2A1. Eye 1994;8(Pt 6):609-14.
18.	O’Donnell JJ, Sirkin S, Hall BD. Generalized osseous abnormalities in the Marshall syndrome. Birth Defects Orig Artic Ser 1976;12:299-314.
19.	Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Paediatr 1987;110:43-6.
20.	Takahashi C, Hoshi E. A case similar to Marshall’s syndrome. Plast Reconstr Surg 1986;77:975-80.
21.	Menguy C, Rival JM, Poisson-Salomon AS, Barbier ML, Fournet JP. Marshall’s syndrome. Apropos of a new case. Ann Pediatr 1986;33:339-43.
22.	Fonda G. Low vision correction for high myopia. Surv Ophthalmol 1992;36:313-7.
23.	Singh S, Mithal C, Mithal S. Acceptance of low vision aids in patients of ARMD, myopic degeneration and diabetic retinopathy. Delhi J Ophthalmol 2014;25:20-2.
24.	Scassa C, Cupo G, Bruno M et al. Optical devices in highly myopic eyes with low vision: a prospective study. Clin Ther 2012;163:e115–20.
25.	Okebukola PO, Brieger WR. Providing universal health insurance coverage in Nigeria. Int Q Community Health Educ 2016;36:241-6.
26.	Okpani AI, Abimbola S. Operationalizing universal health coverage in Nigeria through social health insurance. Niger Med J 2015;56:305-10. [PUBMED] [Full text]
27.	Ogun OA, Adediran OA. Non-glaucomatous optic neuropathy in Ibadan: extrapolations to healthcare funding in Nigeria. Ann Ib Postgrad Med 2014;12:103-8.
28.	Onwujekwe O, Hanson K, Ichoku H, Uzochukwu B. Financing incidence analysis of household out-of-pocket spending for healthcare: getting more health for money in Nigeria? Int J Health Plan Manag 2014;29:e174-85.
29.	Ogun OA, Aremu OO, Ajaiyeoba AI. Ocular motor cranial nerve palsy as an indicator of neglected systemic disease in Nigeria: perspective from a Neuro-Ophthalmology Clinic. Neuroophthalmology 2019;43:355-62.