INTRODUCTION
First described by Marshall et al.[1] in 1971, Marshall-Smith syndrome (MSS) is a rare embryonic developmental disorder which is characterized by peculiar skeletal features, facial deformities, neurological abnormalities, failure to thrive, and respiratory complications. Malan et al.,[2] in 2010, showed in his report that MSS is caused by de novo mutations in the NFIX gene at the 13.3 locus of the short arm of (Chromosome 19p13.3) encoding for a transcription factor critical during neurodevelopment and osteogenesis. This mutation results in an abnormal protein formation that likely exerts a dominant-negative effect. According to Schanze et al.[3] 2014, deletion of exon 6 or/and 7 was responsible for MSS phenotype.
Worldwide, with a prevalence of <1/1,000,000, there are around 57 patients described in medical literature till date.[4] There seems to be no gender or racial predilection.
Recent advances, such as airway support, have ensured a longer and better quality of life in such patients who earlier had extremely high mortality and morbidity rate primarily due to respiratory complications. With increase in the case reports, there is an expansion in our understanding of the associated phenotypic variability.
Herein, we are reporting bilateral proptosis in the case of MSS.
CASE REPORT
A 10-year-old male child was brought to the ophthalmology department by his parents with complaints of forward protrusion of both eyes for the past 6 months. He was a diagnosed case of MSS, born out of nonconsanguineous marriage, with an uneventful antenatal period. The parents gave a history of episodes of seizuresand hypoglycemia in the past.
On general examination, he was alert, conscious, and cooperative with stable vitals. His facial features included a long face with prominent forehead, flat midface, coarse eyebrows, shallow orbits, micrognathia, depressed nasal bridge, small upturned nose, low set ears, long slender extremities with prominent heel [Figure 1], scoliosis, and tongue hypertrophy. He had normal hearing and had no respiratory problems.
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Figure 1: Clinical picture of the patient showing characteristic: (a) Facial features; prominent forehead, shallow orbits, prominent eyes, flat nasal bridge with upturned nose, and micrognathia. (b) Long slender limbs with prominent heels
On ophthalmological examination, visual acuity in both eyes was 6/6 for distance with normal intraocular pressure. There was bilateral proptosis with Hertle’s exophthalmometer reading 24 mm in either eye. On retropulsion test, there was no obvious resistance felt. On further examination, hypertelorism was noted along with a lagophthalmos of 1 mm; however, slit-lamp examination did not reveal any evidence of corneal exposure. The posterior segment was found to be normal.
The chest X-ray showed infiltration in right perihilar region. The contrast-enhanced computed tomography head and orbit showed evidence of bilateral proptosis because of shallow orbital cavity Figure 2. A magnetic resonance imaging scan of the brain revealed prominent lateral ventricular body and cerebrospinal fluid spaces. No epileptiform abnormalities were seen in the electroencephalogram. Echocardiogram and electrocardiogram were also normal. Laboratory examinations which included hemogram, peripheral blood smear, erythrocyte sedimentation rate, Mantoux, thyroid function test, serum calcium, serum IGG4, P-ANCA, and C-ANCA all were unremarkable.
Figure 2: (a and b) Skeletal survey at 6 years of age showing long tubular bones with thin cortices. (c) X-ray anteroposterior and lateral view of chest showing right perihilar haziness and vertebral scoliosis. (d) Non contrast CT orbit (NCCT) orbit showing shallow orbits with bilateral proptosis
A provisional diagnosis of MSS with bilateral proptosis was made, and the child was commenced on topical lubricants and has been kept on follow-up.
DISCUSSION
In 1971, Marshall et al.[1] described a novel overgrowth syndrome in two unrelated infants with characteristic extraordinary skeletal maturation, unusual facial features, gross developmental delay, and failure to thrive. The skeletal surveys were similar in both the infants and demonstrated prominent frontal calvarium, small facial bones, hypoplastic mandible, long thin tubular bones, scoliosis, and broad middle phalanges with relatively narrow distal phalanges. Both the infants died of respiratory complications.
Since then, additional clinical variants have been recounted that have accreted to our knowledge of the phenotypic spectrum of the disease: Choanal atresia; deep hand or foot crease; clitorimegaly; hypertrophy of labia majora; hypersegmented sternum and sacrococcyx; interdigital webbing and soft-tissue palmar pads; hydronephrosis; high arched palate; heart defects laryngeal abnormalities; craniovertebral abnormalities; selective myopathy; and immunological abnormalities.[5,6]
Structural abnormalities in brain morphology have also been reported: macrogyria; corpus callosum abnormalities; polymicrogyria; pachygyria; ventriculomegaly; cerebellar hypoplasia; and small pons.[6,7]
Ophthalmic manifestations in MSS include visual loss due to chronic disc edema, optic neuropathy, amblyopia, and corneal exposure. There are reports of glaucoma, short sightedness, narrow/obstructed tear ducts, and strabismus because of facial dysmorphia, and few cases of optic nerve hypoplasia have also been reported. Travan et al. reported a case of optic nerve hypoplasia with associated septo-optic dysplasia. In 2015, Herman et al. demonstrated optic nerve hypoplasia along with bilateral posterior embryotoxon in their patient.[7,8]
The management of this clinical entity depends on the primary complaint of the patient. In 2010, Mitsukawa and Satoh performed the first reported surgical treatment for facial dysmorphism and successfully corrected midface retrusion and exophthalmos in their patient.[9] Similarly, in 2020, Bettina Knie et al. performed a fronto-orbital advancement surgery for craniosynostosis. Although the surgeries were uneventful, there was some degree of relapse in both the cases as was expected with the patient’s growth.
Due to small number of known cases, many aspects of the syndrome are yet to be identified. However, early and aggressive airway management might increase survival into adulthood. The clinical examination and radiological studies of our case closely approximate with the other cases of MSS but with essentially good prognosis. Surgical intervention could be of great value in reducing proptosis and improving the quality of life in such patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the parents have given their consent for images and other clinical information to be reported in the journal. The parents understand that name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
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Marshall-Smith syndrome. Am J Hum Genet 2010;87:189–98.
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