Hallermann-Streiff syndrome (HSS) is a very rare congenital syndrome characterized by distinctive craniofacial morphology, congenital cataract, microphthalmia, hypotrichosis, skin atrophy, and proportionate short stature. It is also called oculo-mandibulo-facial syndrome.
After being discussed by Aubry in the late 1800s, it was reported as an independent disease by Hallermann in 1948 and Streiff in 1950. It is a rare disease with only about 200 cases reported worldwide. 1) There is no gender difference, and most cases occur as sporadic mutations. There is a report of monozygotic twins, with one pair both affected. 1)
The causative gene has not been identified, and involvement of the GJA1 gene is ruled out due to differences in phenotype. Developmental disorder of the second pharyngeal arch is considered the basis of craniofacial abnormalities.
QHas the causative gene for this disease been identified?
A
The causative gene has not been identified. Analysis using next-generation sequencing (WES/WGS) is ongoing, but identification has not been achieved at this time. 1) Most cases occur as sporadic mutations, although a small number of familial reports spanning 2 to 3 generations exist.
Cardiovascular complications: VSD, ASD, tetralogy of Fallot, pulmonary valve stenosis, PDA, aortic stenosis, etc. have been reported.3)
Sims et al. (2023) reported a case of monozygotic twins (female, born at 32 weeks).1) Both infants exhibited all seven major signs of François, and underwent lens extraction and near-total capsulectomy for spontaneously absorbing cataracts. Both developed bilateral exudative retinal detachment, and Twin 2 underwent full-thickness corneal transplantation for perforation of a Descemetocele. Final best-corrected visual acuity was 20/260 and 20/130 for Twin 1, and 20/130 for Twin 2.
QCan cataracts in Hallermann-Streiff syndrome disappear spontaneously without surgery?
A
Spontaneous absorption (liquefaction) of cataracts has been reported, but residual lens material can cause chronic inflammation and glaucoma.1) Early surgical intervention is recommended to prevent amblyopia and avoid complications.
The causative gene for HSS has not been identified, and even next-generation sequencing has not elucidated it. 1) The following mechanisms are considered for its pathogenesis.
Second branchial arch developmental disorder: Underlying craniofacial abnormalities
Scleral collagen abnormality: Frayed collagen fibers are observed under electron microscopy 1)
Overall reduction and insufficient sulfation of glycosaminoglycans: Cause of corneal and scleral fragility 1)
Most cases occur as sporadic mutations, but familial reports spanning 2–3 generations also exist. 2)
Systemic evaluation: MRI (corpus callosum abnormalities, airway assessment), echocardiography (screening for congenital heart disease), polysomnography (evaluation of sleep apnea)
In cases with only mild facial abnormalities, diagnosis may be delayed. In a patient first diagnosed with HSS at age 68, the discovery of blue sclera during cataract surgery led to the diagnosis. 2)
A multidisciplinary approach (ophthalmology, plastic surgery, otorhinolaryngology, anesthesiology, dentistry, pediatrics) is essential.
Cataract management
Early surgery: Perform early lens extraction to prevent amblyopia, without waiting for spontaneous absorption.
Surgical technique: Lens extraction with near-total capsulectomy is recommended, because residual lens material can become a focus of inflammation for uveitis and glaucoma. 1)
Postoperative correction: Intraocular lens implantation is difficult due to severe microcornea and microphthalmos. Refractive correction is achieved with aphakic spectacles (+36 to +38 D). 1)
Glaucoma and Corneal Management
Pharmacotherapy: Combination of timolol, cosopt, latanoprost, and oral acetazolamide1)
Release of angle closure: Goniosynechialysis (GSL) is performed 2)
Corneal calcification: Treated with EDTA chelation therapy 2)
Corneal Descemetocele perforation: Full-thickness penetrating keratoplasty is performed. Corrected visual acuity of 20/130 was maintained at 1 year and 3 months postoperatively. 1)
Management of postoperative inflammation: For persistent anterior chamber inflammation after cataract surgery, fibrin dissolution by intracameral injection of tPA (tissue plasminogen activator) is attempted. 2)
Exudative retinal detachment: There is a report of poor response to oral prednisolone. 1) Management requires individualized treatment based on each case.
Respiratory management: Severe obstructive and central sleep apnea may require tracheostomy (reported cases: Twin 1 at 3 months of age, Twin 2 at 10 months of age). 1)
QWhy is an intraocular lens not inserted after cataract surgery?
A
In HSS, severe microcornea and microphthalmos (corneal diameter 7–7.75 mm, axial length 9–10 mm) prevent sufficient space for intraocular lens insertion. 1) Postoperatively, the eye remains aphakic, and refractive correction is achieved with specialized glasses for high hyperopia (+36 to +38 D).
The diverse ophthalmic complications in HSS are thought to arise from a common basis of collagen abnormalities in the sclera and cornea.
Collagen/Matrix Abnormalities: Electron microscopy reveals frayed collagen fibers, and a general decrease in glycosaminoglycans with insufficient sulfation leads to scleral and corneal fragility. 1)
Mechanism of Blue Sclera: Thinning and disorganization of scleral collagen fibers allow the underlying choroid to show through, resulting in a blue hue. Scleral thinning can be objectively confirmed by AS-OCT. 2)
Mechanism of Exudative Retinal Detachment: It is inferred that impaired transscleral outflow of intraocular fluid due to scleral collagen abnormalities causes choroidal venous congestion, leading to exudative retinal detachment. 1)
Cataract and Inflammation Cascade: Congenital cataracts may spontaneously liquefy, but residual lens material can serve as a nidus for chronic inflammation, causing persistent uveitis and glaucoma. 1) Persistent inflammation after cataract surgery is suggested to involve a hypersensitivity reaction to lens material. 2)
Mechanism of angle closure: Shallow anterior chamber due to short axial length (9–10 mm) leads to angle closure, causing glaucoma. 2)
Mechanism of corneal descemetocele: Chronic stress on fragile corneal stromal cells, combined with stromal thinning from steroid eye drops, is thought to lead to descemetocele formation. 1)
7. Latest Research and Future Perspectives (Investigational Reports)
Elucidation of genetic basis: The molecular and genetic basis of HSS remains unknown, and ongoing research using next-generation sequencing is being conducted. 1) Identification of the causative gene is expected to improve diagnostic accuracy and lead to future therapeutic development.
Lymphatic drainage therapy for nasal obstruction: A case has been reported in which facial lymphatic drainage performed during treatment of lower limb lymphedema incidentally led to complete resolution of nasal obstruction, suggesting involvement of the lymphatic system and a new therapeutic possibility. 3)
Systematization of multidisciplinary management across life stages: In this syndrome, which involves abnormalities in multiple organs and tissues, the development of comprehensive management plans for each stage from the neonatal period to adulthood is considered an important issue. 2)
Sims DT, Mattson NR, Huang LC, et al. Hallermann-Streiff syndrome in concordant monozygotic twins with congenital cataracts, exudative retinal detachments, and one case of corneal perforation requiring keratoplasty. Cornea. 2023;42(7):899-902.
Shimada A, Takayanagi Y, Ichioka S, Ishida A, Tanito M. Hallermann-Streiff syndrome diagnosed in the seventh decade of life. Am J Ophthalmol Case Rep. 2022;27:101595.
Godoy ACS, Godoy HJP, Godoy JMP. Hallermann-Streiff Syndrome and Lower Limb Lymphedema with Nasal Obstruction. Case Rep Med. 2022;2022:1520880.
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