Neuhauser syndrome is a rare congenital disease also called megalocornea-mental retardation (MMR) syndrome. It was first reported in 1975 1). The main features are the triad of megalocornea without elevated intraocular pressure, intellectual disability, and hypotonia 2). Even only megalocornea and intellectual disability have been proposed as minimal diagnostic criteria 2,3).
It follows an autosomal recessive inheritance pattern. Only about 40 cases have been reported to date 2,4). Most are sporadic and diagnosed in infancy or early childhood. There is no gender difference and no geographic or racial predilection. Consanguinity has been reported in 11% of cases 2). Verloes et al. suggested that based on phenotypic variability, it may be classified into at least four subtypes 3).
Note that isolated megalocornea is X-linked recessive, occurring in 90% of males, and the causative gene locus is Xq23 5). It is important to note that the inheritance pattern differs from that of megalocornea in Neuhauser syndrome.
Megalocornea is a congenital abnormality in which the corneal diameter is larger than normal. It is defined as a horizontal corneal diameter of 12 mm or more in newborns and 13 mm or more in adults. In Neuhauser syndrome, the absence of elevated intraocular pressure distinguishes it from corneal enlargement due to congenital glaucoma. The cornea is usually transparent and histologically normal.
The symptoms of Neuhauser syndrome are diverse. Systemic symptoms have a greater impact on daily life than ocular symptoms 2).
The most prominent ophthalmic finding is megalocornea. It is generally defined as a corneal diameter of 12.5 mm or more (13 mm or more in adults) without elevated intraocular pressure3,5).
Anterior Segment Findings
Megalocornea: Corneal diameter ≥12.5 mm. Bilateral, non-progressive, and symmetrical.
Deep anterior chamber: Characteristic of anterior megalophthalmos.
Iridodonesis: A finding reflecting zonular weakness. May also be accompanied by phacodonesis.
Thin central corneal thickness (CCT): Reported to be ≤482 μm. Corneal diameter and central corneal thickness show a negative correlation (r = -0.77)4).
Other Anterior Segment Findings
Iris hypoplasia/atrophy: Part of anterior segment dysgenesis.
Embryotoxon: An abnormal finding in the peripheral cornea.
Arcus senilis / Crocodile shagreen: Corneal degenerative findings presenting at a young age.
Krukenberg spindle: Pigment deposition on the posterior corneal surface.
Strabismus and nystagmus have also been reported in Neuhauser syndrome.
The severity of intellectual disability varies greatly among cases. In addition to motor delay, language development delay may be disproportionately prominent. Some cases are complicated by intractable epilepsy, and neurological prognosis is diverse. See the “Prognosis” section for details.
Neuhauser syndrome follows an autosomal recessive inheritance pattern1). Consanguineous marriage is observed in 11% of reported cases2).
In 2014, Davidson et al. identified a novel missense mutation in the CHRDL1 gene in patients diagnosed with MMR syndrome4). X-linked mutations in CHRDL1 cause X-linked megalocornea (MGC1)5), which may explain the ocular phenotype of Neuhauser syndrome. However, extraocular symptoms (intellectual disability, hypotonia, etc.) cannot be explained by CHRDL1 mutations alone, so Davidson et al. suggested that “MMR syndrome may be a digenic or polygenic disorder in some cases”4).
Ventroptin (a BMP antagonist) encoded by CHRDL1 has been shown to be essential for anterior segment development5). Phenotypic heterogeneity is high, and Verloes et al. proposed that it can be classified into at least four subtypes3).
In addition to a complete ophthalmic examination, the following measurements are necessary.
Neurological and developmental evaluations are recommended. Brain imaging often reveals delayed myelination, cerebral cortical atrophy, and agenesis of the corpus callosum in many cases 6). In a report by Davidson et al., white matter changes were detected on brain MRI even in patients with X-linked megalocornea and normal cognitive function, suggesting central nervous system involvement in CHRDL1-related pathology 4).
The most important differential diagnosis for megalocornea is congenital glaucoma (buphthalmos).
| Finding | Neuhauser Syndrome | Congenital Glaucoma |
|---|---|---|
| Intraocular pressure | Normal | Elevated |
| Descemet’s membrane rupture | None | Haab’s striae |
| Central corneal thickness | Thin | Normal to thick |
Davidson et al. have shown that B-mode ultrasound measurement of axial length and anterior chamber depth is a reliable clinical tool for differentiating megalocornea (anterior megalophthalmos) from congenital glaucoma 4).
Congenital glaucoma typically presents with the triad of tearing, photophobia, and blepharospasm. These are absent in Neuhauser syndrome.
Other differential diagnoses:
The most important differentiating point is intraocular pressure. In Neuhauser syndrome, intraocular pressure is normal, whereas in congenital glaucoma it is elevated. Additionally, the presence or absence of Descemet membrane rupture (Haab’s striae), central corneal thickness (thin vs. normal to thick), axial length (normal vs. elongated), and the triad of tearing, photophobia, and blepharospasm are useful for differentiation.
There is currently no curative treatment for Neuhauser syndrome. Management focuses on reducing the burden of complications.
Follow-up by a multidisciplinary team is recommended for patients with MMR.
Patients and their families should also be provided with information on resources for rare diseases, such as clinical trials and patient support groups.
Megalocornea is usually non-progressive, but glaucoma associated with angle abnormalities, cataracts, and lens dislocation may occur over time. Long-term regular ophthalmologic examinations are necessary. In particular, intraocular pressure measurement and anterior segment evaluation are important.
The cause of megalocornea is thought to be delayed anterior growth of the optic cup during the embryonic period. The cornea is transparent, corneal thickness is normal, and no histological abnormalities are observed. It is a congenital anomaly in which the anterior segment is large relative to the eyeball, and is also called anterior megalophthalmos.
The CHRDL1 gene (Xq23) was identified as the causative gene for X-linked megalocornea (MGC1) by Webb et al. in 2012 5). Ventroptin, encoded by CHRDL1, acts as a bone morphogenetic protein (BMP) antagonist and plays an essential role in anterior segment development 5). In 2014, Davidson et al. reported a novel CHRDL1 missense mutation in a case of MMR syndrome, but since it does not explain the extraocular symptoms, the possibility of a digenic or polygenic disorder has been suggested 4).
Brain imaging studies show delayed myelination, cerebral cortical atrophy, and hypoplastic corpus callosum in many cases 6). Cerebral hypomaturation is thought to underlie intellectual disability and motor delay 1,2).
Hypotonia can be a precursor to cerebral palsy, spastic diplegia, and choreoathetoid movements 1).
The long-term outcome of Neuhauser syndrome varies greatly among cases.
In addition to intellectual disability and motor delay, many cases present with intractable epilepsy and disproportionate language development delay 1,2). Recurrent respiratory infections are particularly problematic in the first year of life 2).
In cases with several years of follow-up data, such as the 5-year clinical observation report by Margari et al., both dysmorphic features and ophthalmologic findings have been shown to remain almost unchanged from the initial examination 6). On the other hand, hypothyroidism, hypercholesterolemia, and osteopenia have been reported as transient 2,6).
If there is no glaucoma associated with lens dislocation, cataract, or angle abnormalities, visual acuity often remains relatively good 2,4).
Neuhäuser G, Kaveggia EG, France TD, Opitz JM. Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Z Kinderheilkd. 1975;120(1):1-18. doi:10.1007/BF00443795. PMID:1172332.
Gutiérrez-Amavizca BE, Juárez-Vázquez CI, Orozco-Castellanos R, Arnaud L, Macías-Gómez NM, Barros-Nuñez P. Neuhauser syndrome: a rare association of megalocornea and mental retardation. Review of the literature and further phenotype delineation. Genet Couns. 2013;24(2):185-191. PMID: 24032289.
Verloes A, Journel H, Elmer C, Misson JP, Le Merrer M, Kaplan J, Van Maldergem L, Deconinck H, Meire F. Heterogeneity versus variability in megalocornea-mental retardation (MMR) syndromes: report of new cases and delineation of 4 probable types. Am J Med Genet. 1993;46(2):132-137. doi:10.1002/ajmg.1320460206. PMID:8484397.
Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, et al. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness. PLoS One. 2014;9(8):e104163. doi:10.1371/journal.pone.0104163. PMID:25093588; PMCID:PMC4122416.
Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, et al. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am J Hum Genet. 2012;90(2):247-259. doi:10.1016/j.ajhg.2011.12.019. PMID:22284829; PMCID:PMC3276677.
Margari L, Presicci A, Ventura P, Buttiglione M, Dicuonzo F, Lattarulo C, Perniola T. Megalocornea and mental retardation syndrome: clinical and instrumental follow-up of a case. J Child Neurol. 2006;21(10):893-896. doi:10.1177/08830738060210100801. PMID:17005108.
Aviña-Fierro JA, Hernández-Aviña DA. Neuhauser syndrome: the facial dysmorphic phenotype. Rev Med Inst Mex Seguro Soc. 2016;54(1):106-108. PMID: 26820212.
