Megalocornea Mental Retardation (MMR) Syndrome, also known as Neuhauser syndrome, was first described in 1975 by Neuhauser et al. The main features of this rare autosomal recessive congenital disorder are megalocornea in the absence of elevated intraocular pressure, intellectual disability, and hypotonia, though megalocornea and intellectual disability alone have been proposed as the minimal criteria for diagnosis.
There have been about 40 cases of MMR reported thus far and the genetic cause is unknown. Due to a high degree of phenotypic heterogeneity in reported cases, MMR has been proposed to either be a di- or multi-genetic condition or exhibit variable expressivity. In 2014, targeted and whole exome sequencing performed on a patient with MMR found a missense mutation C464G (Cys155Tyr) in the gene CHRDL1. As X-linked mutations of CHRDL1 cause X-linked megalocornea, this mutation explained the patient’s ocular but not the non-ocular phenotypic manifestations. However, CHRDL1 mutations were not found in two brothers with MMR in a 2017 case report, though authors could not fully exclude mutations in copy number variants or non-coding regions. Familial cases have occurred and consanguinity has been reported in 11% of cases thus far, suggesting autosomal recessive inheritance. Most cases of MMR are sporadic, are diagnosed in infancy or early childhood, and occur with equal frequency in males and females. The distribution of reported cases does not appear to demonstrate a geographic or race preference for the development of MMR. The pathogenesis of this condition has not been well-delineated, though brain imaging has revealed delayed myelination in a number of cases, suggesting cerebral hypomaturation may play a role.
A full history and physical should be performed, including inquiring of consanguinity, family history of congenital glaucoma, megalocornea, and other ocular or neurologic conditions. In addition to a full ocular exam, a thorough neurologic and developmental assessment is recommended.
Clinical manifestations/Physical examination
- Megalocornea, intellectual disability, and motor retardation are the most common features of the disease, however, the latter two have variable degrees of severity, thus minor criteria can also be considered.  According to a review by Gutiérrez-Amavizca et al. (2013), the following should be considered as minor criteria: “hypotonia, growth retardation, seizures/abnormal electroencephalography, micro/macrocephaly, brain malformations, craniofacial abnormalities, cardiopathy, osteoarticular abnormality, or refractive errors”. Brain abnormalities can include cerebral cortical atrophy and a hypoplastic corpus callosum. Craniofacial abnormalities can include frontal bossing, epicanthal folds, downward slanting palpebral fissures, dysmorphic ears, micrognathia, high arched palate, broad nasal bridge, and hypertelorism. Osteoarticular abnormalities can include kyphosis/scoliosis, joint hyperlaxity, and long/tapered fingers. Additionally, hypothyroidism, osteoporosis, hypercholesterolemia, and sensorineural deafness have been rarely reported.
- The most prominent ocular finding of MMR is megalocornea, which is generally defined as a corneal diameter ≥12.5mm in the absence of elevated intraocular pressure. However, as noted in a recent review, measuring this can be subject to error, as different technologies use different parameters for their landmarks which can already be difficult to define in vivo. Additional biometric findings of X-linked megalocornea include short radius of curvature, deep anterior chamber, and shortened vitreous depth, giving support to megalocornea’s alternative name, “anterior megalophthalmos”. Other anterior chamber abnormalities include iris hypoplasia/atrophy, iridodonesis, anterior embryotoxon, arcus lipoides, crocodile shagreen, zonular weakness/phacodonesis, and Kruckenberg’s spindle. However, it is not clear how many of the anterior segment findings found in X-linked megalocornea are also found in MMR. Strabismus and nystagmus have also been reported in MMR.
- An additional finding in X-linked megalocornea is normal to thin corneal central thickness (CCT). Two series of patients with X-linked megalocornea were found to have CCTs of 482 microns and under. Another series found corneal diameter and CCT to be inversely related (r=-0.77). This is in contrast to the normal to elevated CCT that can be found in untreated congenital glaucoma, although this has not been uniformly found in the literature and thus should be interpreted with caution.
- The following ophthalmic tests/measurements should be performed in addition to a full ophthalmic exam: corneal diameter, CCT, IOP, refraction, axial length, gonioscopy. Additional measurements could be performed for more academic purposes including AC depth and corneal radius of curvature.
- The main differential diagnosis for the megalocornea component is congenital glaucoma or buphthalmos. Several features, variably present, can be used to differentiate it including: normal IOP, lack of Descemet’s breaks, bilaterality/symmetry, thin CCT, small corneal radius of curvature, normal axial length, shortened vitreous length, presence of Krukenberg’s spindle. Notably, AC depth, vitreous length and axial length have been argued to be consistent measurements for differentiation. Congenital glaucoma will also typically present with the triad of epiphora, photophobia, and blepharospasm.
- An additional diagnosis includes keratoglobus, which has diffuse protrusion without corneal enlargement. It is often progressive with worsening corneal myopia and astigmatism and can develop Descemet’s tears resulting in hydrops.
- A diagnosis of Frank-Ter Haar syndrome should be considered. This autosomal recessive syndrome, caused by biallelic mutations in the SH3PXD2B gene, is characterized by skeletal, ocular, and cardiac abnormalities. The most common ocular findings are megalocornea and hypertelorism with variable rates of congenital glaucoma. Additionally, a lower incidence of neuromotor anomalies and intellectual disability help distinguish this syndrome from MMR.
General treatment and follow up. The management of patients with MMR is largely focused on reducing the burden of disease complications. These measures may include managing hypothyroidism, recurrent infections, and refractory epilepsy. Patients with MMR should be followed by an interdisciplinary medical team of at least an ophthalmologist, geneticist, orthopedist, neurologist, and physical/speech therapists. Patients and their parents should also receive recommendations for rare disease resources, such as clinical trials and advocacy organizations.
Based on cases reported thus far, long term outcomes for patients with MMR vary considerably. In addition to experiencing significant intellectual disability and motor retardation, many patients suffer from refractory epilepsy and disproportionate delays in language development. Hypotonia, present in 68% of reported cases, may be a precursor to the development of cerebral palsy, spastic diplegia, and/or choreoathetotic movement. Patients with MMR can also experience recurrent respiratory infections, in part from poor chest wall tone and breathing mechanics, particularly in the first year of life. A 2015 case reported hypogammaglobulinemia in a patient with MMR, the first proven immunodeficiency associated with this condition. Cases that included years of follow-up findings demonstrate that both the dysmorphic features and ophthalmological findings remain largely unchanged from the initial patient encounter. Conversely, hypothyroidism, hypercholesterolemia, and osteopenia have been reported to be transient. A brain MRI performed at age 2 years in a patient with MMR showed reduced areas of hypomyelination compared to a MRI performed at 1 year of age, which coincided with continued neurological development in the infant.
- ↑ 1.0 1.1 1.2 1.3 1.4 Neuhäuser G, Kaveggia EG, France TD, et al. Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited. Zeitschrift fur Kinderheilkunde. 1975;120(1):1-18.
- ↑ 2.0 2.1 2.2 Del Giudice E, Sartorio R, Romano A, et al. Megalocornea and mental retardation syndrome: two new cases. American journal of medical genetics. 1987;26(2):417-420.
- ↑ 3.0 3.1 3.2 Davidson A, Cheong S-S, Hysi P, et al. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser Syndrome and central corneal thickness. PLoS ONE. 2014;9(8):1-12.
- ↑ 4.0 4.1 4.2 Antinolo G, Rufo M, Borrego S, et al. Megalocornea-Mental Retardation Syndrome: An Additional Case. American Journal of Medical Genetics. 1994;52(2):196-197.
- ↑ 5.0 5.1 5.2 Santolaya J, Grijalbo A, Delgado A, et al. Additional case of Neuhäuser megalocornea and mental retardation syndrome with congenital hypotonia. American journal of medical genetics. 1992;43(3):609-611.
- ↑ 6.0 6.1 Gebril OH, Cheong SS, Hardcastle AJ, et al. Absence of CHRDL1 and FOXC1 sequence changes in two brothers with Megalocornea-Mental Retardation Syndrome. Journal of Neurology, Neurological Science, and Disorders. 2017;3(1):28-32.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Gutiérrez-Amavizca BE, Juárez-Vázquez CI, Orozco-Castellanos R, et al. Neuhauser syndrome: a rare association of megalocornea and mental retardation. Review of the literature and further phenotype delineation. Genetic counseling. 2013;24(2):185-191.
- ↑ Meire FM. Megalocornea. Clinical and genetic aspects. Documenta ophthalmologica advances in ophthalmology. 1994;87(1):1-121.
- ↑ 9.0 9.1 9.2 Atik T, Atik SS, Çoğulu O, et al. Megalocornea Should Be Investigated in Cases with Hypotonia and Mental Retardation: Neuhauser Syndrome--An Easily Missed Diagnosis. Genetic counseling. 2015;26(4):443-445.
- ↑ Barisic I, Ligutic I, Zergollern L. Megalocornea-mental retardation syndrome: report of a new case. Journal of Medical Genetics. 1996;33:882-883.
- ↑ 11.0 11.1 11.2 Kimura M, Kato M, Yoshino K, et al. Megolocornea: mental retardation syndrome with delayed myelination. American journal of medical genetics. 1991;38(1):132-133.
- ↑ 12.0 12.1 Mukherjee S, Juneja M. Megalocornea – mental retardation syndrome. Indian Pediatrics. 2005;42:835-836.
- ↑ 13.0 13.1 13.2 13.3 13.4 Margari L, Presicci A, Ventura P, et al. Megalocornea and mental retardation syndrome: clinical and instrumental follow-up of a case. Journal of Child Neurology. 2006;21(10):893-896.
- ↑ 14.0 14.1 14.2 14.3 Sarkozy A, Mingarelli R, Brancati F, et al. Primary hypothyroidism and osteopenia associated with Neuhauser syndrome. American Journal of Medical Genetics. 2002;111(4):412-414.
- ↑ Tominaga N, Kondoh T, Kamimura N, et al. A case of megalocornea-mental retardation syndrome complicated with bilateral sensorineural hearing impairment. Pediatrics International. 1999;41:392-394.
- ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Ong APC, Zhang J, Vincent AL, McGhee CNJ. Megalocornea, anterior megalophthalmos, keratoglobus and associated anterior segment disorders: A review. Clin Exp Ophthalmol. 2021 Jul;49(5):477-497. doi: 10.1111/ceo.13958. Epub 2021 Jun 27. PMID: 34114333
- ↑ 17.0 17.1 17.2 17.3 Vail D. Adult hereditary anterior megalophthalmus sine glaucoma: a definite disease entity. Arch Ophthalmol 1931; 6:39-62.
- ↑ 18.0 18.1 18.2 18.3 18.4 Meire FM, Delleman JW. Biometry in X linked megalocornea: pathognomonic findings. Br J Ophthalmol. 1994;78:781-785.
- ↑ Naritomi K, Chinen Y, Tohma T. Megalocornea-mental retardation syndrome: An additional case report. Jap J Human Genet 42, 461–465 (1997). https://doi.org/10.1007/BF02766950
- ↑ Han J, Young JW, Frausto RF, Isenberg SJ, Aldave AJ. X-linked Megalocornea associated with the novel CHRDL1 gene mutation p.(Pro56Leu*8). Ophthalmic Genet. 2015;36(2):145-148. doi:10.3109/13816810.2013.837187
- ↑ 21.0 21.1 Amini H, Fakhraie G, Abolmaali S, Amini N, Daneshvar R. Central corneal thickness in Iranian congenital glaucoma patients. Middle East Afr J Ophthalmol. 2012;19(2):194-198. doi:10.4103/0974-9233.95248
- ↑ Oberacher-Velten I, Prasser C, Lorenz B. Evolution of central corneal thickness in children with congenital glaucoma requiring glaucoma surgery. Graefes Arch Clin Exp Ophthalmol. 2008;246(3):397-403. doi:10.1007/s00417-007-0690-6
- ↑ Türkyilmaz A, Sager S, Topcu B, et al. Novel SH3PXD2B variant identified by whole-exome sequencing in a Turkish newborn with Frank-Ter Haar Syndrome. Clinical Dysmorphology. 2022;31(1):45-49.
- ↑ Aktas Z, Karaca EE, Dogan N, et al. Congenital glaucoma as an ophthalmic manifestation of Frank-Ter Haar syndrome. International Ophthalmology. 2014;34(2):351-354.