pectus excavatum

Elsahy-Waters Syndrome

Clinical Characteristics
Ocular Features: 

Structural anomalies of periocular tissues are common.  Hypertelorism, proptosis, and telecanthus may be striking.  Colobomas or clefts of the upper lid are frequently seen.  The eyebrows are bushy and synophyrs may be present across a broad nasal bridge.  Megalocornea, downslanting lid fissures, glaucoma and cataracts have also been reported but are uncommon.

Systemic Features: 

The skull has been described as brachycephalic.  The midface is flat due to maxillary hypoplasia. The lower jaw is prominent and some patients have mandibular prognathism.  A bifid uvula or partial clefting of the palate are common.  Low-set and posteriorly rotated ears have been reported as well.

 Both pectus excavatum and pectus carinatum have been described.  The teeth have dysplastic enamel and often have obliterated pulp chambers and dental cysts.  Their roots may be shortened and deformed and they are often lost early.  Vertebrae may have fusion of the spines, particularly in the cervical area.  A mixed type of hearing loss is common and some degree of intellectual disability is often evident, especially in older individuals.  Most males have some degree of hypospadias.  Cryptorchidism has been reported in one individual.

Brain imaging in one case revealed no abnormalities.

Genetics

This disorder results from biallelic mutations in the CDH11 gene (16q21).  The parents have been consanguineous in most reports and no vertical transmission has been documented making autosomal recessive the most likely pattern of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Eyelid and palatal defects may be surgically repaired and assistive hearing devices may be of benefit.  Special education is also likely to be helpful.

References
Article Title: 

Myopathy, Mitochondrial Anomalies, and Ataxia

Clinical Characteristics
Ocular Features: 

Ocular findings are variable.  One of three individuals with compound heterozygous mutations had a pigmentary retinopathy with pallor of the optic nerve but no visual abnormalities.  Her sister had only optic nerve pallor.  The eyes are described as "small" and "close-set".

No ocular findings were reported for the family with autosomal dominant inheritance.

Systemic Features: 

Ataxia, short stature, and gait difficulties from an early age are consistent findings.  Some patients are never able to walk.  Motor development is generally delayed.  Truncal and limb ataxia is a feature.  Some degree of intellectual disability is generally present and speech is often delayed.  

The face is long with a myopathic appearance.  Both micrognathia and a prominent jaw may be seen.  The palate is highly arched.  Patients are described as hypotonic and there is generalized muscle weakness both proximal and distal.  Distal sensory impairment has been described in the family with presumed dominant inheritance and there may be psychiatric symptoms of anxiety, depression, and schizophrenia.  Dysmetria with dysdiadochokinesis is often present and a fine intention tremor has been observed.

Mitochondria in fibroblasts exhibit abnormal dynamics and occur in a fragmented network.  Muscle biopsies reveal changes consistent with myopathy.  Serum creatine kinase may be elevated.

Genetics

Compound heterozygous mutations in the MSTO1 gene (1q22) have been found in two families with 3 affected individuals suggesting autosomal recessive inheritance.  In a third family, heterozygous mutations in the same gene were found in a mother and 3 of her adult children, consistent with autosomal dominant transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Marfan Lipodystrophy Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are large resulting in high myopia and apparent proptosis.  The palpebral fissures usually slant downwards and ectopia lentis may be present.  

Systemic Features: 

This syndrome shares many features of Marfan syndrome (154700) such as tall stature, dislocated lenses, myopia, high arched palate, aortic root and valvular anomalies, arachnodactyly, high arched palate, lax and hyperextensible joints, and pectus excavatum.  In addition, MFLS patients have retrognathia, intrauterine growth retardation, scarce or absent subcutaneous fat, a progeroid facies, and sometimes macrocephaly.  Postnatal growth and psychomotor development have been reported to be normal albeit with slow weight gain.

Genetics

This condition is transmitted as an autosomal dominant as the result of heterozygous mutations in FBN1 (15q21.1).  The same gene is mutated in 6 other conditions in this database including Marfan Syndrome (154700) with which it shares some features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual features such as ectopia lentis can be surgically corrected.  Patients with high myopia require frequent evaluation for retinal tears and detachments.  Cardiac monitoring likewise is important to monitor for aortic valve prolapse and dilation of the aortic root.

References
Article Title: 

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics
Ocular Features: 

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders.  Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen.  There may be considerable asymmetry in the manifestations in the two eyes.  Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present.  Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks. 

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported.  Subnormal vision has been reported in some patients.

Systemic Features: 

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet.  Limited forearm rotation and wrist extension may be present.  The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent.  Camptodactyly and clinodactyly are common.  Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted.  The muscles seem "firm" to palpation.  Restrictive lung disease has been reported.  Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36.  However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11).  Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this condition.  Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References
Article Title: 

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID: 
24726473

Brittle Cornea Syndrome 2

Clinical Characteristics
Ocular Features: 

Corneal thinning and extreme fragility are characteristic of BCS2.  Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue.  Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well.  Some patients have sclerocornea that obscures the normal limbal landmarks.  The sclera is also thin and the underlying pigmented uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.

Systemic Features: 

Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present.  Hearing impairment with mixed sensorineural/conductive defects is common.

Genetics

This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27).  Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea. 

BCS2 has many clinical similarities to brittle cornea syndrome 1 (229200) which results from homozygous mutations in ZNF469.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.

References
Article Title: 

Brittle cornea syndrome: recognition, molecular diagnosis and management

Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis. 2013 May 4;8(1):68. [Epub ahead of print]

PubMed ID: 
23642083

Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance

Burkitt Wright EM, Spencer HL, Daly SB, Manson FD, Zeef LA, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GC. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-77. Erratum in: Am J Hum Genet. 2011 Aug 12;89(2):346.

PubMed ID: 
21664999

Multiple Endocrine Neoplasia, Type IIB

Clinical Characteristics
Ocular Features: 

Corneal nerves are medullated and appear prominent.  Neuromas of the lid margins and sometimes the conjunctiva are common features.  Thickening of the entire eyelids may be present.

Systemic Features: 

Some manifestations may be seen in early childhood.  Prominent physical features include full lips, thickened eyelids, high arched palate and a marfanoid habitus.  Medullary carcinoma of the thyroid is almost always present and can be the cause of death in relatively young individuals. Metastases are usually to the regional lymph nodes or to liver, lungs, or bone. Pheochromocytomas and megacolon secondary to gastrointestinal neuromas are commonly seen.  The esophagus sometimes lacks normal motility for the same reason.  Neuromas often lead to thickening of the lips and tongue and can also appear as pedunculated nodules on these structures.  Cafe-au-lait spots and increased pigmentation of the hands, feet, and circumoral areas are frequently present.  Many patients have dysmorphic features suggestive of Marfan syndrome including a typical habitus, pectus excavatum, scoliosis, and pes cavus. Proximal myopathy and peripheral neuropathy are sometimes seen.

Another form of multiple endocrine neoplasia, called MEN2A, differs in the absence of mucosal neuromas and the marfanoid habitus.  MEN2A patients are more likely to have parathyroid hyperplasia.

Genetics

This is an autosomal dominant disorder caused by mutations in the tyrosine kinase domain of the RET gene (10q11.2). This disorder (MEN2B) may be allelic to MEN2A.  Perhaps half of MEN2B cases occur sporadically and in these the mutant RET allele is usually of paternal origin.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment of local lesions is sometimes indicated.  Biochemical testing for pheochromocytoma should be done before any surgery.

References
Article Title: 

Marfan Syndrome

Clinical Characteristics
Ocular Features: 

Marfan syndrome typically has skeletal, ocular and cardiovascular abnormalities.  The globe is elongated creating an axial myopia and increasing the risk of rhegmatogenous retinal detachments.  Ectopia lentis is, of course, the classical ocular feature and is often if not always congenital with some progression.  The lenses most frequently dislocate superiorly and temporally and dilating the pupils often reveals broken and retracted lens zonules.  Phacodenesis and iridodenesis are commonly present even in the absence of evident lens dislocations. Cataracts develop several decades earlier than in unaffected individuals. The cornea is generally several diopters flatter than normal and there is an increased risk of open angle glaucoma.  There is considerable clinical variation among patients.

Systemic Features: 

Patients with the Marfan phenotype are usually tall with disproportionately long limbs (dolichostenomelia) and digits (arachnodactyly).   Patients frequently have scoliosis or kyphoscoliosis.  The joints are lax and hyperflexible although contractures can also occur.  The sternum is often deformed, either as a pectus excavatum, or sometimes pectus carinatum.  The hard palate is high and narrow resulting in crowding of the teeth and maloccclusion.  The defect in fibrillin is responsible for the weakness in connective tissue that leads to frequent cardiac valve malfunction, especially insufficiency of the aortic valve resulting from aortic dilatation, tear, and rupture.  The latter is often life-threatening as aortic dissection can be fatal.  Mitral valve prolapse is seen as well.  Cardiovascular disease is primarily responsible for the shortened life expectancy in this disease, more pronounced among males.

Genetics

As many as 25% of cases are caused by new mutations, but familial cases usually follow an autosomal dominant pattern of inheritance.  Autosomal recessive inheritance is claimed for several individuals in a consanguineous Turkish family.  Mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (15q21.1) are considered responsible for the typical phenotype.  The exact nature of the fibrillin defect is unknown but the result is a generalized weakness in connective tissue.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani syndrome (608328) which is allelic to the Marfan syndrome.

Mutations in FBN1 have also been found in cases with isolated autosomal dominant ectopia lentis (129600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Isometric exercises such as weight lifting should be avoided as should contact sports in which blunt trauma to the chest may occur because of the weakened aortic wall due to cystic changes that predispose the athlete to aortic dissection.  A dislocated and/or cataractous lens may need to be removed from the visual axis, and, of course, periodic retinal examinations for retinal holes and retinal detachments should be made.   Beta-adrenergic blockade reduces the risk of aortic dilatation and improves survival.

Pravastatin has been reported to reduce aortic dilation in marfan mice.

References
Article Title: 

Pravastatin reduces marfan aortic dilation

McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H, Black A, Kearney S, Kay E, Hill AD, Dietz HC, Redmond JM. Pravastatin reduces marfan aortic dilation. Circulation. 2011 Sep 13;124(11 Suppl):S168-73.

PubMed ID: 
21911808
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