cryptorchidism

Microphthalmia, Syndromic 3

Clinical Characteristics
Ocular Features: 

Microphthalmia or clinical anophthalmia is the major ocular malformation in this disorder but optic nerve hypoplasia or even aplasia may also be present.  Colobomas and congenital cataracts may be seen.

Systemic Features: 

Esophageal atresia and sometimes tracheoesophageal fistula sometimes coexist. The ears can be low-set and malformed and sensorineural hearing loss is often present.  Facial palsy has been reported.  The penis may be small and combined with cryptorchidism while physical growth retardation is common.  Other less common malformations include cleft palate, vertebral anomalies, cardiac anomalies, body asymmetry, and microcephaly.  A few patients have had radiologically evident CNS malformations such as dilated ventricles, hippocampal hypoplasia, abnormal white matter, and holoprosencephaly.  However, intellectual development and function have been normal in other patients.

Genetics

This is an autosomal dominant disorder secondary to heterozygous mutations in the SOX2 gene (3q26.33).  Chromosomal aberrations involving this region of chromosome 3 have also been found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Depending upon the severity of malformations, life expectancy can be normal but some patients have died in the neonatal period.  Certain defects such as those of the heart, palate and esophagus can be surgically repaired.  Hearing device can be helpful but no treatment is available for the eyeball malformations.

References
Article Title: 

Microphthalmia, Syndromic 1

Clinical Characteristics
Ocular Features: 

Microphthalmia is often a part of other ocular and systemic anomalies.  The full range of essential features of Lenz microphthalmia remains unknown but is often diagnosed in males when colobomas and microcornea are associated with mental deficits together with urogenital and skeletal anomalies.  Microphthalmos may be unilateral and ocular cysts are common.  The globes may be sufficiently small that anophthalmia is sometimes diagnosed but this is a misnomer as some ocular tissue is always present.   Sixty per cent of eyes have colobomas which are often bilateral and may involve the optic disc, choroid, ciliary body, and iris.  Blindness is common.  

Systemic Features: 

A large number of associated systemic anomalies have been reported with this type of microphthalmia.  Skeletal features include microcephaly, spinal deformities, high arched palate, pectus excavatum, absent or dysplastic clavicles (accounting for the narrow or sagging shoulders), and digital anomalies including syndactyly, duplicated thumbs and clinodactyly.  Physical growth retardation is evident by shortness of stature.   Urogenital malformations are present in 77% of individuals and include hypospadius, cryptorchidism, hydroureter, and renal dysgenesis.  Dental anomalies include oligodontia and irregular lower incisors that may be widely spaced.  Some degree of intellectual disability is present in 63%.  The ears may be abnormally shaped, low-set, rotated posteriorly, and anteverted. 

Genetics

This is a rare X-linked disorder that is apparently due to an unknown mutation at Xq27-Xq28.  No male-to-male transmission has been observed but affected males rarely reproduce as a result of various urogenital anomalies.

A somewhat similar X-linked syndrome of microphthalmia, sometimes called OFCD syndrome (syndromic 2 microphthalmia; 300166) has been reported to be caused by mutations in BCOR (Xp11.4).  This MCOPS2 disorder is often considered to be X-linked dominant with lethality in males.

Another X-linked non-syndromic form of microphthalmia with colobomas has been reported (Microphthalmia with Coloboma, X-Linked; 300345).  In addition there is a similar disorder of simple Microphthalmia with Coloboma that is inherited either in an autosomal dominant or autosomal recessive pattern (605738, 610092, 611638, 613703, 251505 ).

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment beyond supportive care for specific health issues. 

References
Article Title: 

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 8 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families with autosomal recessive inheritance (NS2) (605275) patterns have been reported with biallelic mutations in LZTR1.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 Oct;20(10):1175-1185.

PubMed ID: 
29469822

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

Pages

Subscribe to RSS - cryptorchidism