genitourinary anomalies

3MC Syndromes

Clinical Characteristics
Ocular Features: 

The major ocular features involve the periocular structures.  These result in the typical facial dysmorphism and include hypertelorism, blepharoptosis, blepharophimosis, and highly arched eyebrows. Ptosis, unilateral or bilateral, can be present.

One patient was reported to have unilateral aniridia and a corneal leucoma.  Tear duct atresia was reported in another individual.

Systemic Features: 

Systemic features are highly variable in their presence and severity.   Facial clefting, growth deficiency, cognitive impairment, and hearing loss are present about half the time in some combination while craniosynostosis, urogenital anomalies, and radioulnar synostosis are seen in about a third of individuals.  More rare features include cardiac defects and abdominal midline defects (omphalocele and diastasis recti).

Genetics

This condition (3MC) is now postulated to include at least 3 disorders (Malpuech-Michels-Mingarelli-Carnevale syndromes) and considered here as a single autosomal recessive disease complex with overlapping clinical features that requires genotyping for diagnostic separation.  These are: 3MC1 syndrome (257920) resulting from homozygous mutations in the MASP1 gene (3q27.3), 3MC2 syndrome (265050) caused by mutations in the COLEC11 gene (2p25.3) and 3MC3 (248340) with mutations in the COLEC10 gene (8q24.12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective general treatment has been reported.

References
Article Title: 

COLEC10 is mutated in 3MC patients and regulates early craniofacial development

Munye MM, Diaz-Font A, Ocaka L, Henriksen ML, Lees M, Brady A, Jenkins D, Morton J, Hansen SW, Bacchelli C, Beales PL, Hernandez-Hernandez V. COLEC10 is mutated in 3MC patients and regulates early craniofacial development. PLoS Genet. 2017 Mar 16;13(3):e1006679. doi: 10.1371/journal.pgen.1006679. eCollection 2017 Mar.

PubMed ID: 
28301481

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat Genet. 2011 Mar;43(3):197-203.

PubMed ID: 
21258343

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 
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