cryptorchidism

Bosma Arhinia Microphthalmia Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia or clinical anophthalmia are usually present.  Iris colobomas are frequent features.  Occluded or absent nasolacrimal ducts have been reported.

Systemic Features: 

Arhina with anosmia is the most striking feature but it is usually accompanied by midface hypoplasia, a highly arched (or cleft) palate, and preauricular pits.  The nasal bones along with the cribriform plate, and other septal structures may be missing.  Maxillary and paranasal sinuses, together with the olfactory bulbs are often absent.  Intelligence is usually normal.

Choanal atresia is often present.  Hypogonadotropic hypogonadism with micropenis and cryptorchidism is an important feature in males.  Females may experience pubertal delay with menarche anomalies.  

Genetics

Heterozygous mutations in the SMCHD1 gene (18p11) are responsible for this disorder.  There is considerable clinical heterogeneity with many carriers having only minor manifestations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been described.

References
Article Title: 

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, Yoshiura KI, Oufadem M, Beck TJ, McGowan R, Magee AC, Altmuller J, Dion C, Thiele H, Gurzau AD, Nurnberg P, Meschede D, Muhlbauer W, Okamoto N, Varghese V, Irving R, Sigaudy S, Williams D, Ahmed SF, Bonnard C, Kong MK, Ratbi I, Fejjal N, Fikri M, Elalaoui SC, Reigstad H, Bole-Feysot C, Nitschke P, Ragge N, Levy N, Tuncbilek G, Teo AS, Cunningham ML, Sefiani A, Kayserili H, Murphy JM, Chatdokmaiprai C, Hillmer AM, Wattanasirichaigoon D, Lyonnet S, Magdinier F, Javed A, Blewitt ME, Amiel J, Wollnik B, Reversade B. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017 Feb;49(2):249-255.

PubMed ID: 
28067911

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 1

Clinical Characteristics
Ocular Features: 

Nystagmus, strabismus and sometimes optic atrophy have been noted.  Poor fixation may be present.   

Systemic Features: 

This progressive disorder can be evident at birth based on the facial dysmorphism.  The face is triangular, the forehead is prominent, the nose is small, the ears appear large and low-set.  The mouth appears wide with a thin upper lip.  Early development may be near normal for the first 6 months but thereafter psychomotor regression and slow physical growth are evident.  Patients have microcephaly and seldom achieve normal milestones.  Spasticity in the extremities and truncal hypotonia with distal muscle atrophy are evident.  The face appears triangular, the forehead is prominent, the nose is small, and the ears appear large and low-set.  Pectus carinatum and pes varus may be present.   Males often have cryptorchidism.

Brain imaging has revealed cerebellar atrophy and "while matter abnormalities".  Sural nerve biopsies show evidence of infantile neuroaxonal dystrophy.

Some individuals are less severely affected, retain the ability to speak, and are able to walk at least into the second decade of life.

Genetics

Based on transmission patterns this condition is inherited as an autosomal recessive caused by mutations in in the NALCN gene (13q32.3-q33.1.

For somewhat similar disorders caused by mutations in other genes see IHPRF2 (616801) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Hypotonia, Infantile, with Psychomotor Retardation

Clinical Characteristics
Ocular Features: 

Abducens nerve palsy with characteristic strabismus (esotropia) can be present.

Systemic Features: 

Mothers may note decreased fetal movements.  Severe generalized hypotonia can be evident at birth, requiring tube feeding and respiratory assistance.  Death may occur before 6 months of age but with intense supportive care children can live for several years.  Brain imaging may show enlarged lateral ventricles and thinning of the corpus callosum in some individuals but no abnormalities in others.  Muscle biopsies can show severe myopathic changes with increased fibrosis, variation in fiber size, and small atrophic fibers.  Cardiac septal defects have been reported.  Delayed psychomotor development is a common feature.

Genetics

Homozygous mutations in the CCDC174 gene (3p25.1) are responsible for this condition so far reported in only two families with 6 children affected.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

CDC174, a novel

Volodarsky M, Lichtig H, Leibson T, Sadaka Y, Kadir R, Perez Y, Liani-Leibson
K, Gradstein L, Shaco-Levy R, Shorer Z, Frank D, Birk OS. CDC174, a novel
component of the exon junction complex whose mutation underlies a syndrome of
hypotonia and psychomotor developmental delay
. Hum Mol Genet. 2015 Nov
15;24(22):6485-91.

PubMed ID: 
26358778

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

Kabuki Syndrome 1

Clinical Characteristics
Ocular Features: 

The facial features and specifically the periocular anomalies are diagnostic and responsible for the eponymic designation (resembling the make-up of actors of a Japanese theatrical form known as Kabuki). The lid fissures are long and narrow and the lateral third of the lower lids are often everted.  The eyebrows are highly-arched and broad with some sparsity especially in the lateral portion.  The eyelashes are thick and ptosis is often noted. Strabismus may be present.  Blue sclerae have been reported.

Some patients may have extreme microphthalmia.

Systemic Features: 

Post-natal growth delay and short stature are present as a result of anomalies in the vertebrae often with secondary scoliosis.  Persistence of the fetal fingertip pads is common. Hypotonia and joint hypermobility have been noted and some degree of intellectual disability is common.  Seizures have been reported but these are not common. Cleft lip and palate are seen in about a third of patients and the palate is highly arched in about 75%.  The teeth are small, frequently malformed and widely spaced.  Feeding difficulties are common.  Anal anomalies such as imperforate anus, anovestibular fistulas, and an anteriorly placed opening may be present, especially in females.  A small penis, hypospadias, and cryptorchidism are common in males.

An ill-defined immune deficit seems to be a common feature as evident by susceptibility to infections, primarily otitis media in infants and later recurrent sinopulmonary infections.   The majority of patients have hypogammaglobulinemia with a variable pattern of antibody abnormalities resembling common variable immune deficiency and especially low levels of serum IgA.  

Hearing loss is seen in nearly half of patients, some of which is no doubt due to recurrent otitis media but CT radiography has demonstrated dysplastic morphology of inner ear structures and the petrous bone.  The ears are large and cupped and preauricular pits may be present as well.

Biliary atresia and a variety of morphological anomalies of the kidney have been reported.  Renal failure can occur.  Perhaps as many as 58% of patients have congenital heart defects, mostly septal in location. 

Genetics

Heterozygous mutations in KMT2D (12q13.12) (also called MLL2) are responsible for Kabuki syndrome 1 but parental transmission to offspring is rare and the majority of patients occur sporadically.  There is also an X-linked form (Kabuki 2) caused by mutations in KDM5A (Xp11.3).  Insufficient clinical data regarding the X-linked phenotype so far has precluded the ability to distinguish the two disorders without genotyping.

Residual genetic heterogeneity remains, however, as a substantial proportion of patients do not have mutations in the two mutant genes known.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no general treatment for this condition.  Management guidelines are available (Management of Kabuki Syndrome).

References
Article Title: 

MLL2 and KDM6A mutations in patients with Kabuki syndrome

Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013 Sep;161A(9):2234-43. 

PubMed ID: 
23913813

Filippi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features have not been fully described.  The most consistent features are long eyelashes, thick (bushy) eyebrows, and 'visual disturbance'.  Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism.  Optic atrophy and proptosis have been noted. 

Systemic Features: 

Intrauterine growth retardation is sometimes seen.  Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic.  Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia.  Mental and physical delays are common.  The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger.  Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia. 

Genetics

Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome

Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmuller J, Thiele H, Nurnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nurnberg P. Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32.

PubMed ID: 
25439729

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: 

Baraitser-Winter Syndrome 1

Clinical Characteristics
Ocular Features: 

Ptosis (both unilateral and bilateral), hypertelorism, prominent epicanthal folds, and colobomata are common.  The iris stroma may be dysplastic and correctopia has been observed.  Visual acuity has not been measured.

Systemic Features: 

Postnatal growth retardation leads to short stature.  Microcephaly and morphological aberrations in the brain such as lissencephaly, agenesis of the corpus callosum and pachygyria are present.  Seizures and developmental delays are common.  Hearing loss is sensorineural in type.

The ears are low-set and the posterior hair line may be low as well.  The nasal bridge appears broad and the nose appears short. Male genitalia are often underdeveloped.  Bicuspid aortic valves, patent ductus arteriosus, and aortic stenosis have been reported.

Genetics

Heterozygous mutations in the ACTB gene (7p22.1) are responsible for this apparent autosomal dominant syndrome.  However, all patients have been sporadic.

This condition is clinically similar to Baraitser-Winter syndrome 2 (614583) which is a unique entity caused by a mutation in ACTG1

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available.

References
Article Title: 

New ocular finding in Baraitser-Winter syndrome

Rall N, Leon A, Gomez R, Daroca J, Lacassie Y. New ocular finding in Baraitser-Winter syndrome. Eur J Med Genet. 2017 Oct 9. pii: S1769-7212(17)30156-8. doi: 10.1016/j.ejmg.2017.10.006. [Epub ahead of print].

PubMed ID: 
29024830

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

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: 

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