microphthalmia

Microphthalmia, Syndromic 10

Clinical Characteristics
Ocular Features: 

Microphthalmia seems to be a common feature.  The globes have anterior-posterior dimensions of 5-8 mm.  No internal ocular structures can be visualized and individuals are likely blind.  The corneal diameters in two patients were measured at 3-4 mm.  The optic nerves have been described as ‘slender’ on brain imaging.

Systemic Features: 

Head circumference ranges from the 10th to the 25th percentile at birth  Psychomotor development has been described as normal during the first 6 to 8 months but is followed by rapid deterioration in performance with spasticity, vomiting and continuous crying.  An MRI on one 3 day old patient was reported as normal while at 15 months of age there was atrophy of the vermis and corpus callosum and at 8 years of age the atrophy of these structures was even more extensive.  Similar atrophy patterns were seen in the two other patients and eventually all cerebral while matter is lost and there is atrophy of the brainstem as well. 

Genetics

Three children from 3 consanguineous Pakistani families have been reported but no locus or mutation has been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

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: 

Microphthalmia, Syndromic 5

Clinical Characteristics
Ocular Features: 

One or both eyes may be small, sometimes resembling clinical anophthalmia. Other ocular anomalies such as coloboma, microcornea, cataracts, and hypoplasia or agenesis of the optic nerve have been reported.

A pigmentary retinopathy has been described.  The retinal vessels are often attenuated and sometimes sparse.  The optic nerves and chiasm are frequently absent or hypoplastic as seen on the MRI.  ERG and VEP responses are inconsistent but are generally abnormal indicating photoreceptor malfunction.  

Systemic Features: 

Patients have a variety of systemic abnormalities including pituitary dysfunction, joint laxity, hypotonia, agenesis of the corpus callosum, and seizures.  Hypothyroidism and deficiencies of growth hormone, gonadotropins, and cortisol are present in some patients.  Developmental delay and cognitive impairment are frequently present but mental functioning is normal in some patients.  The genitalia of males are often underdeveloped.  Patients are often short in stature.

Genetics

This is an autosomal dominant condition secondary to heterozygous mutations in the OTX2 gene (14q22.3).  A variety of point mutations as well as microdeletions involving the OTX2 gene have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the syndrome but surgical and/or endocrinological treatment may be used to correct individual features.  Special education and low vision aids may be helpful in selected patients.

References
Article Title: 

Heterozygous mutations of OTX2 cause severe ocular malformations

Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet. 2005 Jun;76(6):1008-22. Apr 21. Erratum in: Am J Hum Genet. 2005 Aug;77(2):334..

PubMed ID: 
15846561

Microphthalmia, Syndromic 6

Clinical Characteristics
Ocular Features: 

Ultrasound evaluation reveals globe size to vary widely from extremely small (6 mm) to normal axial length. Clinical anophthalmia is often diagnosed.  Both anophthalmia and microphthalmia may exist in the same individual. True anophthalmia has been confirmed in some patients in which no ocular tissue was detectable with ultrasound examination.  In such cases the optic nerves and chiasm are often missing as well.  Iris colobomas are common and these may extend posteriorly.  Myopia is sometimes present.

The ERG reveals generalized rod and cone dysfunction in some eyes, but may be normal in others. In many eyes the ERG is nonrecordable. Cataracts are frequently present.

Systemic Features: 

Digital and hand anomalies are common.  The hands are often described as broad and the thumbs may be low-placed.  The nails can appear dysplastic and postaxial polydactyly is often present.  Mild webbing of the fingers has been reported as well.  Microcephaly and the cranium can be misshapen. A high arched palate is often present and clefting has also been noted.  Micrognathia may be present. Some evidence of physical growth retardation is often evident.

Pituitary hypoplasia is not uncommon and may be associated with hypothyroidism and cryptorchidism with hypospadias, and a small or bifid scrotum.

The brain anomalies vary considerably.  Many patients have mild to moderate developmental delays with some learning difficulties. Sensorineural hearing loss is often present. Hypoplasia of the vermis, thinning of the corpus callosum, widening of the lateral ventricles, and occasional generalized cortical atrophy, at least in older individuals, have been described.

Genetics

This is an autosomal dominant condition caused by a point mutation in BMP4 (bone morphogenetic protein-4) (14q22-q23).  A number of chromosomal deletions involving this gene have also been identified in individuals who have this syndrome but since contiguous genes such as OTX2 and SIX6 may also be involved, the phenotype is more likely to be associated with other anomalies including genital hypoplasia, pituitary hypoplasia, absence of the optic nerves and/or chiasm, developmental delay, digital malformations, and cerebellar dysplasia.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataracts can be removed in selected individuals with potential visual function.  Socket prostheses should be considered in anophthalmia and extreme microphthalmia.  Low vision devices, Braille, and mobility training should be initiated early when appropriate.  Hearing evaluations should be done as soon as practical.

Learning specialists and special education facilities should be available for selected patients.  Polydactyly, syndactyly, skull, and cleft palate repairs may be indicated.

References
Article Title: 

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways

Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet. 2008 Feb;82(2):304-19.

PubMed ID: 
18252212

Familial Acorea, Microphthalmia and Cataract Syndrome

Clinical Characteristics
Ocular Features: 

The pupil is obscured or absent secondary to fibrous overgrowth.  Microcornea and microphthalmia are present.  Iridocorneal adhesions are commonly seen on ultrasonic examination and anterior chamber angles may be narrow.  The corneas are clear but thickened centrally.  Nystagmus and esotropia have been reported.

The iris is rudimentary with a poorly developed stromal pattern and sometimes eccentrically located holes.  The ultrasound may reveal remnants of degenerative lens capsules.  Axial length in infants has been measured at about 14.7 mm but increases to 17 mm in children.  In adults the axial length is about 20 mm.  Refractive errors of +20-21 diopters have been measured.  Visual acuity is poor from birth but can be improved to some extent following pupiloplasty and lens extraction.  Intraocular pressure can be normal but one patient developed an increase in the 4th decade of life.  OCT and direct visualization of the fundus in several cases revealed normal retinal architecture and anatomy.

Systemic Features: 

None reported.  Specialty examinations failed to find any hearing loss or neurological deficits.

Genetics

The single 4 generation family tree reported is consistent with autosomal dominant inheritance.  Several likely loci on chromosomes 1, 5, 8, 11, and 17 have been reported but no candidate gene has been identified. 

Other conditions in which small pupils are found are Pierson syndrome (609049) and Warburg micro syndrome (600118) but these are associated with significant systemic abnormalities.  

Congenital microcoria (156600) is an autosomal dominant disorder with mild axial myopia and goniodysgenesis resulting from an unidentified mutation on chromosome 13.  Glaucoma is a common finding as is some iris hypoplasia.  Despite some clinical similarities, this is likely a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some improvement in visual acuity has been reported following lensectomy and reconstruction of the pupil.

References
Article Title: 

Microphthalmia and Anophthalmia, ALDH1A3 Associated

Clinical Characteristics
Ocular Features: 

Patients have a variety of ocular malformations including microphthalmia and clinical anophthalmia.  Some have orbital cysts. Imaging may reveal hypoplastic optic nerves and chiasms.

Systemic Features: 

Both cardiac (pulmonary stenosis and septal defects) and neurological deficits (autism spectrum disorders and 'intellectual disability') have been reported.  Birth weight and head circumference are often low.  However, brain imaging has revealed no consistent malformations.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the gene ALDH1A3 (15q26.3) which encodes the enzyme retinaldehyde dehydrogenase.  Mutations in ALDH1A3 impair the enzymatic oxidation of retinaldehyde important to the synthesis of retinoic acid, a key signaling molecule in eye development. 

However, mutations in other genes important to ocular development such as GJA3 and SOX2 (a transcription factor) may result in a similar phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the ocular problems is available.

References
Article Title: 

ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Fares-Taie L, Gerber S, Chassaing N, Clayton-Smith J, Hanein S, Silva E, Serey M, Serre V, G?(c)rard X, Baumann C, Plessis G, Demeer B, Br?(c)tillon L, Bole C, Nitschke P, Munnich A, Lyonnet S, Calvas P, Kaplan J, Ragge N, Rozet JM. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia. Am J Hum Genet. 2013 Feb 7;92(2):265-70.

PubMed ID: 
23312594

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Persistent Hyperplastic Primary Vitreous

Clinical Characteristics
Ocular Features: 

Persistence and hyperplasia of the embryonic vitreous in most individuals results in significant ocular morbidity.  It results from a transcription factor deficiency in retinal ganglion cells which in turn negatively impacts development of the retinal vasculature.  As a consequence, the fetal hyaloid vasculature fails to regress and its persistence leads to a retrolental mass.

PHPV usually occurs unilaterally and affected eyes are generally blind from birth. Leukocoria secondary to the presence of a retrolental fibrovascular stalk is easily visible.  Nystagmus is frequently present and some patients have microphthalmos. The anterior segment may also be involved as evidenced by the presence of peripheral anterior synechiae, corneal opacities, cataracts, and glaucoma.  Contracture of the retrolental tissue In the posterior chamber results in the ciliary processes being pulled centrally and can lead to hemorrhage and retinal detachment. 

The clinical manifestations can make it difficult to distinguish from Norrie disease.

Systemic Features: 

No consistent systemic signs have been reported in PHPV individuals.

Genetics

The majority of PHPV cases occur sporadically, but families with transmission patterns compatible with both autosomal recessive and autosomal dominant patterns have been reported.

A six-generation family has been reported in which affected members had homozygous mutations in ATOH7 (10q21.3).  Based on mouse studies, this gene is expressed in the developing optic cup at the time that coincides with retinal ganglion cell formation.  Mice with absence of functioning Atoh7 lack retinal ganglion cells and optic nerves and develop PHPV.

A single family with presumed bilateral PHPV in 3 generations in a pattern consistent with autosomal dominant inheritance has been reported (611308).  However, no genotyping was reported and only the proband and his father had ophthalmologic examinations.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No medical or surgical treatment is effective.  The majority of individuals have no light perception.

References
Article Title: 

Mowat-Wilson Syndrome

Clinical Characteristics
Ocular Features: 

Most reports of Mowat-Wilson disorders provide only incomplete ocular findings and the full phenotype remains to be described.  Most of the reported findings are part of the facial phenotype, such as downward slanting palpebral fissures, and 'wedge-shaped' eyebrows with the medial portion visibly wider than the temporal region.  Hypertelorism, strabismus and telecanthus have also been noted.  However, optic nerve atrophyor aplasia, RPE atrophy, microphthalmia, ptosis, and cataracts are sometimes present while strabismus is more common.  Iris and other uveal colobomas may be present and at least one patient has been reported with retinal aplasia.  There may be considerable asymmetry in the features among the two eyes.

Systemic Features: 

This is a highly complex dysmorphic developmental disorder with unusual progression of facial features.  Birth weight and length are usually normal but later there is general somatic and mental growth delay with microcephaly (pre- and post natal), short stature, intellectual disability, and epilepsy (70%).  Hypotonia has been noted at birth.  A significant proportion (~50%) of patients have Hirschsprung disease with megacolon.  Congenital heart defects are common, many involving septal openings.  Hypospadias is often present with or without other genitourinary anomalies.  Teeth are often crowded and crooked.  The earlobes may be flattened and may have a central depression.

The facial features are present in early childhood but as they mature the upper half of the nasal profile becomes convex, while the nasal tip becomes longer and overhangs the philtrum.  The eyes appear more deeply set.  The chin lengthens and prognathism becomes apparent.  IQ levels cannot be determined but many individuals exhibit behavioral or emotional disturbances.

Genetics

Heterozygous mutations in ZEB2 (2q22.3) are responsible for most cases (81%) of this disorder.  A large number of molecular mutations, many of the nonsense type, have been reported. About 2-4% of patients have cytogenetic alterations involving the 2q22 region.

Another disorder with microcephaly, intellectual disability and Hirschsprung disease is Goldberg-Shprintzen syndrome (609460) with mutations in the KIAA1279 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment may be directed at specific defects but there is no treatment for the general disorder. Individuals can live to adulthood. Treatment is largely symptomatic.  Physical and speech treatment can be helpful if initiated early.

References
Article Title: 

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and

Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S,
Cordelli DM, Abdalla E, Accorsi P, Adam MP, Ajmone PF, Badura-Stronka M, Baldo C,
Baldi M, Bayat A, Bigoni S, Bonvicini F, Breckpot J, Callewaert B, Cocchi G,
Cuturilo G, De Brasi D, Devriendt K, Dinulos MB, Hjortshoj TD, Epifanio R,
Faravelli F, Fiumara A, Formisano D, Giordano L, Grasso M, Gronborg S, Iodice A,
Iughetti L, Kuburovic V, Kutkowska-Kazmierczak A, Lacombe D, Lo Rizzo C, Luchetti
A, Malbora B, Mammi I, Mari F, Montorsi G, Moutton S, Moller RS, Muschke P,
Nielsen JEK, Obersztyn E, Pantaleoni C, Pellicciari A, Pisanti MA, Prpic I,
Poch-Olive ML, Raviglione F, Renieri A, Ricci E, Rivieri F, Santen GW, Savasta S,
Scarano G, Schanze I, Selicorni A, Silengo M, Smigiel R, Spaccini L, Sorge G,
Szczaluba K, Tarani L, Tone LG, Toutain A, Trimouille A, Valera ET, Vergano SS,
Zanotta N, Zenker M, Conidi A, Zollino M, Rauch A, Zweier C, Garavelli L.
Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and
recommendations for care. Genet Med. 2018 Jan 4. doi: 10.1038/gim.2017.221. [Epub
ahead of print].

PubMed ID: 
29300384

Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Bourchany A, Giurgea I, Thevenon J, Goldenberg A, Morin G, Bremond-Gignac D, Paillot C, Lafontaine PO, Thouvenin D, Massy J, Duncombe A, Thauvin-Robinet C, Masurel-Paulet A, Chehadeh SE, Huet F, Bron A, Creuzot-Garcher C, Lyonnet S, Faivre L. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome. Am J Med Genet A. 2015 Apr 21. [Epub ahead of print]

PubMed ID: 
25899569

The behavioral phenotype of Mowat-Wilson syndrome

Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype of Mowat-Wilson syndrome. Am J Med Genet A. 2012 Feb;158A(2):358-66. doi: 10.1002/ajmg.a.34405.

PubMed ID: 
22246645

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am J Med Genet A. 2009 Mar;149A(3):417-26. Review.

PubMed ID: 
19215041

Clinical and mutational spectrum of Mowat-Wilson syndrome

Zweier C, Thiel CT, Dufke A, Crow YJ, Meinecke P, Suri M, Ala-Mello S, Beemer F, Bernasconi S, Bianchi P, Bier A, Devriendt K, Dimitrov B, Firth H, Gallagher RC, Garavelli L, Gillessen-Kaesbach G, Hudgins L, K?SS?SSri?SSinen H, Karstens S, Krantz I, Mannhardt A, Medne L, M?ocke J, Kibaek M, Krogh LN, Peippo M, Rittinger O, Schulz S, Schelley SL, Temple IK, Dennis NR, Van der Knaap MS, Wheeler P, Yerushalmi B, Zenker M, Seidel H, Lachmeijer A, Prescott T, Kraus C, Lowry RB, Rauch A. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet. 2005 Apr-Jun;48(2):97-111

PubMed ID: 
16053902

CHARGE Syndrome

Clinical Characteristics
Ocular Features: 

Both ocular and systemic abnormalities are highly variable, even within families.  Among the most common ocular features are unilateral or bilateral ocular colobomas (80%).  These involve the iris most frequently but they may extend into the posterior chamber and rarely involve the optic nerve.  A significant number of patients with uveal colobomas have an associated microphthalmia.  The lid fissures often slant downward.  A few patients have congenital cataracts, optic nerve hypoplasia, persistent hyperplastic vitreous, and strabismus.

Systemic Features: 

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

Genetics

Many cases occur sporadically but family patterns consistent with autosomal dominant inheritance are common as well.  Advanced paternal age may be a factor in de novo cases.  Sequence variants of multiple types have been reported in the CHD7 gene (8q12.1-q12.2) in more than 90% of familial patients.  The gene product is a DNA –binding protein that impacts transcription regulation via chromatin remodeling.

Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) has been considered to be allelic to CHARGE syndrome but may be the same disorder since mutations in CHD7 are responsible and many patients have other features characteristic of the syndrome described here.

Several patients with classical features of the CHARGE syndrome and de novo mutations in the SEMA3E gene (7q21.11) have also been described.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is lesion dependent but focused on airway, feeding, and cardiac defects at least initially.  Regular ophthalmologic and audiologic evaluations are recommended beginning in infancy.  Evidence for hypogonadism should be evaluated if puberty is delayed.  Nutrition must be monitored especially in those with serious feeding problems.  Hearing devices, with speech, occupational, and education therapy may be required.

References
Article Title: 

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