macrocephaly

Cataracts, Congenital, With Short Stature and Minor Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Early-onset cataracts are the main ocular feature of this syndrome.  A nonconsanguineous Korean family with 4 affected individuals has been reported.  Cataracts were diagnosed at various ages, including one adult, one juvenile, and one infant.  All had horizontal nystagmus and reduced vision even after surgical removal of the lenses.  

Systemic Features: 

Macrocephaly and short stature are consistent features.  Brachydactyly of the fingers is usually present.  The feet are described as "flat" and contain accessory navicular bones.

Genetics

A 3 generation Korean family with 4 affected members has been reported.  Three living members and a deceased grandfather had cataracts in an autosomal dominant pattern.  A mutation in the BRD4 gene (19p12.12) mutation segregated with the cataract phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical removal of the cataractous lenses may be helpful in selected individuals but amblyopia is likely present as postoperative vision may remain below normal.

References
Article Title: 

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Kenny-Caffey Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

Congenital cataracts have been reported in one patient.  There is a report of pseudopapilledema in a 6 year old and another patient has been described with tortuous and dilated retinal vessels.  The hyperopia is likely the result of the small globes.  In an autopsied patient microscopic calcification was noted in the cornea and the retina.

Systemic Features: 

Hypocalcemia and hyperphosphatemia similar to hypoparathyroidism is seen in individuals with KCS2 but it may be transient and self-limited.  Macrocephaly with short stature is characteristic.  Alopecia, delayed closure of the anterior fontanel, and apparent thickening of the cortex in long bones may be seen.  Males have small testicles but there is no evidence regarding fertility.  In an autopsied case no parathyroid tissue could be identified.  Brain imaging may show calcification in the basal ganglia, dentate nuclei, and parts of the cerebrum and cerebellum.  Intelligence is normal.

Genetics

Several heterozygous mutations in the FAM111A gene (11q12.1) have been found.  Many of these seem to be new mutations but there are a number of published families in which there was transmission from mother to child (of both sexes).

Heterozygous mutations in the same gene are responsible for the autosomal dominant  allelic disorder known as Gracile Bone Dysplasia (602361). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normalization of serum calcium and phosphorous levels would likely be beneficial but complete correction of all the findings is unlikely.  Removal of congenital cataracts should be considered.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Ocular findings in Kenny's syndrome

Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten BW. Ocular findings in Kenny's syndrome. Arch Ophthalmol. 1979 May;97(5):896-900.

PubMed ID: 
444124

Tenorio Syndrome

Clinical Characteristics
Ocular Features: 

The eyebrows appear bushy.  Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjogren syndrome.

Systemic Features: 

Infants appear large at birth with a large forehead and macrocephaly.  Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’.  Dentition is delayed.  Recurrent stomatitis and gastroesophageal reflux have been noted.  Closure of the fontanels is delayed.  Hypotonia and hyperflexible joints can be a feature.

Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus.  Psychomotor development and milestones are delayed.  Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present.  There was considerable clinical variation among the six reported patients. 

Genetics

Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

A new overgrowth syndrome is due to mutations in RNF125

Tenorio J, Mansilla A, Valencia M, Martinez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillen-Navarro E, Gordo G, Mansilla E, Garcia-Santiago F, Gonzalez-Casado I, Vallespin E, Palomares M, Mori MA, Santos-Simarro F, Garcia-Minaur S, Fernandez L, Mena R, Benito-Sanz S, del Pozo A, Silla JC, Ibanez K, Lopez-Granados E, Martin-Trujillo A, Montaner D; SOGRI Consortium, Heath KE, Campos-Barros A, Dopazo J, Nevado J, Monk D, Ruiz-Perez VL, Lapunzina P. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41.

PubMed ID: 
25196541

Watson Syndrome

Clinical Characteristics
Ocular Features: 

Iris nodules similar to those seen in neurofibromatosis are found in some but not all patients with Watson syndrome.

Systemic Features: 

Short stature and low normal intelligence are the most consistent features.  Pulmonic stenosis and cafe-au-lait spots are also common.   The macrocephaly is relative and not striking.  Neurofibromas have been seen in a minority of patients.

Genetics

Mutations in the NF1(17q11.2) gene have been identified in members of several large pedigrees with an apparent autosomal dominant pattern.

It remains uncertain if this condition is allelic to neurofibromatosis I(162200) or if Watson syndrome is the result of mutations in contiguous genes.

The LEOPARD syndrome(151100) shares some clinical similarities such as short stature, pulmonic stenosis, cognitive deficits and cafe-au-lait spots but is caused by mutations in PTPN11.   The phenotype also resembles Noonan syndrome in some aspects.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for this condition but multidisciplinary management is recommended for isolated problems.

References
Article Title: 

Watson syndrome: is it a subtype of type 1 neurofibromatosis

Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991 Nov;28(11):752-6.

PubMed ID: 
1770531

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features: 

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References
Article Title: 

Strømme Syndrome

Clinical Characteristics
Ocular Features: 

The core complex of Stromme syndrome consists of intestinal atresia and ocular abnormalities of the anterior segment.  The ocular anomalies consist of variable amounts of angle dysgenesis, anterior synechiae, corneal leukoma, iris colobomas and hypoplasia, sclerocornea, cataracts, and sometimes microcornea.  However, microphthalmia, tortuous retinal vessels, and optic nerve hypoplasia may also be present.  Hypertelorism and deep-set eyes have been described.  Glaucoma has not been reported.  Only about 10 cases have been reported since Stromme 's first report in 1993.  Most patients have been too young for reliable acuity testing. 

Systemic Features: 

The phenotype is highly variable.  The ears are often large and low-set.  Microcephaly is often present along with a cleft palate and micrognathia.  The intestinal atresia seems to involve the jejunum primarily and is usually surgically correctable.  The duodenum may also be involved and intestinal malrotation has been described.  Myopathic changes in the myocardium have been seen along with small cardiomyoctes.  Microcephaly seems to be progressive.  Short stature has been noted and the amount of developmental delay is highly variable.  Renal hypodysplasia and hydronephrosis have been described.

Some patients seem to develop and function almost normally while more severely affected individuals may not live beyond early infancy or childhood.

Genetics

Compound heterozygous mutations in the CENPF gene (1q41) segregate with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Infants do well following intestinal surgery.  Ocular surgery has not been reported.

References
Article Title: 

Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF

Filges I, Bruder E, Brandal K, Meier S, Undlien DE, Waage TR, Hoesli I, Schubach M, de Beer T, Sheng Y, Hoeller S, Schulzke S, Rosby O, Miny P, Tercanli S, Oppedal T, Meyer P, Selmer KK, Stromme P. Stromme Syndrome is a Ciliary Disorder Caused by Mutations in CENPF. Hum Mutat. 2016 Jan 28. doi: 10.1002/humu.22960. [Epub ahead of print].

PubMed ID: 
26820108
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