growth retardation

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

Trichomegaly Plus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelashes are described as ‘long’, and the eyebrows are bushy.  The majority of individuals have poor vision secondary to severe receptor dysfunction.  Night blindness and severe photophobia are features in some cases.  Both retinal and choroidal atrophy have been diagnosed in the first 5 years of life and most patients have a progressive and extensive pigmentary retinopathy.

Systemic Features: 

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

Genetics

Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this condition.  Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.   

The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown.  They were described as having visual impairment from birth and profound photophobia.  Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis.  ERG responses were unrecordable.  These individuals apparently did not have other somatic, psychomotor or neurologic deficits.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.

References
Article Title: 

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

LEOPARD Syndrome

Clinical Characteristics
Ocular Features: 

Ocular hypertelorism is a characteristic of all forms of the LEOPARD syndrome.  The lid fissures may be downward slanting.  Combined with the inverted triangle facies, the appearance is similar to that of the Noonan syndrome (163950).

Systemic Features: 

This is a multisystem disorder manifest in skin, heart, skeletal, genital, neurologic and auditory systems.  Generalized lentiginosis is characteristic but they may not be present until age 4 or 5 years following the appearance of cafe-au-lait spots.  Some patients have patchy scalp hair loss.  The facies bears some resemblance to the Noonan syndrome but usually without the short, webbed neck.  Sensorineural hearing loss is found in 20% of individuals.  Cardiac conduction defects, pulmonic stenosis, and hypertrophic cardiomyopathy are often (85%) present.  Cognitive defects are present in 30% of patients and some individuals have been described as mentally retarded.  Juvenile behavior may be evident in the presence of normal intelligence.  Hypospadias, cryptorchidism, and gonadal infantilism have been seen in some patients.  The ears are often malformed (87%).  Thoracic skeletal anomalies have been described in 75% of patients.  Although somatic growth is described as slow, short stature is present in less than half of patients.

Rare patients without lentigines are said to resemble the Noonan syndrome (163950) in appearance.

Genetics

Heterozygous mutations in the PTPN11 gene (12q24) are most frequently responsible for this autosomal dominant disorder.  The same gene is mutated in more than half of patients with the Noonan syndrome (NS1)(163950) with which it is allelic.  Other mutations that cause what is called LEOPARD syndrome are RAF1 and BRAF.

Other types of LEOPARD syndrome such as LEOPARD syndrome 2 (611554) are far more rare but also share mutations with Noonan syndrome (RAF1 mutations in Noonan syndrome 5) (611553) and LEOPARD syndrome 3 (613707) with mutations in BRAF similar to that seen in NS7 (613706).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Assistive hearing devices, especially cochlear implants, may be helpful.  Special education can be of value in more mildly affected individuals.Treatment of cryptorchidism is similar to that of other children.

References
Article Title: 

GAPO Syndrome

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature.  One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus.  White eyelashes have been described.  Myelinated nerve retinal nerve fibers may be prominent.

Systemic Features: 

This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology.  The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown.  The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal.  Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time.  Anomalous blood vessels such as dilated scalp veins are sometimes evident.   Hypogonadism has been reported in both sexes.  Individuals are subject to recurrent ear and respiratory infections. 

Genetics

GAPO occurs in both sexes.  Homozygous mutations in the ANTXR1 gene (2p13.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at individual problems.  Prompt treatment of respiratory infections is important.

References
Article Title: 

Mutations in ANTXR1 cause GAPO syndrome

Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9.

PubMed ID: 
23602711

Ophthalmic findings in GAPO syndrome

Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52.

PubMed ID: 
10197743

Williams Syndrome

Clinical Characteristics
Ocular Features: 

Blue irides (77%) and a lacey or stellate pattern (74%) of the iris are characteristic.  The stroma appears coarse with radial or cartwheel striations.  The iris collarette is usually absent or anomalous.  Features of the Peters' anomaly may be present.  The periorbital tissues are described as 'full' and prominent.  Strabismus (usually esotropia) occurs in more than half of patients.  Retinal vessel tortuosity is present in 22% of patients.  Cataracts may be found in younger individuals but are uncommon. Hyperopia is the most common refractive error.  Keratoconus has been described in at least 3 patients.

Systemic Features: 

The phenotype is variable, likely depending upon the size of the deletion.  Cardiovascular disease, primarily hypertension and large vessel stenosis, are among the most important features.  The elastin arteriopathy lead to thickened arterial walls with peripheral pulmonary stenosis and supravalvular aortic stenosis.  The facies is considered unique with bitemporal narrowing, a wide mouth, full lips, malocclusion, small jaw, and prominent earlobes.  The teeth are small and widely spaced.  Connective tissue abnormalities include joint hyperextensibility, hernias, lax skin, hypotonia, and bowel/bladder diverticulae.  Small birth size is common and infants often fail to thrive but at puberty patients can experience a growth spurt.  Ultimate height in adults is usually in the third centile.

Vocal cord anomalies and paralysis can result in a hoarse voice.  A sensorineural hearing loss is common among adults but hyperacusis is often present in young children.

Hypercalcemia and hypercalciuria are common and some (10%) have hypothyroidism.

Most individuals have some cognition difficulties and delays but normal intelligence has also been reported.  Patient personalities consist of anxiety, attention deficit disorder, marked friendliness and a high level of empathy.  Visiospatial construction is often impaired.  Most adults are unable to live independently.

Genetics

This is a deletion syndrome but included in this database because the major features are due to the loss of a single gene (ELN).  The deletion segment consists of 1.4-1.8 Mb at 7q11.23 containing as many as 28 genes.   Most cases occur sporadically but parent-child transmission and affected siblings have been reported.  The recurrence risk is low.

Increased tortuosity of the retinal arterioles is also a feature of Fabry disease (301500) and of a condition known as isolated retinal arteriolar tortuosity (611773, 180000).

Treatment
Treatment Options: 

Feeding issues should be addressed early in infants who fail to thrive.  Early intervention with speech and physical therapy plus special education can be helpful.  Psychological evaluations may help in managing behavioral issues.

Hypertension can often be managed medically but surgery may be required for vascular stenoses.   Hypercalcemia and hypothyroidism often respond to medical therapy. Strabismus, vessel narrowing, and valvular malfunctions can be treated surgically.

References
Article Title: 

The iris in Williams syndrome

Holmstrom G, Almond G, Temple K, Taylor D, Baraitser M. The iris in Williams syndrome. Arch Dis Child. 1990 Sep;65(9):987-9.

PubMed ID: 
2221973

Ocular findings of Williams' syndrome

Hotta Y, Kishishita H, Wakita M, Inagaki Y, Momose T, Kato K. Ocular findings of Williams' syndrome. Acta Paediatr Scand. 1990 Aug-Sep;79(8-9):869-70.

PubMed ID: 
2239289

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Hoyeraal-Hreidarsson Syndrome

Clinical Characteristics
Ocular Features: 

Little is known about the ocular signs in this rare disorder.  As many patients have systemic features of dyskeratosis congenita, however, it is possible that some of the ocular findings such as conjunctival and corneal scarring and lid margin distortion might be similar.  Hoyeraal-Hreidarsson syndrome, though, is a more severe disease and many infants may die before the mucocutaneous manifestations appear.  At least one patient has had an exudative retinopathy similar to that seen in Revesz syndrome (268130).  Epiphora and a preretinal hemorrhage have also been reported.

Systemic Features: 

Features of pancytopenia usually appear after 5 months of age while growth retardation and microcephaly are evident soon after birth.  The marrow may show progression to myelodysplasia.  Birth weight is usually low.  Truncal ataxia and axial hypotonia have been reported and MRI imaging reveals cerebellar hypoplasia.  Global developmental delay is a common feature and a few patients have seizures.  Susceptibility to infection has been noted but the basis for an immunodeficiency remains elusive.  Some patients have signs of dyskeratosis congenita such as sparse hair, nail dysplasia, and a reticular pattern of skin pigmentation.

Genetics

This is an X-linked disorder resulting from mutations in the DKC1 gene (Xq28) active in telomere maintainence.  As expected, the vast majority of affected individuals are male but at least 3 females have been reported. The same gene is also mutated in the X-linked form of dyskeratosis congenita (305000) suggesting that the two are allelic or that both are the same disease.  There are clear clinical differences, however, as severe developmental delay, immunodeficiency, cerebellar hypoplasia, and microcephaly are generally not present in the latter disorder.

There is evidence for telomere length variations in this syndrome and in dyskeratosis congenita.  Homozygous mutations in RTEL1 (regulator of telomere length helicase 1) (20q13.33) have also been found in these conditions.

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

No effective treatment has been reported.

References
Article Title: 

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: 

Cockayne Syndrome, Type B

Clinical Characteristics
Ocular Features: 

The eyes are deep-set.  Congenital cataracts are present in 30% of infants.  The aggressive course of this form of CS has precluded full delineation of the ocular features but infants have been described with microphthalmos, microcornea and iris hypoplasia. 

Systemic Features: 

Evidence of somatic and neurologic delays is present at birth or shortly thereafter with microcephaly and short stature.  Infants never develop normal milestones and may not grow in size beyond that of a 6 month-old child.  Communication skills are minimal.  They have a progeroid appearance, age rapidly, and most do not live beyond 5 years of age.   Feeding problems are common with considerable risk of aspiration, a common cause of respiratory infections and early death.  Severe flexion contractures develop early and may interfere with motor function.  Tremors and weakness contribute as well.  The skin is sensitive to UV radiation in some but not all patients.  However, the frequency of skin cancer is not increased.  Endogenous temperature regulation may be a problem. 

At least some cases with what has been called cerebro-oculo-facio-skeletal syndrome have been genotypically documented to have type B CS, the severe form of Cockayne syndrome.

Genetics

This is an autosomal recessive disorder resulting from mutations in ERCC6 (10q11) rendering the excision-repair cross-complementing protein ineffective in correcting defects during DNA replication.  Mutations in this gene account for about 75% of CS patients.  However, using date of onset and clinical severity, type A CS (216400) disease is far more common even though the ERCC8 mutations are found in only 25% of individuals.  Type A CS (216400) also has a somewhat later onset and is less severe in early stages.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation is type III is unknown.

Some patients have combined  phenotypical features of cerebrooculofacioskeletal syndrome (214150) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Feeding tubes may be necessary to maintain nutrition.  Protection from the sun is important.  Physical therapy can be used to minimize contractures.  Cataract surgery might be considered in selected cases as well as assistive devices for hearing problems but the limited lifespan should be considered. 

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Tyrosinemia, Type II

Clinical Characteristics
Ocular Features: 

Keratitis is the outstanding ocular manifestation but not all patients have corneal involvement.  Symptoms include photophobia, pain, tearing, and redness which may occur as early as one year of age.  Corneal neovascularization, ulceration and scarring may lead to decreased visual acuity.  Linear and star-like corneal opacities in the epithelium resembling dendrites (pseudodendritic keratitis) have been described together with thickening of the conjunctiva.  The corneal lesions do not stain.  The conjunctival epithelium, fibrocytes, and blood vessel endothelial cells contain an accumulation of large inclusion bodies and tyrosine crystal-like structures. 

Systemic Features: 

Hydroxyphenylpyruvic acid is elevated in the urine and serum tyrosine levels are increased as the result of a defect in tyrosine aminotransferase.  Some patients have severe mental and somatic retardation.  The palms and soles can have painful punctate keratosis which may extend to the digits.  Developmental milestones such as walking are often delayed.  The keratotic lesions may be up to 2 cm in size. 

Genetics

Tyrosinemia type II is an autosomal recessive disorder caused by mutations in the tyrosine aminotransferase (TAT) gene at 16q22.1-q22.3. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The hyperkeratosis and corneal opacities may improve with a diet low in phenylalanine and tyrosine but can recur after liberalization of the diet.  Benefits, if any, on CNS symptoms are unknown. 

References
Article Title: 

Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation

Pena-Quintana L, Scherer G, Curbelo-Estevez ML, Jimenez-Acosta F, Hartmann B, Roche F, Meavilla-Olivas S, Perez-Cerda C, Garcia Segarra N, Giguere Y, Huppke P, Mitchell GA, Monch E, Trump D, Vianey-Saban C, Trimble ER, Vitoria-Minana I, Reyes-Suarez D, Ramirez-Lorenzo T, Tugores A. TYROSINEMIA TYPE II: Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation. Clin Genet. 2017 Mar 3. doi: 10.1111/cge.13003. [Epub ahead of print].

PubMed ID: 
28255985

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