cirrhosis

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

Fructose Intolerance

Clinical Characteristics
Ocular Features: 

Dense cataracts have been reported in the first decade of life in several patients.

Systemic Features: 

Abdominal pain, vomiting and hypoglycemia usually appears in infancy upon the introduction of fructose or sucrose to the diet.  Some infants have a more severe reaction to such sugars with lethargy, seizures and coma.  Older children and adults develop a protective aversion to fruits and sweets.  Chronic ingestion leads to liver cirrhosis, renal tubule damage, growth retardation, and even malnutrition.  Adults may also have hypoglycemia and metabolic acidosis when challenged with sucrose and fructose.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ALDOB gene (9q31.1).  However, several heterozygous patients with symptoms have been reported and such individuals may be predisposed to hyperuricemia.  Multiple mutations have been identified in the ALDOB gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a fructose restricted diet is highly effective but must be strictly enforced to allow normal growth.

References
Article Title: 

Hereditary fructose intolerance

Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998 May;35(5):353-65. Review.

PubMed ID: 
9610797

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

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the 'molar tooth sign' in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 34 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities to Meckel syndrome (249000) and Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Jul 25. pii: S0161-6420(18)30686-9. doi: 10.1016/j.ophtha.2018.05.026. [Epub ahead of print].

PubMed ID: 
30055837

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

KID Syndrome

Clinical Characteristics
Ocular Features: 

Superficial punctate keratopathy leads to recurrent corneal erosions and eventually scarring and neovascularization.  Progressive opacification requiring PK often occurs.  These individuals may also suffer loss of eyebrows and eyelashes with trichiasis and thickening of the lid margins.  Corneal erosions and keratoconjunctivitis sicca cause incapacitating symptoms.

Systemic Features: 

The skin may be diffusely erythematous and scaly.  This often becomes patchier with well-demarcated areas especially in skin folds of the neck, axillae, and groin.  Older patients with likely autosomal recessive disease have hepatomegaly and may suffer cirrhosis and liver failure.  Short stature and mental retardation have also been noted.  The hearing loss is neurosensory in type.  Epidermal glycogen deposition has been found in one patient with the presumed recessive disorder.

In the presumed autosomal dominant disease, growth failure, mental retardation and liver disease do not seem to be present.  However, oral and skin squamous cell carcinomas, as well as malignant pilar tumors of the scalp may lead to early death.

Genetics

It is uncertain if one or more entities are represented by the KID syndrome.  Many cases are sporadic but others seem to be transmitted in autosomal recessive or autosomal dominant patterns.  The locus of the mutation is unknown in the recessive form.  In the dominant form, a mutation has been found in the connexin-26 gene, GJB2, gene located at 13q12.11.

See Hereditary Mucoepithelial Dysplasia (158310) for a somewhat similar but unique genodermatosis.  Another is IFAP (308205) but cataracts and hearing loss are not features.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The use of ocular lubricating preparation may supply significant relief from symptoms but scarring may eventually necessitate penetrating keratoplasty.  The threat of skin cancers and fatal hepatic failure requires monitoring throughout life.

References
Article Title: 
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