vascular anomalies

Neurofibromatosis Type I

Clinical Characteristics
Ocular Features: 

Melanocytic iris hamartomas, sometimes called Lisch nodules, are considered pathognomonic of this disease but are found in only about 75% of patients.  These appear as sharply defined, smooth masses on the stromal surface and consist of spindle cells of melanocytic origin.  Their presence correlates with the severity of skin freckles and cafe-au-lait spots.  Also characteristic of neurofibromatosis 1 are eyelid fibromas causing ptosis and the familiar horizontal S-sign in the upper lid margin but these are only found in one-third of patients.  Ciliary body cysts have been reported to occur at a frequency of 78%, or 10 times more frequently than in unaffected individuals.  Nearly half of patients have occludable anterior chamber angles (Types 1 and 2).

Gliomas of the optic nerves, chiasm or optic tracts are slow growing astrocytomas that occur in about 15% of children at a mean age of about 5 years.  While these comprise the most common intracranial tumors in NF1, they typically have a benign course and may even regress.  However, some present as precocious puberty and severe loss of acuity may occur before discovery.

Vascular lesions of the retina are also sometimes seen and may be responsible for rubeosis and neovascular glaucoma.

Systemic Features: 

Vascular anomalies are often seen and those that impact blood supply to the kidneys can induce severe hypertension especially in children (pheochromocytomas are also a risk).  Coarctations and aneurysmal anomalies can obstruct the blood supply to major organs, sometimes acutely.  Some degree of cognitive impairment and sometimes mental retardation can be seen in nearly half of patients, even in the absence of other obvious neurological deficits.  Short stature, tibial pseudoarthrosis, sphenoid dysplasia, and scoliosis are common.  Osteopenia and frank osteoporosis are seen in approximately half of patients.  A small percentage of patients develop malignant peripheral nerve sheath tumors (lifetime risk 8-13%).  Rare patients develop other malignancies, primarily sarcomas.

Diagnosis is based on the presence of some combination of typical features such as cafe-au-lait spots, Lisch nodules, neurofibromas, optic pathway gliomas, axillary or groin freckling, and bone dysplasia.  The underlying disease is progressive and the accuracy of diagnosis improves in older patients.

Genetics

The typical disease is caused by mutations in the NF1 gene (17q11.2) and inherited as an autosomal dominant disorder.  However, about half of patients have new mutations with males having the higher mutation rate.  Penetrance is nearly 100% among those who have mutations in NF1. There is evidence that the gene product is a tumor suppressor protein (neurofibromin) and the clinical features can also result from deactivation of both copies of the gene via the two hit mechanism of Knudson.  This has been proposed as a mechanism to explain the high degree of variability of clinical disease within families as the expression depends upon which cell lines experience postzygotic somatic mutations.

Watson syndrome (193520) is also the result of NF1 mutations and shares some clinical features such as neurofibromas, Lisch nodules, shortness of stature, cognitive deficits, and cafe-au-lait spots.  It may be an allelic disorder.

Neurofibromatosis type II (101000), with less cognitive problems, results from mutations in NF2.  Lisch nodules are less common in type II but acoustic neuromas are more common than in type I.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the underlying disease but lifelong monitoring is necessary because of the widespread manifestations and serious threat of complications such as visual impairment, renal hypertension and ischemia of major organs.

References
Article Title: 

Alagille Syndrome

Clinical Characteristics
Ocular Features: 

The ocular findings in Alagille syndrome are often of little functional significance but can be sufficient to suggest the diagnosis without further study of the systemic features.  Posterior embryotoxon is found in 95% of individuals while iris abnormalities such as ectopic pupils are seen in 45%, abnormal fundus pigmentation is common (hypopigmentation in 57%, diffuse pigment speckling in 33%), and optic disc anomalies have been reported in 76%.  One study found that 90% of individuals have optic disk drusen by ultrasonography.  The anterior chamber anomalies are considered by some to be characteristic of Axenfeld anomaly.  The presence of these ocular findings in children with cholestasis should suggest Alagille syndrome.  Ocular examination of the parents can also be helpful in this autosomal dominant disorder as some of the same changes are present in one parent in more than a third of cases.

Systemic Features: 

A variety of  systemic features, some of them serious malformations, occur in Alagille syndrome.  Among the most common is a partial intrahepatic biliary atresia leading to cholestasis and jaundice.  Skeletal malformations include 'butterfly' vertebrae, shortened digits, short stature, a broad forehead, and a pointed chin.  The tip of the nose may appear bulbous.  These features have suggested to some that there is a characteristic facial dysmorphology.  Vascular malformations are common including aneurysms affecting major vessels, valvular insufficiency, coarctation of the aorta, and stenosis and these are often responsible for the most serious health problems.  In fact, vascular events have been reported to be responsible for mortality in 34% of one cohort.  Chronic renal insufficiency develops in a minority of patients.  This disorder should always be considered in children with cholestasis, especially when accompanied by cystic kidney disease.  Brain MRIs may show diffuse or focal hyperintensity of white matter even in the absence of hepatic encephalopathy.

Genetics

This is an autosomal dominant condition secondary to various mutations in the JAG1 gene located on chromosome 20 (20p12).  Penetrance is nearly 100% but there is considerable variation in expression.  A far less common variant of this disorder, ALGS2 (610205), is caused by a mutation in the NOTCH2 gene (1p13-p11).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No cure is available but individual organ disease may be treatable.  The ocular abnormalities generally do not cause vision difficulties.

Reversible of white matter changes has been noted in a single child following liver transplantation.

 

References
Article Title: 

CT-defined phenotype of pulmonary artery

Rodriguez RM, Feinstein JA, Chan FP. CT-defined phenotype of pulmonary artery
stenoses in Alagille syndrome. Pediatr Radiol. 2016 Apr 4. [Epub ahead of print].

PubMed ID: 
27041277

Alagille syndrome: clinical and ocular pathognomonic features

El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol. 2010 Jul 28. pii: 192165A5-8631-4C06-9C47-9AD63688B02A. [Epub ahead of print]

PubMed ID: 
20677167

Ocular abnormalities in Alagille syndrome

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999 Feb;106(2):330-7.

PubMed ID: 
9951486
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