GNAS

Pseudohypoparathyroidism, Type 1A

Clinical Characteristics
Ocular Features: 

Cataracts and nystagmus are sometimes present.  Optic neuritis and papilledema have been reported and can result in optic atrophy.  The combination of cataracts and swelling of the optic nerves in children requires evaluation for hypocalcemia.

Systemic Features: 

The title refers to a group of conditions that have organ resistance to parathyroid hormone.  The phenotype is variable since there usually is a usually some degree of end-organ resistance to other hormones such as gonadotropins and TSH as in the PHP1A disorder described here.  The grouped clinical features are often referred to as Albright hereditary oseodystrophy or AHO.

Short stature with a short neck, a round face, chubby cheeks, and a depressed nasal bridge are usually present.  There may be cognitive deficits and some patients are considered to be mentally retarded.  The fourth and fifth metacarpals and sometimes metatarsals are characteristically short.   The teeth are late to erupt and can have an enamel deficit.  End organ resistance to other hormones may lead to signs of hypothyroidism and hypogonadism.  Calcification of subcutaneous tissues can result in palpable hard nodules and calcium deposition in basal ganglia and choroidal plexus may be demonstrable.  Some patients experience hypocalcemic tetany and seizures.  Hypocalcemia and hyperphosphatemia are often present along with elevated serum parathyroid hormone levels.

Genetics

This transmission pattern is likely modified by the effects of imprinting which also can modify the phenotype.  Mutltigenerational family patterns have an excess of maternal transmission.  The full phenotype is more likely expressed among maternally transmitted cases whereas partial or incomplete expression is more often seen among individuals who received the paternal allele. 

Heterozygous muttions in the GNAS1 gene (20q13.32) plays a role in this disease.  Signal transduction failure likely plays a major role in the failure of organs to respond to the appropriate hormone.

Several subtypes of pseudohypoparathyroidism have been reported but some do not have ocular signs.  However, type 1C (612462) patients can have cataracts and nystagmus with an almost identical phenotype to that of IA and may be the same condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment focuses on normalization of calcium and phosphate serum levels.  A deficiency of vitamin D should also be corrected and has been reported to correct at least some of the lens opacities.  Cataract removal can be considered.

References
Article Title: 

McCune-Albright Syndrome

Clinical Characteristics
Ocular Features: 

This disorder is of interest to ophthalmologists because compression of the optic nerve can occur from fibrous dysplasia of the canal.  However, this occurs only in some cases.  The risk of optic neuropathy is higher in patients with elevated levels of growth hormone.

Systemic Features: 

This disorder is clinically heterogeneous because of the variable degree of involvement of all bony tissue.  The primary manifestations are secondary to endocrine dysfunction and fibrous dysplasia.  Thyrotoxicosis, Cushing syndrome, pituitary gigantism, hearing deficits, and precocious puberty (in both sexes) are common.  The skin often has a cafe-au-lait pattern of pigmentation.

Genetics

Postzygotic activating mutations in the GNAS gene on chromosome 20 (20q13.2) are likely responsible for this disorder although too few familial cases have been reported to document a mode of inheritance.  It has been suggested that an autosomal dominant lethal gene is involved with survival only in the presence of significant mosaicism.

Treatment
Treatment Options: 

Recent evidence suggests that early treatment (before age 18 years) in patients with elevated growth hormone levels using pharmacologic intervention, surgery, and/or radiotherapy is associated with less optic neuropathy compared with patients who are treated later.  The impact on hearing impairment is less certain and awaits further studies.

Not all patients have significant optic nerve compression. Decompression of the optic nerve canal is beneficial in about half of cases in which significant nerve encasement is present but should be performed only when progressive optic neuropathy occurs, especially when growth hormone levels are elevated.

References
Article Title: 

McCune-Albright syndrome

Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis. 2008 May 19;3:12.

PubMed ID: 
18489744
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