Handbook of Genetic Counseling/McCune Albright Syndrome

McCune Albright Syndrome

Introduction

Establish rapport with small talk and introduce myself
Briefly discuss the topics to be covered during the appointment
Assess the concerns of the family and ask if they have any questions today

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Elicit Medical History - Clinical Progress Sheet

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Elicit Family History Update

Any changes in family history?
Any new births or plans for pregnancy?

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Definition

McCune Albright syndrome is a disorder characterized by polyostotic fibrous dysplasia accompanied by café au lait spots and endocrine disorders esp. precocious puberty in girls. The patient is fracture prone, and deformity and shortening of the bones may develop.

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Genetic Etiology

Mode of inheritance:
- Thought to be sporadic although there have been a few familial occurrences.
- Believed to be a somatic mutation disorder
Molecular Genetics:
- Identification of activating mutations in the GNAS1 gene
G proteins are involved in signal transduction pathways that affect the production of cAMP
An overactive cAMP pathway stimulates growth and function of the gonads, adrenal cortex, specific pituitary cells, osteoblasts, and melanocytes
- Mutations in the gene render it functionally constitutive.
- Proposal that this a disorder of mosacicism (nonmocaicism is thought to be a lethal condition)
Chromosome location
- Chromosome 20

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Incidence

Described in 1936-1937 by McCune and Albright respectively- since then >100 cases have been reported
The frequency of diagnosis in females vs. males is 3:2

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Clinical Features

Endocrine Abnormalities:
- Precocious puberty occurs in over 50% of the female cases and has been reported for males as well
  - Menstruation, breast development, and pubic hair growth can occur during the first months of life
  - Usually caused by ovarian cysts that secrete estrogen into the blood stream
  - Many women with MAS are fertile in adulthood
- Hyperthyroidism:
  - 50% of patients with MAS have thyroid gland abnormalities
  - Enlargement=goiter
  - Pituitary thyroid-stimulating hormone (TSH) levels are low in these patients, while thyroid hormone levels may be normal or elevated
  - Excessive secretion of growth hormone has been seen in a few patients
Most develop course facies, enlarged hands/feet, and arthritis characteristic of acromegaly
Associated with gigantism and gynecomastia
- Adrenal Enlargement:
  - Rarely seen
  - Excessive secretion of the adrenal hormone cortisol caused by the hyperfunction of the anterior pituitary
  - Results in cushing syndrome
Weight gain, obesity of the face and trunk, skin fragility and cessation of growth in children
Treatment: removal of adrenal glands or use of drugs that block cortisol synthesis
Bone Disease (polyostotic fibrous dysplasia):
- Abnormal fibrous tissue growth in many bones
- In affected areas, normal bone is replaced by irregular masses of fibroblast cells leads to deformity and/or thickening of the bones
  - When this occurs in weight bearing bones such as the femur, limping, deformity, and fractures can result
  - Many children have unequal arm/leg length even in the absence of fractures
- Regions of fibrous dysplasia are also common in the skull and jaw bones
  - May result in facial asymmetry
- Severity of bone involvement varies
- Know known hormonal or medical treatment has been proven effective.
- Some surgical procedures such as grafting, pinning, and casting have been used to correct fracture and deformity (skull and jaw changes are often corrected surgically to improve appearance)
Skin abnormalities:
- Flat areas of increased pigment may be found = café au lait spots
- These spots are usually present at birth, and they usually do not become more extensive
- The pattern of pigmentation is unique
  - Starts or ends abruptly at the midline on the abdomen in front or at the spine in the back
  - A few have spots confined to small areas such as the nape of the neck or crease of the buttocks

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Natural history

Pigmentation is usually evident in infancy
Bone dysplasia may progress throughout childhood
The sexual precocity is often unusual, with menstruation occurring before breast and pubic hair development.
Precocious puberty may lead to short stature

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Testing

Currently, testing for a mutation in the GNAS1 gene is done for research purposes.
It is not a routine test that can be ordered.

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Differential Diagnosis

Hemihypertrophy, a sporadic condition, has as its most significant feature- limb length asymmetry and sometimes, facial asymmetry. Between 5-8% of these children will develop an intra-abdominal tumor, either Wilms tumor of the kidney or hepatoblastoma.

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