Genetic Pathologies Flashcards
A 7-year-old girl is brought to the clinic with a 6-month history of progressive breast enlargement and irregular, painless vaginal bleeding. She has also complained of intermittent leg pain but has no history of trauma. Physical examination reveals Tanner stage 3 breast development and multiple irregular, large café-au-lait macules with “coast of Maine” borders on her trunk and neck. Laboratory evaluation reveals undetectable luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, which remain low after a gonadotropin-releasing hormone (GnRH) stimulation test. X-rays of the femur reveal areas of lytic bone lesions.
What is the most likely diagnosis?
a. McCune-Albright Syndrome
b. Neurofibromatosis Type 1
c. Constitutional precocious puberty
d. Albright hereditary osteodystrophy
e. Struma ovarii
a. McCune-Albright Syndrome
Explanation:
This girl’s findings of GnRH-independent precocious puberty, irregular café-au-lait macules, and fibrous dysplasia of bone (manifesting as lytic lesions) are characteristic of McCune-Albright Syndrome (MAS). The undetectable gonadotropins and lack of response to GnRH stimulation confirm the diagnosis of GnRH-independent precocious puberty, which is due to autonomous estrogen secretion caused by the activating mutation in the GNAS gene.
What are the hallmark features of McCune-Albright Syndrome?
Precocious puberty: Typically GnRH-independent.
Café-au-lait macules: Irregular “coast of Maine” borders.
Fibrous dysplasia of bone: Presents with bone pain, fractures, or lytic lesions.
Associated endocrinopathies: Hyperthyroidism, growth hormone excess, or Cushing syndrome.
What genetic mutation is responsible for McCune-Albright Syndrome, and what does it lead to?
Mutation: Activating mutation in the GNAS gene.
Effect: Constitutive activation of G-protein signaling, leading to autonomous hormone secretion and abnormal tissue growth.
How is McCune-Albright Syndrome diagnosed?
Clinical findings: Precocious puberty, café-au-lait macules, and fibrous dysplasia.
Imaging: X-rays showing lytic bone lesions.
Genetic testing: Identifying GNAS mutations (not always required for diagnosis).
What is the treatment for precocious puberty in McCune-Albright Syndrome?
Aromatase inhibitors (e.g., letrozole) to reduce estrogen production.
Manage other endocrinopathies (e.g., antithyroid drugs for hyperthyroidism).
How do café-au-lait macules differ in neurofibromatosis type 1 (NF1) vs. McCune-Albright Syndrome?
NF1: Smooth borders (“coast of California”).
McCune-Albright Syndrome: Irregular borders (“coast of Maine”).
What complications can arise from fibrous dysplasia in McCune-Albright Syndrome?
Bone pain, deformities (e.g., shepherd’s crook deformity in femur).
Increased risk of fractures due to weakened bones.
What is the reverse mutation of the GNAS activating mutation seen in McCune-Albright Syndrome, and what condition does it cause?
The reverse mutation is a loss-of-function mutation in the GNAS gene, which causes Albright Hereditary Osteodystrophy (AHO).
What are the Key Features of Albright Hereditary Osteodystrophy
Pseudohypoparathyroidism (Type 1A or Type 1B):
PTH resistance: High PTH levels with hypocalcemia and hyperphosphatemia.
The kidneys fail to respond to PTH, leading to impaired calcium reabsorption and phosphate excretion.
Classic skeletal abnormalities: Short stature, Shortened 4th and 5th metacarpals (brachydactyly), Obesity and a round face, Subcutaneous calcifications
Café-au-lait macules: If present, they have smooth (“coast of California”) borders.
No precocious puberty or endocrinopathies like those seen in McCune-Albright Syndrome.
Pseudohypoparathyroidism is autosomal dominant or recessive?
Autosomal dominant
maternally transmitted mutations (imprinted GNAS gene).
GNAS1-inactivating mutation (coupled to PTH receptor) that encodes the Gs protein α subunit, leading to the inactivation of adenylate cyclase when PTH binds to its receptor, causing end-organ resistance (kidney and bone) to PTH.
