Mccune– Albright Syndrome

This syndrome is characterized by polyostotic fibrous dysplasia, hyperpigmented cutaneous patches, and endocrinological abnormalities including precocious puberty, thyrotoxicosis, acromegaly or gigantism, and Cushing’s syndrome. The extent of the mosaic activating mutations determine the severity of the disease in the various organs where Gs α plays an important role. The pituitary and the surrounding tissues are affected in 20– 30% of the cases. A third of patients present in childhood and may develop gigantism, especially if there is hypogonadism due to excess prolactin, although the combination of early puberty and GH excess may result in a normal final height. The pituitary shows hyperplasia in just under half of the cases with micro or macroadenomas in the rest. These patients present a challenge for treatment as the surrounding fibrous dysplasia in the bones renders difficult surgical access. Combination treatment with dopamine, somatostatin agonists, and GH- receptor antagonist can provide biochemical control.

Multiple endocrine neoplasia type 1 and type 4

MEN1 and MEN4 are an autosomal dominant disorders which are described elsewhere (see Section 4, ‘Parathyroid, Calcium and Bone Metabolism Disorders’). Following prolactinomas and clinically non- functioning adenomas, acromegaly is third commonest pituitary tumour type to occur in MEN1 syndrome, although plurihormonal adenomas are also characteristic of MEN1. In patients with MEN1- related GH excess, especially in childhood, GHRH- secreting pancreas neuroendocrine tumours should be considered. MEN4 has been described in a few patients with an MEN1- like phenotype and germline mutations in cell cycle inhibitor genes, such as p27 (CDKN1B), p15 (CDKN2B), p18 (CDKN2C), and p21 (CDKN1A). The most common tumour type is somatotroph adenomas, including a case with childhood- onset disease.

carney complex

This is an autosomal dominant condition caused by a loss- of- function mutation in the protein kinase A regulatory subunit gene (PRKAR1A) in over 70% of the cases, with others mapping to 2p16. A single patient with duplication of the activating subunit of protein kinase A (PRKACB) has also been described. It is characterized by spotty cutaneous pigmentation, cardiac and other myxomas, and endocrine overactivity, particularly Cushing’s syndrome due to nodular adrenal cortical hyperplasia. Abnormal GH dynamics can be detected in two third of cases and with 10% of the patients developing true adenomas.

Familial isolated Pituitary Adenomas

Patients with FIPA usually have no other endocrine abnormality. The genetic background and the clinical characteristics are heterogeneous.

X- linked Acrogigantism (XLAG)

 Patients with germline or mosaic duplication in the GPR101 gene, which is located on the X chromosome, develop infant onset ac romegaly diagnosed < 2 years. Patients have pituitary hyperplasia or adenoma, secreting usually both GH and prolactin. The majority of the patients are females with a de novo germline mutations, while males are either have mosaic mutation or inherited the mutation from their mother. Unless treated, these patients develop extreme tall stature. As the whole gland is involved, treatment is challenging with either total hypophysectomy, combination medical treatment or radiotherapy.

Aryl Hydrocarbon Receptor Interacting Protein Loss- of- function heterozygous germline mutations in the AIP gene cause young- onset acromegaly with incomplete (20– 30%) penetrance. Most patient have acromegaly manifesting in the second decade, with prolactinomas occurring in 10% of the cases and other pituitary tumour types rarely. Patients with AIP mutations usually have early- onset, with 50% reporting onset of symptoms in the second decade. The invariably sparsely granulated adenomas may show invasive growth and respond poorly to somatostatin analogue therapy. Genetic cascade screening can identify carrier family members leading to earlier diagnosis and better chance of a cure.

FIPA Families Currently Without a Known Mutation

 The majority (89%) of the FIPA families do not harbour known disease- causing mutations. Patients in these families have an age of onset similar to sporadic pituitary adenoma patients and the associated tumour types are wider than in AIP or XLAG cases. About half of the families are homogenous (i.e. all affected family members have the same pituitary adenoma type) with the other half presenting with heterogeneous type of adenomas, acromegaly and prolactinoma being the most common tumour types. While penetrance is 100% in XLAG and 20– 30% in AIP kindreds, it is somewhat lower in AIP- negative FIPA families.

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مواضيع ذات صلة

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer

Screening for Genetic Susceptibility to Disease

Pharmacogenomics

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes

Genetic Basis of Cancer

Conditional Mutations Can Be Used to Study Essential Genes in Yeast

Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity

Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function