Albright Hereditary Osteodystrophy

Syndrome presenting with round face, short stature, short neck, and obesity. Subcutaneous and intracranial calcifications, seizures, and neuromuscular problems such as fatigue and muscle cramps. Pseudohypoparathyroidism and hypocalcemia.

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Pseudohypoparathyroidism Type IA. Strictly, Albright Hereditary Osteodystrophy relates to type IA only. However, for completeness, Pseudohypoparathyroidism Type IB is included here. Do not confuse Albright Hereditary Osteodystrophy with McCune-Albright Syndrome.

Exact incidence is unknown; however, in Japan the incidence is estimated to range from 3 to 4 per 1,000,000 live births.

Autosomal dominant inheritance. In type IA, the genetic defect involves the α subunit of the stimulatory G protein (which is either defect or only produced in minimal amounts) that couples pathways for transmembrane signaling and enhances the production of cyclic adenosine monophosphate (cAMP). The gene encoding for this α subunit of the G protein (GNAS1) has been mapped to the long arm of chromosome 20 (20q13.2). Occasionally, a small terminal deletion on chromosome 2 may exist. Full expression occurs in patients with maternal transmission, whereas only partial expression occurs in paternally transmitted cases. All patients are heterozygous, leaving them with one normal allele for the α subunit, which is not only required for parathormone, but also for many other peptide hormones (e.g., adrenocorticotropin [ACTH], thyrotropin, glucagon, gonadotropins, antidiuretic hormone). Consequently, these patients may clinically exhibit some resistance to the effects of all these hormones. Although type IB also is autosomal dominant inherited, the underlying defect is different. The mutation has been mapped to 20q13.3 (i.e., close to the GNAS1 gene region). Hormonal resistance appears to be caused by limited or absent responsiveness of the kidneys to parathormone. The skeletal lesions in these patients are evidence of an intact bone response to parathormone.

Increase in parathyroid hormone release and deficient end-organ responsiveness, either because of germline mutation in the gene encoding G α subunit, thus decreasing expression or function of G protein (type IA), or presumably a receptor defect (type IB).

Hypocalcemia associated with hyperphosphatemia occurs in type IA but not in type IB. The activity of protein G is reduced in type IA but is normal in type IB. Hyperparathyroidism in combination with hypocalcemia is caused by either secondary hyperparathyroidism or pseudohyperparathyroidism. Administration of exogenous parathormone is used to assess the renal and osseous response. The concentration changes of calcium, phosphate, calcitriol, and cAMP in the plasma and of phosphate and cAMP in the urine are measured. Serum concentration for estrogen is low but concentrations of Luteinizing Hormone (LH) and Follicular Stimulating Hormone (FSH) are high (reflecting involvement of G protein in the actions of all these hormones). CT scan of the head may reveal calcifications of the choroid plexus and basal ganglia.

Morphologically, patients with pseudohyperparathyroidism type IA often present with a round face, short stature and neck, obesity, brachydactyly with short metacarpals, mental retardation, cataract, and delayed tooth eruption with enamel hypoplasia. Intracranial and subcutaneous calcifications, neuromuscular problems such as fatigue and muscle cramps, and seizures are common. Other endocrinologic signs may include pseudohypoparathyroidism with parathyroid hyperplasia, hypocalcemic tetany, hypothyroidism, (secondary to thyrotropin resistance), deficient prolactin release, partial resistance to antidiuretic hormone, and arterial hypertension. Oligomenorrhea (secondary to gonadotropin resistance), seizures, and impaired olfaction have been described in pseudohyperparathyroidism type IA.

Chronic hypocalcemia is treated by oral calcium and vitamin D supplements. Assess the airway for difficult intubation secondary to facial anomaly. Surgery should be postponed until serum calcium concentration reaches normal levels. If surgery is urgent, intravenous calcium therapy must be given under continuous ECG monitoring.

Respiratory and/or metabolic alkalosis must be avoided because it further decreases the ionized serum calcium concentration. Arterial blood gases and pH should be monitored regularly in the perioperative period. No data are available concerning the anesthetic technique. Regional anesthesia is an option; however, mental retardation and osseous anomalies may result in difficulties.

Citrate in blood transfusions but also administration of fresh-frozen plasma and albumin-containing solutions may result in hypocalcemia. Close monitoring and intravenous bolus doses of calcium chloride or calcium gluconate are required.

McCune-Albright Syndrome: This disorder presents with the triad of polyostotic fibrous dysplasia, café au lait skin pigmentation, and autonomous endocrine hyperfunction. The most common form of autonomous endocrine hyperfunction is gonadotropin-independent precocious puberty, but affected individuals also may suffer from hyperthyroidism, hypercorticism, pituitary gigantism, and/or acromegaly. Nonendocrine abnormalities include hypophosphatemia, chronic liver disease, tachycardia, and rarely sudden death, possibly from cardiac arrhythmias.