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.
Albright hereditary osteodystrophy
This infant with obesity, round face, and short neck shows some
of the typical features of this disorder.
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
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 ...