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Pseudohypoparathyroidism type 1A
Pseudohypoparathyroidism type 1A (PHP1a) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by renal resistance to parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thydroid stimulating hormone (TSH), gonadotropins and growth-hormone-releasing hormone (GHRH); and a constellation of clinical features known as Albright hereditary osteodystrophy (AHO; see this term).
ORPHA:79443Classification level: Disorder
Prevalence of PHP (1a and 1b) has been estimated at 1/295,000 in a Japanese study. The prevalence of PHP (1a, 1b and pseudopseudohypoparathyroidism (PPHP); see these terms) has been estimated at 1/150,000in Italy.
Onset of endocrine symptoms occurs during childhood, although cases with severe hypothyroidism at neonatal screening have been reported. Patients present with varying degrees of AHO features (including obesity). Ectopic ossifications may range from absent to extensive and generate severe pain. Developmental delay is highly variable, even in families with the same mutation. PTH resistance is not typically present at birth but develops over time, in some patients from a few months of age. Other symptoms related to hypocalcemia include: numbness, seizures, tetany, cataract or dental problems. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). It is usually asymptomatic. Gonadal dysfunction with delayed or incomplete sexual maturation, amenorrhea or oligomenorrhea and/or infertility is very frequent. Growth hormone (GH) deficiency is present in around 60% of patients, while resistance to calcitonin and to epinephrine is rare. Hormone resistance may develop over time, up until late adulthood. Rheumatologic complications have also been reported. The evolution of bone mineralization remains unclear.
In about 70-80% of cases, PHP-Ia is caused by haploinsufficiency due to maternally-inherited heterozygous inactivating mutations in the GNAS gene (20q13). In a subset of patients negative for these mutations, methylation defects at the same locus have been reported.
Diagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. AHO is diagnosed both clinically and on X-ray, showing typical shortening of the 4th metacarpal. Diagnosis is confirmed by genetic testing.
Differential diagnoses include primary hypothyroidism, secondary hyperparathyroidism due to vitamin D deficiency, and other types of PHP.
Antenatal diagnosis is possible when a disease causing mutation in the family is known.
Transmission is autosomal dominant with parental imprinting. Resistance to hormones develops only after maternal inheritance. In de novo mutations (25% of cases), hormone resistance is associated with a mutation on the maternal allele of the gene. In cases where methylation defects are found, genetic counseling may be difficult or impossible.
Management and treatment
Treatment is based on maintaining normocalcemia and, when possible, normalizing serum levels of PTH, with an active form of vitamin D (alfacalcidol or calcitriol) and calcium supplementation. Associated endocrinopathies should be treated when present (particularly hypothyroidism, growth hormone deficiency and hypogonadism) with levothyroxine and sex hormones. GH replacement therapy should be started as soon as possible. There is no treatment for AHO. Subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.
With proper treatment, prognosis is good, but quality of life may be affected by subcutaneous ossifications and the presence of severe short stature and obesity. Life expectancy is normal provided that endocrine disorders are correctly treated.