Long-term follow-up of a pseudohypoparathyroidism type 1A patient with missense mutation (Pro115Ser) in exon 5

Pseudohypoparathyroidism (PHP) refers to end-organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH). The patients with PHP type Ia (PHP-Ia), one of the 4 types of PHP, show resistance to other peptide hormones as well as clinical features of Albright hereditary osteodystrophy (AHO), a constellation of short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Here we report clinical follow-up for a long-term period in a PHP-Ia case who had a missense mutation leading to the substitution of proline by serine (Prol115Ser) in exon 5 which has been reported previously in only two patients. An 11-year-old boy applied for hand spasm to our hospital. On physical examination, he had short stature, round-shaped face and brachydactly. Laboratory evaluation revealed PTH and TSH resistance. Molecular genetic analysis of the GNAS gene revealed a P115S substitution. The patient was followed up for 13 years. Normocalcaemia was achieved with reduced doses of calcitriol (0.25 μg/day) and calcium supplements (40 mg/kg/day). Daily requirement for levothyroxine supplementation was still high (2.3 μg/kg) to achieve euthyroidism. His pubertal development was Tanner stage V and he has no gonadotropin resistance. To our knowledge, this is the first report concerning long-term follow-up of this rare mutation. We believe that despite the genetic heterogeneity of AHO, phenotype/genotype correlations of this kind of rare mutations may help to understand progress of the disease.     

Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Besides PTH resistance, PHP-Ia patients have Albright's hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright's hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.     

A Novel Mutation Causing Pseudohypoparathyroidism 1A with Congenital Hypothyroidism and Osteoma Cutis

Various inactivating mutations in guanine nucleotide-binding protein, alpha-stimulating activity polypeptide1 (GNAS1) gene have been described with poor phenotype correlation. Pseudohypoparathyroidism type 1a (PHP1a) results from an inactivating mutation in the GNAS1 gene. Hormone resistance occurs not only to parathyroid hormone (PTH), but typically also to other hormones which signal via G protein coupled receptors including thyroid stimulating hormone (TSH), gonadotropins, and growth hormone releasing hormone. In addition, the phenotype of Albright hereditary osteodystrophy (AHO) is observed, which may include short stature, round facies, brachydactyly, obesity, ectopic soft tissue or dermal ossification (osteoma cutis) and psychomotor retardation with variable expression. We present a 2-year-old boy with PHP 1A who initially presented at age 3 weeks with congenital hypothyroidism. By 17 months of age, he manifested osteoma cutis, psychomotor retardation, obesity, brachydactyly and resistance to PTH with normocalcemia and mild hyperphosphatemia. Genetic analysis revealed a novel mutation in exon 13 of GNAS1 in our patient. This mutation, c.1100_1101insA, resulted in a frameshift and premature truncation of bases downstream. This mutation was also found in the mother of this patient who was also noted to have short stature, obesity, brachydactyly and non progressive osteoma cutis, but no hormone resistance.We report a novel heterozygous mutation causing PHP1A with PTH and TSH resistance and AHO which has not been described previously. PHP1A is also a rare presentation of congenital hypothyroidism.     

Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency

Deficiency of protein Gs (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright's hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with Gs deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.     

GH secretion in a cohort of children with pseudohypoparathyroidism type Ia

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by Albright's hereditary osteodistrophy (AHO) and resistance to hormones that act via the alpha subunit of the Gs protein (Gsalpha) protein, ie PTH, TSH, FSH/LH, and, as recently described in limited series, GHRH. However, the current lack of data on GHRH secretion, obesity and short stature included in the AHO phenotype hampers interpretation of GH secretory status and its effects on these subjects. We evaluated GH secretion after GHRH plus arginine (Arg) stimulus, IGF-I levels and anthropometric features in an exclusively pediatric population of 10 PHP-Ia subjects. Of our PHP-Ia children, 5 out of 10 (50%) showed impaired GH responsiveness to the provocative test, with a lower prevalence than the 75-100% previously reported. A negative correlation (p=0.024) was found between GH secretion and body mass index (BMI), whereas no correlation emerged between GH and IGF-I values (p=0.948). Height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects. In the 5 GH-deficient patients, GHRH resistance could arguably be responsible for hormonal impairment; however, 3 of them were obese, showing normal stature and IGF-I levels: the increased BMI in these subjects could influence GH secretion and its effects. In conclusion, GH deficiency is frequent among PHP-Ia children and its prevalence is variable, two factors indicating that GH secretory testing should be part of the routine management of this patient group. It could be argued that GHRH resistance is the pathogenetic mechanism in most patients, but further studies on GHRH secretion are needed to define which values can be considered as raised. Lastly, because BMI has been indicated as a major determinant of evoked adult GH response to provocative testing, GH levels related to increased BMI also in childhood could be helpful in defining GH assessment in obese or overweight PHP-Ia children.     

Pseudohypoparathyroidism and idiopathic hypoparathyroidism: relationship between serum calcium and parathyroid hormone levels and urinary cyclic adenosine-3',5'-monophosphate response to parathyroid extract.

Forty patients with hypocalcemia and/or Albright's hereditary osteodystrophy were studied. Based on the estimation of serum calcium and parathyroid hormone (PTH) levels as well as the urinary cAMP response to infusions with parathyroid extract, it was possible to classify all of the patients studied as cases with idiopathic hypoparathyroidism (n = 6, low PTH, normal cAMP response), pseudohypoparathyroidism (PHP) type I (n = 18, high PTH, low cAMP response) and type II (n = 2, high PTH, normal cAMP response), as well as pseudopseudohypoparathyroidism (n = 14, normal PTH, normal cAMP response). In three cases studied at the age of 12, 17, and 23 yr, the signs of Albright's hereditary osteodystrophy were not observed. PTH levels were unusually high for a given serum calcium concentration in some patients with PHP, the increased PTH levels were, however, normalized during iv calcium infusions. In two young children with PHP, a gradual increase of serum PTH levels occurred despite persistent normocalcemia over a period of 3 yr. This suggests that factors other than hypocalcemia or frequent small unobservable falls of the serum calcium concentration, such as a deficient formation of 1,25-dihydroxyvitamin D3, secretion of an abnormal PTH, or an abnormal metabolism of the hormone, may contribute to the secondary hyperparathyroidism in PHP.     

PSEUDOHYPOPARATHYROIDISM: INHERITANCE AND EXPRESSION OF DEFICIENT RECEPTOR-CYCLASE COUPLING PROTEIN ACTIVITY

Pseudohypoparathyroidism, Type I (PSP-I) is a familial disorder characterized by secondary hyperparathyroidism, resistance of urinary cyclic adenosine-3', 5'-monophosphate (cAMP) excretion to exogenous parathyroid hormone (PTH), and by effects upon other hormones, including thyrotrophin (TSH) hyperresponsiveness to thyroliberin (TRH). In the present study, 12 PSP-I patients in five families exhibited partial deficiency of receptor-cyclase coupling protein (N protein) in blood cells, in association with the skeletal findings of Albright's hereditary osteodystrophy. In one father and six mothers of PSP-I patients, deficient N protein activity was associated with normal urinary cAMP responses to PTH. In this group of seven parents, five had Albright's osteodystrophy, two exhibited secondary hyperparathyroidism, and two had TSH hyperresponsiveness to TRH. In a sixth family with none of the features of Albright's osteodystrophy, N protein deficiency did not correlate with urinary cAMP responsiveness to PTH. In this kindred, one mother with N protein deficiency, but normal urinary cAMP responsiveness to PTH had raised serum levels of immunoreactive PTH. We conclude that in the majority of families with PSP-I the urinary cAMP response to PTH is an inadequate indicator of the genetic defect. In such families, deficiency of N activity more consistently points to metabolic defects, including secondary hyperparathyroidism and TSH hyperresponsiveness, even when urinary cAMP responses are normal.     

Pseudohypoparathyroidism or hypoparathyroidism? A misleading clinical presentation

We report the case of a 27-year old woman who presented hypocalcemia and hyperphosphoremia during her first pregnancy. Her phenotype was in favor of Albright's hereditary osteodystrophy: short stature, obesity, round face, brachymetacarpy and mental retardation. However, the diagnosis of pseudohypopara thyroidism type Ia was ruled out due to low PTH level (10 pg/ml). The patient's 22q11 microdeletion was suspected and identified because of the association of severe neonatal hypocalcemia, abnormal face and renal malformation in her children. Deletion 22q11 leads to various syndromes, including Di George syndrome, also referred to as CATCH 22 syndrome (Cardiac defect (C), Abnormal face (A), Thymic hypoplasia (T), Cleft palate (C) and Hypocalcemia (H)). Retrospectively, the patient presented with symptoms suggestive of CATCH 22: abnormal face, hypernasal voice suggestive of velopharyngeal insufficiency, mental retardation, recurrent otitis in childhood. It is also noteworthy that there was an idiopathic thrombocytopenic purpura. In conclusion, while the phenotype was suggestive of Albright's hereditary osteodystrophy, the constatation of a low PTH level would cast doubt on this diagnosis. Furthermore, the 22q11 microdeletion should be searched by FISH (Fluorescence In Situ Hybridization) in all patients with hypopara thyroidism of unknown origin, even in the absence of cardiac malformations. Finally, it seems that patients with CATCH 22 would be predisposed to auto-immune disease as a result of thymic dysfunction.     

Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy

CONTEXT: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright's hereditary osteodystrophy (AHO), and reduced Gsalpha activity caused by GNAS mutations. OBJECTIVE: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features. METHODS: Gsalpha activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members. RESULTS: Two patients showed modest decreases in erythrocyte Gsalpha activity. Instead of Gsalpha point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes. CONCLUSIONS: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gsalpha mutations have been excluded should be evaluated for epigenetic alterations within GNAS.     

Pseudohypoparathyroidism type Ib in 2015

The term pseudohypoparathryoidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by resistance to the action of parathyroid hormone (PTH) that activates cAMP signaling in target cells. Together with pseudohypoparathyroidism, Albright hereditary osteodystrophy (AHO) and progressive osseous heteroplasia (POH) represent rare, related and deeply impairing disorders encompassing heterogeneous features, such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones. The two main subtypes, PHP-Ia and PHP-Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster respectively, while mutations in the PRKAR1A and PDE4D genes (also involved in mediating cAMP signalling) have been demonstrated in patients with acrodysostosis, a disease of bone formation with characteristics similar to AHO. The molecular overlap among these disorders indicates the need for different classification models and seriously alters our understanding of the mechanisms through which GNAS defects, together with the new recently described defects involving other components of the cAMP signalling cascade, cause AHO-related disorders.     

Identification of a novel GNAS mutation for pseudohypoparathyroidism in a Chinese family

Pseudohypoparathyroidism (PHP) is a heterogeneous group of diseases characterized by hormone resistance to receptors that stimulate adenylate cyclase. PHP-Ia patients show specific Gs-alpha protein deficiency, PTH/TSH/gonadotropin resistance, and a phenotype characterized by Albright hereditary osteodystrophy (AHO). Many heterozygous mutations in the GNAS gene encoding the Gs protein have been identified in PHP-Ia. We describe two boys with hypocalcemia and elevated serum levels of PTH in a Chinese family. The 13 exons of the GNAS gene were amplified using 15 pairs of GNAS-specific primers and analyzed by direct sequencing. We found a novel frame shift mutation in exon 11 of the GNAS gene identified in both of the two boys and their mother. This report provides another example of a Gs-alpha mutation leading to PHP.     

Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib

CONTEXT: Pseudohypoparathyroidism (PHP) types Ia and Ib, are caused by mutations in GNAS exons 1-13 and GNAS methylation defects, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO and hormone resistance is limited to PTH and, as reported in one paper, TSH. No study addressed the question of GH deficiency in PHP-Ib patients. OBJECTIVES: The objective of the study was to screen patients with clinically diagnosed PHP-Ib for genetic defects and investigate the presence of resistance to TSH and GHRH. PATIENTS/METHODS: We investigated GNAS differential methylation and STX16 microdeletions in genomic DNA from 10 patients with clinical diagnosis of sporadic PHP-Ib, i.e. PTH resistance without AHO. Resistance to GHRH was assessed by GH response to GHRH plus arginine. Thyroid function and ultrasonography were also evaluated. RESULTS: Molecular analysis showed GNAS cluster imprinting defects in all PHP-Ib patients and the first de novo STX16 deletion in one apparently sporadic patient. Subclinical or clinical hypothyroidism due to resistance to TSH was present in nine of 10 patients, whereas a preserved GH response to a GHRH plus arginine test was present in all patients, with one exception. CONCLUSIONS: We report the first molecular analysis of Italian patients with PHP-Ib. Clinical investigation shows that, like PHP-Ia patients, PHP-Ib patients are resistant to TSH, whereas they maintain a normal responsiveness to GHRH, at variance with PHP-Ia patients. These data provide new information on this rare disease and emphasize the clinical heterogeneity of genetic defects within GNAS.     

Completely skewed X-inactivation in a mentally retarded young female with pseudohypoparathyroidism type IB and juvenile renin-dependent hypertension

Genetic analysis of the GNAS gene was performed in a patient with idiopathic renin-dependent hypertension, PTH resistance, and Albright's hereditary osteodystrophy-like characteristics such as a round face, short stature, obesity, and mental retardation (IQ, 49). Mutational analysis showed no mutations in exons 1-13 or in any exon-intron boundary. However, methylation-status analysis revealed a bialleic methylation defect in GNAS exon 1A, indicating that a GNAS-imprinting defect is the cause of her PTH resistance, as commonly observed in pseudohypoparathyroidism type IB. The imprinting defect, however, could not explain her renin-dependent hypertension and Albright's hereditary osteodystrophy-like phenotype. There are many types of X-linked mental retardation. Syndromic X-linked mental retardation, such as X-linked alpha-thalassemia mental retardation syndrome and Rett syndrome, is reportedly associated with abnormal imprinting. To further investigate this unexplained phenotype, we tested whether this patient showed skewed X-inactivation (SXI) presumably as a result of postinactivation selection against cells with a mutated gene on the active X-chromosome. Completely SXI was observed in the DNA from her leukocytes, urinary sediment, and renal tissue. A mutation of the X-chromosome might be correlated with this phenotype because of a close association between completely SXI and X-chromosomal mutation.     

Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients

Brachydactyly, classically described as shortening of III, IV, and V metacarpals and I distal phalanx, is the typical and most specific sign of Albright's hereditary osteodystrophy, a peculiar phenotype reported in subjects with pseudohypoparathyroidism type Ia (PHP-Ia) caused by mutations in the GNAS gene, which encodes for the alpha-subunit of the stimulatory G protein (Gsalpha). It has been reported in 70% of PHP subjects from routine radiological examinations, but there are no specific data for hand alterations in genetically characterized PHP-Ia subjects. We evaluated the metacarpophalangeal pattern profile in 14 GNAS-mutated PHP-Ia subjects and determined the prevalence and patterns of left hand bone shortening. To search for genotype/phenotype correlations, we compared metacarpophalangeal pattern profiles in subjects with identical mutations. Shortening below -2 SD score (SDS) was present in at least one bone in each subject, with a prevalence of 100%; however, great variability existed between subjects and between hand bone segments. Between subjects, shortening ranged from -2 to -10.4 SDS and involved 1-19 hand bones (5.3-100%). Between segments, III-IV metacarpals were the most compromised (-10.4 and -10.0 SDS, respectively); V metacarpals and I-IV distal phalanges were the most frequently shortened (85.7%). Overall, bone length median values revealed shortening below -2 SDS in all metacarpals and all distal phalanges, i.e. brachymetacarpia and brachytelephalangy, that cluster together. These segments were shortened in 64.3-85.7% of patients, significantly differing from proximal and middle phalanges, which were shortened in 21.4-50%. Even if these hand alterations were a constant and typical finding in our PHP-Ia population, cluster analysis in subjects with the same genotypes did not generally show a genotype/phenotype correlation. Variability between subjects may be the result of complex interactions between GNAS defects and other genetic or epigenetic factors. In conclusion, hand shortening analysis in 14 genetically characterized patients showed typical brachymetacarpia and brachytelephalangy. Further studies in PHP-Ia subjects without GNAS mutations and in other brachydactyly syndromes will determine whether the pattern described is also specific.     

GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.

We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.     

Gene abnormality associated with resistance to parathyroid hormone

Pseudohypoparathyroidism (PHP) is characterized by PTH-resistant hypocalcemia and hyperphosphatemia. Patients with PHP-Ia exhibit Albright osteodystrophy and resistance to TSH and other hormones in addition to PTH. PHP-Ia is caused by heterozygous inactivating mutations in the GNAS1 gene which encodes Gsalpha protein. In PHP-Ib, resistance to PTH is confined to the renal tubules. Recent reports describe a paternally imprinted disorder in a region including the GNAS1 gene as the cause of PHP-Ib.     

Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy

Albright's hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and sc calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. Different inactivating mutations of the gene GNAS1 encoding Gsalpha lead to a reduced Gsalpha protein activity in patients with AHO and pseudohypoparathyroidism type Ia or without resistance to PTH (pseudopseudohypoparathyroidism). We investigated 29 unrelated patients with AHO and pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism and their affected family members performing functional and molecular genetic analysis of Gsalpha. In vitro determination of Gsalpha protein activity in erythrocyte membranes was followed by the investigation of the whole coding region of the GNAS1 gene using PCR, nonisotopic single strand conformation analysis, and direct sequencing of the PCR products. All patients showed a reduced Gsalpha protein activity (mean 59% compared with healthy controls). In 21/29 (72%) patients, 15 different mutations in GNAS1 including 11 novel mutations were detected. In addition we add five unrelated patients with a previously described 4 bp deletion in exon 7 (Delta GACT, codon 189/190), confirming the presence of a hot spot for loss of function mutations in GNAS1. In eight patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gsalpha. We conclude that biochemical and molecular analysis of Gsalpha and its gene GNAS1 can be valuable tools to confirm the diagnosis of AHO. However, in some patients with reduced activity of Gsalpha, the molecular defect cannot be detected in the exons encoding the common form of Gsalpha.     

Father to son transmission of decreased Ns activity in pseudohypoparathyroidism type Ia

We found both renal resistance to endogenous and exogenous PTH and reduced activity of the stimulatory guanine nucleotide-binding regulatory protein (Ns) of adenylate cyclase in a man with clinical signs of pseudohypoparathyroidism type Ia (PHP-Ia). Both of his children also had reduced Ns levels and short stature. The girl, 11 yr old, had evidence of partial resistance to PTH, while the son, age 7 yr, had no apparent abnormalities in calcium metabolism or response to administered PTH. Variable expression of the metabolic abnormalities of PHP during childhood has been previously described. The occurrence of reduced Ns activity in father and son is consistent with autosomal dominant inheritance for the primary biochemical defect of PHP-Ia in this family.     

The inhibitory adenylate cyclase coupling protein in pseudohypoparathyroidism

Deficient activity of the adenylate cyclase stimulatory coupling protein (Ns) has been demonstrated in many patients with pseudohypoparathyroidism type I (PHP) who have Albright's hereditary osteodystrophy and multiple hormone resistance. Since an abnormality in the activity of the related adenylate cyclase inhibitory coupling protein (Ni) could influence hormone responsiveness, we measured pertussis toxin-catalyzed [32P]ADP ribosylation of the 40,000-dalton alpha-subunit of Ni (Ni alpha) in erythrocyte membranes from patients with PHP and normal subjects. There were no significant differences in the amounts of Ni alpha in membranes from normal subjects, patients with PHP who have low Ns associated with Albright's hereditary osteodystrophy and multiple hormone resistance, and patients with PHP who have normal Ns. Abnormal Ni is not likely to cause hormone resistance in patients with PHP who have normal Ns or to influence hormone responsiveness in patients with PHP who have low Ns.