Emily L. Germain-Lee

Paternal imprinting of Gαs in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a

Albright hereditary osteodystrophy (AHO) is characterized by multiple somatic defects secondary to mutations in the GNAS1 gene. AHO patients with mutations on maternally inherited alleles are resistant to multiple hormones (e.g., PTH, TSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to presumed tissue-specific paternal imprinting of the alpha chain of G(s) as demonstrated in murine renal proximal tubule and fat cells. Studies in human tissues thus far revealed imprinting only in pituitary. Because mild hypothyroidism due to TSH resistance occurs in most PHP type 1a patients, we investigated whether Galpha(s) is imprinted in thyroid. Examination of eight normal thyroids demonstrated significantly greater expression from the maternal GNAS1 allele, with paternal Galpha(s) transcripts accounting for only 25.9-40.4%. Expression of NESP55, XLalpha(s), and 1A was uniallelic. We conclude that Galpha(s) is incompletely imprinted in the thyroid, which provides an explanation for mild TSH resistance in PHP type 1a.

Hypercalcemia in children and adolescents

Purpose of review In this review, we define hypercalcemia levels, common causes for hypercalcemia in children, and treatment in order to aid the practicing pediatrician. Recent findings One rare cause of hypercalcemia in the child is familial hypocalciuric hypercalcemia (also termed familial benign hypercalcemia). Mutations that inactivate the Ca2+-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous. Summary Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However, the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due to osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are, therefore, effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.

Genetic Basis for Resistance to Parathyroid Hormone

Pseudohypoparathyroidism (PHP) is associated with biochemical hypoparathyroidism (i.e. hypocalcemia and hyperphosphatemia) due to parathyroid hormone (PTH) resistance rather than to PTH deficiency. Patients with PHP type 1a have a generalized form of hormone resistance plus a constellation of developmental defects termed Albright hereditary osteodystrophy (AHO). Within PHP type 1a families some individuals will show AHO but have normal hormone responsiveness, a variant phenotype termed pseudo-PHP. By contrast, patients with PHP type 1b manifest only PTH resistance and lack features of AHO. These various forms of PHP are due to defects in the GNAS1 gene that lead to decreased expression or activity of the α-subunit of the stimulatory G protein (Gsα). Tissue-specific genomic imprinting of GNAS1 accounts for the variable phenotypes of patients with GNAS1 defects.

Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1

Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.

Central Hypothyroidism and Sturge- Weber Syndrome

Sturge-Weber syndrome is a rare disorder manifesting with a facial port-wine birthmark and a vascular malformation of the brain. Infants and children present with seizures and stroke-like episodes with focal neurologic deficits. Our previous investigations revealed that growth-hormone deficiency occurs with an increased prevalence in Sturge-Weber syndrome, presumably secondary to involvement of the hypothalamic-pituitary axis. We have continued to screen for hormonal abnormalities in patients with Sturge-Weber syndrome, specifically those from our multidisciplinary center for patients with this condition. We describe 2 children out of 83 (2.4%) with Sturge-Weber syndrome and brain involvement who were evaluated at our center and diagnosed with central hypothyroidism, based on clinical signs and laboratory findings. This prevalence is much higher than that of central hypothyroidism in the general population. Although it is well-known that anticonvulsants can lead to abnormalities in thyroid function tests, including central hypothyroidism, patients with Sturge-Weber syndrome carry the additional risk of developing hypothalamic-pituitary dysfunction, secondary to their central nervous system dysfunction. Therefore, it is important that patients with Sturge-Weber syndrome undergo routine thyroid-function testing, especially in the face of any clinical manifestations.

Growth hormone deficiency in Sturge–Weber syndrome

Sturge–Weber syndrome (SWS) is a disorder involving central nervous system abnormalities that may increase the risk of hypothalamic–pituitary dysfunction. Records of 19 patients with suspected growth hormone deficiency (GHD), identified from a registry of 1653 patients with SWS, were reviewed; nine patients with GHD were found.

Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy

Albright hereditary osteodystrophy (AHO) is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO) cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the α-subunit of the stimulatory G protein (Gαs). When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a). When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed pseudopseudohypoparathyroidism (PPHP). Mice with targeted disruption of exon 1 of Gnas (Gnas E1−/+) replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet been reported in Gnas E1+/− mice, at least not those that had been analyzed by us up to 3 months of age. Here we now show that Gnas E1−/+ animals develop SCO over time. The ossified lesions increase in number and size and are uniformly detected in adult mice by one year of age. They are located in both the dermis, often in perifollicular areas, and the subcutis. These lesions are particularly prominent in skin prone to injury or pressure. The SCO comprise mature bone with evidence of mineral deposition and bone marrow elements. Superficial localization was confirmed by radiographic and computerized tomographic imaging. In situ hybridization of SCO lesions were positive for both osteonectin and osteopontin. Notably, the ossifications were much more extensive in males than females. Because Gnas E1−/+ mice develop SCO features that are similar to those observed in AHO patients, these animals provide a model system suitable for investigating pathogenic mechanisms involved in SCO formation and for developing novel therapeutics for heterotopic bone formation. Moreover, these mice provide a model with which to investigate the regulatory mechanisms of bone formation.

Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature.

Background:  Multiple miliary osteoma cutis (MMOC) is a rare nodular skin disease characterized by tiny bone nodules which usually form on the facial skin, typically in middle age. The aetiology of this phenomenon is poorly understood.

Report on the Second Endocrine Aspects Of Duchenne Muscular Dystrophy Conference December 1-2, 2010, Baltimore, Maryland, USA.

a Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, USA b Osteogenesis Imperfecta and Albright Clinics, The Kennedy Krieger Institute, USA c Department of Neurology, The Johns Hopkins School of Medicine, USA d Department of Neuroscience, The Johns Hopkins School of Medicine, USA e Department of Pediatrics, Division of Pediatric Endocrinology, The Johns Hopkins School of Medicine, USA f The Parent Project Muscular Dystrophy, USA

Endogenous fecal losses of calcium compromise calcium balance in pancreatic-insufficient girls with cystic fibrosis ☆

OBJECTIVE Bone mineral density is compromised in individuals with cystic fibrosis (CF); calcium is the major bone mineral. This study examined the impact of endogenous fecal calcium (V(endo)) losses on calcium balance in girls with CF. Study design V(endo) was measured in 12 girls with CF (aged 7-18 years): 7 younger, premenarcheal girls with compromised nutritional status; and 5 older, postmenarcheal girls with adequate nutritional status. V(endo) was measured as the amount of intravenously administered (42)Ca, a calcium stable isotope, in stool relative to urine over 6 days. V(endo) was compared between pre- and postmenarcheal girls by Students t test. Actual calcium balance [absorbed calcium-(urinary calcium (V(u))+V(endo))] was compared with estimated balance (assuming V(endo)=1.6 mg/kg/day calcium) by paired t test. RESULTS V(endo) was 99.3+/-42.3 mg/day. By body weight, V(endo) was highest among premenarcheal girls (3.37+/-1.09 mg/kg/day), resulting in excess losses (>1.6 mg/kg/day) of 55.0+/-45.7 mg/day. Over 1 year, this represents 20.1+/-16.7 g of unattained bone calcium or 6.7+/-4.2% of the bone calcium content of these girls. CONCLUSIONS V(endo) is a significant source of calcium loss in individuals with CF and may limit calcium availability for bone mineral deposition.