The case
A 5-year-old girl with a history of hypothyroidism in infancy presented to the endocrinology clinic of a tertiary hospital. Physical examination showed that she was obese with a blood pressure of 115/59 mmHg and a pulse rate of 103 bpm. She weighed 42.2 kg (>97th percentile) and measured 116.3 cm in height (50–75th percentile). The child's BMI was 31.2 kg/m2 (>97th percentile) and she had a round face, broad chest, obese abdomen, and short neck, digits, and metacarpals (Figure 1a–c). Her third, fourth and fifth digits were particularly short (Figure 1b) and she had a positive knuckle sign (the appearance of a dimple at the position of the fourth knuckle on clenching of the hand), which results from a short fourth metacarpal. Albright hereditary osteodystrophy was suspected at that initial visit because of these clinical findings on physical examination.
Figure 1 | Features suggestive of Albright hereditary osteodystrophy in the patient.
a | Photo of the patient at 5 years of age showing an obese phenotype, round face, broad chest, short neck and digits consistent with pseudohypoparathyroidism type 1a. b | Photo of the patient's hand at 5 years of age showing brachyphalangism of the fingers, especially the third through fifth digits. c | Photo of the patient's feet at 5 years of age showing brachyphalangism of the toes. d | Bone-age radiograph of the patient at 7 years of age showing premature fusion of the epiphyses of the distal phalanges of the thumb, midphalanges of both the second and fifth fingers, and shortening of the third through fifth metacarpals. Her bone age was read as 13 years at a chronological age of 7 years and 8 months.
A mineral panel performed at the time showed that this child had a serum ionized calcium level of 1.03 mmol/l (normal range 1.07–1.15 mmol/l), serum phosphate level of 2.36 mmol/l (normal range 1.62–1.91 mmol/l) and serum parathyroid hormone (PTH) level of 19.6 ng/l (normal range 0.74–5.58 ng/l).
The patient was born at 41 weeks of gestation by cesarean section owing to a nuchal cord. She weighed 2.8 kg at birth, and 5.4 kg at 6 months of age; thereafter, she began to gain weight excessively. The patient's initial newborn screening test, done on the second day of her life, showed an elevated serum TSH level of 27.3 mIU/l (normal level <20 mIU/l in the first 48 h of life), and a total T4 level of 148 nmol/l (normal range 78.4–157.4 nmol/l). Her repeat newborn screening test, done 13 days later, showed a serum TSH level of 12.3 mIU/l (normal level <15 in the second week of life) and a total T4 level of 130 nmol/l.
The child's excessive weight gain was investigated when she was 8 months old; at that time, thyroid function tests showed that she had an elevated serum TSH level of 7.58 mIU/l (normal range 0.8–6.3 mIU/l at 1–11 months of age), and a total T4 level of 96.1 nmol/l (normal range 78.4–157.4 nmol/l). She was started on levothyroxine 25 
g once daily at the age of 8 months.
During the patient's initial endocrine evaluation at 5 years of age, a detailed family history was obtained, as Albright hereditary osteodystrophy and pseudohypoparathyroidism type 1a (PHP1a) were suspected. Her father is of normal height (172.7 cm, 25th percentile) and obese (90.7 kg), with a BMI of 30.4 kg/m2. He has a history of sleep apnea and hypercholesterolemia. The patient's mother is short (147.3 cm, <5th percentile) and of normal weight (54.4 kg), with a BMI of 25.1 kg/m2. She has short digits. The child's maternal grandfather was short (162.6 cm tall, <5th percentile), with short digits and type 2 diabetes mellitus. Her only sibling, a brother, is healthy and at the 10th percentile for both height and weight.
After the evaluation at 5 years of age, the child's treatment for hypothyroidism continued (25 g once daily levothyroxine). Furthermore, for the treatment of pseudohypoparathyroidism she was prescribed calcium carbonate 1,250 mg twice daily (50 mg/kg elemental calcium daily), and calcitriol (active vitamin D) 0.25 g twice daily. The patient had regular, 4-monthly check-ups at the clinic from the age of 5 years. At the age of 6 years, the patient underwent the following laboratory tests for evaluation of her growth hormone–insulin-like growth factor I (IGF-I) axis: IGF-I levels, growth-hormone stimulation testing, and pituitary MRI scan. Her IGF-I level was 11 nmol/l (normal range 6.8–38.9 nmol/l). However, growth-hormone stimulation testing using simultaneous arginine and levodopa administration led to a diagnosis of growth-hormone deficiency. Her basal, serum growth-hormone concentration was 0.3 g/l and her peak growth-hormone concentration was 1.4 g/l (normal level 
7.5 g/l) 60 min after the administration of growth-hormone secretagogues. Her MRI scan showed a pituitary gland in the low–normal range for size. At age 6 years and 4 months, the patient was started on recombinant human growth hormone at a dose of 0.3 mg/kg weekly.
At 7 years of age, abdominal palpation revealed a new finding: that of discrete, firm, subcutaneous masses, each measuring 
1 cm 
2 cm, which represented subcutaneous calcifications. In addition, the patient developed acanthosis nigricans on her neck folds and axillae, which is suggestive of insulin resistance (Figure 2). The diagnosis of insulin resistance was confirmed by simultaneous fasting insulin, C-peptide, and glucose estimation and calculation of homeostasis model assessment of insulin resistance (Table 1).1, 2, 3, 4 The child was prepubertal for both pubic hair and breast development at this age.
The child's bone age—assessed by the Greulich and Pyle method5—was concordant with her chronological age in early childhood, but became progressively advanced as she got older. Namely, her bone age was read as 13 years at a chronological age of 7 years and 8 months (Table 1, Figure 1d).
Genetic analysis was performed to discover whether the 7-year-old child and her mother had mutations in the GNAS gene, because heterozygous, inactivating mutations in GNAS are the cause of Albright hereditary osteodystrophy. The genetic analysis was performed at the DNA diagnostic laboratory at Johns Hopkins University, MD, USA by previously described techniques.6, 7 The child's genotype showed a mutation, in which a single nucleotide sequence variation at position 85 (NT85C>T) was identified in one GNAS allele. This change caused the substitution of a stop codon for glutamine at amino acid residue 29 (Q29X). The child's mother carried the same mutation.
The patient's baseline IGF-I level of 11.0 mmol/l rose to 60.4 mmol/l after 8 months of growth-hormone therapy, and to 54.0 mmol/l 13 months after initiation of therapy. The child's BMI also improved on growth-hormone treatment—her BMI SD score (SDS) decreased from 4.4 when she started on growth hormone at age 6 years and 4 months of age to 3.7 at age 7 years and 8 months, when she was taken off growth hormone; her height SDS also increased (Table 1). However, the child's insulin resistance worsened slightly while she was on growth-hormone therapy. When the patient was 7 years and 8 months old, her health-insurance carrier declined to reauthorize her growth-hormone therapy because of her advanced bone age (Figure 1d).
At 7 years and 10 months of age, the patient's full-scale intelligence quotient was evaluated using a Wechsler Intelligence Scale for Children–Fourth Edition, and her general cognitive ability score was determined to be in the low–average range of intellectual functioning.
The patient has continued her follow-up visits to the endocrine clinic every 4 months for management of hypothyroidism with levothyroxine, PHP1a with calcium and vitamin D, and weight management by lifestyle modification. The child's lifestyle modification program consists of 30 min of daily exercise at school and the institution of portion control and healthier food choices with restriction of sugar-containing drinks. She has had no adverse effects from her medications. She was last seen at age 9 years and 3 months. At that visit, the patient's BMI SDS was 3.66 and her height SDS was 0.81. She will continue her follow-up visits to the endocrinology clinic for the rest of her childhood and adolescence and will be transitioned to the adult endocrinology service when she turns 18 years old.
Discussion of diagnosis
Albright hereditary osteodystrophy is a genetic syndrome characterized by a distinctive set of developmental and skeletal defects that include short, stocky physique, round face, mental retardation, heterotopic ossification, and brachymetaphalangism.8 Although height during childhood may be normal, adult height is often subnormal.
The differential diagnoses of a child with this phenotype include exogenous obesity, Cushing syndrome, severe hypoparathyroidism, Prader–Willi syndrome, and Laurence–Moon–Biedl–Bardet syndrome. A diagnosis was reached in the patient described above by reviewing her family history, establishing the components of the Albright hereditary osteodystrophy phenotype, such as short fourth metacarpals, and connecting her history of subclinical hypothyroidism to her PTH-resistant state.
The molecular basis for Albright hereditary osteodystrophy is heterozygous mutation of the gene that encodes the G-stimulatory subunit (Gs
) of guanine nucleotide-binding protein—the GNAS gene—that is located at chromosome 20q13.2. This type of mutation leads to a loss of expression or function of the Gs. It impairs the transmission of stimulatory signals to adenylate cyclase, which limits cyclic AMP generation necessary for hormone action.9
The GNAS gene is subject to imprinting. Patients with Albright hereditary osteodystrophy who have GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones, such as PTH, TSH, gonadotropins, growth-hormone-releasing hormone, and glucagon.10, 11 These defects lead to PHP1a. On the other hand, patients with Albright hereditary osteodystrophy who have GNAS mutations on paternally inherited alleles have only the phenotypic features of Albright hereditary osteodystrophy without hormonal resistance, a condition termed pseudopseudohypoparathyroidism.9 Whereas resistance to PTH, TSH, growth-hormone-releasing hormone, follicle-stimulating hormone, and luteinizing hormone may lead to clinical manifestations, the blunted, cyclic AMP response to glucagon documented by Brickman et al.10 in patients with PHP1a seems to be subclinical, as their glucose response is intact. Obesity occurs more frequently and is more severe in PHP1a than in pseudopseudohypoparathyroidism.12
More than 50 different loss-of-function mutations of GNAS have been reported in more than 70 affected individuals. Pohlenz et al.13 have reported a missense mutation, which results in the amino-acid substitution (Lys338Asn) in codon 338 of exon 12 of the GNAS gene associated with congenital hypothyroidism in Albright hereditary osteodystrophy, though they did not state the precise mechanism by which this mutation leads to hypothyroidism. A Q35X mutation in exon 1 has been associated with growth-hormone deficiency,7 whereas a de novo, missense mutation, W281R in exon 11, has been linked to progressive osseous heteroplasia, a rare, autosomal-dominant condition that presents in childhood as dermal ossification that progresses to involve deep skeletal muscles.14 The Q29X mutation of the patient we investigated has been reported in a cohort by Germain-Lee et al. However, to our knowledge this is the first detailed description of a phenotype that includes Albright hereditary osteodystrophy, morbid obesity, acanthosis nigricans, insulin resistance, growth-hormone deficiency, hypothyroidism, and subcutaneous calcification.
PHP1a accompanied by growth-hormone deficiency and hypothyroidism was first described in 1995.15 In addition to the Albright hereditary osteodystrophy phenotype, biochemical and hormonal derangements in PHP1a lead to characteristic patterns of presentation. Many patients with this condition present with subclinical hypothyroidism in infancy,13, 15 as did the patient described, whereas others present with hypocalcemic seizure, and/or muscle spasms, short stature, learning disabilities and psychomotor retardation.16
The biochemical profile in patients suspected of having PHP1a shows evidence of PTH resistance, with elevated serum concentrations of PTH and phosphate, and low or normal serum levels of ionized calcium. Subnormal peak growth-hormone levels of <7.5 g/l are commonly found when growth-hormone stimulation tests are carried out.15 The patient described had a peak growth-hormone level of 1.4 g/l.
The short stature of patients with PHP1a results from a combination of several factors, such as epiphyseal defects and resistance to growth-hormone-releasing hormone.15 This hormone resistance results in the inability of growth-hormone-releasing hormone to stimulate pituitary somatotropes to produce growth hormone.
The bone ages of children with PHP1a are more advanced than would be expected for their stage of sexual maturation. Premature epiphyseal fusion occurs selectively in the hands and feet of affected patients.17, 18 Furthermore, the phalanges of patients either lack epiphyses or have epiphyses that are partially fused when they first develop, which makes accurate assessments of bone age very difficult.18 This abnormal epiphyseal fusion is postulated to result from the loss of Gs, which induces resistance to parathyroid-hormone-related protein which, in turn, promotes premature differentiation of proliferating chondrocytes into hypertrophic chondrocytes.19, 20, 21 This series of events leads to early closure of the growth plate and limb-reduction defects. Despite early fusion of the epiphyses in the phalanges, the epiphyses of long bones may remain open, thus improvement of height with growth-hormone therapy is still possible.
In patients with PHP1a, soft-tissue calcification has been reported in various body parts, especially in the subcutaneous tissues, and rarely in the brain and cardiac septum.22 Persistent hyperparathyroidism is believed to have some causative role in this abnormal calcification. This situation is distinct from progressive osseous heteroplasia,14 a rare condition that causes dermal ossification that was described earlier.
The patient discussed here had insulin resistance, but this condition has not commonly been described in patients with PHP1a. Furthermore, acanthosis nigricans is not a typical finding of this syndrome, although Germain-Lee et al.7 reported a case of acanthosis nigricans in a cohort of 13 patients with PHP1a who had normal HbA1c and fasting insulin levels. A case of Albright hereditary osteodystrophy-like syndrome in a patient with a normal GNAS gene that was complicated by type 2 diabetes mellitus with severe insulin resistance, growth-hormone deficiency and diabetes insipidus has been described.23 Long et al.12 reported that obesity is a more prominent feature of PHP1a than of pseudopseudohypoparathyroidism, and that severe obesity is characteristic of PHP1a. They postulated that paternal imprinting of Gs occurs in the hypothalamus such that maternal, but not paternal, Gs mutations lead to loss of the melanocortin signaling cascade, which is important for energy balance. This loss will, in turn, lead to greater alteration in energy balance and notably greater insulin resistance in individuals with PHP1a (as seen in this patient) than is seen in those with pseudopseudohypoparathyroidism.
The insulin receptor belongs to a large class of tyrosine kinase receptors, and is structurally distinct from the heptahelical Gs receptors. The development of insulin resistance in this patient most probably resulted from the combined effects of obesity, growth-hormone treatment, a family history of type 2 diabetes mellitus, and abnormal melanocortin signaling, as noted above. Obesity is the most common cause of insulin resistance in children.24 Obesity is postulated to represent a subclinical inflammatory state that promotes the production of proinflammatory factors, such as interleukin 6 and tumor necrosis factor, which are involved in the pathogenesis of insulin resistance.25 Growth hormone antagonizes insulin's effects on glucose metabolism by inhibiting insulin-induced glucose uptake through the inhibition of insulin receptor substrate-2-associated phosphatidylinositol-3-kinase activity, without affecting glucose transporter 4 translocation.26 A family history of type 2 diabetes mellitus conveys not only heritable genetic information, but also reveals familial behaviors and social norms that may exacerbate the individual's risk for insulin resistance and frank diabetes.27
Treatment and management
The defect in PHP1a leads to resistance to multiple hormones that mediate their actions through cyclic AMP.28 These include PTH, TSH, growth-hormone-releasing hormone, gonadotropins, glucagon, and possibly TSH-releasing hormone.29 Patients with Gs deficiency could, therefore, develop hypothyroidism, hypogonadism, growth-hormone deficiency, and pseudohypoparathyroidism, depending on the degree of Gs activity in a specific tissue.15
Hypoparathyroidism
The initial medical management of all patients with severe, symptomatic hypocalcemia should be with intravenous calcium. The recommended initial dose for newborn babies , infants and children is 0.5–1.0 ml/kg of 10% calcium gluconate administered over 5 min. Administration of oral calcium and 1-hydroxylated vitamin D metabolites, such as calcitriol, is recommended for patients with symptomatic hypocalcemia. The goals of therapy are to maintain serum total and ionized calcium levels within the reference range and to reduce PTH levels to near normal. This normalization is important because elevated PTH levels in patients with PHP1a could cause increased bone remodeling and lead to secondary hyperparathyroid bone disease.30 The patient described did not present with symptomatic hypocalcemia, so she did not receive intravenous calcium. She required oral calcium and calcitriol to maintain her serum calcium concentrations in the normal range.
Growth-hormone deficiency
Some children with PHP1a have hypothalamic growth-hormone deficiency and may benefit from therapy with recombinant human growth hormone to achieve optimal final height. In those patients in whom defective growth-hormone secretion is suspected, the epiphyseal defects, commonly mischaracterized as bone-age advancement, should not disqualify these children from being considered for growth-hormone therapy. In addition to its effect on statural growth, growth-hormone therapy also seems to improve body composition in patients with PHP1a. This patient's brief treatment with growth hormone resulted in improvements in both height and BMI SDSs (Table 1).
Hypothyroidism
Most patients with PHP1a present with subclinical hypothyroidism before the onset of hypocalcemia. Hypothyroidism is treated with thyroid hormone replacement using levothyroxine at age-appropriate and weight-appropriate doses. The aim of management is to normalize levels of TSH and free T4. This patient is currently on 100 g of levothyroxine daily for management of hypothyroidism.
Hypogonadism
Common reproductive dysfunctions in persons with PHP1a include delayed puberty, oligomenorrhea and infertility.30 Each condition requires age-appropriate therapy; for example, low-dose estrogenic formulations are used to induce puberty in adolescent girls with delayed puberty. The patient described is still prepubertal at 9 years of age, so it is too early to determine whether she will require estrogen therapy, but her pubertal development is being closely monitored.
Obesity and insulin resistance
Patients with PHP1a who also have a family history of type 2 diabetes mellitus may have familial risk factors for development of insulin resistance, prediabetes and type 2 diabetes mellitus. Growth-hormone therapy improves body composition, but may worsen insulin resistance. Lifestyle modifications should be incorporated in the management of patients with PHP1a phenotype who may be at risk of metabolic syndrome. Early introduction of oral insulin-sensitizing agents, such as metformin, may be necessary when lifestyle modification is ineffective, especially in patients with prediabetes. Currently, the patient described here is on lifestyle modification only.
Conclusions
Children diagnosed with PHP1a should be further evaluated for associated endocrinopathies, such as resistance to growth-hormone-releasing hormone, which may lead to growth-hormone deficiency. Preliminary data suggest that the short stature of patients with PHP1a may be ameliorated with growth-hormone therapy in some cases.15 The advanced bone age seen in PHP1a is due to a chondrocytic signaling defect, and not excess production of sex hormone; therefore, bone-age advancement should not preclude affected children from being considered for growth-hormone therapy. However, a combination of growth-hormone therapy, family history of type 2 diabetes mellitus, and obesity in these children might lead to metabolic complications, such as insulin resistance, prediabetes and type 2 diabetes mellitus.
