First described by Fuller Albright et al. in 1942, Albright hereditary osteodystrophy falls within a spectrum of disorders of parathyroid hormone resistance that are termed pseudohypoparathyroidism. It is an autosomal dominant disease1,2.
A 1978 report by Gertner et al. described a case of femoral head osteonecrosis in a young boy with pseudohypoparathyroidism; however, this child did not have the characteristic phenotype of Albright hereditary osteodystrophy and, on investigation, he was normocalcemic3. To our knowledge, there have not been any previously identified cases of Legg-Calvé-Perthes disease in a patient diagnosed with Albright hereditary osteodystrophy.
In this paper, we report on a patient with both Albright hereditary osteodystrophy and Legg-Calvé-Perthes disease of the hip. The parents of the patient consented to the submission of the data and photographs concerning the case for publication.
A girl was born, after thirty-nine weeks of gestation, by cesarean section, which was performed because of a breech presentation. Her mother had taken prescribed labetalol throughout her pregnancy because of previously existing hypertension. The family history was unremarkable for any genetic conditions, and no parental consanguinity was known. At birth, the patient weighed 3240 g and was 45 cm long. The Apgar scores were 6 at one minute, 8 at five minutes, and 9 at ten minutes.
Early development and growth were unremarkable through the first year. However, by the time the child was twelve months of age, the parents became concerned about a possible developmental delay as she had not yet begun to speak and did not demonstrate a hand preference. She would not pull herself into a standing position and she resisted weight-bearing, flexing the hips, and extending the legs while being held in a position to encourage standing or walking. On examination, she was noted to have dysmorphic features such as a large tongue and low-set ears. In addition, she had deeply tethered skin creases in the upper limbs and blue-to-pink collagenous subcutaneous lesions on the abdomen. A diagnosis of constitutional motor delay was made, and she was referred to a physiotherapist.
By seventeen months of age, the patient still had not developed walking skills and propelled herself along the floor using her legs while in a seated position. It was only at twenty-four months that she began to walk without support, but she still moved hesitantly.
As a result of the continued developmental delay and dysmorphic features, an initial chromosomal investigation was performed. It was negative for Prader-Willi/Angelman syndrome and was interpreted as a normal karyotype.
At twenty-one months of age, the patient's height was in the 10th to 25th percentile, but her weight exceeded the 95th percentile. She was referred to a pediatric endocrinologist, who found plagiocephaly (asymmetrical distortion of the skull), a markedly round face with midface hypoplasia, underdeveloped ears, and abnormally spaced, small, "peg-like" teeth (Figs. 1-A and 1-B). She had a depressed nasal bridge with a short nose and a long, well-formed philtrum. The tongue was quite prominent.
The patient was noted to have unusually shaped hands and feet, with thickened, small toenails. The fingers were short with prominent pads. She demonstrated bilateral potter's thumb (shortening of the distal phalanx of the thumb) with increased thumbnail width-to-length ratios. The fourth metacarpophalangeal joint was noted to be proximally displaced and she had clinodactyly of the small finger bilaterally (Fig. 2-A). The fourth and fifth toes also demonstrated clinodactyly bilaterally. A radiograph of the hands revealed short metacarpals and diffuse abnormalities of mineralization (Fig. 2-B)1.
Because of her dysmorphic appearance and the persistence of the obesity, additional investigations were undertaken to screen for pituitary function problems. The results of laboratory analyses were consistent with anemia, hypothyroidism, and hypoprolactinemia.
Midway through her third year of life, the patient began to experience lower abdominal discomfort that radiated to the left knee. At the age of three years and eleven months, an abdominal radiograph demonstrated Legg-Calvé-Perthes disease of the left hip joint. Evaluation of the hip demonstrated a painless passive range of motion, which was normal in all planes except abduction; abduction was limited to 45°.
On the basis of the above findings, a diagnosis of Legg-Calvé-Perthes disease was made. As the patient's prognosis was deemed to be favorable, nonoperative treatment consisting of ibuprofen for symptomatic pain relief and physiotherapy to improve abduction of the left hip was started.
When the patient was four years of age, an endocrine evaluation revealed marked hypocalcemia (calcium level, 1.57 mg/dL [0.39 mmol/L]) with hyperphosphatemia (phosphate level, 2.77 mg/dL [0.89 mmol/L]). The circulating parathyroid hormone level was found to be markedly elevated (194 pg/mL [194 ng/L]). Genetic testing revealed the presence of the 187del4 mutation in exon 7 of the GNAS1 gene—the genotype of Albright hereditary osteodystrophy4.
When the patient was four years and four months of age, follow-up radiographs of the hips (Fig. 3, A and B) demonstrated flattening and fragmentation of the left femoral capital epiphysis with widening of the physis consistent with a diagnosis of Legg-Calvé-Perthes disease. However, new bone growth within the lateral aspect of the epiphysis indicated healing when the radiographs were compared with the abdominal radiographs made at three years and eleven months of age. The hand radiograph indicated a bone age of approximately five years and nine months (Fig. 2-B), which was determined to be abnormally accelerated for her chronological age1,5.
When the patient was six years of age (two years after diagnosis), hip radiographs (Fig. 3, C and D) showed the left femoral capital epiphysis to be confluent without fragmentation. There were no noticeable metaphyseal cysts. She was clinically asymptomatic at this point, maintaining a full pain-free range of motion without observed gait abnormalities.
Recent advances in genetics have linked the Albright hereditary osteodystrophy phenotype to mutations in the expression of Gsa, the alpha subunit of the stimulatory guanine nucleotide binding protein. Encoded by exons 1-13 of the GNAS gene (20q13.3), mutations of Gsa have been shown to cause parathyroid hormone resistance. By inactivating the exons of GNAS that are responsible for the encoding of GSa, cAMP levels are, in turn, unable to become elevated in response to stimulation by hormones (such as parathyroid hormone). Thus, the resulting broad physiological cellular resistance to elevated (or normal) circulating parathyroid hormone levels has been postulated to contribute to the phenotype of patients with this mutation4.
Albright hereditary osteodystrophy is characterized by variable phenotypic features that include short stature, obesity (usually a weight greater than the 90th percentile despite the small stature), a round face, a short neck, a flattened nasal bridge, subcutaneous ossification, and developmental delay. Abnormal dentition is also noted in some cases. While the severity of these features varies, even within families, the hallmark of the phenotype lies in the brachydactyly. Most commonly, patients present with potter's thumb, which is shortening of the distal phalanx of the thumb and is seen in this condition as an increased nail width-to-length ratio. Metacarpal shortening can also be present with this condition, and it most commonly affects the third, fourth, and fifth digits. Clinically, a dimple can be seen over the knuckles of the clenched fist of patients with metacarpal shortening; this has been termed the Archibald sign1,4,5.
When the characteristic phenotype of Albright hereditary osteodystrophy is accompanied by biochemical alterations such as hypocalcemia and hyperphosphatemia with a high circulating parathyroid hormone level, this indicates a generalized failure to respond to parathyroid hormone. In these cases, the disorder is termed pseudohypoparathyroidism Ia. Patients with the characteristics of Albright hereditary osteodystrophy who do not demonstrate the above biochemical aberrations are grouped into a category called pseudo-pseudohypoparathyroidism5.
In addition to the phenotypic constellation of signs resulting from parathyroid hormone resistance, patients with Albright hereditary osteodystrophy commonly show marked resistance to other hormones, such as thyroid stimulating hormone, gonadotropins, and glucagon. Thyroid-stimulating-hormone resistance can result in hypothyroidism, which typically is not accompanied by a goiter or any detectable levels of circulating antithyroid antibodies in the blood. High levels of circulating thyroid-stimulating hormone can be noted with a low or normal free thyroxine (FT4) level present in the serum. Gonadotropin resistance can lead to delayed puberty, oligomenorrhea, and infertility in women. Signs in men, such as testicular atrophy, are less prevalent. Typically, patients present with high or, more commonly, normal levels of circulating gonadotropins, but there is an impaired response from the target organs. Glucagon resistance accompanying Albright hereditary osteodystrophy has not been shown to result in clinically important alterations in the hepatic response to glucose, although alterations in functioning have been noted secondary to decreased levels of circulating cAMP6.
In Legg-Calvé-Perthes disease, osteonecrosis develops in the region of the immature proximal femoral epiphysis. The exact etiology is unknown; however, many hypotheses center on vascular insufficiency. Patients are predominantly young boys (4:1 male:female ratio) between four and nine years of age7-10. Classically, patients present with a painless intermittent limp. Thigh or knee pain may develop as the disease progresses. In some cases, pain is limited to the knee. Clinically, the hip shows a limited range of flexion, abduction, and internal rotation.
If detected in a child with a skeletal age of less than six years or with a chronological age of less than eight years, the outcome is generally good and does not require surgical treatment. Older children, however, may require surgical intervention such as varus femoral osteotomy or innominate osteotomy10-12.
While it is likely that the development of these two conditions in a single patient is a coincidence, there was initial concern that the aforementioned cellular insensitivity to hormonal signaling (mainly parathyroid hormone) might result in the inability to both mobilize calcium and activate osteoblasts. This could have impeded successful remodeling of the hip following resolution of the active phase of the Legg-Calvé-Perthes insult. Thus, the effect of Albright hereditary osteodystrophy on the prognosis for the hip in this patient was unknown at the time of diagnosis. Two years later, it was more apparent.
The constellation of metabolic and hormonal abnormalities associated with Albright hereditary osteodystrophy did not have an appreciably negative effect on the natural history of Legg-Calvé-Perthes disease in this case. The radiographic trend demonstrating continued healing of the left femoral capital epiphysis is consistent with previously published accounts of healing in otherwise normal children7,10-12. Thus, a young age at the time of diagnosis of Legg-Calvé-Perthes disease remained a good indicator of a positive prognosis and, as of the most recent follow-up visit (when the patient was six years old), the prognosis had not been adversely affected by the concomitant Albright hereditary osteodystrophy.