Clinical Case of Mccune-Albright-Braitsev Syndrome (MAS)

Introduction

McCune–Albright–Braitsev syndrome (MAS) is a genetically determined disease characterized by a widespread fibrous bone dysplasia, an emergence of café-au-lait hyperpigmentation spots on the body, and various endocrinopathies, the most common of which is precocious puberty [1].

This is an orphan disease, the incidence of which ranges between 1 case per 100 thousand through 1 million of the population. The disease can emerge in children regardless of gender but in girls, it is registered 2 times more often, which is related to more pronounced symptoms of precocious puberty at this syndrome manifestation.

The pathogenesis of MAS is based on a mutation in the GNAS gene, which provides the synthesis of a specific protein NESP55 stimulating the α-subunit of the G protein (Gαs) with the following activation of cAMP production. This mutation causes excessive G protein signaling (Gαs), which further brings about a spontaneous increase in intracellular cAMP, hyperactivation of glycoprotein hormone receptors, autonomous cell proliferation, and increased hormone secretion [2].

It has been found that the GNAS mutation develops before the end of 10 weeks after fertilization and affects the system originating from all 3 germ layers: endoderm (thyroid gland and most organs of the gastrointestinal tract), ectoderm (hypothalamic-pituitary system, epidermis, and cranial bones,) and mesoderm (gonads, adrenal glands, and pelvic bones) [1][2].

Among the variety of clinical manifestations of MAS, the most common is bone injuries related to the development of fibrous dysplasia foci. Excessive Gαs signaling results in the proliferation of multipotent mesenchymal stromal cells and the generation of cavities filled with fibrous tissue. Most often, the diaphyses of long tubular bones such as humerus, femur, tibia, and fibula are involved in the pathological process but flat bones, in particular, cranial bones, spine, and pelvic bones cannot be excluded [1][2].

The second most common clinical manifestation of this syndrome is the emergence of cafe-au-lait hyperpigmentation foci with distinctive uneven jagged edges. As a rule, spots are detected at the child’s birth, and their size and number may increase with aging. The levels of ACTH and melanostimulating hormone remain normal. The emergence of pigment spots is stipulated by the generation of mutant melanocytes, which synthesize large amounts of melanin under the influence of the high cAMP level, resulting from excessive Gαs signaling [3].

Among the various endocrine disorders found in MAS, the most common is precocious sexual development (PSD) of the isosexual type, which can begin at the age of 6 months to 7 years; the average age of onset of the first signs is 3 years [1]. The development mechanism is related to the uncontrolled activation of the Gas transmitter, which causes the excessive stimulation of receptors for FSH and LH in the ovaries of girls, as well as the synthesis and secretion of estrogens. Regardless of gonadotropins, gonadotropin-independent PSD is being formed. Hyperactivation of receptors for FSH and LH in the ovaries can result in the generation of estrogen-producing cysts with the capability of further spontaneous regress [2].

Considering the high variability of clinical manifestations of this syndrome, the present paper represents a rare clinical case involving the cardiac conduction system in the pathological process that requires more careful monitoring at case follow-up.

Description of a clinical case

Female patient K., 9 years old, was hospitalized in 2020 in the pediatric endocrinology department with complaints about enlarged mammary glands and periodic bleeding from the genital tract in a history. Previously in 2019, she contacted a gynecologist in terms of complaints about enlarged mammary glands. An objective examination (2019) fixed sexual development (Tanner): Ma II P I Ax I Me I. On the left buttock, a café-au-lait spot was revealed.

A laboratory and instrumental examination (2019) was as follows: Estradiol was 5.0 pg/ml (6.0–27.0), LH was <0.10 mIU/ml (<0.1–0.14), FSH was 0.60 mIU/ml (0.5–4.52), Prolactin monomeric was 84.98% (up to 60%). The results of the pelvic organs ultrasound were within the age norm. According to the X-ray examination of the hands, the bone age corresponded to 7 years (the certificate age was 7 years and 2 months). There was made a diagnosis of “Precocious sexual development (PSD). Albright-Braitsev syndrome? Hyperprolactinemia”. A dynamic examination was recommended.

During a dynamic examination, it was found that the growth rate was 8.12 cm/year, SDS of the growth rate was +3.4. A repeat X-ray of the hands revealed an advance in bone age by 1 year and 2 months: the predicted height considering bone age was 157 cm according to Bayley-Pinneau. In addition, the following features were identified: a persistently elevated prolactin level, fluctuations in the estradiol level from 5 to 430.8 pg/ml, pre-pubertal FSH and PH values, and recurrent ovarian cysts revealed during the ultrasound of the pelvic organs.

In order to confirm the gonadotropin-independent variant of PSD, a test with an analog of gonadotropin-releasing hormone (Diferelin) was performed. As an increase in LH of more than 6 U/l during stimulation was not revealed, the test confirmed gonadotropin-independent PSD, which is characteristic of MAS.

In order to identify foci of fibrous dysplasia, osteoscintigraphy of the whole body and X-ray radiography of the upper and lower extremities were performed. Osteoscintigraphy revealed signs of focal lesions in the lower third of the right humerus. On the X-ray pattern of the right humerus, the bone structure was heterogeneous with areas of compaction, at the level of the lower third, it was with a predominance of osteoporosis. At the border of its middle and lower third parts, there was an area of rarefied bone tissue with clear sclerotic contours measuring 1×1.7 cm. Dynamic X-ray radiography of the left hand showed that the bone age corresponded to 9–10 years (the certificate age was 9 years and 5 months). The bone structure of the metacarpal bone III of the right hand was heterogeneous. The patient was consulted by an orthopedic traumatologist: fibrous dysplasia at the level of the middle third and lower third of the right humerus was fixed.

Considering the fact that patients with MAS have a high probability of developing pituitary adenomas, a contrast-enhanced MRI of the brain was performed to exclude pathological formations in the hypothalamic-pituitary region. MR signs of a heterogeneous structure of the pituitary gland were detected in post-contrast series.

In the case of MAS, defects in cardiomyocytes may emerge manifesting themselves as tachycardia and various rhythm disturbances. In order to exclude injuries in the conduction system of the heart, an ECG was performed, which revealed sinus arrhythmia and the phenomenon of a shortened PQ interval. Daily ECG monitoring revealed a tendency toward tachycardia, episodes of sinus arrhythmia during sleep, and a single supraventricular extrasystole. During sleep, 4 episodes of pauses were recorded due to the sinoauricular block with an RR duration of up to 1.1 s.

To exclude endocrinopathies, in particular, hyperthyroidism with nodular goiter and acromegaly, which may be components of MAS, an ultrasound of the thyroid gland was performed. Results showed no pathology; TSH, free T4, free T3, growth hormone, and IGF-1 were within normal limits.

A biochemical blood test revealed an increase in the level of alkaline phosphatase up to 352 U/l (0–240), which may indicate the process of bone resorption.

To confirm the diagnosis, the patient was discharged for a telemedicine consultation at the federal state budgetary institution “National Medical Research Center of Endocrinology” of the Russian Ministry of Health. Based on the data provided, MAS was diagnosed. Considering the satisfactory prognosis for growth, a slight advance in bone age, and the absence of data on hyperestrogenism and ovarian cysts at the time of examination, there were no indications for antiestrogenic therapy. The patient was recommended to undergo dynamic monitoring (by an endocrinologist, gynecologist, neurologist, cardiologist, ophthalmologist, and orthopedic traumatologist), X-ray monitoring of the humerus once a year, ECG monitoring, fundus examination, and dynamic MRI of the pituitary gland with contrast enhancement.

Discussion

The presented clinical examination almost completely coincides with the clinical data described in the literature. A special feature of this case is the involvement of the cardiac conduction system in the pathological process, which is rare according to the literature data [4]. Despite the relatively favorable course of MAS in this patient including the small size of the foci of fibrous osteodysplasia with their asymptomatic course, the monostotic nature of the lesion, and the absence of indications for anti-estrogenic therapy, the injury of cardiomyocytes puts her at risk for the development of sudden cardiac death syndrome, which must be taken into account during further dynamic examination.

It is worth noting that currently in Russia, there are no clinical recommendations for the diagnosis and treatment of MAS in children; and information on large-scale molecular genetic studies is limited. There are molecular genetics methods, which can identify the activating GNAS mutation, but they are rarely used in clinical practice on the score of the high rate of false-negative results [5]. This is stipulated by the fact that peripheral blood samples have a low level of mosaicism, which can lead to a negative test result, despite the specific clinical picture of the disease. To increase the sensitivity of the test, it is recommended to use biopsies of the affected tissue areas but they are hard to collect in everyday medical practice [6]. Currently, the diagnosis is made according to the totality of clinical data added with laboratory and instrumental studies, which may indicate MAS.

Specific treatment for MAS has not been developed considering the multiorgan nature of the lesions and the high variability of clinical manifestations. In the case of severe fibrous dysplasia, bisphosphonates can be applied but the effectiveness of their use in children with MAS has not been proven to this date. For the treatment of precocious puberty in girls, the 3rd generation of aromatase inhibitors (letrozole) or antiestrogens (tamoxifen, toremifene, fulvestrant) can be prescribed to reduce hyperestrogenism but generally accepted treatment regimens have not been developed [7]. The absence of signs of hyperestrogenism and ovarian cysts at the time of the last examination, as well as a satisfactory growth prognosis and a slight advance in bone age of the patient, attest to no indications for prescribing these drugs.

Conclusion

The presented clinical case demonstrates one of the variants of clinical manifestations of MAS. Considering the multiorgan nature of the lesions and the high variability of possible symptoms, such patients require broad awareness among doctors of various profiles and an interdisciplinary approach to prevent the development of severe complications and ensure the timely initiation of therapy.