Auxological and Endocrinological Features in Children With McCune Albright Syndrome: A Review.

McCune-Albright syndrome is a rare and challenging congenital sporadic disease involving the skin and skeletal and endocrine systems with a prevalence ranges from one in 100,000 to 1,000,000. In addition to the classical triad of fibrous dysplasia of bone, café au lait pigmented skin lesions and precocious puberty, other multiple endocrinological features, including hyperthyroidism, growth hormone excess, hypercortisolism, and hypophosphatemic rickets, have been reported. A brief review of the syndrome in children is here reported.

A case report of Proteus syndrome (PS).

BACKGROUND: Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia. CASE PRESENTATION: Herein, a PS case with atypical clinical features and syndromes was reported, to improve the understanding of the diagnosis and treatment of the disease. The case was a 3-year-and-11-month-old male child. He was admitted due to a primary diagnosis of McCune-Albright syndrome. After admission, the lesion samples from the milk coffee spots, and nodular thickening skin at hands and feet were subjected to genetic screening. Genetic testing results confirmed the diagnosis of PS. CONCLUSIONS: Based on the clinical manifestations, laboratory tests, imaging data, and literature reviewing, the etiology, diagnosis, treatment and prognosis of PS have been analyzed and discussed.

Gynecologic and reproductive outcomes in fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. METHODS: Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. RESULTS: Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35 years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. CONCLUSIONS: Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population.

Phenotypic testicular abnormalities and pubertal development in boys with McCune-Albright syndrome.

Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune-Albright syndrome (MAS). On the basis of such analysis, we concluded that:1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP.

Short stature and growth hormone deficiency: unexpected manifestations of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare disease characterised by triad of monostotic or polyostotic fibrous dysplasia, café au-lait skin spots and a variety of endocrine disorders; precocious puberty (PP) being the most common presenting symptom in female patients. Hyperfunction endocrinopathies including hyperthyroidism, growth hormone excess and cortisol excess are typical presentations in MAS. We present a case of 21-year-old woman with clinical and radiological characteristics of MAS triad; she presented with short stature which was attributed to both growth hormone deficiency and PP. Growth hormone deficiency in MAS has not been reported in English medical literature.

Scoliosis in Fibrous Dysplasia/McCune-Albright Syndrome: Factors Associated With Curve Progression and Effects of Bisphosphonates.

Scoliosis is a complication of fibrous dysplasia/McCune-Albright syndrome (FD/MAS); however, risk factors and long-term outcomes are unknown. Bisphosphonates are commonly used; however, it is unknown whether their use decrease the risk of progressive scoliosis. Clinical data from the National Institutes of Health (NIH) cohort study was reviewed. Cobb angles were measured, and variables associated with scoliosis progression were identified. Of 138 subjects with available radiographs, 84 (61%) had scoliosis, including 55 (65%) classified as mild (Cobb angle >10 to ≤30 degrees), 11 (13%) as moderate (>30 to ≤45 degrees), and 18 (22%) as severe (>45 degrees). Total skeletal disease burden was highly associated with scoliosis severity (p < 0.0001). Endocrinopathies associated with scoliosis included fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (p < 0.001) and hyperthyroidism (p < 0.001). Bone turnover markers, including osteocalcin and NTX-telopeptides, were associated with severe scoliosis (p < 0.01). Associations were identified between Cobb angle and functional metrics, including leg length discrepancy (p < 0.01), hip range of motion (p < 0.05), and strength of the gluteus medius and maximus (p < 0.01). Longitudinal analyses were conducted in 69 subjects who had serial radiographs over a median 4.9-year period (range, 0.9 to 14.7 years). Twenty-two subjects were treated with bisphosphonates; there was no difference in Cobb angle progression compared to untreated subjects (0.10 versus 0.53 degrees/year, p = 0.36). Longitudinal data was available for 10 of 12 subjects treated with spinal fusion; one had instrumentation failure, but in nine subjects Cobb angles were stable with 6.1 years of follow-up (range, 0.9 to 14.7 years). Two fatalities from scoliosis-associated restrictive lung disease occurred in subjects managed non-operatively. Scoliosis occurs frequently in patients with polyostotic FD, and may be potentially fatal. The primary risk factor for progressive scoliosis is total skeletal disease burden. Treatable features that contribute to scoliosis progression include leg length discrepancy, FGF23-mediated hypophosphatemia, and hyperthyroidism. Current data do not support routine use of bisphosphonates to prevent progression of spinal curvature. Spinal fusion is frequently effective in providing long-term stability, and may be lifesaving. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Bone marrow failure and extramedullary hematopoiesis in McCune-Albright syndrome.

In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), bone and bone marrow are, to varying degrees, replaced by fibro-osseous tissue typically devoid of hematopoietic marrow. Despite the extensive marrow replacement in severely affected patients, bone marrow failure is not commonly associated with FD/MAS. We present a 14-year-old girl with FD/MAS, who developed pancytopenia and extramedullary hematopoiesis (EMH) with no identified cause, in the setting of iatrogenic thyrotoxicosis and hyperparathyroidism. Pancytopenia, requiring monthly blood transfusions, persisted despite multiple strategies to correct these endocrinopathies. Due to worsening painful splenomegaly, likely as a result of sequestration, splenectomy was performed. Following splenectomy, pancytopenia resolved and patient has since been transfusion-independent. We report the first detailed case of bone marrow failure and EMH in FD/MAS. The etiology of marrow failure is likely multifactorial and related to the loss of marrow reserve due to extensive polyostotic FD, exacerbated by iatrogenic thyrotoxicosis and hyperparathyroidism. Mini Abstract: A patient with fibrous dysplasia developed bone marrow failure and extramedullary hematopoiesis. The etiology likely involved loss of hematopoetic marrow space and uncontrolled endocrinopathies. Splenectomy was therapeutic.

Determinants of impaired quality of life in patients with fibrous dysplasia.

BACKGROUND: Fibrous dysplasia is a rare bone disorder, commonly associated with pain, deformity and fractures, which may significantly impact on quality of life. In this study we evaluate quality of life in patients with fibrous dysplasia using the Short Form-36 and the Brief Pain Inventory questionnaires. Data were compared with those of the general Dutch population. RESULTS: Out of 138 patients from a cohort of 255 patients with fibrous dysplasia that were sent questionnaires assessing quality of life and pain, the response rate was 70.3%, with 97 patients, predominantly female (65%), completing the questionnaires. Monostotic fibrous dysplasia was predominant (n = 62, 64%). Fibrous dysplasia patients had significantly lower quality of life outcome scores than the general Dutch population for all tested domains of the Short Form-36 except for the "Mental health" and the "Role emotional" domains. More severe forms of fibrous dysplasia, had the more severe Short-Form-36 quality of life outcomes, but there was no significant difference in Brief Pain Inventory domains between different subtypes of fibrous dysplasia. Quality of life was lower in patients with higher disease burden, as reflected by high skeletal burden scores (p = 0.003) and high levels of P1NP (p = 0.002). CONCLUSION: We demonstrate impairments in all domains of quality of life, except for 'Mental health' and 'Role emotional' domains, across the wide spectrum of fibrous dysplasia including its milder forms. We identified high skeletal burden scores, reflecting disease severity, as the most consistent predictor of impaired quality of life. Our findings hold significant clinical implications as they draw attention to the clinically unmet need to address quality of life issues in the management of patients with all subtypes of fibrous dysplasia, including its milder forms.

Health-related quality of life and a cost-utility simulation of adults in the UK with osteogenesis imperfecta, X-linked hypophosphatemia and fibrous dysplasia.

BACKGROUND: Health-related quality of life of adults with osteogenesis imperfecta (OI), fibrous dysplasia (FD) and X-linked hypophosphatemia (XLH) remains poorly described. The aim of this study was to describe the HRQoL of adults with osteogenesis imperfecta, fibrous dysplasia and X-linked hypophophataemia and perform a cost-utility simulation to calculate the maximum cost that a health care system would be willing to pay for a hypothetical treatment of a rare bone disease. RESULTS: Participants completed the EQ-5D-5 L questionnaire between September 2014 and March 2016. For the economic simulation, we considered a hypothetical treatment that would be applied to OI participants in the lower tertile of the health utility score. A total of 109 study participants fully completed the EQ-5D-5 L questionnaire (response rate 63%). Pain/discomfort was the most problematic domain for participants with all three diseases (FD 31%, XLH 25%, OI 16%). The economic simulation identified an expected treatment impact of +2.5 QALYs gained per person during the 10-year period, which led to a willing to pay of £14,355 annually for a health care system willing to pay up to £50,000 for each additional QALY gained by an intervention. CONCLUSIONS: This is the first study to quantitatively measure and compare the HRQoL of adults with OI, FD and XLH and the first to use such data to conduct an economic simulation leading to healthcare system willingness-to-pay estimates for treatment of musculoskeletal rare diseases at various cost-effectiveness thresholds.

Long-term outcomes of letrozole treatment for precocious puberty in girls with McCune-Albright syndrome.

OBJECTIVE: McCune-Albright syndrome (MAS) is a rare disorder with a broad spectrum including precocious puberty (PP) due to recurrent estrogen-secreting ovarian cysts. This study evaluates the long-term safety and efficacy of letrozole treatment in large cohort of girls with MAS-associated PP. DESIGN: Retrospective cohort analysis. METHODS: Clinical data, including history and physical examination, bone age, and pelvic ultrasounds, were reviewed on 28 letrozole-treated girls. Adult height was reviewed for 42 historical controls. Outcomes included rate of skeletal maturation, growth velocity, predicted adult height and adult height. RESULTS: Twenty-eight girls received letrozole treatment. Treatment duration was 4.1 ± 2.6 years (mean ± 1 s.d.) (range: 0.5-10.9) and mean follow-up was 6.0 ± 3.3 years (range: 0.5-15.0), for a total of 135.9 person-years of follow-up. Letrozole treatment was highly effective at decreasing the rate of skeletal maturation, with a decline in change in bone age over change in chronological age (ΔBA/ΔCA) from 1.7 (IQR: 2.3) to 0.5 (IQR: 0.4) (P < 0.0001), and growth velocity Z-scores, which declined from 2.2 ± 2.3 to -0.6 ± 1.6 (P = 0.0004). Predicted adult height Z-scores increased significantly from -2.9 ± 3.2 to -0.8 ± 1.5 for subjects on treatment (P = 0.004). Four subjects who completed treatment reached adult height Z-scores ranging from -1.5 to 1.7 (median: -0.6), which were increased in comparison with untreated historical controls (P = 0.02). There was no change in uterine size or ovarian volumes, and no adverse events over the treatment period. CONCLUSIONS: In this study with the longest follow-up to date, letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity and predicted adult height.

Displasia fibrosa poliostótica: presentación de un caso / Polyostotic fibrous displasia: a case report

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Disease severity and functional factors associated with walking performance in polyostotic fibrous dysplasia.

The purpose of this study was to determine the association between measures of disease severity, impairment, and ambulation ability in persons with polyostotic fibrous dysplasia (PFD). A cross-sectional sample of 81 patients (ages 5-57) with polyostotic fibrous dysplasia was evaluated as part of an ongoing study. Subjects were scored on the Skeletal Disease Burden Score (SDBS), completed a 9-minute walk test (9MW), manual muscle testing (MMT), and measurements of range of motion (ROM). Correlations between continuous variables were calculated using the Pearson correlation coefficient and ordinal variables by Spearman correlation coefficient. It was found that subjects with more severe disease walked slower than those with less skeletal disease, with the exception of the youngest subjects. Walking velocity was faster in subjects with better hip strength and range of motion and slower in those with bilateral coxa vara. Those subjects with more severe disease had less range of motion, were weaker at the hips, and more likely to have leg length discrepancy. Skeletal disease severity was associated with hip weakness, leg length discrepancy, and loss of range of motion. In most cases, findings did not differ in the presence or absence of associated endocrinopathies. Skeletal disease severity, MMT and ROM each has an impact on walking efficiency in persons with PFD. These findings suggest that treatment focused on strategies to improve or, at least, maintain hip strength and range of motion, correct leg length discrepancies and hip malalignment may help preserve ambulation ability in persons with PFD and that treatment should begin at a young age.

Aspectos clínicos en dos casos de seudohipoparatiroidismo ( Ia y Ib) y estudio molecular del locus GNAS / Clinical features of two cases of pseudohypoparathyroidism ( I a and I b) and molecular analysis of GNAS

El seudohipoparatiroidismo (PHP) es una entidad rara, caracterizada por resistencia tisular a la hormona paratiroidea (PTH). Los 2 subtipos principales, PHP-Ia y PHP-Ib, son causados por alteraciones en el gen GNAS (20q13.3), que codifica para la proteína Gsα, esencial para la acción de la PTH y otras hormonas. El PHP-Ia se asocia a diversas alteraciones hormonales, osteodistrofia hereditaria de Albright (AHO) y actividad reducida de Gsα. Está causado por mutaciones inactivantes del gen GNAS. El PHP-Ib presenta resistencia aislada a la PTH, sin AHO y con actividad Gsα normal o levemente baja. Se asocia a defectos en la impronta de GNAS. Se presentan 2 casos con PHP-Ia y PHP-Ib, ahondando en su clínica y en el diagnóstico diferencial frente a afecciones similares (AU)

Pseudohypoparathyroidism (PHP) is a rare disorder, characterized by a tissue resistance to parathyroid hormone (PTH). The two main subtypes of PHP, PHPIa and PHPIb, are caused by alterations in the GNAS locus (20q13.3), which encodes the Gs protein, essential for the action of PTH and other hormones. PHP-Ia is associated with several hormone resistances, Albright hereditary osteodystrophy (AHO), and reduced Gsα activity. It is caused by inactivating mutations in the GNAS gene. PHPIb presents with isolated resistance to PTH, without AHO and with normal to low Gsα activity. It is related to imprinting defects in GNAS. Two unrelated cases of PHP-Ia and PHP-Ib are presented here, focusing on their clinical aspects and in the differential diagnosis with similar pathologies (AU)

Dental perspectives in fibrous dysplasia and McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare multisystem disorder characterized by the triad of polyostotic fibrous dysplasia (FD), endocrine disorders, and café-au-lait skin pigmentation. Ninety percent of MAS patients have FD lesions in the craniofacial area, resulting in significant orofacial deformity, dental disorders, bone pain, and compromised oral health. Maxillomandibular FD is also associated with dental developmental disorders, malocclusion, and high caries index. There are limited data on the outcomes of dental treatments in maxillomandibular FD/MAS patients, because clinicians and researchers have limited access to patients, and there are concerns that dental surgery may activate quiescent jaw FD lesions to grow aggressively. This report highlights current perspectives on dental management issues associated with maxillomandibular FD within the context of MAS.

Visual field improvement after pituitary tumor surgery in patients with McCune-Albright syndrome.

BACKGROUND: McCune-Albright syndrome (MAS) is a rare, sporadic congenital disorder, in which optic neuropathy may cause devastating visual consequences. Pituitary adenoma with overproduction of growth hormone (GH) is present in approximately two-thirds of MAS patients, and its role in the pathogenesis of MAS-associated optic neuropathy has not been studied. METHODS: Three MAS patients with GH-secreting pituitary adenoma and optic chiasm compression diagnosed between January 2008 and November 2010 were included in this case series. Transsphenoidal pituitary resection was performed in all 3 patients. Neuro-ophthalmologic evaluation was performed at presentation and every 6 months during follow-up. RESULTS: Of the 3 patients, 2 were female and 1 was male; their ages ranged from 17 to 27 years. Visual acuity ranged from 20/20 to 20/200 before surgery and all had visual field loss. The patients were followed up for 6-18 months with substantial improvement in their visual fields. CONCLUSIONS: GH-secreting pituitary adenoma may contribute to optic nerve damage, at least partially, in MAS patients. Pituitary surgery may be important for visual recovery in some MAS patients in whom there is compression of the optic chiasm.

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.

Pubertad precoz periférica: fundamentos clínicos y diagnóstico-terapéuticos / Peripheral precocious puberty: clinical, diagnostic and therapeutical principles

La pubertad precoz periférica (PPP) es el resultado de la aparición anormalmente precoz de la pubertad, debido al aumento de esteroides sexuales sin evidenciarse activación del eje hipotálamo-hipófiso-gonadal. Es una patología mucho más infrecuente que la pubertad precoz central (PPC) y es secundaria a trastornos de origen genético o a patologías adquiridas muy heterogéneas. En los últimos años, los avances moleculares han contribuido notablemente en el conocimiento de la fisiopatología de algunos de estos trastornos, muy en particular, en el síndrome de McCune-Albright y la testotoxicosis. Asimismo, las técnicas de imagen y de cuantificación hormonal han permitido mejorar el diagnóstico precoz de trastornos adquiridos, especialmente, patología tumoral causante de PPP. Desafortunadamente, los avances médicos objetivados en el diagnóstico no se han visto reflejados en el tratamiento médico del síndrome de McCune-Albright y la testotoxicosis. A pesar de haber probado diversas opciones terapéuticas en ambos trastornos, a día de hoy, los resultados son muy desalentadores, especialmente en el síndrome de McCune-Albright. A nuestro entender, este fracaso se sustenta en la ausencia de ensayos clínicos bien diseñados con la inclusión de un número adecuado de pacientes seguidos hasta el final de su crecimiento(AU)

Peripheral precocious puberty (PPP) is the result of the presence of precocious puberty due to the increase of sex steroids with no evidence of activation of the hypothalamic-pituitary-gonadal axis. It is much less common than central precocious puberty (CPP) and it is secondary to either genetic disorders or very heterogeneous acquired diseases. In recent years, molecular advances have made remarkable progress in understanding the pathophysiology of some of these disorders, most notably in McCune-Albright syndrome and testotoxicosis. In addition, new imaging techniques and better hormone assays have improved the early diagnosis of acquired disorders, particularly tumour disease causing PPP. Unfortunately, medical advances in the diagnosis of these disorders have not been reflected in the medical treatment of McCune-Albright syndrome and testotoxicosis. Despite having tried various treatment options in both disorders, the results are very disappointing, especially in patients with McCune-Albright syndrome. To our knowledge, this failure is based on the absence of well-designed clinical trials that include an adequate number of patients followed up until the end of their growth(AU)