Intersexual Births: The Epistemology of Sex and Ethics of Sex Assignment.

This article aims to analyse a possible manner of approaching the birth of intersexual children. We start out by summing up what intersexuality is and how it is faced in the dominant clinical practice (the "treatment paradigm"). We then argue against this paradigm, in favour of a postponement of genital surgery. In the second part of this paper, we take into consideration the general question of whether only two existing sexes are to be recognized, arguing in favour of an expansion of sex categories. In the third part, we illustrate the reasons supporting provisional sex attribution: the child's best interest and respect for their developing moral autonomy. This position aims to increase the child's well-being and self-determination, limiting parents' freedom to take decisions on behalf of others, in particular, those decisions concerning basic aspects of their children's personal identity.

Growth hormone-Insulin-like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome.

CONTEXT: In fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro-osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). GH hypersecretion has been described in 10%-20% of MAS-BFD patients. Aim of the study was to determine the impact of GH-insulin like growth factor 1 (IGF1) axis hyperactivity on MAS-BFD morbidities and the efficacy of GH excess therapy. DESIGN AND PATIENTS: A multicentric cross-sectional analysis was conducted on three different MAS cohorts. From 195 MAS patients, 37 subjects (19%) with GH excess were identified and compared with 34 MAS controls without GH hypersecretion. RESULTS: Mean head circumference SDS was significantly higher in GH excess: 4.025 SDS vs 0.683 SDS (P < .0001). The risk of optic neuropathy (Odds ratio 4.231; P = .039), hearing deficit (Odds ratio 2.961; P = .0481), facial asymmetry (Odds ratio 6.563; P = .0192), malignancies (Odds ratio 15.24; P = .0173) were higher in GH excess group. Overall, pharmacotherapy (octreotide alone 10-30 mg/mo or with pegvisomant 10-20 mg/d) was effective in IGF1 normalization (IGF1 Z-score between -2 and +2 SDS) in 21/29 patients (72.4%) with good compliance to the regimen. Late diagnosis and GH excess treatment after 16 years old of age was associated with an increased risk of optic neuropathy (Odds ratio 4.500; P = .0491) and growth of pituitary adenomas (Odds ratio 7.846; P = .050). CONCLUSIONS: GH-IGF1 hyperactivity increases risk of morbidities in MAS. Medical therapy is effective in normalizing IGF1 in most patients, and early treatment during paediatric age is associated with a decreased risk of optic neuropathy and GH-secreting adenomas growth.

Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome.

BACKGROUND: McCune-Albright syndrome (MAS) is characterized by the triad of polyostotic bone fibrous dysplasia (PFD), endocrine disorders, and café-au-lait skin pigmentation. Ninety percent of MAS patients have fibrous dysplasia (FD) craniofacial lesions. Osteonecrosis of the jaw (ONJ) has been described as an adverse side effect of bisphosphonate therapy. The aim of the study was to investigate evidence of clinical and/or radiological signs of ONJ in FD/MAS pediatric patients due to bisphosphonate therapy and describe odontoiatric tools in this population. METHODS: Thirteen FD/MAS patients were enrolled. All patients during pediatric age have been treated with pamidronate infusions. They underwent complete oral clinical examination. Ortopantomography and/or CT were evaluated in all cases. RESULTS AND CONCLUSIONS: No patient developed ONJ. None of them showed radiological signs different from jaw FD. In spite of the low number of patients enrolled, results confirm that, in this population, ONJ can be ruled out as a chronic adverse side effect of bisphosphonate therapy.

Changing Pattern of Femoral Deformity During Growth in Polyostotic Fibrous Dysplasia of the Bone: An Analysis of 46 Cases.

BACKGROUND: In polyostotic fibrous dysplasia (PFD) affecting the femur, 6 types of stable femoral deformities have been identified, ranging from the mild type 1 to the most severe type 6. The purpose of our study was to identify the type of deformity present at diagnosis in children with PFD affecting the femur, and to investigate possible changes in the original type with growth. METHODS: Twenty-seven children affected by either PFD or McCune-Albright syndrome, with 46 affected femurs, were consecutively observed from 1994 to 2010. Radiographs of the pelvis and femurs were taken at diagnosis, and afterward at regular intervals of 6 to 12 months depending on the clinical evolution of each case. Radiographs of the femurs taken at 3 and 7 years after diagnosis were selected to assess the evolution of the femoral deformity. Deformities were classified according to the femoral shape, neck-shaft angle value, and the presence of shepherd's crook deformity evaluated on AP radiographs. RESULTS: The average age of the patients at diagnosis was 5 years (range, 2 to 11 y). At diagnosis, 30 femurs were type 1; 12, type 2; 1, type 3; 1, type 4; and 2, type 5. Three years later, 39% of the femurs had maintained the original deformity present at diagnosis, whereas only 13% did so 7 years after diagnosis.Predictors of change to a more severe type were: younger age at diagnosis, McCune-Albright syndrome, rapid spreading of fibrodysplastic tissue from the trochanteric area to the proximal femoral shaft, cortical thinning of the proximal femur, calcar osteolysis, and presence of an intertrochanteric cystic-like lesion eroding the calcar. CONCLUSIONS: In children with PFD affecting the femur, 61% of the femoral deformity present at diagnosis switched to a more severe type of deformity within 3 years from diagnosis, whereas 87% either shifted to a more severe type of deformity or already had corrective surgery within 7 years after diagnosis. LEVEL OF EVIDENCE: Level IV.

Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism.

BACKGROUND: Subcutaneous recombinant human parathormone [rhPTH (1-34)] has been introduced for hypoparathyroidism treatment, allowing avoidance of vitamin D and calcium side effects. OBJECTIVE: Our objective was to evaluate rhPTH (1-34) safety and efficacy in pediatric patients with genetically proved syndromic hypoparathyroidism. METHODS: The study was a 2.5-year self-controlled trial on six pediatric patients (four males, two females, age 9.8±5.1 years) with syndromic hypoparathyroidism including three with autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, two with DiGeorge syndrome, and one with hypoparathyroidism-deafness-renal dysplasia syndrome. We compared patients' clinical and biochemical outcome of conventional treatment based on oral administration of calcium (1-1.5 g/day in three doses) plus oral calcitriol (6.5-33 ng/kg per day in two to three doses) with the outcome obtained with rhPTH (1-34) (teriparatide, 12.5 µg bid). Therapy shift was conducted introducing rhPTH (1-34) while progressively withdrawing calcium and vitamin D. Blood calcium, phosphorus, alkaline phosphatase, and urinary calcium-to-creatinine ratio (mg/mg) before and during rhPTH therapy were compared. RESULTS: rhPTH treatment allowed complete calcium and vitamin D withdrawal in two patients, calcium withdrawal in three and reduction of vitamin D dose in two. During rhPTH (1-34), mean blood calcium, phosphorus, and alkaline phosphatase were not significantly modified, whereas significant reduction of the calciuria-to-creatininuria ratio (0.55±0.31 vs. 0.1±0.1, p=0.02) was obtained. The number of tetanic episodes was reduced in four patients during teriparatide treatment compared to conventional treatment. CONCLUSION: In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1-34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff.

Improved sperm count and motility in young men surgically treated for cryptorchidism in the first year of life.

INTRODUCTION: The timing of surgery in cryptorchidism has been debated for a long time. Reports on histology suggest better fertility outcomes with early surgery, whereas evidence of long-term improved fertility still lacks sound data. The aim of this study is to analyze sperm count and motility in a cohort of young men operated on during the first 2 years of life for cryptorchidism. PATIENTS AND METHODS: A total of 78 young men (age, 18-26 years) surgically treated for cryptorchidism in the second year of life were recalled to evaluate testicular volume and sperm count and motility. Of the 78 young men, 51 accepted to participate to clinical and sperm evaluation. Relationship between total sperm count (TSC), sperm motility (SM), and age at surgery was investigated by Student t-test and Fisher test. Patients were divided into two groups: those patients who were submitted to surgery in their first year of life (Group A) and those patients who were submitted to surgery in their first and the second year of life (Group B). We investigated the ratio of those patients with normal sperm count to those patients with abnormal sperm count (we defined as normal TSC > 15 million and SM > 15%) and compared the mean TSC and SM in the two groups. RESULTS: TSC were slightly but not significantly higher in the first group (45.5 ± 15.5 million/mL vs. 36.5 ± 23.6 million/mL, p = 0.107) and SM (30.5% ± 11.3% vs. 26.5% ± 15.4%, p = 0.341). The percentage of patients with normal sperm count and motility were significantly higher in the first group: normal TSC was found in 26 of 27 patients (96.3%) in Group A versus 18 of 24 patients (75.0%) in Group B (p = 0.042), normal SM was found in 26 of 27 patients (96.3%) versus 16 of 24 patients (66.7%), respectively (p = 0.008). In the two groups, no statistically significant difference was found neither in the proportion of patients with bilateral cryptorchidism, in the position of the testes, nor in the ratio of subjects treated with hormonal therapy before being operated on. CONCLUSIONS: In formerly cryptorchid subjects submitted to surgery in the first 2 years of life, the percentage of patients with normal sperm count and motility is higher than 95%, with even better fertility prognosis if orchiopexy is performed in the first year of life.

20 novel point mutations and one large deletion in EXT1 and EXT2 genes: report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis.

BACKGROUND: Hereditary multiple exostosis represents the most frequent bone tumor disease in humans. It consists of cartilage deformities affecting the juxta-ephyseal region of long bones. Usually benign, exostosis could degenerate in malignant chondrosarcoma form in less than 5% of the cases. Being caused by mutations in the predicted tumor suppressor genes, EXT1 (chr 8q23-q24) and EXT2 (chr 11p11-p12) genes, HMEs are usually inherited with an autosomal dominant pattern, although "de novo" cases are not infrequent. AIM: Here we present our genetic diagnostic report on the largest Southern Italy cohort of HME patients consisting of 90 subjects recruited over the last 5years. RESULTS: Molecular screening performed by direct sequencing of both EXT1 and EXT2 genes, by MLPA and Array CGH analyses led to the identification of 66 mutations (56 different occurrences) and one large EXT2 deletion out of 90 patients (74.4%). The total of 21 mutations (20 different occurrences, 33.3%) and the EXT2 gene deletion were novel. In agreement with literature data, EXT1 gene mutations were scattered along all the protein sequence, while EXT2 lesions fell in the first part of the protein. Conservation, damaging prediction and 3-D modeling, in-silico, analyses, performed on three novel missense variants, confirmed that at least in two cases the novel aminoacidic changes could alter the structure stability causing a strong protein misfolding. CONCLUSIONS: Here we present 20 novel EXT1/EXT2 mutations and one large EXT2 deletion identified in the largest Southern Italy cohort of patients affected by hereditary multiple exostosis.

Combined treatment with bicalutamide and anastrozole in a young boy with peripheral precocious puberty due to McCune-Albright Syndrome.

McCune-Albright Syndrome (MAS) is a congenital endocrine disorder due to mosaic tissutal hyper-function. We describe a boy with a molecularly confirmed MAS, clinically evident with congenital café-au-lait spots, bone fibrous dysplasia, hyperthyroidism, and renal phosphate wasting syndrome. At 4.6 years of age he disclosed a rapid progression of peripheral puberty, so we decided to treat him with bicalutamide 25 mg/day and anastrozole 1 mg/day. Combined third generation aromatase inhibitors - competitive androgen receptor blockers were employed in familial male precocious puberty (FMPP). Combined treatment was performed for 49 months from the age of 4.6 to 6.7 years. The patient underwent clinical, laboratory, and instrumental evaluation twice a year from the first admission to the current age. This treatment caused a rapid normalization of growth velocity, subsequent reduction of penile androgenization, and stabilization of testicular volume. The therapy was well tolerated for all its duration and neither side effects, nor secondary hypothalamic activation were noted. This report provides further evidence of effectiveness and safety of combined third generation aromatase inhibitors - competitive androgen receptor blockers in male precocious peripheral puberty, firstly employed in male MAS, and contributes to expand the spectrum of disorders in which their employment may reveal promising.

Surgical enucleation of testicular leydigioma in a young child: case report and literature review.

BACKGROUND: The leydigioma is the most frequent interstitial neoplasm of the testis. Clinical symptoms of all leydigioma usually are isosexual precocious pseudo-puberty due to autonomous testosterone overproduction, suppressed gonadotropin levels and a testis mass. Nowadays its therapy is debated. DESIGN AND METHODS: We report a case of a young child treated in 2008 for a leydigioma of the testis with atypical clinical behavior. Testicular oncologic markers and hormonal profile were assessed. RESULTS: The patient was treated successfully with organ-confined surgery. CONCLUSION: We want to confirm the safety of conservative surgery against radical orchiectomy and review the literature of the last decade on this debated matter.

Continuous subcutaneous hydrocortisone infusion (CSHI) in a young adolescent with congenital adrenal hyperplasia (CAH).

Congenital adrenal hyperplasia (CAH) is an autosomal recessive enzymatic defect caused by mutations or deletions of the cytochrome P450 21-hydroxylase CYP21 gene. Oral therapy with glucocorticoids and mineralcorticoids is administered to prevent adrenal crisis and to control hyperandrogenism. During puberty this type of therapy is difficult to manage owing to physiological and hormonal changes and poor compliance. We describe a case of a pubertal boy affected by CAH, in whom continuous subcutaneous infusion of hydrocortisone led to improved metabolic control and compliance.

Cushing syndrome due to ectopic adrenocorticotropic hormone secretion in a 3-year-old child.

Ectopic adrenocorticotrophic hormone (ACTH) secretion is a rare cause of Cushing syndrome in paediatric age, due to tumours arising from different tissues. To date, only 11 reports of ACTH-secreting pancreatic tumours in children and adolescents exist in the literature. We present a paediatric case of Cushing syndrome caused by ectopic ACTH secretion. This was caused by a large acinar cell carcinoma that developed in the pancreas of a 3-year-old girl.

HDR syndrome: a novel "de novo" mutation in GATA3 gene.

Human GATA3 haploinsufficiency leads to HDR (hypoparathyroidism, deafness, and renal dysplasia) syndrome. The development of a specific subset of organs in which this transcription factor is expressed appears exquisitely sensitive to gene dosage. We report on a 14-year-old patient with symptomatic hypoparathyroidism, sensorineural bilateral deafness, unilateral renal dysplasia, bilateral palpebral ptosis, and horizontal nystagmus. Fundoscopy displayed symmetrical pseudopapilledema, and brain CT scan revealed basal ganglia calcifications. FISH analysis did not disclose any microdeletion in the 22q11.2 or 10p14 regions. GATA3 mutation analysis identified a heterozygous deletion of GG nucleotides at codon 36 and 37 (c.108_109delGG) in exon 2 causing a frameshift with a premature stop codon after a new 15-aminoacid sequence. Restriction endonuclease analysis performed in parents was negative. Our patient carries a novel "de novo" GATA3 mutation, providing further evidence that HDR syndrome is caused by haploinsufficiency of GATA3, which may be responsible for a complex neurologic picture besides the known triad.

Phalangeal quantitative ultrasound in children with phenylketonuria: a pilot study.

Bone alterations in phenylketonuria (PKU) have been detected, especially with increasing age, in several studies by using different radiologic techniques. Quantitative ultrasound (QUS) assesses skeletal status by measuring the amplitude-dependent speed of sound (AD-SoS) and the bone transmission time (BTT), mainly dependent on mineral density and cortical thickness. Bone condition in 30 children and adolescents (mean age 15.1 +/- 6.4 y) affected by PKU was evaluated by phalangeal QUS, considering its relationship with their clinical, biochemical and therapeutic features. Measured AD-SoS Z-Score and BTT Z-Score were 0.27 +/- 1.42 and -0.26 +/- 1.21, respectively. In patients with previous fractures, the two QUS parameters were lower than in patients without history of fracture (p < 0.001 and p = 0.006, respectively). AD-SoS Z-Score and BTT Z-Score were negatively correlated with plasma phenylalanine (Phe) concentration in the year before QUS (p = 0.005 and p < 0.001, respectively) and with age (p < 0.001 for both parameters). These results parallel the previous findings obtained by different radiologic tools and suggest phalangeal QUS as an attractive option for the regular evaluation and longitudinal monitoring of bone condition in children and adolescents affected by PKU.

Persistent hyperestrogenism after precocious puberty in young females with McCune-Albright syndrome.

In this review we report the literature about ovarian function of young women with McCune-Albright Syndrome and describe our personal experience in the follow-up of a small cohort.Collectively, the existing data demonstrate that ovarian hyperfunction with ovarian cysts and hyperestrogenism persists in those women who had precocious puberty. The recording of menstrual cycles and the analysis of gonadotropin and estrogen secretion indicate that, when hypothalamic-pituitary pubertal activation begins, alternating episodes of gonadotropin control and ovarian autonomy can be seen. The persistence of estrogen hypersecretion causes menstrual disturbances and hypofertility. The long term consequences of this condition are hypothesized to be an increased risk of ductal breast cancer, which seems to be higher when growth hormone hypersecretion is also present. Therefore, young MAS women should receive counseling regarding fertility and ongoing surveillance for the development of estrogen related diseases.

Multiple bone fractures in an 8-year-old child with cow's milk allergy and inappropriate calcium supplementation.

The case of an 8-year-old boy with severe bone mass reduction and 4 fractures as a result of an unsupervised diet established to treat cow's milk allergy is presented. Endocrine, genetic and orthopedic pathologies were excluded. While vitamin D intake had always been appropriate, his calcium intake had been inadequate for many years. This clinical report suggests that both vitamin D and calcium supplementation are necessary when a cow's milk protein-free diet is prescribed, even when a hypo- or non-allergenic formula is provided.

Image diagnosis in McCune-Albright syndrome.

McCune-Albright syndrome consists of polyostotic fibrous dysplasia, precocious puberty and cafè-au-lait skin lesions. Bone lesions are characterized by the presence of fibrous connective tissue with a characteristic whorled pattern and containing trabeculae of immature non-lamellar (woven) bone. They may be solitary (monostotic) or multiple (polyostotic). Commonly involved bones include the femur, tibia, ribs and facial skeleton. In the fibula pseudo-cystic areas and 'ground glass'-like areas, in the femur 'shepherd crook' deformation due to weight on a less resistant bone and secondary to many cortical microfractures, are typical. MRI gives the exact delimitation of the lesions and is especially indicated in the followup of monostotic forms and in the outcome of surgical corrections. Bone scintigraphy with technetium 99 is essential in the follow-up of the disease. Ultrasonography is very useful in ovarian cyst follow-up and in the detection of thyroid and adrenal nodules and testicular microlithiasis.

Laparoscopic management of ovarian cysts in peripheral precocious puberty of McCune-Albright syndrome.

Ovarian cysts are common in peripheral precocious puberty in McCune-Albright syndrome (MAS). The clinical course of these cysts is unpredictable due to episodes of hyperestrogenism typical of MAS ovarian hyperfunction. In persistent and recurrent large ovarian cysts with sustained estrogen hypersecretion and relevant clinical disturbances (increased linear growth and bone age maturation, vaginal bleeding and psychological disturbances) treatment is mandatory. Experimental courses of estrogen-blocking drugs may have insufficient or nil therapeutic effects. In these cases and when molecular analysis is required to obtain MAS diagnosis as in isolated peripheral precocious puberty, surgery is the option. Laparoscopy minimizes surgical aggression and facilitates obtaining tissue samples for molecular analysis, and sometimes relieves hyperestrogenism with the excision of hyperactive ovarian areas. It can be conducted with trans-umbilical laparoscopic ovarian cystectomy (TULOC) before 3 years of age and with traditional techniques afterwards.

Genetics of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare proteiform disease due to postzygotic, somatic mutations at codon R201 of the GNAS1 gene that results in cellular mosaicism. Different methods have been used in the molecular analysis of DNA samples from several tissues of patients with one or more MAS signs, with various mutation detection rates. We review data from the literature to investigate whether patient inclusion criteria for GNAS1 analysis, the molecular methods used to search for R201 mutations, and the type of tissues analysed, can influence the mutation detection rate in MAS. Our study indicates that to overcome the problems related to GNAS1 analysis in MAS, sensitive and specific molecular methods must be used to look for the mutation from all available affected tissues and from easily accessible tissues, and even more so in the presence of atypical and monosymptomatic forms of MAS.

Bisphosphonate treatment of bone fibrous dysplasia in McCune-Albright syndrome.

One of the main features of McCune-Albright syndrome is bone fibrous dysplasia (BFD) often associated with severe clinical outcomes, such as bone pain, bone deformities and pathological fractures. Medical treatment with bisphosphonates started 15 years ago. Recent trials in pediatric patients with BFD have shown encouraging results. We evaluated long-term efficacy and safety of pamidronate treatment of BFD in children and adolescents with MAS. The drug was administered at 4 month-1 year intervals according to alkaline phosphatase levels. The study included 14 patients (10 females and 4 males between the ages of 5.3 and 18.7 years) with moderate or severe BFD. Follow up lasted 1.9-9 years. Bone pain, fractures, deformities, and bone turnover markers were evaluated before every therapeutic course. The study shows the beneficial effects of long-term bisphosponate treatment on BFD lesions leading to reduced fracture rate and bone pain, and radiological evidence of long bone lesion healing.

McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age.

Gonadal hyperfunction is the most frequent endocrine dysfunction in females with McCune-Albright syndrome (MAS). Peripheral precocious puberty is usually the first MAS manifestation in children, characterized by episodes of hypersecretion of estrogens with a consequent reduction in gonadotropin secretion. Little is known about the course of this endocrine disease in adolescence and during young adult life. The aim of this study was to evaluate ovarian function in 10 females with MAS (age 11.4-20.1 years) to detect the persistence of autonomous ovarian hyperfunction throughout and following adolescence, after at least 1 year wash out of any treatment for precocious puberty. LH, FSH, estradiol, prolactin, androgen secretion, ovarian and breast sonography in luteal and follicular phases of some menstrual cycles were evaluated. We demonstrated the persistence of some ovarian autonomy, documented by hyperestrogenism and/or low or absent gonadotropin secretion and/or ovarian cysts.