Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.

Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.

Major Issues of Care in Thalassemia Major Children Refugees.

Beta thalassemia major (ßTM) is the most common inherited hemoglobinopathy. Management essentially focuses on preventing and treating complications. Conventional treatment is based on a regular blood transfusion program, and chelation therapy. Management essentially focuses on preventing and treating complications. Severe complications of ßTM are very rarely seen in children in Europe. In the context of the migrant crisis, pediatricians will be confronted with the challenge of managing severe complicated ßTM. We report the case of 2 Syrian 10-year-old twin girls who arrived to France with numerous and severe complications of ßTM: hemochromatosis, alloimmunization, hypopituitarism, osteopenia… Their clinical management, which led to successful vital and functional improvement, is reported in this article.

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Patients' perceptions on the usability of the SurePal™ self-injection device for Omnitrope®: a questionnaire-based observational study conducted in paediatric patients in France.

BACKGROUND: A questionnaire-based survey was conducted to evaluate attitudes towards a reusable self-injection system, SurePal™, among paediatric patients with growth disturbances who were prescribed treatment with somatropin (Omnitrope®) as part of routine clinical practice. METHODS: This cross-sectional survey was incorporated into the multinational, multi-centre, noninterventional PAtients TReated with Omnitrope® (PATRO) Children study. Questions were mainly focused on five areas: the attractiveness of SurePal™; training received; use of the device; opinion of the low-drug wastage system; experience compared with previous devices used (among pretreated patients). RESULTS: Final results from participants in France are reported. Completed questionnaires were returned by 409 participants. Most patients (55%) were male and 89% were recombinant human growth hormone (rhGH)-treatment naïve. Around 57% of children completed the questionnaire by themselves, while 43% had help from a family member/other person. The mean (standard deviation) age of all participants was 11.3 (3.6) years, and most patients were aged 10-12 years (n = 126) or 13-15 years (n = 117). Overall, 86% of patients reported that preparing SurePal™ for injection was easy/very easy. Similarly, 83% reported that performing injections with SurePal™ was easy/very easy. The attractiveness of SurePal™ was rated as good/excellent by the majority (85%) of patients; this proportion was similarly high (> 80%) across all age groups. The dose-memory function was rated as helpful/very helpful by 54% of patients. Of the 174 patients who reported using the low drug-waste feature, 90% found it to be helpful/very helpful. Among the 24 pretreated patients, 17 reported that SurePal™ was better/much better than their previous device. CONCLUSIONS: This questionnaire-based survey conducted in a large cohort of paediatric patients with growth disturbances from France confirms the ease of use of SurePal™ to support daily administration of Omnitrope® across all age groups. The demonstrated acceptability of the device may help to improve patient adherence to long-term daily treatment with rhGH.

Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature.

BACKGROUND: Somatotropinoma, a pituitary adenoma characterised by excessive production of growth hormone (GH), is extremely rare in childhood. A genetic defect is evident in some cases; known genetic changes include: multiple endocrine neoplasia type 1 (MEN1); Carney complex; McCune-Albright syndrome; and, more recently identified, aryl hydrocarbon receptor-interacting protein (AIP). We describe seven children with somatotropinoma with a special focus on the differences between genetic and sporadic forms. METHODS: Seven children who presented in our regional network between 1992 and 2008 were included in this retrospective analysis. First-type therapy was somatostatin (SMS) analogues or transsphenoidal surgery. Control was defined as when insulin-like growth factor-1 (IGF-1) levels were within the normal range for the patient's age at 6 months after therapy, associated with decreasing tumour volume. RESULTS: Patients were aged 5-17 years and the majority (n = 6) were male. Four patients had an identified genetic mutation (McCune-Albright syndrome: n = 1; MEN1: n = 1; AIP: n = 2); the remaining three cases were sporadic. Accelerated growth rate was reported as the first clinical sign in four patients. Five patients presented with macroadenoma; invasion was noted in four of them (sporadic: n = 1; genetic: n = 3). Six patients were treated with SMS analogues; normalisation of IGF-1 occurred in one patient who had a sporadic intrasellar macroadenoma. Multiple types of therapy were necessary in all patients with an identified genetic mutation (4 types: n = 1; 3 types: n = 2; 2 types: n = 1), whereas two of the three patients with sporadic somatotropinoma required only one type of therapy. CONCLUSIONS: This is the first series that analyzes the therapeutic response of somatotropinoma in paediatric patients with identified genetic defects. We found that, in children, genetic somatotropinomas are more invasive than sporadic somatotropinomas. Furthermore, SMS analogues appear to be less effective for treating genetic somatotropinoma than sporadic somatotropinoma.

Secondary adrenal insufficiency in the acute phase of pediatric traumatic brain injury.

PURPOSE: A high incidence of secondary adrenal insufficiency (AI) has been reported several months after a traumatic brain injury (TBI) in pediatric patients. Data from studies in adults suggest that AI may occur during the acute phase of TBI, with potential negative effects in the management of these vulnerable patients. The aim of this study was to describe the prevalence and the characteristics of AI in the acute phase of pediatric TBI. METHODS: Adrenal function was systematically evaluated in patients admitted to the pediatric intensive care unit following a TBI. Serial measurements of cortisol (9 samples) and adrenocorticotropic hormone (ACTH) were drawn from the second morning to the third morning post admission. Secondary AI was defined as all cortisols < 200 nmol/l (6 µg/dl) with ACTH < 12 pmol/l. RESULTS: Twenty-eight patients (2-15 years old) were evaluated. Secondary AI occurred in ten (36%) patients. AI was more frequent in patients with intracranial hypertension (p < 0.05). Patients with AI required longer mechanical ventilation (p < 0.05), and a non-significant trend for a higher Pediatric Logistic Organ Dysfunction score (p = 0.09) and greater norepinephrine dose (p = 0.11) was observed. CONCLUSIONS: Secondary AI is frequent during the acute phase of pediatric TBI, particularly when intracranial hypertension is present. Systematic assessment of pituitary function after TBI appears to be essential. A randomized clinical trial is warranted to evaluate the benefits of hormonal replacement therapy in TBI patients with AI.