Hypothalamo- pituitary (HP) development is dependent on the communication between the oral ectoderm and the overlying neural ectoderm. This occurs through a complex spatiotemporal genetic cascade of transcription factors and signalling molecules, intrinsic or extrinsic to the developing Rathke’s pouch, the primordium of the anterior pituitary (AP) (see Figure 1). The mature pituitary gland is situated at the base of the brain, within the sella turcica recess of the sphenoid bone, and centrally regulates growth, metabolism, reproduction, development, and homeostasis through the regulation of endocrine glands throughout the body. It consists of three lobes; the anterior and intermediate lobes derived from the oral ectoderm, and the posterior lobe derived from the neural ectoderm. A series of tightly regulated steps resulting in cell proliferation and differentiation give rise to the five different specialized AP cell types that secrete the six AP hormones: somatotrophs [growth hormone (GH)], thyrotrophs [thyroid- stimulating hormone (TSH)], gonadotrophs [luteinizing hormone (LH) and follicle- stimulating hormone (FSH)], lactotrophs [prolactin (PRL)], and the corticotrophs [adrenocortico tropic hormone (ACTH)]. Specific hypothalamic peptides travel via the hypophyseal portal system from the hypothalamus to the AP, where they bind to their specific receptors on each cell type to stimulate AP hormone production, that in turn target organs throughout the body to perform distinct roles in endocrine regulation.

Fig1. A genetic cascade of transcription factors and signalling molecules involved in hypothalamo- pituitary embryonic development.

Deficiencies in one or more of the six AP hormones is termed congenital hypopituitarism (CH), with GH deficiency being the most common and often seen in isolation. CH severity varies widely, presenting in the early neonatal period or later in childhood, with severe cases resulting in fatality. Disordered embryogenesis can give rise to a range of midline craniofacial and brain structural abnormalities associated with CH, which may manifest as highly variable disorders, such as holoprosencephaly (HPE), septo- optic dysplasia (SOD), and Kallmann syndrome (KS), which is characterized by hypogonadotropic hypogonadism (HH) with anosmia.

Septo- Optic Dysplasia

SOD (n = 1/10,000 live births) is a heterogeneous variable dis order, characterized by optic nerve hypoplasia (ONH), midline neuroradiological abnormalities (such as agenesis of the corpus callosum and absence of the septum pellucidum), and pituitary hypoplasia with endocrine deficits with up to ~40% of SOD patients presenting with normal endocrinology. Other associated features are developmental delay, seizures, visual impairment, precocious puberty, obesity, anosmia, sensorineural hearing loss, and cardiac anomalies, illustrating the complexity of the disorder.

Intriguingly, SOD is associated with a younger maternal age when compared to mothers of children with isolated defects of the HP axis for reasons unknown, although in some cases it may be due to excessive maternal drug and alcohol use. ONH occurs in 75– 80% of SOD patients (unilateral [12%] or bi lateral [88%]), with microphthalmia or anophthalmia occurring in rare severe cases. Endocrine dysfunction may occur later. The known association of midline abnormalities with hypo pituitarism suggests a common developmental origin of the hypo thalamus, pituitary, and midline structures within the brain. Mutations in the transcriptional repressor HESX1 were the first to be associated with the pathogenesis of rare cases of SOD, p.R160C being the first HESX1 mutation described in association with the condition. Murine transgenic studies of HESX1 revealed phenotypes that were highly reminiscent of SOD in the mice, supporting the requirement of the gene for midline and HP de velopment, and a role for mutations in the gene in the aetiology of SOD. Subsequently, human mutations have been cloned into mouse models and studied in depth. Since then, mutations in SOX2 and OTX2 were identified in SOD patients with severe bilateral eye defects including microphthalmia or anophthalmia, and SOX3 mutations were identified in SOD patients with abnormalities of the hypothalamus, pituitary, infundibulum, and corpus callosum, respectively. Mutations in genes implicated in KS have also been implicated in SOD. Three patients with an SOD phenotype, for example, were reported to have heterozygous mutations in FGFR1 that altered receptor signalling, with one predicted to affect splicing. The same report described an SOD patient with an FGF8 mutation affecting splicing and altered ligand binding. Another FGF8 mutation was identified in an SOD patient with microcephaly and neurological defects, and in a patient with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency, respectively , making FGF8 a candidate for SOD, and HPE as well as KS. Additionally, KAL1 mutations and the PROKR2 mutation, p.R268C, previously implicated in normosmic HH and KS, were reported in three unrelated pedigrees with SOD [20]. Heterozygous missense TCF7L1 variants have been identified in two unrelated SOD patients [21], following studies using a conditional Tcf7L1 murine deletion that resulted in forebrain defects and partially penetrant dwarfism, thus suggesting a role for TCF7L1 in the aetiology of SOD. Table 1 summarizes the causative genes implicated in the aetiology of SOD and the subsequent HP- related disorders discussed in this chapter.

Table1. Inheritance patterns of mutations in causative genes implicated in congenital hypopituitarism

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة: نهج البلاغة مصدر صافٍ للفكر والمعرفة ومحصِّنٌ من الشبهات

العتبة العباسية المقدسة تطلق محاضرات محفل نهج البلاغة الأسبوعي في ذي قار

العتبتان المقدستان الحسينية والعباسية تدعوان للمشاركة في مهرجان الشموع بنسخته السادسة والعشرين

بالتعاون مع مستشفى الكفيل.. قسم الشؤون الطبّية يواصل إقامة البرنامج التدريبي لملاكاته النسوية

المزيد

الآخبار الصحية

الصحة العالمية تكشف حقيقة انتشار فيروس نيباه خارج الهند

متى يصبح محيط الخصر "مؤشر خطر"؟

دراسة تكشف دور "العوامل الوراثية" في تحديد عمر الإنسان

رائحة كريهة في الجسم.. "علامة خفية" أخطر مما تتصور

المزيد

الآخبار التكنلوجية

مايكروسوفت تكشف عن الجيل الثاني من شرائحها للذكاء الاصطناعي

خرافة "ثمانية أكواب يوميا".. كم من الماء يحتاج جسمك فعليا؟

هل توجد حياة خارج كوكبنا؟.. اكتشاف جديد يثير اهتمام العلماء

اكتشاف الخلايا المسؤولة عن فقدان ذاكرة الطفولة

المزيد

مواضيع ذات صلة

هرمونات و مركبات شبيهة بالهرمونات

الغدة الثايموسية The Thymus

آلية تنظيم إفراز الهرمون

كيف تؤدي الهرمونات عملها على الخلية ؟

الهرمونات البروتينية والبيبتيدات

الغدد الصم

الهرمون

أنواع الغدد في الجسم

الكالسيترول (Calcitriol)

Atrial Natriuretic Factor

البيبتايد العصبي (Neuropeptide- y NPY)

الليبتين (Leptin)