Combined pituitary hormone deficiency (CPHD) is defined as the presence of at least two or more pituitary hormone deficiencies including GH, TSH, PRL, ACTH, LH, and FSH deficiencies. Mutations in the genes encoding transcription factors PROP1, POU1F1, LHX3, and LHX4, which are critical for normal pituitary development, often result in unique patterns of CPHD that reflect their differential expression during organogenesis. Depending on the deficiencies in the patient, the phenotypic features may include those of hypothyroidism, delayed or absent puberty which may lead to infertility, intellectual disability, midline defects such as cleft lip or palate, and short stiff neck (specifically caused by LHX3 mutations). The early acting transcription factors LHX3 and – 4, as opposed to the later acting PROP1 and POU1F1, cause deficiencies of most, if not all, pituitary hormones, often referred to as panhypopituitarism or multiple pituitary hormone deficiency (MPHD). Mutated forms of all four genes affect somatotroph cell development and therefore all may give rise to severe short stature, reflecting why growth hormone deficiency (GHD) occurs with a higher prevalence. CPHD with differing endocrine deficits may also stem from mutations in HESX1, SOX3, and OTX2.

CPHD patients with mutations in genes that are implicated in KS have also been described, once again demonstrating genetic overlap with KS. For example, a CPHD patient with right microphthalmia, right renal aplasia and severe developmental delay had a hemizygous variant in KAL1 that was predicted to be pathogenic. The known PROKR2 p.R85H mutation was identified in a CPHD patient with GH, TSH, ACTH, LH and FSH deficiencies, and a microphallus; suggesting neonatal gonadotropin- releasing hormone (GnRH) deficiency and thus features of HH/ KS. Furthermore, the PROKR2 p.L173R variant initially identified in KS patients, that affects targeting to the cell surface receptor, has since been frequently identified in both CPHD and SOD patients. A novel PROKR2 variant, p.R248W, predicted to be deleterious in a CPHD patient, where a glutamine substitution at this highly conserved residue had previously been described, was identified in a patient with HH. A novel loss of function mutation in FGFR1, p.R448W, was also recently identified in a patient with GH and TSH deficiency.

Furthermore, the transcription factor GLI2, a component of the sonic hedgehog (SHH) signalling pathway known to be implicated in HPE and other midline neurodevelopmental anomalies, has now been implicated in CH in the absence of midline brain defects. Interestingly, patients with GLI2 mutations may have variable phenotypes ranging from isolated GHD (IGHD) to CPHD, in combination with variable polydactyly, cleft lip/ palate, diabetes insipidus, dysmorphic features, and an ectopic posterior pituitary (EPP) on MRI. This does not seem to be apparent for all components of the SHH pathway, for example mutations in the SHH gene itself seem to exclusively cause HPE, with no reported cases of CH to date.

Despite these reports implying a genetic overlap between CPHD and HH/ KS, and HPE and CH cases respectively, digenic inheritance cannot be ruled out here, where another mutation may be responsible for the aetiology of at least one of the deficiencies in their CPHD. Incomplete or variable penetrance of a mutation often occurs in many of these families, especially when GLI2 or HESX1 mutations are present, where a heterozygous mutation with functional consequences in the child is present in the unaffected parent or a parent with a mild form of the disease, respectively.

isolated Growth Hormone Deficiency

Congenital IGHD has an incidence between 1/ 4000 and 1/ 10 000 live births and is the most prevalent isolated pituitary hormone deficiency. The majority of cases are sporadic with a small percentage (3– 30%) of familial cases, and the aetiology of most patients is unknown. GH- releasing hormone (GHRH) released from the hypothalamus binds to its receptor (GHRHR) on somatotrophs resulting in the syn thesis and release of GH, in the presence of the transcription factor POU1F1. Children with IGHD manifest with moderate to severe short stature associated with a poor growth velocity and delayed skeletal maturation. Recombinant human GH (rhGH) is used to treat the condition and generally achieves a good response in patients.

There are four main genetic forms of IGHD. Type 1A autosomal recessive IGHD harbour complete deletions of GH1 and these patients present with severe growth failure in the first 6 months of life with undetectable GH concentrations. These patients frequently develop anti- GH antibodies after receiving exogenous GH, which pre vent the growth response expected on commencing rhGH therapy. Heterogeneous homozygous GH1 deletions (~6.7 Kb long), were the first, and remain the most common, GH1 gene alteration in patients with IGHD type IA. Since then, many other severe loss of function GH1 mutations have subsequently been described.

Type IB GHD is associated with recessive GH1 and GHRHR mutations, the latter also being known as Sindh dwarfism. GHD due to GHRHR mutations differs from the classical IGHD phenotype, as patients have limited facial dysmorphism and no microphallus, yet still manifest AP hypoplasia (APH) on MRI. These patients originate from consanguineous pedigrees in Brazil or the Indian subcontinent and usually harbour loss of function GHRHR mutations. The first and most common GHRHR mutation is p.E72X, resulting in a truncated protein devoid of both the transmembrane and intracellular domains. The p.W273S, p.A176V, and p.K329E substitutions have since been reported among many others, with the latter failing to show any cAMP response following administration of GHRH in in vitro studies. However, there is some phenotypic variability; an unusually mild form of IGHD in two unrelated families with a novel partial loss of function homozygous GHRHR mutation, p.P79L, has recently been described. The patients were compound homozygous with a second variant in GHRHR, p.R4Q, that did not appear to compromise the cAMP pathway.

Type II GHD, the most common autosomal dominant form of the disease, is often caused by heterozygous GH1 mutations that affect splicing, resulting in exon skipping. The shorter 17.5kDa GH isoform, resulting from the skipping of exon 3, has been reported to exert a dominant negative effect on GH secretion, with expression levels directly related to severity of the disorder. Other heterozygous GH1 missense mutations, such as p.E32A, p.R178H, and p.R183H have also been described in this form of GHD. These patients have variable height deficit (occasionally within the normal range) and severity, and may develop additional pituitary hormone deficiencies over time, including ACTH, TSH, and LH/ FSH deficiencies. To date, no mutations in GHRH have been described in association with IGHD. However, mutations in genes encoding early (HESX1, SOX2, SOX3, and OTX2) or late (PROP1 and POU1F1) transcription factors implicated in murine and human pituitary development, have been reported in patients with IGHD.

Mutations in RNPC3 have recently been associated with IGHD. The ribonucleic acid (RNA)- binding region (RNA recognition motifs [RRM]) containing 3 on chromosome 1 encodes a 65K protein component of the U12- type spliceosome. Its two RRM motifs suggest interaction with one of the small nuclear RNAs of the minor spliceosome. Biallelic mutations in RNPC3 have been described in three sisters with severe IGHD and pituitary hypoplasia, where anomalies were identified in the splicing of multiple U12- type introns in patient cells. Despite the unknown direct mechanism underlying the GHD, a subset of 21 genes were found to be affected by this particular splicing. Interestingly, these genes encoded proteins with relevant functions in pituitary development, such as SPCS2 and SPCS3 that encode subunits of the signal peptidase complex, implicated in post- translational processing of preprohormones such as preproghrelin to proghrelin.

An induced lethal point mutation in rnpc3 in a zebrafish model resulted in the formation of aberrant U11- and U12- containing snRNAs that sufficiently impaired the efficiency of U12- type splicing, thus causing arrested development in the intestine, liver, and pancreas. This is the only rnpc3 loss of function in vivo model reported to date. Analysis of the zebrafish transcriptome revealed that efficient mRNA processing is critical for the growth and proliferation of cells during vertebrate development.

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

Hypothalamic neuroendocrine neurons: endocrine and central effects

cellular Structure of the Pituitary

Blood Supply of the Hypothalamus and Pituitary

Development of the Hypothalamus and Pituitary

Pituitary Gland

Hypothalamic Neural Connections

Hypothalamic-Pituitary Anatomy

Hypothalamic Control of the Pituitary Gland

الغدة النخامية Pituitary gland

الغدة النخامية Pituitary Gland

الهرمون المضاد لإدرار البول Anti-diuretic Hormone , ADH

هرمون الأوكسي توسين Oxytocin , OT