Ways to Improve the Diagnosis of Growth Hormone Deficiency

Developmen

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsufficiency. Methods: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. Results: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. Conclusion: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions

Genetic findings in short Turkish children born to consanguineous parents

IntroductionThe diagnostic yield of genetic analysis in the evaluation of children with short stature depends onassociated clinical characteristics, but the additional effect of parental consanguinity has not beenwell documented.MethodsThis observational case series of 42 short children from 34 consanguineous families was collected bysix referral centres of paediatric endocrinology (inclusion criteria: short stature and parentalconsanguinity). In eighteen patients (12 families, Group 1), the clinical features suggested a specificgenetic defect in the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and a candidategene approach was used. In others (Group 2) a hypothesis-free approach was chosen (gene panels,microarray analysis, and whole-exome sequencing), further subdivided into 11 patients with severeshort stature (height <-3.5 SDS) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10patients with syndromic short stature (group 2b) and were 3 patients with nonspecific isolated GHdeficiency (group 2c).ResultsIn all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, andSTAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1,and 17p13.3 microdeletions. In group 2c no genetic cause was found. Homozygous, compoundheterozygous and heterozygous variants were found in 21, 1 and 4 patients, respectively.ConclusionGenetic testing in short children from consanguineous parents has a high diagnostic yield, especiallyin cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature

Molecular mechanisms involved in pulmonary arterial hypertension development

Pulmonary arterial hypertension (PAH) is an elevation in pulmonary arterial pressure, characterized by symptoms of dyspnea, chest pain, decrease in exercise tolerance-fatigue, syncope and, if untreated, PAH leads to right heart failure. In PAH, there is an imbalance between mediators of vasodilation and vasoconstriction (e.g. nitric oxide and prostacycline – potent vasodilators, platelet inhibitor and antimitogens are decreased in PAH, while thromboxane, vasoconstrictor and platelet activator is increased in PAH, resulting in smooth muscle hypertrophy of small vessels, adventitial and intimal proliferation, and plexiform vascular lesions with vascular thrombosis). Standard diagnostic procedures for PAH include physical examination, pulmonary function testing, radiographic imaging, transthoracic echocardiography, right heart catheterization. Current drugs include synthet c prostanoids (iloprost, epoprostenil, beraprost, treprostinil) – vasodilators and antiplatelet agents. Phosphodiesterase-5 inhibitors decrease the breakdown of cGMP, increasing its intracellular levels, leukotriene receptor antagonist, – zafirlukast, decreases pulmonary arterial and venous pressure. Endothelin receptor blockers, bosentan, decrease pulmonary vascular resistance and improve results of functional tests. Other treatments are: anticoagulants, calcium-channel blockers, positive airway pressure therapy for obstructive sleep apnea, or oxygen for hypoxemia, and surgery. In conclusion, although there are some promising drugs in therapy of PAH, there is a need to develop new ones, together with surgical approaches, in order to increase the survival of patients with PAH. Gene and cell therapy could be expected as future perspectives

The short mRNA isoform of the immunoglobulin superfamily, member 1 gene encodes an intracellular glycoprotein

Mutations in the immunoglobulin superfamily, member 1 gene (IGSF1/Igsf1) cause an X-linked form of central hypothyroidism. The canonical form of IGSF1 is a transmembrane glycoprotein with 12 immunoglobulin (Ig) loops. The protein is co-translationally cleaved into two sub-domains. The carboxyl-terminal domain (CTD), which contains the last 7 Ig loops, is trafficked to the plasma membrane. Most pathogenic mutations in IGSF1 map to the portion of the gene encoding the CTD. IGSF1/Igsf1 encodes a variety of transcripts. A little studied, but abundant splice variant encodes a truncated form of the protein, predicted to contain the first 2 Ig loops of the full-length IGSF1. The protein (hereafter referred to as IGSF1 isoform 2 or IGSF1-2) is likely retained in most individuals with IGSF1 mutations. [...

Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying IGSF1 Mutations

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants

Primers used for cloning and mutagenesis.

<p>Primers used for cloning and mutagenesis.</p