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Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review is to shed light on the lessons learned from consanguineous pedigrees with the help of three fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity – from congenital hyperinsulinism, a typically single cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth – the most complex developmental phenomenon.

Congenital hyperinsulinism (CHI) is a potentially life-threatening cause of severe hypoglycemia in the neonatal and infant period. • The incidence of CHI has been estimated to be around 1 in 50,000 in non-consanguineous populations and as high as 1 in 2,500 in areas with a higher rate of consanguinity. • Certain countries with high rates of consanguinity have a much higher infant and neonatal mortality rate than the rest of the world. Novel Insights• Three novel homozygous variants are reported in genes ABCC8 and KCNJ11 causing CHI in three Kurdish consanguineous families. Two of these families have a notable history of unexplained neonatal deaths. • A small but significant percentage of all unexplained neonatal deaths could be due to undiagnosed CHI. Therefore, especially in regions with a high prevalence of consanguinity, undiagnosed CHI can contribute to higher infant and neonatal mortality rates. AbstractIntroduction: Neonatal hypoglycemia due to congenital hyperinsulinism (CHI) is a potentially life-threatening condition. Biallelic pathogenic variants in K ATP channel subunit genes (ABCC8, KCNJ11), causing severe forms of CHI, are more prevalent in regions with a significant rate of consanguinity and may lead to unexplained neonatal deaths. We hypothesized that K ATP channel gene variants are the cause of CHI in three unrelated children from consanguineous

Introduction. Among children born small for gestational age, 10-15% fails to catch-up and remains short (SGA-SS). The underlying mechanisms are mostly unknown. We aim to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods. Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age, and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results. The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic gene variants (P/LP) affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%) we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. Conclusions. The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role of the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and from intracellular regulation and signalling.

IntroductionThe growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far.AimsTo discover genetic etiology of short stature in children with diagnosed GHD from families with short stature.MethodsFifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent &lt;-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio &lt;-2 SD or &gt;+2 SD), IGF-1 levels &lt;0 for age and sex specific SD and peak GH concentration &lt;10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines.ResultsThe age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2).ConclusionsIn children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.