PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
- MeSH
- Algorithms MeSH
- Child MeSH
- Genetic Testing * methods MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation genetics MeSH
- Dwarfism genetics diagnosis MeSH
- Consanguinity * MeSH
- Growth Disorders genetics diagnosis MeSH
- Child, Preschool MeSH
- Pedigree MeSH
- Exome Sequencing methods MeSH
- Body Height genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Iraq MeSH
Purine de novo purine synthesis involves 10 reactions catalysed by six enzymes, including phosphoribosylformyglycinamidine synthase (PFAS). To date, genetic defects of three of these enzymes, namely ATIC, ADSL and PAICS, have been characterised in humans. Here, we report for the first time two individuals with PFAS deficiency. Probands were identified through metabolic and genetic screening of neurologically impaired individuals. The pathogenicity of the variants was established by structural and functional studies. Probands C1 and C2 presented with prematurity, short stature, recurrent seizures and mild neurological impairment. C1 had elevated urinary levels of formylglycineamide riboside (FGAr) and bi-allelic PFAS variants encoding the NP_036525.1:p.Arg811Trp substitution and the NP_036525.1:p.Glu228_Ser230 in-frame deletion. C2 is a 20-year-old female with a homozygous NP_036525.1:p.Asn264Lys substitution. These amino acid changes are predicted to affect the structural stability of PFAS. Accordingly, C1 skin fibroblasts showed decreased PFAS content and activity, with impaired purinosome formation that was restored by transfection with pTagBFP_PFAS_wt. The enzymatic activities of the corresponding recombinant mutant PFAS proteins were also reduced, and none of them, after transfection, corrected the elevated FGAR/r levels in PFAS-deficient HeLa cells. While genetic defects in purine de novo synthesis are typically considered in patients with severe neurological impairment, these disorders, especially PFAS deficiency, should also be considered in milder phenotypes.
- MeSH
- Humans MeSH
- Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor * genetics deficiency metabolism MeSH
- Young Adult MeSH
- Mutation MeSH
- Purine-Pyrimidine Metabolism, Inborn Errors * genetics MeSH
- Child, Preschool MeSH
- Purines * biosynthesis MeSH
- Check Tag
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
The purpose of this study is to elucidate the genetic causes and phenotypic presentation of nonfamilial tall stature (nFTS) and to compare these findings with those of familial tall stature (FTS) from the same population that was previously studied. Children with nFTS (defined as a height > + 2 SDs with both parents' heights < + 2 SDs) underwent endocrine and anthropometric examinations and genetic testing (karyotyping, SHOX gene dosage analysis and next-generation sequencing of 786 growth-associated genes). Exome sequencing was performed in patients with negative genetic results and a height > + 3 SDs. A total of 55 children with nFTS were enrolled. The median height was + 2.8 SD (2.4-3.2 SD), and the median midparental height was + 0.7 SD (0.4-0.9 SD). Genetic causes of tall stature were identified in 6/55 (11%) children. Specifically, four children had gonosomal aneuploidy (47,XXY [2x], 47,XXX, 48,XXXX), one had a heterozygous complex rearrangement including SHOX gene duplication, and one carried a pathogenic variant in the TGFBR2 gene leading to Loeys-Dietz syndrome. A genetic cause of tall stature was significantly less common in nFTS (11%) than in our previously published cohort with FTS (32%). Conclusion: Cytogenetic abnormalities were the predominant genetic alteration identified in children with nFTS, confirming the justification of karyotype analysis in this cohort. The probability of genetic alterations was greater in children with FTS than in those with nFTS. Our findings suggest that the current guidelines for complex investigation are efficient for children with nFTS but need revision in children with FTS. What is known - what is new • Although tall stature is generally considered beneficial, it can be associated with health risks which need to be recognized in time. Tall stature without intellectual impairment is usually considered to be polygenic. • However, the cause of familial tall stature was monogenic more often than it was thought previously. • Children with non-familial and apparently non-syndromic tall stature have never been systematically investigated. • Monogenic causes of non-familial tall stature were observed in 11% of patients, including a participant with Loeys-Dietz syndrome.
- MeSH
- Chromosome Aberrations * MeSH
- Child MeSH
- Phenotype MeSH
- Genetic Testing MeSH
- Karyotyping MeSH
- Humans MeSH
- Adolescent MeSH
- Growth Disorders * genetics MeSH
- Child, Preschool MeSH
- Short Stature Homeobox Protein MeSH
- Exome Sequencing MeSH
- Body Height * genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Genetic factors play a crucial role in determining human height. Short stature commonly affects multiple family members and therefore, familial short stature (FSS) represents a significant proportion of growth disorders. Traditionally, FSS was considered a benign polygenic condition representing a subcategory of idiopathic short stature (ISS). However, advancements in genetic research have revealed that FSS can also be monogenic, inherited in an autosomal dominant manner and can result from different mechanisms including primary growth plate disorders, growth hormone deficiency/insensitivity or by the disruption of fundamental intracellular pathways. These discoveries have highlighted a broader phenotypic spectrum for monogenic forms of short stature, which may exhibit mild manifestations indistinguishable from ISS. Given the overlapping features and the difficulty in differentiating polygenic from monogenic FSS without genetic testing, some researchers redefine FSS as a descriptive term that encompasses any familial occurrence of short stature, regardless of the underlying cause. This shift emphasizes the complexity of diagnosing and managing short stature within families, reflecting the diverse genetic landscape that influences human growth.
AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
- MeSH
- Diabetes Mellitus, Type 1 * epidemiology genetics MeSH
- Diabetes Mellitus, Type 2 * epidemiology genetics diagnosis MeSH
- Child MeSH
- Cohort Studies MeSH
- Humans MeSH
- Mutation genetics MeSH
- Infant, Newborn, Diseases * genetics MeSH
- Infant, Newborn MeSH
- Consanguinity MeSH
- Nucleoside Transport Proteins genetics MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Iraq MeSH
INTRODUCTION: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. CASE PRESENTATION: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 μg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 μg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. CONCLUSION: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.
- MeSH
- Adult MeSH
- Duane Retraction Syndrome * genetics pathology MeSH
- Phenotype MeSH
- Upper Extremity pathology MeSH
- Hypopituitarism * genetics MeSH
- Kidney pathology MeSH
- Humans MeSH
- Human Growth Hormone * MeSH
- Child, Preschool MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Case Reports MeSH
Křivice je onemocnění rostoucího organismu, které vzniká v důsledku poruchy homeostázy vápníku a fosfátů, což má za následek narušení apoptózy hypertrofických chondrocytů v růstové ploténce. Hypofosfatemie vázaná na chromosom X (X-linked hypophosphatemia, XLH) je vzácná dědičná porucha skeletu charakterizovaná nadměrnou produkcí fibroblastového růstového faktoru 23 (fibroblast growth factor 23, FGF23), což vede k renálním ztrátám fosfátů, hypofosfatemii a defektní mineralizaci kostí, která způsobuje křivici, osteomalacii, deformity skeletu, nízký vzrůst, bolest, snížený lineární růst a sníženou fyzickou funkčnost. Konvenční léčba XLH spočívá v podávání fosfátových solí a aktivního vitaminu D a může být spojena se špatnou tolerancí a vznikem komplikací. Burosumab je plně humánní monoklonální protilátka typu imunoglobulinu podtřídy 1 (IgG1) anti-FGF23, která inhibuje nadměrnou aktivitu intaktního FGF23 (iFGF23), čímž zvyšuje renální reabsorpci fosfátů, sérových koncentrací fosfátů a vede ke zlepšení známek křivice. Uvádíme kazuistiku chlapce s XLH, který byl po nedostatečně účinné konvenční terapii fosfáty a kalcitriolem převeden na léčbu burosumabem s dobrým účinkem na ústup známek křivice a zlepšení kvality života.
Rickets is a disease of the growing organism that results from a disturbance of calcium and phosphate homeostasis, which leads to impaired apoptosis of hypertrophic chondrocytes in the growth plate. X chromosome-linked hypophosphatemia (XLH) is a rare inherited skeletal disorder characterized by excessive production of fibroblast growth factor 23 (FGF23), leading to renal phosphate loss, hypophosphatemia and defective bone mineralisation, causing rickets, osteomalacia, skeletal deformities, short stature, pain, reduced linear growth and reduced physical function. Conventional treatment of XLH involves the administration of phosphate salts and active vitamin D and may be associated with poor tolerance and the development of complications. Burosumab is a fully human IgG1 anti-FGF23 monoclonal antibody that inhibits the excessive activity of intact FGF23 (iFGF23), thereby increasing renal phosphate reabsorption, increasing serum phosphate levels and improving rickets symptoms. We present a case report of a boy with XLH who was switched to treatment with burosumab after insufficiently effective conventional phosphate and caLcitrioL therapy, with a good effect on rickets remission and improved quality of life.
- Keywords
- burosumab,
- MeSH
- Familial Hypophosphatemic Rickets * diagnosis drug therapy genetics pathology MeSH
- Fibroblast Growth Factor-23 MeSH
- Phosphates adverse effects therapeutic use MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use MeSH
- Hypophosphatemia MeSH
- Calcitriol therapeutic use MeSH
- Humans MeSH
- Child, Preschool MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
OMIM 273750 (3-M) syndrome is a rare cause of severe short stature with variable dysmorphic features caused by pathogenic variants in several genes including cullin7 gene (CUL7). Hypogonadism and hypospadias have been described in only a few males. We report a patient with CUL7 pathogenic variant who had bifid scrotum and perineal hypospadias at birth. He entered puberty spontaneously at age 12 years and appropriately completed pubertal development by 15 years. Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed. This case highlights the importance of careful pubertal monitoring as pubertal dysfunction may be associated with 3-M syndrome.
- Publication type
- Journal Article MeSH
- Case Reports MeSH
BACKGROUND: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. SUMMARY: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. KEY MESSAGES: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.
The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.
- MeSH
- beta-N-Acetylhexosaminidases metabolism MeSH
- Phenotype MeSH
- Glycosylation MeSH
- Intellectual Disability * genetics MeSH
- Disease Models, Animal * MeSH
- Brain pathology metabolism MeSH
- Mice MeSH
- N-Acetylglucosaminyltransferases * metabolism genetics deficiency MeSH
- Neurodevelopmental Disorders pathology genetics enzymology MeSH
- Body Weight MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
