The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.

INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed 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 (P/LP) gene variants 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 for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Case report: Severe hypertension-induced priapism in an infant with unrecognized autosomal recessive polycystic kidney disease.

Priapism is a urologic emergency requiring prompt management. There are three types of priapism: stuttering (intermittent), non-ischemic (high-flow/arterial), and ischemic (low-flow/veno-occlusive). Here, we present the first case of an infant with recurrent non-ischemic priapism as the first sign of severe hypertension. An 11-month-old infant was admitted to the hospital for high-flow priapism. On admission, he was found to have severe hypertension that required a combination of five antihypertensive drugs; abdominal ultrasound showed polycystic kidneys, splenomegaly, and a parenchymal liver lesion. The priapism resolved spontaneously and did not recur again after the initiation of antihypertensive treatment. Genetic analysis confirmed autosomal recessive polycystic kidney disease (ARPKD). We found no other explanation for the priapism, such as genital trauma, hematologic disease, or anything else. Decreased nitric oxide (NO) bioavailability seen in patients with hypertension seems to be the principal mechanism of hypertension causing priapism. This hypothesis is supported by animal models of genetically modified mice lacking nitric oxide synthase. The same mechanism is thought to be the genesis of priapism and other complications, such as pulmonary hypertension, in patients with sickle cell disease. We present a case of severe hypertension-associated priapism in a child with unrecognized ARPKD. The endothelial dysfunction with decreased NO bioavailability seen in patients with hypertension may be the principal pathogenic mechanism.

NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy.

CONTEXT: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. OBJECTIVES: To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. DESIGN, SETTINGS AND PATIENTS: Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ -2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. RESULTS: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. CONCLUSIONS: NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.

Short stature in a boy with atypical progeria syndrome due to LMNA c.433G>A [p.(Glu145Lys)]: apparent growth hormone deficiency but poor response to growth hormone therapy.

Background Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by pathogenic variants in the LMNA gene, which leads to premature aging. The median life expectancy is shortened to 13 years due to cardiovascular complications. Case report We present a boy born with a pathogenic LMNA variant c.433G > A, which causes atypical progeria syndrome (APS) and was previously described in one single patient. When investigated for poor growth prior to the diagnosis of APS, his laboratory tests revealed growth hormone (GH) deficiency and magnetic resonance imaging (MRI) of the midbrain showed partial empty sella. GH treatment had only a limited and transient effect. His first ischemic complication manifested at age 4.2 years; at the age of 7 years, he had a fatal haemorrhagic stroke. Conclusion To the best of our knowledge, this is the first patient with APS showing partial empty sella and GH deficiency that might have contributed to his poor growth. GH failed to improve long-term outcome.