Severe Postnatal Growth Failure Research Articles

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Genetics for the pediatric endocrinologists – 2 Primordial short stature in children and adolescents

Primordial short stature (PSS) is an extremely rare group of monogenic disorders characterized by profound global growth failure commencing in the fetal life and continuing postnatally for the rest of the life. It is suspected when there is an extreme degree of proportionate short stature and global growth failure with or without microcephaly, and without any evidence of known skeletal dysplasia. The cardinal features of PSS include severe intrauterine and postnatal growth failure, severe postnatal short stature, primary microcephaly, characteristic facial features, and variable intellectual disability. The most common genetic etiology is monogenic except for Silver–Russell syndrome, where an epigenetic mechanism is a predominant cause of primordial dwarfism. This review demonstrates a holistic approach to the diagnosis and management of PSS in children and adolescents.

Crk haploinsufficiency is associated with intrauterine growth retardation and severe postnatal growth failure

Crk haploinsufficiency is associated with intrauterine growth retardation and severe postnatal growth failure

Neonatal morbidities and postnatal growth failure in very low birth weight, very preterm infants.

To assess postnatal growth in infants with and without major neonatal morbidities. This study is based on analysis of data collected by the Israel Neonatal Network on VLBW infants (≤1500g) born in Israel from 2009 to 2018. Postnatal growth was assessed in two 5years epochs: 2009-2013 (n=4583) and 2014-2018 (n=4558). Outcome was considered as severe, mild and no postnatal growth failure (PNGF). Morbidities included respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, patent ductus arteriosus and grades 3-4 intraventricular haemorrhage. Multinomial logistic regression analyses with the generalised estimating equation approach were applied. The study population composed 9141 infants. Of them, 2089had at least one major morbidity and 7052 infants had none. In infants with no morbidities, 2.1% had severe PNGF, 23.7% mild PNGF and 74.2% had no PNGF, as compared to 13.6%, 43.9% and 42.5%, respectively, in infants with any major neonatal morbidity (p<0.0001). Despite enormous advances in neonatal care, postnatal growth remains a challenge in VLBW infants, particularly in infants with major neonatal morbidities. Along with efforts to decrease morbidity, a more personalised plan and follow-up may be required in infants with major morbidities, given their high risk for diminished growth and potentially, adverse neurodevelopmental outcomes.

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

ContextSevere forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.ObjectiveThis work aims to identify the genetic cause of growth failure in 3 “classical” GHI individuals.MethodsA novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.ResultsWe identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.ConclusionNovel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Genetic causes of growth hormone insensitivity beyond GHR.

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.

The Wiedemann-Rautenstrauch or Neonatal Progeroid Syndrome: Report of a Patient with Gingival Hyperplasia and Severe Anterior Open Bite

Introduction: The Wiedemann-Rautenstrauch syndrome (WRS) is a rare progeroid syndrome with an autosomal recessive pattern of inheritance. The main clinical features include severe intrauterine and postnatal growth failure, distinctive facial appearance, hydrocephaly, prominent scalp veins, absence of subcutaneous fat, sparse hair of the scalp, eyebrows, and eyelashes, generalized lipoatrophy, psychomotor delay, progressive neurological deterioration, and short life expectancy. Natal teeth and micrognathia are reported as the oral manifestations of this syndrome. Case Presentation: Here is the report of a 6.5-year-old female patient with clinical signs of WRS referred to the Department of Periodontology of Shiraz School of Dentistry with the chief complaint of toothache and gingival hyperplasia. Carious teeth were extracted, and excess gingival tissue was removed through a surgical procedure under general anesthesia. The patient was the first case with a concomitant severe anterior open bite. Conclusions: Therapies for WRS are symptomatic, requiring the coordinated efforts of a team of specialists. Dentists and oral surgeons can be recruited by pediatricians and family physicians to improve the quality of life of such patients.

Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.

A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI)

BackgroundThe most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. ObjectiveTo characterize the molecular defect in a patient with short stature and partial GHI. Patient and methodsThe boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height −2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. ResultsBiochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. ConclusionsWe reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency.

IGF deficiency caused by a homozygous loss-of-function of IGF1 is a very rare cause of growth failure. This paper comments on an original research paper in this issue on a novel patient with this condition, confirming its main clinical features (severe prenatal and postnatal growth failure, severe microcephaly, retrognathia, sensorineural deafness and severe global developmental delay) and adding information about the variability of the growth hormone secretion, IGF1 concentration and insulin sensitivity.

Effect of Short-Term Morbidities, Risk Factors and Rate of Growth Failure in Very Low Birth Weight Preterms at Discharge.

Very low birth weight (VLBW) infants often demonstrate postnatal growth failure (PGF). We aimed to analyze incidence and risk factors for PGF in surviving VLBW infants hospitalized more than 28 days. Fenton growth chart (2013) was used for Z-scores for birth weight (BW) and discharge weight. Infants with a decrease in their Z-scores at discharge >1 were considered as 'PGF group' and with a decrease >2 were considered as 'severe PGF group'. One hundred and forty-one of 148 (95.3%) infants had PGF, 88 of 141 (62.4%) had severe PGF. There were significant differences in gestational age, birth and discharge weight, and days to regain BW, age of first and full enteral feeding, duration of parenteral nutrition, lipid emulsions, intubation and hospitalization between groups (p < 0.05). Vasopressor treatment, nosocomial infection, patent ductus arteriosus and bronchopulmonary dysplasia rates were significantly higher in severe PGF group (p < 0.05). PGF remains a serious problem in our unit. All VLBW preterm infants should be followed for PGF.

A second GH Receptor pseudoexon mutation causing frameshift and severe postnatal growth failure

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A novel GHR pseudoexon mutation causing frameshift and severe postnatal growth failure

A novel GHR pseudoexon mutation causing frameshift and severe postnatal growth failure

Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation.

Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes.

STAT5B deficiency: Impacts on human growth and immunity

Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics.

Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013.

Very low birth weight infants often gain weight poorly and demonstrate growth failure during the initial hospitalization. Although many of the major morbidities experienced by these infants during their initial NICU stays have decreased in recent years, it is unclear whether growth has improved. We studied 362 833 infants weighing 501 to 1500 g without major birth defects born from 2000 to 2013 and who were hospitalized for 15 to 175 days at 736 North American hospitals in the Vermont Oxford Network. Average growth velocity (GV; g/kg per day) was computed by using a 2-point exponential model on the basis of birth weight and discharge weight. Postnatal growth failure and severe postnatal growth failure were defined as a discharge weight less than the 10th and third percentiles for postmenstrual age, respectively. From 2000 to 2013, average GV increased from 11.8 to 12.9 g/kg per day. Postnatal growth failure decreased from 64.5% to 50.3% and severe postnatal growth failure from 39.8% to 27.5%. The interquartile ranges for the hospitals participating in 2013 were as follows: GV, 12.3 to 13.4 g/kg per day; postnatal growth failure, 41.1% to 61.7%; and severe postnatal growth failure, 19.4% to 36.0%. Adjusted and unadjusted estimates were nearly identical. For infants weighing 501 to 1500 g at birth, average GV increased and the percentage with postnatal growth failure decreased. However, in 2013, half of these infants still demonstrated postnatal growth failure and one-quarter demonstrated severe postnatal growth failure.

Low energy intake during the first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely preterm infants

ObjectivesPoor weight gain during the first weeks of life in preterm infants is closely associated with the risk of developing the retinopathy of prematurity (ROP) and insufficient nutrition might be...

Hip Pathology in Majewski Osteodysplastic Primordial Dwarfism Type II

Majewski osteodysplastic primordial dwarfism type II (MOPDII) is characterized by severe prenatal and postnatal growth failure with microcephaly, characteristic skeletal dysplasia, an increased risk for cerebrovascular disease, and insulin resistance. MOPDII is caused by mutations in the pericentrin (PCNT) gene and is inherited in an autosomal-recessive manner. This study aimed to determine the incidence of hip pathology in patients with molecularly confirmed MOPDII and to describe the functional outcomes of surgical treatment. Thirty-three enrolled patients had a clinical diagnosis of MOPDII. Biallelic PCNT mutations or absent pericentrin protein was confirmed in 25 of these patients. Twelve patients (7 female) had appropriate clinical and radiographic records at this institution and were included in this study. The data collected included age at presentation, age at surgery, sex, body weight and height, weight-bearing status at diagnosis, and the clinical examination. Four patients (31%) had coxa vara: 3 unilateral and 1 bilateral. Three unilateral patients had in situ pinning at a mean age 4 years. The patient with bilateral coxa vara had valgus osteotomy at the age of 5 years. Two children had bilateral hip dysplasia and subluxation with no surgery. One patient had bilateral developmental hip dislocations. The patient was treated by open reduction-spica cast and 2 years after surgery, coxa valga was noted. Another patient was diagnosed at an age of 12 years with bilateral avascular necrosis of the hips. Four patients did not have hip pathology. Hip pathology is common among children with MOPDII; coxa vara is the most frequent diagnosis. Routine clinical and radiographic hip evaluation is important. The capital femoral epiphysis appears to slip down along the shaft, giving the appearance of a proximal femoral epiphysiolysis. A hip diagnosed with slipped capital femoral epiphysis in early life may progress to severe coxa vara. Level IV.

Population-based study shows improved postnatal growth in preterm very-low-birthweight infants between 1995 and 2010

To assess whether the postnatal growth of preterm very-low-birthweight (VLBW) infants, as determined by measures of postnatal growth failure (PNGF), improved during the period 1995-2010 and to evaluate postnatal growth by gestational age (GA) and intrauterine growth groups. The study was based on the Israel national VLBW infant database and comprised 13 531 VLBW infants of 24-32 weeks' GA, discharged at a postmenstrual age of ≤40 weeks. Z-scores were determined for weight at birth and discharge. Severe and mild PNGF was defined as a decrease >2 and 1-2 z-scores, respectively. Three time periods were considered: 1995-2000, 2001-2005 and 2006-2010. Multinomial logistic regression was used to assess the independent effect of time period on PNGF. Severe PNGF decreased from 11.7% in 1995-2000 to 7.2% in 2001-2005 and 5.2% in 2006-2010. Infants born in 2006-2010 had sixfold lower odds for severe PNGF than babies born in 1995-2000 (adjusted odds ratio 0.17, 95% confidence interval 0.14-0.21) and <twofold lower odds for mild PNGF (adjusted odds ratio 0.42, 95% confidence interval 0.39-0.48). We demonstrated a marked decline in PNGF among preterm VLBW infants from 1995-2000 to 2006-2010. This decline was even present in extremely premature infants.