The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard ...deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.
Aim
To map somatic growth patterns throughout Fontan palliation and summarise evidence on its key modifiers.
Methods
Databases were searched for relevant articles published from January 2000 to ...December 2021. Height and weight z scores at each time point (birth, Glenn procedure, Fontan procedure and >5 years after Fontan completion) were pooled using a random effects meta‐analysis. A random effects meta‐regression model was fitted to model the trend in z scores over time.
Results
Nineteen studies fulfilled eligibility criteria, yielding a total of 2006 participants. The z scores for height and weight were markedly reduced from birth to the interstage period, but recovered by about 50% following the Glenn procedure. At >10 years after the Fontan procedure, the z scores for weight seemed to normalise despite persistent lower height, resulting in increased body mass index. The review revealed a number of modifiers of somatic growth, including aggressive nutritional management, timing of Glenn/Fontan, prompt resolution of complications and obesity prevention programmes in adolescence and adulthood.
Conclusion
This review mapped the somatic growth of single ventricle patients and summarised key modifiers that may be amendable to improvement. These data provide guidance on strategies to further optimise somatic growth in this population and may serve as a benchmark for clinical follow‐up.
Abstract
Children born small for gestational age (SGA), defined as a birth weight and/or length below −2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and ...include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ∼10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below −2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk.
Based on a thorough literature search, the causes and consequences of small birth size for gestational age are described, as are the results of GH treatment.
Catel‐Manzke syndrome, also known as micrognathia‐digital‐syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre‐Robin sequence and ...bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel‐Manzke‐like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel‐Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel‐Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS‐associated Catel‐Manzke syndrome and expand the indication for diagnostic testing.
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.
Insulin like growth factors-1 (IGF-1) is essential for normal
and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase ...receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for gestational age (SGA) girl in whom discordant postnatal growth persisted and her appropriate for gestational age (AGA) brother.
A girl born with a low weight and length -2.3 and -2.4 standard deviation (SD) score (SDS), respectively but borderline low head circumference (-1.6 SD) presented with a height of -1.7 SDS, in contrast to a normal height twin brother (0.0 SDS). IGF-1 resistance was suspected because of elevated serum IGF-1 levels.
Sequencing revealed the presence of a previously described pathogenic heterozygous mutation (p.Glu1050Lys) in the SGA girl which was not present in the parents nor in the AGA twin brother.
The pathogenic
mutation in this girl led to intrauterine growth retardation followed by partial postnatal catch-up growth. Height in mid-childhood was in the lower half of the reference range, but still 1.7 SD shorter than her twin brother.
Whole-exome sequencing has emerged as a fast and effective tool for the elucidation of genetic defects underlying both rare and common human diseases. Increased availability and decreased costs of ...next-generation sequencing have enabled investigators to use this approach not only in individual patients with rare diseases, but also to screen large cohorts or populations for the genetic determinants of diseases. Within the field of endocrinology, exome sequencing has led to major advancements in our understanding of many disorders including adrenal disease, growth and puberty disorders and type 2 diabetes mellitus, as well as a multitude of rare genetic syndromes with prominent endocrine involvement. In this Review, we provide an overview of these new insights and discuss the role that exome sequencing is expected to have in endocrine research and future clinical practice.
ACP5 deficiency is known to cause spondyloenchondrodysplasia (SPENCD), which is characterized by various autoimmune and neurological symptoms in addition to short stature.
Two siblings from a ...consanguineous Turkish family, a girl aged 13 years (P1) and a boy aged 8 years (P2), presented to their endocrinologist with progressive growth failure and severe short stature (-5 SDS). They had no comorbid conditions and, on physical examination, there were no signs of an overt skeletal dysplasia with normal appearance of extremities. Other than a low baseline IGF-1, extensive laboratory workup, including growth hormone stimulation and IGF-1 generation tests, was normal. Exome sequencing was performed.
Exome sequencing identified the presence of a homozygous frameshift mutation (p.Ser258Trpfs*39) in ACP5 in both siblings, which was confirmed by Sanger sequencing. This specific mutation has previously been described in patients with SPENCD. Additional workup in the two siblings showed distinct features of skeletal dysplasia on X-rays consistent with SPENCD, but none of the common autoimmune or neurological abnormalities associated with this condition.
Severe short stature can be the only presenting sign of ACP5 deficiency and the latter could therefore be considered as a rare cause in the differential diagnosis of severe, proportionate growth failure.
Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides ...rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in
, and
predicted as damaging were found to be shared between the four tall family members. Three of the five genes (
, and
) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes.
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