The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel ...genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.
Aim
To study long‐term disease course for females with early‐onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare ...management to support guideline development.
Method
Twelve females with early‐onset dystrophinopathy were followed for a median period of more than 17 years (range 1–36).
Results
One patient died owing to end‐stage cardiac failure. Cardiac abnormalities were observed in three of the remaining 11 participants. Respiratory function was reduced in seven of 10 participants. Fatigue, myalgia, lower back pain, and arthralgia were reported in more than six of the participants. Functional status varied from exercise intolerance to wheelchair dependency. Most or all of the 10 participants reported restrictions in participation in work (n = 10), household duties (n = 10), sports (n = 9), and education (n = 8). Only a few participants received followed‐up pulmonary (n = 2) or rehabilitation (n = 3) care.
Interpretation
Females with early‐onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation. The whole spectrum should be acknowledged in the healthcare setting. Neuromuscular and cardiac follow‐up are indispensable. Additional respiratory assessment and rehabilitation care are expected to improve health status and support daily activities and participation.
What this paper adds
No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy.
Female participants with early‐onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia.
None of participants worked full time, all felt restricted in paid work, and most felt restricted in education.
Most participants showed decreased lung function, while only one was symptomatic.
Availability of rehabilitation care may improve support for daily activities and participation for females with early‐onset dystrophinopathy.
What this paper adds
No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy.
Female participants with early‐onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia.
None of participants worked full time, all felt restricted in paid work, and most felt restricted in education.
Most participants showed decreased lung function, while only one was symptomatic.
Availability of rehabilitation care may improve support for daily activities and participation for females with early‐onset dystrophinopathy.
This original article is commented on by Politano on pages 1001–1002 of this issue.
Abstract
Context
The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known.
Objective
To develop a clinical score for selecting children with short stature ...for genetic testing and evaluate the efficacy of treatment.
Design and Setting
Case series with an IGF1R defect identified in a university genetic laboratory.
Patients and Interventions
Of all patients with sufficient clinical data, 18 had (likely) pathogenic mutations (group 1) and 7 had 15q deletions including IGF1R (group 2); 19 patients were treated with GH.
Main Outcome Measures
Phenotype and response to GH treatment.
Results
In groups 1 and 2, mean (range) birth weight, length, and head circumference (HC) SD scores (SDSs) were −2.1 (−3.7 to −0.4), −2.7 (−5.0 to −1.0), and −1.6 (−3.0 to 0.0), respectively. At presentation, height, HC, and serum IGF-1 SDSs were −3.0 (−5.5 to −1.7), −2.5 (−4.2 to −0.5), and +1.2 (−1.3 to 3.2), respectively. Feeding problems were reported in 15 of 19 patients. A clinical score with 76% sensitivity is proposed. After 3 years of GH treatment 1.1 (0.2) mg/m2/d height gain in groups 1 (n = 12) and 2 (n = 7) was 0.9 SDS and 1.3 SDS (at a mean IGF-1 of 3.5 SDS), less than reported for small for gestational age (1.8 SDS).
Conclusion
A clinical score encompassing birth weight and/or length, short stature, microcephaly, and IGF-1 is useful for selecting patients for IGF1R analysis. Feeding problems are common and the growth response to GH treatment is moderate.
A clinical score (based on birth size, height, head circumference, and IGF-1) can select patients for IGF1R analysis. The response to GH therapy is moderate in carriers of heterozygous IGF1R defects.
Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on “more common” RNDs, leaving ...a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.
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.
Background:
C-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in ...tall stature, a Marfanoid phenotype, and skeletal abnormalities. A similar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain.
Case:
Here we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain.
Objectives:
The objective of the study was to investigate the functional and structural effects of the NPR2 mutation.
Methods:
Guanylyl cyclase activities of wild-type vs mutant NPR2 were analyzed in transfected human embryonic kidney 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation.
Results:
CNP-stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected human embryonic kidney 293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilization by ATP. Coimmunoprecipitation showed that wild-type and mutant NPR2 can form stable heterodimers, suggesting a dominant-positive effect. In accordance with augmented endogenous receptor activity, plasma N-terminal pro-CNP (a marker of CNP production in tissues) was reduced in the proband.
Conclusions:
We report the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.
The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired ...causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.
Abstract
Context
C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor ...(natriuretic peptide receptor-B NPR-B, gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type).
Design
History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant.
Results
Mother’s height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband’s skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B.
Conclusions
We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.
Context:
Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many ...syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly.
Objective:
To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure.
Design:
Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene.
Setting:
An academic pediatric endocrinology clinic.
Patients or Other Participants:
Two adult siblings (male patient P1 and female patient 2 P2) presented with a history of severe postnatal growth failure (adult heights: P1, −6.8 SD score; P2, −4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28.
Intervention(s):
Single nucleotide polymorphism microarray and exome sequencing.
Results:
Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect.
Conclusions:
In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.
PDF
