Delphi consensus on the diagnosis and treatment of patients with short stature in Spain: GROW-SENS study.

PURPOSE: To identify consensus aspects related to the diagnosis, monitoring, and treatment of short stature in children to promote excellence in clinical practice. METHODS: Delphi consensus organised in three rounds completed by 36 paediatric endocrinologists. The questionnaire consisted of 26 topics grouped into: (1) diagnosis; (2) monitoring of the small-for-gestational-age (SGA) patient; (3) growth hormone treatment; and (4) treatment adherence. For each topic, different questions or statements were proposed. RESULTS: After three rounds, consensus was reached on 16 of the 26 topics. The main agreements were: (1) diagnosis tests considered as a priority in Primary Care were complete blood count, biochemistry, thyroid profile, and coeliac disease screening. The genetic test with the greatest diagnostic value was karyotyping. The main criterion for initiating a diagnostic study was prediction of adult stature 2 standard deviations below the target height; (2) the main criterion for initiating treatment in SGA patients was the previous growth pattern and mean parental stature; (3) the main criterion for response to treatment was a significant increase in growth velocity and the most important parameter to monitor adverse events was carbohydrate metabolism; (4) the main attitude towards non-responding patients is to check their treatment adherence with recording devices. The most important criterion for choosing the delivery device was its technical characteristics. CONCLUSIONS: This study shows the different degrees of consensus among paediatric endocrinologists in Spain concerning the diagnosis and treatment of short stature, which enables the identification of research areas to optimise the management of such patients.

Orthopedic concerns of a child with short stature.

PURPOSE OF REVIEW: Pediatric short stature poses severe concerns to the patient, parents, and physicians. Management for pediatric short stature is still widely debated due to heterogenous etiological factors and treatment options. This review will address the approach to pediatric short stature, commonly within the subset of skeletal dysplasia resulting in disproportionate short stature. The following will be discussed: the etiology, clinical, and radiological evaluations, and management for pediatric short stature. RECENT FINDINGS: Early recognition of short stature and appropriate referrals is shown to benefit the patient and reduce parental concern. A multidisciplinary team, comprising an orthopedic surgeon, is fundamental to provide holistic care and ensure overall good quality of life. Advancements in clinical diagnostic tools and diversified treatment modalities today provides optimism in managing pediatric short stature. SUMMARY: Skeletal dysplasia can be treated with good prognosis if diagnosed and managed early. Thorough clinical, radiological, laboratory, and even genetic investigations are important to differentiate and manage various types of skeletal dysplasia. Our review will provide a comprehensive and up-to-date approach to skeletal dysplasia for pediatric orthopedic surgeons, and indications for physicians to refer patients with suspected short stature to pediatric orthopedic surgeons.

Current state of the art in treatment of Mendelian disease: Skeletal dysplasias.

The current state of the art in treatment of Mendelian disease, specifically skeletal dysplasias, benefits tremendously from Dr. Victor McKusick's early delineation and standardization of the nomenclature surrounding these conditions. Through close observation and careful description of each dysplasia to flesh out the nosologic backbone of the genetic skeletal disorders, individuals with the same diagnosis were identified and grouped together for genetic interrogation. These efforts have resulted in the identification of the genetic etiology of nearly all recognized skeletal disorders. This, in turn, is leading to disease-specific treatment for many of the skeletal dysplasias in this new era of precision medicine. Furthermore, Dr. McKusick's natural history descriptions of many genetic skeletal disorders helped to establish the baseline disease state against which the effect of new treatment is compared.

Review of economic analysis of available interventions on idiopathic short stature: A protocol for systematic review and meta-analysis.

BACKGROUND: Idiopathic short stature (ISS) causes a high economic burden worldwide. As part of a research project that synthesizes economic evidence for Korean medicine treatment of ISS, we describe the methods that will be used for the comprehensive review of articles that analyze health-related economic evaluation for available interventions for ISS using a systematic review methodology. METHODS: Eight electronic English, Korean, and Chinese databases will be searched from their inception until December 2020 to identify studies on the economic evaluation of available interventions on ISS, without language, study design, or publication status restrictions. From the included studies, the effectiveness, utility, and cost data will be collected as the outcome measures by two researchers independently. Descriptive analysis of individual studies will be conducted. If it is judged that the interventions and outcomes of the included studies are sufficiently homogeneous, we will attempt a quantitative synthesis through meta-analysis using Review Manager version 5.4 software (Cochrane, London, UK). RESULTS: This study will summarize the evidence regarding the economic evaluation of available interventions for ISS. CONCLUSIONS: The findings of this review will help clinicians and patients in evidence-based decision-making in clinical settings and help policy makers develop effective policies and distribute resources based on the available evidence.

How should we investigate children with growth failure?

The early diagnosis of short stature is essential for effective management and treatment. Investigations for children with growth failure are required to distinguish between idiopathic short stature due to physiological variants (familial short stature, and constitutional delays of growth and puberty, or both), primary causes of short stature, such as syndromic and/or genetic defects and skeletal dysplasia, and secondary growth deficits due to endocrine or other chronic disorders such as celiac disease, Crohn's disease, malnutrition, renal, anorexia nervosa or other chronic diseases.

Microcephalic Osteodysplastic Primordial Dwarfism, Type II: a Clinical Review.

PURPOSE OF THE REVIEW: This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial dwarfism, type II (MOPDII). RECENT FINDINGS: Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.

Exploring Splicing-Switching Molecules For Seckel Syndrome Therapy.

The c.2101A>G synonymous change (p.G674G) in the gene for ATR, a key player in the DNA-damage response, has been the first identified genetic cause of Seckel Syndrome (SS), an orphan disease characterized by growth and mental retardation. This mutation mainly causes exon 9 skipping, through an ill-defined mechanism. Through ATR minigene expression studies, we demonstrated that the detrimental effect of this mutation (6±1% of correct transcripts only) depends on the poor exon 9 definition (47±4% in the ATRwt context), because the change was ineffective when the weak 5' or the 3' splice sites (ss) were strengthened (scores from 0.54 to 1) by mutagenesis. Interestingly, the exonic c.2101A nucleotide is conserved across species, and the SS-causing mutation is predicted to concurrently strengthen a Splicing Silencer (ESS) and weaken a Splicing Enhancer (ESE). Consistently, the artificial c.2101A>C change, predicted to weaken the ESE only, moderately impaired exon inclusion (28±7% of correct transcripts). The observation that an antisense oligonucleotide (AONATR) targeting the c.2101A position recovers exon inclusion in the mutated context supports a major role of the underlying ESS. A U1snRNA variant (U1ATR) designed to perfectly base-pair the weak 5'ss, rescued exon inclusion (63±3%) in the ATRSS-allele. Most importantly, upon lentivirus-mediated delivery, the U1ATR partially rescued ATR mRNA splicing (from ~19% to ~54%) and protein (from negligible to ~6%) in embryonic fibroblasts derived from humanized ATRSS mice. Altogether these data elucidate the molecular mechanisms of the ATR c.2101A>G mutation and identify two potential complementary RNA-based therapies for Seckel syndrome.

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.

[Evaluation of a Self-Help Supported Counseling Concept for Children and Adolescents with Disproportional Short Stature]. / Evaluation eines selbsthilfegestützten psychosozialen Interventionsangebotes für Kinder und Jugendliche mit disproportionalem Kleinwuchs.

BACKGROUND: Disproportionate short stature may impair the quality of life (QoL) of patients and their families. This study aimed to evaluate a self-help supported counseling concept to increase the QoL of the participants. METHODS: QoL data from 58 children/adolescents (8-17 years) with a diagnosis of achondroplasia was collected at 2 measurement points during one year using the the QoLISSY questionnaire (self-/parental report). Differences before and after participation vs. non-participation in the intervention were evaluated using a linear mixed model. RESULTS: The longitudinal results show a greater increase of QoL in the active intervention group compared to a passive control group (p=0,005). The increase in the self-reported QoL of affected patients was significantly higher than for the parent-report (p=0,048). CONCLUSIONS: The study shows that patients with achondroplasia benefit from a self-help supported counseling concept. However, this should be tested in a randomized trial.

Inherited neurovascular diseases affecting cerebral blood vessels and smooth muscle.

Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.

Psychosocial short stature with psychosis: a case report.

OBJECTIVE: Our objective was to report and describe a case of psychosocial short stature in an adolescent girl with psychotic features. Psychosocial short stature is a rare condition in which emotional stress or deprivation in childhood profoundly reduces growth, leading to persistent short stature. This disorder is variably known as psychosocial dwarfism, hyperphagic short stature or maternal deprivation dwarfism. In the literature, psychosocial short stature has not been associated previously with psychosis. CONCLUSIONS: We formulate that our patient's short stature, developmental regression and psychotic features were culminations of insecure mother-child attachment, personal traumatic experiences, immigrant status, high family expressed emotions and social isolation. Neuropsychiatric influences were critically regarded due to our patient's fluctuations in behaviour and affect, in the setting of cortical volume loss on brain MRI. Diagnostic hypotheses included childhood disintegrative disorder or childhood-onset schizophrenia. The management plan involved inpatient family psychoeducation, a pharmacological trial with an atypical antipsychotic and community mental health service follow-up for family therapy and psychotherapy.

A novel homologous model for gene therapy of dwarfism by non-viral transfer of the mouse growth hormone gene into immunocompetent dwarf mice.

The possibilities for non-viral GH gene therapy are studied in immunocompetent dwarf mice (lit/lit). As expression vector we used a plasmid previously employed in immunodeficient dwarf mice (pUBI-hGH-gDNA) by replacing the human GH gene with the genomic sequence of mouse-GH DNA (pUBI-mGH-gDNA). HEK-293 human cells transfected with pUBI-mGH-gDNA produced 3.0 µg mGH/10(6) cells/day compared to 3.7 µg hGH/10(6) cells/day for pUBIhGH- gDNA transfected cells. The weight of lit/lit mice treated with the same two plasmids (50 µg DNA/mouse) by electrotransfer into the quadriceps muscle was followed for 3 months. The weight increase up to 15 days for mGH, hGH and saline treated mice were 0.130, 0.112 and 0.027 g/mouse/day. Most sera from hGH-treated mice contained anti-hGH antibodies already on day 15, with the highest titers on day 45, while no significant anti-mGH antibodies were observed in mGH-treated mice. At the end of 3 months, the weight increase for mGH-treated mice was 34.3%, while the nose-to-tail and femur lengths increased 9.5% and 24.3%. Mouse-GH and hGH circulating levels were 4-5 ng/mL 15 days after treatment, versus control levels of ~0.7 ng GH/mL (P<0.001). In mGH-treated mice, mIGF-I determined on days 15, 45 and 94 were 1.5- to 3-fold higher than the control and 1.2- to 1.6-fold higher than hGH-treated mice. The described homologous model represents an important progress forming the basis for preclinical testing of non-viral gene therapy for GH deficiency.

Successful outcome of allogeneic stem cell transplantation in Seckel syndrome.

Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six-yr-old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations.

[Clinical condition and therapy of bone diseases].

Skeletal dysplasia is the term which represents disorders including growth and differentiation of bone, cartilage and ligament. A lot of diseases are included, and new disorders have been added. However, the therapy of most bone diseases is less well-established. Achondroplasia, hypochondroplasia, and osteogenesis imperfecta are most frequent bone diseases. There is no curative treatment for these diseases, however, supportive therapies are available ; for example, growth-hormone therapy for achondroplasia and hypochondroplasia, and bisphosphonate therapy for osteogenesis imperfecta. In addition, enzyme replacement therapy for hypophosphatasia is now on clinical trial.

De Sanctis-Cacchione Syndrome in a female infant - Case report / Sindrome de De Sanctis-Cacchione em lactente do sexo feminino - Relato de caso

The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported.

A síndrome de de Sanctis-Cacchione é a forma mais rara e grave do xeroderma pigmentoso e é caracterizada por microcefalia, hipogonadismo, alterações neurológicas e retardo mental e de crescimento, com poucos casos publicados. Relatam-se os achados clínicos compatíveis com essa síndrome e a terapêutica instituída em uma lactente de um ano e nove meses, com diagnóstico prévio de xeroderma pigmentoso.

De Sanctis-Cacchione syndrome in a female infant--case report.

The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported.

Metatropic dysplasia in four-year-old boy--physiotherapy and orthopaedic care problems--case report.

Metatropic dysplasia is a rare skeletal dysplasia caused by a mutation in the VDRL4 gene. Characteristic abnormalities include tubular bones with short diaphyses and wide metaphyses, delayed ossification of the ischio/pubic bone, and platyspondyly. The main problem is progressive kyphoscoliosis, which significantly limits the patient's motor development. Another complication is compression of the cervical spinal cord, which reverses any improvements in the child's motor performance. The paper presents a description of a 4-year-old boy with metatropic dysplasia treated by orthopaedic bracing and spinal cord decompression surgery at the C1-2 level. Particular attention is paid to physiotherapy, which allowed restoration of motor functions to match the needs of daily activity.