Indications for genetic diagnosis in children with growth hormone deficiency and born small for gestational age.

INTRODUCTION: The aim of the study is to analyze patients who do not respond adequately to human recombinant growth hormone (rhGH) treatment. MATERIAL AND METHODS: Four boys were analyzed: three patients diagnosed with SNP at the ages of 1) 8 years and 2 months, 2) 13 years and 2 months, 3) 16 years and 6 months, and patient 4) at the age of 6 years and 11 months - born small for gestational age (SGA). They underwent rhGH treatment. RESULTS: The expected growth improvement was not observed in all boys. Patient 1 was diagnosed with aortic coarctation, and after each attempt to increase the rhGH dose, nocturnal vomiting occurred - epilepsy was diagnosed. Patient 2 had severe foot pain. Patient 3 had delayed puberty - hypogonadotropic hypogonadism was diagnosed. Patient 4 had dysmorphic features. Genetic tests revealed the following: 1) mixed gonadal dysgenesis - modifying treatment; 2) Fabry disease - enzyme treatment and rhGH improved growth; 3) Kallmann syndrome - discontinuing rhGH for testosterone supplementation; 4) KBG syndrome. CONCLUSIONS: 1. The presence of dysmorphic features and symptoms atypical for growth hormone deficiencies could warrant genetic diagnostics before initiating treatment. 2. Lack of significant improvement in growth is an indication for reevaluation of patients who have not completed growth. 3. Genetic studies in this patient group often elucidate the causes of slow growth rate. 4. The case authors have developed a proposal for a multicentre program aimed at establishing indications for genetic diagnosis in children diagnosed with SNP and SGA treated with rhGH.

Congenital Telangiectatic Erythema: Scoping Review.

BACKGROUND: Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a red skin rash occurring on sun-exposed areas of the body, and an increased risk of cancer. CTE is one of many genodermatoses and photodermatoses associated with defects in DNA repair. CTE is caused by a mutation occurring in the BLM gene, which causes abnormal breaks in chromosomes. OBJECTIVE: We aimed to analyze the existing literature on CTE to provide additional insight into its heredity, the spectrum of clinical presentations, and the management of this disorder. In addition, the gaps in current research and the use of artificial intelligence to streamline clinical diagnosis and the management of CTE are outlined. METHODS: A literature search was conducted on PubMed, DOAJ, and Scopus using search terms such as "congenital telangiectatic erythema," "bloom syndrome," and "bloom-torre-machacek." Due to limited current literature, studies published from January 2000 to January 2023 were considered for this review. A total of 49 sources from the literature were analyzed. RESULTS: Through this scoping review, the researchers were able to identify several publications focusing on Bloom syndrome. Some common subject areas included the heredity of CTE, clinical presentations of CTE, and management of CTE. In addition, the literature on rare diseases shows the potential advancements in understanding and treatment with artificial intelligence. Future studies should address the causes of heterogeneity in presentation and examine potential therapeutic candidates for CTE and similarly presenting syndromes. CONCLUSIONS: This review illuminated current advances in potential molecular targets or causative pathways in the development of CTE as well as clinical features including erythema, increased cancer risk, and growth abnormalities. Future studies should continue to explore innovations in this space, especially in regard to the use of artificial intelligence, including machine learning and deep learning, for the diagnosis and clinical management of rare diseases such as CTE.

Neurofibromatosis-Noonan syndrome and growth deficiency in an Iranian girl due to a pathogenic variant in NF1 gene.

BACKGROUND: Mutations in NF1 gene could cause allelic disorders with clinical spectrum of Neurofibromatosis type 1 to Noonan syndrome. Here, a 7-year-old Iranian girl is described with Neurofibromatosis-Noonan syndrome due to a pathogenic variant in NF1 gene. METHODS: Clinical evaluations were performed along with genetic testing using whole exome sequencing (WES). The variant analysis including pathogenicity prediction was also done using bioinformatics tools. RESULTS: The chief compliant of the patient was short stature and lack of proper weight gain. Other symptoms were developmental delay, learning disability, inadequate speech skill, broad forehead, hypertelorism, and epicanthal folds, low set ears and webbed neck. A small deletion, c.4375-4377delGAA, was found in NF1 gene using WES. This variant was classified as pathogenic according to ACMG. CONCLUSIONS: NF1 variants may show variable phenotypes among the patients; identifying such variants is helpful in therapeutic management of the disease. WES is considered as an appropriate test to diagnose Neurofibromatosis-Noonan syndrome.

Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome.

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.

Growth hormone therapy in a boy with X-linked spondyloepiphyseal dysplasia tarda: a 3-year observation.

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Long-term Management of a Patient with Apert Syndrome.

AIM AND OBJECTIVE: To present an Apert syndrome patient with midfacial growth deficiency treated with Le Fort III distraction osteogenesis and subsequent two-jaw surgery. BACKGROUND: Apert syndrome is expressed as a severe and irregular craniosynostosis, midfacial hypoplasia, and symmetric syndactyly in the fingers and toes. For craniosynostosis syndromes, treatment planning is complex due to the disharmony between facial profile and occlusion. CASE DESCRIPTION: A 4-year-and-5-month-old boy, diagnosed with Apert syndrome, showed a concave profile accompanied with midfacial hypoplasia, moderate exorbitism, a reversed occlusion of -10.0 mm, an anterior open bite of -5.0 mm, and skeletal class III jaw-base relationship. The patient, aged 15 years and 4 months, underwent a Le Fort III osteotomy, and subsequent osteodistraction was performed via a rigid external distraction (RED) device. His midfacial bone was advanced by approximately 7.0 mm. One year after the distraction, preoperative treatment with 0.018-in preadjusted edgewise appliances was initiated. Two-jaw surgery with a Le Fort I osteotomy and bilateral sagittal split ramus osteotomy was performed after 42 months of preoperative orthodontic treatment. At the age of 20 years and 9 months, his facial profile dramatically changed to a straight profile, and an acceptable occlusion with an adequate interincisal relationship was obtained. A functional occlusion with an excellent facial profile was maintained throughout the 2-year retention period, although the upper dental arch width was slightly decreased, resulting in the recurrence of the left posterior crossbite. CONCLUSION: Our report indicates the necessity of long-term follow-up in patients with craniosynostosis because of syndrome-specific growth and methodologically induced relapse. CLINICAL SIGNIFICANCE: The two-stage operation combining early distraction osteogenesis and postgrowth orthognathic surgery proves to be an effective therapy for correcting midfacial hypoplasia and skeletal mandibular protrusion caused by Apert syndrome.

Pattern of Morphological Variability in Unrepaired Unilateral Clefts With and Without Cleft Palate May Suggest Intrinsic Growth Deficiency.

In individuals with cleft lip and palate (CLP) an iatrogenic effect of operations on subsequent maxillary growth is well-known. Much less is known about the association between occurrence of CLP and intrinsic growth deficiency of the maxillofacial complex. The aim of this study was to compare morphological variability in subjects with unilateral cleft lip and alveolus/palate and unaffected controls using geometric morphometric methods. The research hypothesis was that if subjects with unrepaired unilateral CLP have intrinsic growth deficiency, the pattern of their craniofacial growth variation may differ from that in unaffected individuals. Lateral cephalograms were available of three groups of the same ethnic background (Proto-Malayid): (a) non-syndromic unrepaired unilateral complete cleft lip, alveolus, and palate (UCLP), N = 66, mean age 24.5 years (b) non-syndromic unrepaired unilateral complete cleft lip and alveolus (UCLA), N = 177, mean age 23.7 years, and (c) NORM (N = 50), mean age 21.2 years without a cleft. Using geometric morphometrics shape variability in groups and shape differences between groups was analyzed. Principal component analysis (PCA) was used to examine shape variability, while differences between groups and sexes were evaluated with canonical variate analysis. Sexual dimorphism was evaluated with discriminant function analysis (DA). Results showed that in comparison to NORM subjects, shape variability in UCLA and UCLP is more pronounced in the antero-posterior than in vertical direction. Pairwise comparisons of the mean shape configurations (NORM vs. UCLA, NORM vs. UCLP, and UCLA vs. UCLP) revealed significant differences between cleft and non-cleft subjects. The first canonical variate (CV1, 68.2% of variance) demonstrated that differences were associated with maxillary shape and/or position and incisor inclination, while in females, the CV1 (69.2% of variance) showed a combination of differences of "maxillary shape and/or position and incisor inclination" and inclination of the cranial base. Shape variability demonstrated considerable differences in subjects with UCLA, UCLP, and NORM. Moreover, in subjects with a cleft, within-sample variability was more pronounced in the antero-posterior direction, while in non-cleft subjects, within-sample variability was more pronounced in the vertical direction. These findings may suggest that subjects with unilateral clefts have intrinsic growth impairment affecting subsequent facial development.

Identification of Oliver-McFarlane syndrome caused by novel compound heterozygous variants of PNPLA6.

OBJECTIVES: Oliver-McFarlane syndrome (OMCS) is an autosomal recessive inherited disease resulting from PNPLA6 mutations that results in intellectual impairment and profound short stature. To obtain a better understanding of the genotype-phenotype correlations for PNPLA6-related disorders, we reported the 14th OMCS case and summarized all the reported cases of OMCS. METHODS: We collected clinical biochemical and data and brain MRI data and used whole-exon gene detection and analysis tools to evaluate the pathogenicity of the variants, including PolyPhen-2 and Mutation Taster, and we also generated three-dimensional protein structures and visualized the effects of altered residues with I-TASSER and PyMOL Viewer software. RESULTS: The patient presented with trichomegaly and multiple pituitary hormone deficiencies. Brain MRI showed small pituitary and bilateral paraventricular leukomalacia. Novel variants (c.1491G > T and c.3367G > A) in the PNPLA6 gene were detected in the proband and verified by direct sequencing. Amino acid residues of Gln497 and Gly1123 are predicted to be damaging and destroy the three-dimensional protein structures of the protein. In follow-up, this patient could neither walk nor hold his head erect and had not spoken one word at the age of one year and ten months. Moreover, there is no obvious hot spot mutation in any of the reported allelic variants. Interestingly, the majority of mutations are located in the phospholipid esterase domain, which is responsible for esterase activity. CONCLUSIONS: We identified two novel variants of the PNPLA6 gene in an OMCS patient, which will help to better understand the function of PNPLA6 and genotype-phenotype correlations for PNPLA6-related disorders.

Acquired autoimmune hypothyroidism as a cause of severe growth deficiency in one of the twin sisters.

Acquired autoimmune hypothyroidism is rare in early childhood, however, it must be considered in a 4 year old child with medical his-tory of delayed growth, increased somnolence, difficulty concentrating, and reduced activity. We report on the case of full clinical picture of severe hypothyroidism in one of the twins. Thyroid function deteriorated in one of the sisters, resulting in mental, motor and growth slowdown, remaining undiagnosed for about 2 years, while the other sister developed normally. In the reported case, severe hypothy-roidism and growth deficiency were accompanied by celiac disease. Initiation of L-thyroxine therapy resulted in an immediate response that increased the growth velocity by more than 2.2 times. This confirms the dominant role of thyroid hormones over celiac disease in the growth process, as the catch up effect started before gluten free diet was introduced.

Expanding the clinical spectrum associated with PACS2 mutations.

Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G>A (p.Glu209Lys). Here, we report on a 7-year-old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G>A (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism.

"Lowe syndrome: A particularly severe phenotype without clinical kidney involvement".

Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23-year-old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.

The importance of nutrition for health in patients with transfusion-dependent thalassemia.

Nutrition is increasingly being seen by care providers as important for patients with thalassemia. However, the definition of optimal nutritional support and the means to provide that support remain elusive. This review focuses on the relationships between nutritional status and three common comorbidities in patients with thalassemia: low bone mass, growth deficiency, and diabetes. The association between low bone mass and specific nutrient deficiencies (e.g., vitamin D, zinc) is clear, while the role of nutritional adequacy for young patients with growth deficiencies requires careful analysis to distinguish it from chronic anemia and endocrine insufficiency. Correction of isolated nutritional deficiencies in small cohorts of patients with thalassemia has shown some promise at improving both bone health and linear growth in the short term. However, the long-term safety and acceptability of these practices need to be evaluated. On the whole, there are few well-designed, adequately powered studies of the role of general dietary or specific micronutrients in the cause, treatment, or prevention of these commonly observed morbidities in thalassemia. Until these data are gathered, it is suggested that patients with thalassemia be monitored frequently and that their nutritional deficiencies be corrected when observed in order to advance their overall health and quality of life.

Deletion of 14.7 Mb 2q32.3q33.3 with a marfanoid phenotype and hypothyroidism.

Interstitial 2q deletions are very rare chromosome abnormalities. The 2q32q33 deletion was proposed as a distinct entity with characteristic phenotype. Most patients have feeding problems, growth restriction, moderate to severe developmental delay, speech delay or lack of speech, high, prominent forehead, thin sparse hair, teeth abnormalities and a high or cleft palate. We report on another rare case of interstitial 2q33 deletion found during routine karyotyping and further characterized by the use of a genomic SNP array. The patient presented here has a "Marfanoid" phenotype, hypothyroidism, and a marked tactile hypersensitivity. We concluded that hypothyroidism might be caused by the deletion of the CD28 and/or CTLA4 genes; also cardiological monitoring of patients with the deletion including BMPR2 may be considered in order to prevent the possible medical complications associated with pulmonary hypertension.

Growth profiles of 34 patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) encompasses multiple congenital anomalies and mental retardation and is caused by partial deletions in the short arm of chromosome 4. Prenatal-onset growth deficiency is one of the WHS characteristics. Assessing and recording growth profiles of patients with WHS were the aims of this study. Anonymous questionnaire surveys were conducted with cooperation of a WHS peer-support group in Japan, and data from 34 WHS patients (12 males and 22 females; age, 1-23 years) were retrospectively collected. Height, weight, and head circumference (occipitofrontal head circumference) were measured and plotted on the standard growth charts of healthy Japanese children. Results indicated that most WHS patients showed growth retardation under the 3rd percentile since the first year of life and extremely poor body-weight gain after pubertal age. These findings are characteristic of WHS patients. The assessed growth patterns in this study could help monitoring and documentation of growth of WHS patients.