An unusual case of 17-hydroxylase deficiency presenting with short stature.

17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene and are necessary for the production of cortisol and sex steroids. Females with 17α-hydroxylase deficiency usually present with primary amenorrhea and delayed puberty accompanied by hypertension and electrolyte imbalance. Here, we report the case of a 14-year-old female patient who presented with severe short stature and delayed puberty without any complaint suggestive of 17-hydroxylase enzyme deficiency. Laboratory test results showed low cortisol and dehydroepiandrosterone sulfate (DHEA-S) along with high luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Turner syndrome was excluded after genetic analysis showed a 46,XX karyotype, and 17α-hydroxylase deficiency was diagnosed by detecting a c.1319G>A (p.Arg440His) variation/alternation in the patient's CYP17A1 gene.

Fetal phenotype and diagnosis of autosomal dominant Robinow syndrome due to novel DVL1 variant.

Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.

Cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders harboring RMRP mutations in two Korean children: A case report.

RATIONALE: Cartilage-hair hypoplasia (CHH, OMIM # 250250) is a rare autosomal recessive disorder, which includes cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders. CHH-AD is caused by homozygous or compound heterozygous mutations in the RNA component of the mitochondrial RNA-processing Endoribonuclease (RMRP) gene. PATIENT CONCERNS: Here, we report 2 cases of Korean children with CHH-AD. DIAGNOSES: In the first case, the patient had metaphyseal dysplasia without hypotrichosis, diagnosed by whole exome sequencing (WES), and exhibited only skeletal dysplasia and lacked extraskeletal manifestations, such as hair hypoplasia and immunodeficiency. In the second case, the patient had skeletal dysplasia, hair hypoplasia, and immunodeficiency, which were identified by WES. INTERVENTIONS: The second case is the first CHH reported in Korea. The patients in both cases received regular immune and lung function checkups. OUTCOMES: Our cases suggest that children with extremely short stature from birth, with or without extraskeletal manifestations, should include CHH-AD as a differential diagnosis. LESSONS SUBSECTIONS: Clinical suspicion is the most important and RMRP sequencing should be considered for the diagnosis of CHH-AD.

Children With Idiopathic Short Stature: An Expanding Role for Genetic Investigation in Their Medical Evaluation.

Short stature in children is a common reason for referral to a pediatric endocrinologist. Many genetic, nutritional, psychological, illness-related, and hormonal causes must be excluded before labeling as idiopathic. Idiopathic short stature is not a diagnosis, but rather describes a large, heterogeneous group of children, who are short and often slowly growing. As new testing paradigms become available, the pool of patients labeled as idiopathic will shrink, although most will have a polygenic cause. Given that many of the new diagnoses are involved in growth plate biology, physical examination should assess for subtle dysmorphology or disproportion of the skeleton that may indicate a heterozygous mutation that in its homozygous state would be apparent. When laboratory evaluations are negative, one may consider genetic testing, such as targeted gene or gene panel, comparative genomic hybridization, or whole exome or whole genome sequencing (respectively). With a known genetic diagnosis, targeted therapy may be possible rather than recombinant human growth hormone, where response is generally poorer than that for children with growth hormone deficiency, because the variety of diagnoses may have varying growth hormone sensitivity. A firm diagnosis has heuristic value: to truncate further diagnostic evaluation, alert the clinician to other possible comorbidities, inform the family for genetic counseling, and direct appropriate targeted therapy, if available.

Metabolic Characteristics and Discriminative Diagnosis of Growth Hormone Deficiency and Idiopathic Short Stature in Preadolescents and Adolescents.

Growth hormone deficiency (GHD) and idiopathic short stature (ISS) are the most common types of short stature (SS), but little is known about their pathogenesis, and even less is known about the study of adolescent SS. In this study, nuclear magnetic resonance (NMR)-based metabolomic analysis combined with least absolute shrinkage and selection operator (LASSO) were performed to identify the biomarkers of different types of SS (including 94 preadolescent GHD (PAG), 61 preadolescent ISS (PAI), 43 adolescent GHD (ADG), and 19 adolescent ISS (ADI)), and the receiver operating characteristic curve (ROC) was further used to evaluate the predictive power of potential biomarkers. The results showed that fourteen, eleven, nine, and fifteen metabolites were identified as the potential biomarkers of PAG, PAI, ADG, and ADI compared with their corresponding controls, respectively. The disturbed metabolic pathways in preadolescent SS were mainly carbohydrate metabolism and lipid metabolism, while disorders of amino acid metabolism played an important role in adolescent SS. The combination of aspartate, ethanolamine, phosphocholine, and trimethylamine was screened out to identify PAI from PAG, and alanine, histidine, isobutyrate, methanol, and phosphocholine gave a high classification accuracy for ADI and ADC. The differences in metabolic characteristics between GHD and ISS in preadolescents and adolescents will contribute to the development of individualized clinical treatments in short stature.

FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects.

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.

SOFT syndrome with kohlschutter-Tonz syndrome.

We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.

Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

[Attaching great importance to the scientific assessment of short stature in children]. / 高度重视儿童矮身材的科学评估.

Short stature is a common physical developmental abnormality in children. Without timely and accurate diagnosis, as well as early intervention, it can impose a heavy burden on the children and their families. There are numerous causes for short stature, and the diagnostic process essentially involves identifying its underlying causes. Based on a thorough understanding of the regular patterns of child physical development and the characteristics of individuals at high risk of short stature, a scientific definition of short stature needs to be established, along with standardized diagnostic and treatment protocols, to achieve early diagnosis or referral for short stature. Furthermore, it is necessary to enhance scientific awareness of short stature among parents and primary care pediatricians, in order to avoid over-treatment, missed diagnoses, and misdiagnoses arising from "misconceptions", and to improve the scientific assessment of short stature.

Autosomal recessive otospondylo-mega-epiphyseal dysplasia: comprehensive clinical review of a pediatric cohort.

Autosomal recessive otospondylo-mega-epiphyseal dysplasia (OSMEDB) is characterized by short stature with short limbs, dysmorphic facial features, and hearing loss, which is caused by biallelic, loss-of-function, variants in the COL11A2 gene. Geno-phenotypic data from the medical records of eight affected individuals from five unrelated families was abstracted, recorded in an Excel spreadsheet and analyzed using simple frequency analysis. Either short femora or short extremities with or without other ultrasonographic abnormalities were demonstrated in five patients antenatally. The mean height was -2.29 SDS. Pectus deformity, including either chest asymmetry or pectus excavatum, was present in five patients. Bilateral hearing loss was verified in all patients. Severe speech delay and learning disabilities were present in two patients whose deafness was realized after the age of 12 months. Four novel loss-of-function variants in COL11A2 were found in this cohort. We present novel geno-phenotypic findings in a pediatric cohort with OSMEDB. The age of manifestation of short stature was variable, ranging from birth to middle childhood, and the severity of short stature varied even within the same family. Hearing loss may not be evident in the neonatal period and manifest later in OSMEDB. Intermittent hearing tests should be performed for early intervention of neurolinguistic delay and learning disabilities.

Expanding the phenotype of anauxetic dysplasia caused by biallelic NEPRO mutations: A case report.

The cartilage hair hypoplasia and anauxetic dysplasia (CHH-AD) spectrum encompasses a group of rare skeletal disorders, with anauxetic dysplasia (ANXD) at the most severe end of the spectrum. Biallelic variants in RMRP, POP1, and NEPRO (C3orf17) have previously been associated with the three currently recognized ANXD types. Generally, all types are characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility and dislocations, and extensive skeletal abnormalities visible on radiological evaluation. Thus far, only five patients with type 3 anauxetic dysplasia (ANXD3) have been reported. Here, we describe one additional ANXD3 patient. We provide a detailed physical and radiological evaluation of this patient, in whom we identified a homozygous variant, c.280C > T, p.(Arg94Cys), in NEPRO. Our patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly. We provide an overview of the literature on ANXD3 and discuss our patient's characteristics in the context of previously described patients. This study expands the phenotypic spectrum of ANXD, particularly ANXD3. Greater awareness of the possibility of atlantoaxial subluxation, dental anomalies, and craniosynostosis may lead to more timely diagnosis and treatment.

Aarskog-scott syndrome (AAS): a case report.

BACKGROUND: Aarskog-Scott syndrome (AAS) is a rare developmental disorder characterised by facial dysmorphism, genital and limb anomalies as well as disproportionate acromelic short stature. Clinical diagnosis is based on physical examination and the presence of the most characteristic clinical signs. The diagnosis can be finally confirmed by molecular tests, which identify mutations in the FGD1 gene. CASE REPORT: The report outlines the orthodontic treatment of a 6-year-old male patient, who was diagnosed with AAS syndrome. He presents all facial and oral clinical signs of this syndrome. The extent of maxillary hypoplasia and early dental crowding are so significant that immediate expansion therapy is required. CONCLUSION: Dental management of patients with AAS syndrome represents a challenge for paediatric dentists. The key to improving a patient's aesthetic, functional and psychological condition is making the correct orthodontic decision.

Expanding the phenotype of Seckel syndrome associated with biallelic loss-of-function variants in CEP63.

Seckel syndrome is an ultrarare autosomal recessive genetically heterogenous condition characterized by intrauterine and postnatal growth restriction, proportionate severe short stature, severe microcephaly, intellectual disability, and distinctive facial features including a prominent nose. Up to now, 40 patients with molecularly confirmed Seckel syndrome have been reported with biallelic variants in nine genes: ATR, CENPJ, CEP63, CEP152, DNA2, NIN, NSMCE2, RBBP8, and TRAIP. Homozygosity for nonsense variant (c.129G>A, p.43*) in CEP63 was described in three cousins with microcephaly, short stature, mild to moderate intellectual disability and diagnoses of Seckel syndrome. Here, we report a second family with three siblings who are compound heterozygous for loss-of-function variants in CEP63, c.1125T>G, p.(Tyr375*) and c.595del, p.(Glu199Asnfs*11). All siblings present with microcephaly, prominent nose, and intellectual disability but only one has severe short stature. Two siblings have aggressive behavior, a feature previously not reported in Seckel syndrome. This report adds two novel truncating variants in CEP63 and extends the clinical knowledge on CEP63-related conditions.

Association of Meier-Gorlin and microcephalic osteodysplastic primordial dwarfism type II clinical features in an individual with CDK5RAP2 primary microcephaly.

Autosomal recessive primary microcephaly type 3 (MCPH3) caused by pathogenic variations in CDK5RAP2, is characterized by sensorineural hearing loss, abnormality of skin pigmentation, ocular defects and severe microcephaly associated with neurodevelopmental delay. In this study, we expand the phenotype of MCPH3 as we describe a 10-year-old girl with a biallelic exonic frameshift variant in CDK5RAP2 displaying previously unreported features usually associated with Meier-Gorlin and microcephalic osteodysplastic primordial dwarfism type II (MOPDII). We further describe the clinical phenotype of this form of centrosomal-based primary microcephaly and emphasize the importance of skeletal defect screening in affected individuals.

Robinow Syndrome: A Rare Diagnosis from Pakistan.

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Long-acting PEGylated growth hormone in children with idiopathic short stature: time to reconsider our diagnostic and treatment policy?

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated. Idiopathic short stature is an approved indication for recombinant human growth hormone (rhGH) in the USA but not in most other parts of the world. In a recent article published in this journal, Luo et al reported on the 1-year's results of a multicentre randomized controlled trial (n = 360) on the efficacy and safety of two dosages of long-acting PEGylated rhGH (PEG-rhGH, Jintrolong®) (0.1 or 0.2 mg/kg body weight per week, respectively) in children with ISS compared with an untreated control group. The growth response to the higher dosage was similar to reported data on daily rhGH. In this commentary, we discuss whether the recent data on genetic causes of short stature in children who initially were labelled ISS, and data on the long-term safety of daily rhGH, may influence the balance between risks and benefits of rhGH treatment in children with ISS. We further discuss the pharmacokinetic and -dynamic profile of PEG-rhGH and its potential consequences for long-term safety.

Approach to the Patient With Short Stature: Genetic Testing.

The first step in the evaluation of the short child is to decide whether growth parameters in the context of the history are abnormal or a variant of normal. If growth is considered abnormal, system and hormonal tests are likely to be required, followed by more directed testing, such as skeletal survey and/or genetic screening with karyotype or microarray. In a small percentage of short children in whom a diagnosis has not been reached, this will need to be followed by detailed genetic analysis; currently, exome sequencing using targeted panels relevant to the phenotype is the commonly used test. Clinical scenarios are presented that illustrate how such genetic testing can be used to establish a molecular diagnosis, and how that diagnosis contributes to the management of the short child. New genetic causes for short stature are being recognized on a frequent basis, while the clinical spectrum for known genes is being extended. We recommend that an international repository for short stature conditions is established for new findings to aid dissemination of knowledge, but also to help in the definition of the clinical spectrum both for new and established conditions.