Extreme Short Stature Research Articles

Pregnancy in a woman with extreme short stature and low body weight secondary to a collagen VI-related muscular dystrophy

Pregnancy poses significant physiological demands, and women of extreme short stature may be particularly at risk of complications. Described here are two pregnancies in a woman who was 130 cm tall with a body mass index of 12 kg/m2 and the maternal and neonatal outcomes. The challenges encountered in the care of our patient included cardiorespiratory compromise, management of medication dosing, management of delivery and bleeding risk.

Gait in children with achondroplasia \u2013 a cross-sectional study on joint kinematics and kinetics

BackgroundChildren with achondroplasia have extreme short stature due to short limbs, as well as several other clinical features that may affect their gait. The purpose of this cross-sectional study was to provide a detailed description of gait in children with achondroplasia compared to age-matched controls.MethodsBetween the years 2007 and 2010, 16 children with achondroplasia [mean age 9.6 years (range 5–16; six female)] with no previous history of orthopaedic lower limb surgery and 19 age-matched controls conducted three-dimensional (3D) gait analysis at one occasion. The gait analysis rendered pelvis and lower limb joint kinematics and kinetics, and time and distance data. Descriptive statistics, independent samples t-tests, and Fisher’s exact test were used to describe the cohort including gait data and participant characteristics.ResultsChildren with achondroplasia had kinematic gait pattern deviations in all three planes, especially in the sagittal plane, when compared to the control group. Peak anterior pelvic tilt and peak ankle dorsiflexion were found to be increased. Increased knee flexion was noted at initial contact and again at terminal stance. During stance, children with achondroplasia had a higher peak hip abduction angle and a higher peak knee varus angle in the frontal plane. In the sagittal plane, kinetic gait pattern deviations were found at the hip, knee, and ankle, consistent with a flexion pattern. Compared to the control group, children with achondroplasia walked with reduced walking speed and step length, and increased cadence. There was no difference in walking speed when leg length was taken into account. Normalised step length and normalised cadence, on the other hand, were found to be increased in children with achondroplasia.ConclusionsThe observed gait characteristics in children with achondroplasia are related to anatomical attributes and strategies to increase step length, and hence walking speed.

Clinical and Functional Characterization of a Novel Mutation in AVPR2 Causing Nephrogenic Diabetes Insipidus in a Four-Generation Chinese Family.

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects.Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP.Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved.Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients.

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

ContextSevere forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.ObjectiveThis work aims to identify the genetic cause of growth failure in 3 “classical” GHI individuals.MethodsA novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.ResultsWe identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.ConclusionNovel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature.

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.

Clinical charts for surveillance of growth and body proportion development in achondroplasia and examples of their use.

Clinical surveillance of infants and children with achondroplasia necessitates syndrome‐specific charts due to extreme short stature with deviating body proportions. Height, arm span and leg length develop far below normal population ranges. We present growth and body proportion charts for ages 0–20 years, constructed from semi‐longitudinal standardized measurements of about 450 children, along with some examples of achondroplasia typical and atypical growth pattern. We combine head circumference, height and weight for 0–4 years into one (infancy) page and height and weight for 4–20 years in another (childhood–adolescence) using nonlinear axes to account for the rapidly decreasing growth velocity. Similarly, weight and BMI are based on nonlinear axes to balance wide SD‐channels at higher and narrow SD‐channels at lower levels of weight/BMI. Charts for following sitting height, sitting height/height ratio, arm span, leg and foot length are also presented. Clinical examples illustrating the applicability of the charts include cases of extreme prematurity, extreme head circumference development before and after shunting, achondroplasia complicated by chromosomal or additional genetic abnormality and by growth hormone deficiency as well as of evaluating growth promoting therapy.

Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome.

Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.

Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome

MaterialLinked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA...

Co-occurrence of genomic imbalances on Xp22.1 in the SHOX region and 15q25.2 in a girl with short stature, precocious puberty, urogenital malformations and bone anomalies

BackgroundMutations of SHOX represent the most frequent monogenic cause of short stature and related syndromes. The genetic alterations include point mutations and deletions/duplications spanning both SHOX and its regulatory regions, although microrearrangements are confined to either the downstream or upstream enhancers in many patients. Mutations in the heterozygous state have been identified in up to 60–80% of Leri-Weill Dyschondrosteosis (LWD; MIM #127300) and approximately 4–5% of Idiopathic Short Stature (ISS; MIM#300582) patients. Homozygous or compound heterozygous mutations as well as biallelic deletions of SHOX and/or the enhancer regions result in a more severe phenotype, which is known as Langer Mesomelic Dysplasia (LMD; MIM #249700).Case presentationA 17 year old girl, presented with severe short stature, growth hormone deficiency (GHD), precocious puberty, dorsal scoliosis, dysmorphisms and urogenital malformations. She was born with agenesis of the right tibia and fibula, as well as with a supernumerary digit on the left foot. Array comparative genomic hybridization (aCGH) analysis detected the presence of two distinct duplications on Xp22.1 flanking the SHOX coding sequence and involving its regulatory regions. An additional duplication of 1.6–2.5 Mb on 15q25.2 that included 13 genes was also identified. The girl was adopted and the parent’s DNA was not available to establish the origin of the chromosome imbalances.ConclusionsThe complex phenotype observed in our patient is probably the result of the co-occurrence of rearrangements on chromosomes Xp22.1 and 15q25.2. The duplicated region on 15q25.2 region is likely to contain dosage-sensitive genes responsible for some of the clinical features observed in this patient, whereas the extreme short stature and the skeletal anomalies are likely attributable to the comorbidity of GHD and copy number variants in the SHOX region.

Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action.

GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature and dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical, and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical, and genetic characteristics. The objective of this review is to clarify the definition, identification, and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.

An atypical case of Noonan syndrome with KRAS mutation diagnosed by targeted exome sequencing.

Noonan syndrome (NS) is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES) is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.

A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2

Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation.

Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system.

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

Bone dysplasia

Bone dysplasia is a large group that encompasses 436 rare diseases. Many of them are characterized by short stature or decreased growth velocity during puberty. The diagnosis of short stature due to skeletal dysplasia relies on (i) physical features such as disproportionate trunk/limbs, short limbs or extremities and/or stocky build, (ii) radiographic features to analyze mineralization, maturation and bone morphology, and (iii) whenever possible, the genetic characterization. Bone dysplasia mostly affect many organs, and therefore require multidisciplinary follow-up and care. The role of the pediatric endocrinologist is to assess the growth potential of these patients in coordination with the other caregivers, offer the best management of the growth to limit the psychosocial consequences of the extreme short stature and bone deformities.

Laron Syndrome: Siblings with Extreme Short Stature and Very High Growth Hormone

Primary growth hormone resistance or growth hormone insensitivity syndrome (GHIS), also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance attributable to severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor-1 (IGF-1) and low serum insulin-like growth factor binding protein (IGFBP-3)values. It is an autosomal recessive disorder and to date, more than 70 unique growth hormone receptor (GHR) mutations have been identified in more than 250 GHIS patients. We report the case of an 8-year-old boy and his 12-year-old sister born to first cousin parent that presented with severe short stature who had the classic feature of GH deficiency. Investigations revealed high plasma GH levels in both the cases. Subsequently, IGF-1 and IGFBP-3 assay were done and the levels were found to be very low. These reports along with elevated GH level in the context of typical picture of GH deficiency confirmed the diagnosis of GHIS. Genetic testing could not be done because of unavailability in our context. Regrettably specific therapy in the form of recombinant IGF-1 could not be offered as it is not commercially available in our country.

Novel Fanci Mutations in Fanconi Anemia with Vacterl Association

Introduction: Fanconi anemia (FA) is associated with mutations in at least 18 genes in the FA/BRCA DNA repair pathway. Some patients with FA have features of the VACTERL association (vertebral anomalies, anal atresia, congenital heart disease, trachea-esophageal fistula, esophageal atresia, renal, and limb anomalies [radius and/or thumb]). Any three anomalies are required to be classified as VACTERL association. The presence of this association among cases with FA is considered to be 5%; the frequency of FA among those with VACTERL association is unknown.Objective: To determine the genotype in previously uncharacterized patients with FA and to examine the relationship between genotype and features of VACTERL association.Methods: The NCI FA cohort included 18 unrelated patients with the VACTERL association, among 54 FA patients who had comprehensive examinations including radiologic and ultrasound studies at the NIH Clinical Center (33%). DNA from patients with unknown genotypes was subjected to whole exome sequencing (WES) at the NCI's Cancer Genomic Research Laboratory; one patient's DNA was also studied by sequencing the coding regions of all known FA genes (Haloplex sequencing) at Vrije Universiteit.Results: Mutations in FANCI were identified in three of the 18 patients with the VACTERL association, two at the NCI and the third patient at Vrije Universiteit; there were no FANCI patients among those without the VACTERL association. Mutations in the others with VACTERL were A (N=6), C (N=4), D2 (N=2), J (N=2), and unknown (N=1).NCI-82-1 had multiple birth defects. At 5 9/12 years she had extreme short stature, microcephaly, triangular face, and VACTERL features (fused cervical vertebrae, atrial septal defect [ASD], ventricular septal defect [VSD], duodenal atresia, small kidneys, and absent thumbs). Progressive cytopenias led to stem cell transplantation at age 10 1/2 years, with death a year later from multi-organ failure. WES data identified FANCI mutations: one deletion (p.Ser1268Argfs*5) and one insertion (p.Asp1301Glyfs*3) resulting in premature stop codons.NCI-253-1 was born at 34 weeks with multiple birth defects. At age 3 she had marked short stature, microcephaly, triangular face, and VACTERL features (cervical vertebral anomaly, VSD, patent foramen ovale, horseshoe kidney, and dangling thumb). Haploplex sequencing revealed one novel mutation in FANCI (p.Cys1014Tyr) and one previously reported mutation (p.Tyr487X).NCI 309-1 was one of fraternal twins conceived by in vitro fertilization and delivered at 32 weeks by C-section. At age 8 she had microcephaly, a small, triangular face, small eyes, Chiari malformation, and a small pituitary gland with poorly visualized pituitary stalk. Her VACTERL features included small neck, narrow C5 vertebra, bilaterally hypoplastic thumbs, absent radial pulses, and bilateral ureteric reimplantation for reflux. Her FANCI WES identified two mutations, p.Ser347Pro and p.Gly401Glufs*3.Conclusion: These three cases with FANCI, plus four among 13 with FANCI in the literature constitute seven of 16 cases with FANCI with VACTERL features (44%), significantly higher than the predicted 5%. Recent studies demonstrated that VACTERL features were more frequent than the expected 5% in individuals with FANCB, D1, D2, J, N, and O (Alter and Rosenberg, Mol Syndromol 2013) and L (Vetro et al, Hum Mut 2015). Mutations in FANCI should be added to the genotypes with a very high frequency of the VACTERL phenotype. DisclosuresNo relevant conflicts of interest to declare.

AB069. Effect of osteogenesis imperfecta on children and their families

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder, with features that include increased bone fragility, pathological fractures, blue sclera, dentinogenesis imperfecta and conductive or mixed hearing loss. Clinical variability is wide from children with few fractures and normal stature to children with multiple fractures, long bone deformity, scoliosis and extreme short stature. Although there is no curative treatment, there are several therapeutic tools capable of improving the course of the condition and patient quality of life. We aim to evaluate the effect of OI on the well-being of children with the disorder and their families through a family-centered questionnaire. Sixty children with OI from the Vietnam National Hospital of Pediatrics and/or their parent(s), who attended the first annual family support group in 2011, completed a child and parent questionnaire. Sixty patients participated, 26 female and 34 male. The median age was 6.0 years [interquartile range (IQR), 0.25-18 years]. Of these, 36 (60%) had dentinogenesis imperfect and 23 (38.3%) had a scoliosis. The median number of fractures was 6.0 (IQR 0-30) and median number of hospitalizations due to OI was 5.0 (IQR 0-30). Among patients of school age, 9 (15%) could not go to school due to OI. Almost all parents (93.7%) worried about school social communication of the patients. Among these parents, 100% fear of inferiority with friends and 98.3% fear of broken bones. Most parents (76.2%) were significantly concerned about their child’s health. The parents’ themselves reported psychological concerns, with feelings of desperation (58.4%), anxiety (81.7%) and depression (56.7%). OI appeared to have a significant deleterious effect on the life of the patients and their families. These data provide a baseline from which to evaluate the effectiveness of interventions to improve the medical and psychological needs of this cohort and their families.

The origin of the p.E180 growth hormone receptor gene mutation

Laron syndrome, an autosomal recessive condition of extreme short stature, is caused by the absence or dysfunction of the growth hormone receptor. A recurrent mutation in the GHR gene, p.E180, did not alter the encoded amino acid, but activated a cryptic splice acceptor resulting in a receptor protein with an 8-amino acid deletion in the extracellular domain. This mutation has been observed among Sephardic Jews and among individuals in Ecuador, Brazil and Chile, most notably in a large genetic isolate in Loja, Ecuador. A common origin has been postulated based on a shared genetic background of markers flanking this mutation, suggesting that the Lojanos (and others) may have Sephardic (Converso) Jewish ancestry. Analysis of the population structure of Lojanos based on genome-wide analysis demonstrated European, Sephardic Jewish and Native American ancestry in this group. X-autosomal comparison and monoallelic Y chromosomal and mitochondrial genetic analysis demonstrated gender-biased admixture between Native American women and European and Sephardic Jewish men. These findings are compatible with the co-occurrence of the Inquisition and the colonization of the Americas, including Converso Jews escaping the Inquisition in the Iberian Peninsula. Although not found among Lojanos, Converso Jews also brought founder mutations to contemporary Hispanic and Latino populations in the BRCA1 (c.68_69delAG) and BLM (c.2207_2212delATCTGAinsTAGATTC) genes.

Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Kilic A, Çakmak S, Tuncali T, et al. Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2015;32(6):470-474. doi:10.5114/pdia.2015.56102. APA Kilic, A., Çakmak, S., Tuncali, T., Koz, O., Ozhamamci, E., & Yasun, O. et al. (2015). Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 32(6), 470-474. https://doi.org/10.5114/pdia.2015.56102 Chicago Kilic, Arzu, Seray Külcü Çakmak, Timur Tuncali, Ozlem Koz, Esra Ozhamamci, Oztan Yasun, and Ferda Artuz. 2015. "Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature". Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii 32 (6): 470-474. doi:10.5114/pdia.2015.56102. Harvard Kilic, A., Çakmak, S., Tuncali, T., Koz, O., Ozhamamci, E., Yasun, O., and Artuz, F. (2015). Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 32(6), pp.470-474. https://doi.org/10.5114/pdia.2015.56102 MLA Kilic, Arzu et al. "Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature." Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, vol. 32, no. 6, 2015, pp. 470-474. doi:10.5114/pdia.2015.56102. Vancouver Kilic A, Çakmak S, Tuncali T, Koz O, Ozhamamci E, Yasun O et al. Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2015;32(6):470-474. doi:10.5114/pdia.2015.56102.

Physical growth, puberty and hormones in adolescents with Nodding Syndrome; a pilot study.

BackgroundNodding syndrome is an epidemic symptomatic generalized epilepsy syndrome of unknown cause in Eastern Africa. Some patients have extreme short stature. We hypothesized that growth failure in nodding syndrome is associated with specific endocrine dysfunctions. In this pilot study, we examined the relationship between serum hormone levels and stature, bone age and sexual development.ResultsWe recruited ten consecutive children, 13 years or older, with World Health Organization defined nodding syndrome and assessed physical growth, bone age, development of secondary sexual characteristics and serum hormone levels. Two children with incomplete results were excluded. Of the eight remaining, two had severe stunting (height for age Z [HAZ] score < -3) and three had moderate stunting (HAZ score between-3 and -2). The bone age was delayed by a median 3(range 0-4) years. Serum growth hormone levels were normal in all eight but the two patients with severe stunting and one with moderate stunting had low levels of Somatomedin C (Insulin like Growth Factor [IGF1]) and/or IGF binding protein 3 (IGFBP3), mediators of growth hormone function. A linear relationship was observed between serum IGF1 level and HAZ score. With the exception of one child, all were either pre-pubertal or in early puberty (Tanner stages 1 and 2) and in the seven, levels of the gonadotrophins (luteinising and follicle stimulating hormone) and the sex hormones (testosterone/oestrogen) were all within pre-pubertal ranges or ranges of early puberty. Thyroid function, prolactin, adrenal, and parathyroid hormone levels were all normal.ConclusionsPatients with nodding syndrome may have dysfunctions in the pituitary growth hormone and pituitary gonadal axes that manifest as stunted growth, delayed bone age and puberty. Studies are required to determine if such endocrine dysfunction is a primary manifestation of the disease or a secondary consequence of chronic ill health and malnutrition and if so, whether targeted interventions can improve outcome.