Dynamic analysis of amplitude of low-frequency fluctuation in children with growth hormone deficiency.

OBJECTIVE: Growth hormone (GH) affects brain activities and promotes growth and development. GH is a peptide hormone secreted by the anterior pituitary gland and is tied to behavior and cognitive function. Growth hormone deficiency (GHD) is the most common type of pathological short stature in children. Existing studies provide evidence that GHD may impact functional brain activities. The aim of this study was to investigate dynamic local brain activity in GHD children. METHOD: In this study, we combined amplitude of low-frequency fluctuations (ALFF) and sliding-window techniques to examine the local brain activity of children with GHD. The resting-state functional magnetic resonance imaging (fMRI) data were collected from 26 children with GHD and 15 age- and sex-matched healthy controls (HC). RESULT: Our results showed significant abnormal temporal variability of dynamic ALFF in widespread regions in children with GHD, primarily in the frontal gyrus, temporal gyrus, and parietal lobule. CONCLUSION: The dALFF can capture dynamic changes in brain spontaneous activity, which are related to behavior and cognition. Based on this dynamic local brain activity, the results of this study provide a better understanding of the pathophysiological mechanism in children with GHD.

CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum.

Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India.

BACKGROUND: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. METHODS: Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. RESULTS: 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. CONCLUSION: This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'.

Identification of Diagnostic Variants in FGFR2 and NPR2 Genes in a Chinese Family Affected by Crouzon Syndrome and Acromesomelic Dysplasia, Type Maroteaux.

This study aims to conduct a comprehensive clinical and genetic investigation on a large family with members having various phenotypes, including acromesomelic dysplasia, type Maroteaux (AMDM), idiopathic short stature (ISS), Crouzon syndrome (CS). Prenatal diagnosis was performed on the high-risk fetus. We performed the whole-exome sequencing on three members with AMDM, ISS, or CS. Detailed genotypes and phenotypes were investigated on members of this 4-generation family. Genetic analysis identified three variants, which were designated as p.Val548del, p.Arg989Gln in natriuretic peptide receptor B/guanylate cyclase B (NPR2), and p.Cys342Tyr in fibroblast growth factor receptor-2 (FGFR2). Compound heterozygous variation consisting of p.Val548del and p.Arg989Gln caused AMDM. NPR2 heterozygous variant carriers exhibited normal height or ISS. The p.Cys342Tyr mutation of FGFR2 causes the typical clinical phenotype of CS. The fetus carried the heterozygous p.Val548del and p.Cys342Tyr mutations, with ultrasound results showing exophthalmos, parrot-beaked nose, low and flat frontal skull, and intrauterine growth retardation at the second and third trimesters of gestation. We are reporting those two novel mutations (p.Val548del and p.Arg989Gln) in NPR2 and a p.Cys342Tyr mutation in FGFR2 in an extended Chinese family. This finding extended the genotype-phenotype spectra of ISS, AMDM, and CS related to pathogenic variants.

A novel variant in GNPNAT1 gene causing a spondylo-epi-metaphyseal dysplasia resembling PGM3-Desbuquois like dysplasia.

Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.

Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging From Lethal Skeletal Ciliopathy to Severe Acromesomelic Dysplasia.

Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype-phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A second individual with rhizomelic spondyloepimetaphyseal dysplasia and homozygous variant in GNPNAT1.

Spondyloepimetaphyseal dysplasias (SEMDs) belong to a clinically and genetically heterogeneous group of inherited skeletal disorders defined by a defect in the growth and shape of vertebrae, epiphyses and metaphyses. Rhizomelic SEMD is characterized by a disproportionate small stature caused by severe shortening and deformation of the limbs' proximal bones, with the cranio-facial sphere unaffected. We report a second individual, an 8-year-old girl, with autosomal recessive rhizomelic SEMD associated with a homozygous exonic missense variant, c.226G > A p.(Glu76Lys), in GNPNAT1 identified by trio genome sequencing. Our data corroborate the recent findings of Ain et al. and further delineate the clinical and radiographic features of this form of SEMD associated with rhizomelic dysplasia while outlining a potential hotspot in this newly described genetic disorder.

Whole genome sequencing identifies pathogenic RNU4ATAC variants in a child with recurrent encephalitis, microcephaly, and normal stature.

Biallelic pathogenic variants in RNU4ATAC have been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Although children with MOPD1 have been reported to show profound, life-limiting clinical decompensation at the time of a febrile illness, these episodes including magnetic resonance imaging (MRI) findings have not been well characterized. We present acute MRI brain findings for a 10-year-old girl with homozygous variants in RNU4ATAC (NR_023343.1) n.55G>A, who presented with two episodes of clinical decompensation associated with a febrile illness in early childhood. The pathogenic variants were identified by whole genome sequencing as RNU4ATAC is not captured in most exome products. Her MRI of the brain revealed symmetric, diffusion restriction of the deep gray nuclei that initially pointed to a mitochondrial disease or acute necrotizing encephalopathy. Her phenotype included microcephaly and profound cognitive impairment that can be seen with MOPD1. However, she did not demonstrate clinical or radiographic evidence of a spondyloepimetaphyseal dysplasia or "primordial dwarfism" that is characteristic of this disease. As such, the predominant neurological presentation of this child represents an atypical variant of RNU4ATAC-associated disease and should be a diagnostic consideration for geneticists and neurologists caring for children, particularly in the event of an acute clinical decline.

Skeletal Manifestations of Heritable Disproportionate Dwarfism in Cats as Determined by Radiography and Magnetic Resonance Imaging.

OBJECTIVE: The aim of this study was to characterize the radiographic alignment of thoracic and pelvic limbs and evaluate for intervertebral disc disease in cats with feline disproportionate dwarfism (FDD). STUDY DESIGN: Observational cross-sectional study. Radiographic joint orientation angles were measured in 10 thoracic and pelvic limbs from 5 FDD cats and compared with those angles measured in 24 thoracic limbs and 100 pelvic limbs from skeletally normal cats. Magnetic resonance imaging of the spine was performed in 2 FDD cats for the evaluation of pathology of the intervertebral discs or vertebrae. RESULTS: All limbs from FDD cats possessed deformities. FDD humeri demonstrated procurvatum proximally, and recurvatum distally in the sagittal plane, but showed no difference in the frontal plane. FDD radii possessed excessive recurvatum proximally, and procurvatum distally in the sagittal plane, and varus proximally and valgus distally in the frontal plane. Whereas no torsion was discernible in the humeri, all radii had external torsion. In the frontal plane, FDD femurs exhibited varus both proximally and distally whereas the tibia possessed proximal valgus and distal varus. No torsion in the pelvic limbs was observed. No spinal pathology was detected in the FDD cats included in the original study. CONCLUSION: Feline disproportionate dwarfism results in significant appendicular deformity in all limbs. The incidence of intervertebral disc degeneration in FDD cats is inconclusive.

A case report of Arnold Chiari type 1 malformation in acromesomelic dwarf infant.

Arnold Chiari malformation is one of the commonest cause of congenital hydrocephalus. Cause of fetal development of cerebellar tonsils remains unknown and may be diagnosed at later in life. The association of Arnold Chiari malformation with acromesomelic dwarfism is not known. We report male infant diagnosed with acromesomelic dwarfism at end of gestation period on basis of antenatal ultrasonography findings. An ultrasound scan of infant head at fifth month of birth was performed in view of increasing head circumference that revealed aqueductal stenosis with dilated posterior horn of lateral ventricles in brain.

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants.

We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.

Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine.

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.

Canine DVL2 variant contributes to brachycephalic phenotype and caudal vertebral anomalies.

A frameshift deletion variant in the Wnt pathway gene dishevelled 2 (DVL2) is associated with a truncated, kinked tail ("screw tail") in English Bulldogs, French Bulldogs and Boston Terriers. These breeds are also characterized by distinctive morphological traits, including a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans, caused by defects in genes such as DVL1 and DVL3. Based on these phenotypic and genetic similarities, it has previously been hypothesized that the canine DVL2 variant results in a syndromic phenotype called the Robinow-like syndrome. In our study, we investigated the distribution of the DVL2 variant in 1954 dogs from 15 breeds, identifying breeds with allele variation and enabling the dissection of the genotype-phenotype correlation for the first time. With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects. Altogether, our study strengthens the role of DVL2 as one of the contributors to the "bulldog type" morphology and features on the spectrum of human Robinow syndrome.

Early prenatal presentation of the cartilage-hair hypoplasia / anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia.

Three sibling fetuses identified with limb shortening and thoracic narrowing at twelve weeks' gestation on first trimester ultrasound examination are presented. The parents were non-consanguineous, Caucasian, healthy, of normal stature and had a healthy normal daughter. The radiographic abnormalities were highly suggestive of thanatophoric dysplasia, but molecular analysis failed to identify a pathogenic variant in FGFR3. The three fetuses were found to have identical compound heterozygous mutations in RMRP in trans, one inherited from the mother and one from the father. This represents the early prenatal presentation and fetal findings of metaphyseal dysplasia type McKusick (Cartilage-hair hypoplasia; CHH)/anauxetic dysplasia spectrum of disorders.

Clinical and molecular characterization of four patients with Robinow syndrome from different families.

Robinow syndrome (RS) is a rare heterogeneous disorder characterized by short stature, short-limbs, craniofacial, oro-dental abnormalities, vertebral segmentation defects, and frequently genital hypoplasia. Both autosomal dominant and recessive patterns of inheritance are observed with many causative genes. Here, we present the phenotypes and genotypes of four children with RS from different Indian families. Sequence variants were identified in genes ROR2, DVL1, and DVL3. Our results expand the mutational spectrum of RS and we also highlight the radiological changes in the radius and ulna in patients with ROR2 sequence variants which are primarily characteristic for ROR2 related RS but have been reported in WNT5A related RS.

Revision Arthroplasty with Total Femur Replacement for the Management of Complex Post-traumatic Bone Defect in a Patient with Dwarfism. / Revisionsendoprothetik mit Totalfemurendoprothese zur Behandlung komplexer posttraumatischer Knochendefekte bei einem Patienten mit Zwergwuchs.

Dwarfism leads to an early onset of osteoarthritis of the joints of the lower limb. Due to bone deformities, arthroplasty is challenging. The incidence of implant-associated complications is higher compared to the normal population and often ends up with multiple revision arthroplasties. We report the first case in the literature of a 48-year-old patient with dwarfism who required implantation of a custom-made total femoral replacement due to aseptic stem loosening and a concomitant valgus gonarthrosis.

Intracranial aneurysms in microcephalic primordial dwarfism: a systematic review.

BACKGROUND: Microcephalic primordial dwarfism (MPD) is a heterogeneous group of rare disorders. Recent studies have reported a significant percentage of patients with MPD suffering from a spectrum of cerebrovascular abnormalities, including intracranial aneurysms (IAs) and moyamoya syndrome. The neurological literature has not as yet specifically assessed IAs in this population. This systematic review aimed to assess the clinical behavior, characteristics, treatment modalities and outcomes of IAs in patients with MPD. METHODS: We performed a systematic search in PubMed, Ovid MEDLINE and Ovid EMBASE for cases of MPD with IAs. We included three illustrative cases from our institution. RESULTS: Twenty-four patients with 71 aneurysms were included in this study. Twelve patients (50%) presented with subarachnoid hemorrhage. The majority of patients were aged ≤18 years (70.8%), with a mean age of 16.2 years at presentation. Median aneurysm size was 3 (IQR 1.8-6) mm, and the most frequent locations were the internal carotid (37.3%) and middle cerebral arteries (23.8%). Concomitant moyamoya disease was reported in nine (37.5%) patients. Median age of aneurysm detection in screened patients was significantly lower than in non-screened patients (P=0.02). Microsurgical clipping (55.3%) and endovascular coiling (26.3%) were the most used modalities. Twenty-two cases were managed conservatively. Overall, mortality occurred in 45.8% of cases. CONCLUSIONS: Screening for cerebrovascular disease seems reasonable and effective to detect aneurysms at an earlier age in this population. Efforts in the literature to emphasize early and regular screening for these patients can positively impact outcomes in this population, however more evidence is needed.

Earlier detection of hypochondroplasia: A large single-center UK case series and systematic review.

Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004-2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.