Menkes Disease Research Articles

EP195: Safety and efficacy of Copper Histidinate (CUTX-101) treatment for Menkes disease caused by severe loss-of-function variants in ATP7A

Menkes disease (MD) is a X-linked recessive disorder caused by variants in the copper transporter gene, ATP7A. Although MD patients appear asymptomatic at birth, they develop significant neurological signs and symptoms such as seizures, hypotonia, and failure to thrive approximately 6-10 weeks after birth. Death by 3 years of age is the typical outcome in untreated MD. Copper histidinate (CUTX-101) is being investigated for treatment of this illness.

EP115: Two novel NPR2 variants in a patient with acromesomelic dysplasia - Maroteaux type

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature (adult height < 120 cm), dolichocephaly, acro- and mesomelic shortening of the limbs, short, broad fingers and flat feet. Radiographic findings include bowed radius with a short ulna, dolichocephaly, platyspondyly and narrowing of the lumbar interpedicular distances. Intelligence is unaffected. The condition is typically diagnosed at birth or in infancy, but features become more apparent over time because of the loss of linear growth. AMDM is caused by biallelic loss of function variants in the NPR2 gene which encodes the natriuretic peptide receptor-B (NPR-B). The NPR2 gene encodes a transmembrane receptor that is critical in endochondral bone formation. Forty four percent of variants in NPR2 occur in the ligand binding domain, 8% in the transmembrane domain, 26% in the protein kinase domain and 21% in the nucleotide cyclase domain. A seven-month-old was seen with clinical findings suggestive of a skeletal dysplasia. She was born at 36 weeks following a pregnancy complicated by maternal polysubstance use and poor prenatal care. Clinical findings were shortening of all limb segments, trident hands, weak grasp, and overlapping second and third toes bilaterally. Radiographic findings were shortening of all the long bones with metaphyseal flaring, short and broad metatarsals, metacarpals and phalanges also with mild metaphyseal widening, platyspondyly with mild anterior vertebral body beaking in the upper lumbar spine. Cervical CT examination revealed platyspondyly of the suboccipital vertebrae and decreased AP diameter of the spinal canal at C1 secondary to anterior bowing of the posterior arch. A multi-gene skeletal dysplasia panel identified twelve variants, including two variants in NPR2. NPR2 c.1699G>T was classified as pathogenic, causing a premature termination at amino acid 567 in the kinase homology domain of the transmembrane protein. While classified as a VUS, the c.1123G>A missense variant was predicted to cause a substitution at amino acid 375 and falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. The patient’s mother tested positive for the pathogenic variant and negative for the VUS in NPR2. Acromesomelic dysplasia, Maroteaux type is a rare skeletal dysplasia with limited published phenotypic and molecular information available. The described patient presented a diagnostic conundrum because only one of the variants had been characterized as pathogenic. The variant of uncertain significance is located in the ligand binding domain of the NPR2 gene, in which the majority of reported variants in this gene are found. In silico algorithms predict this variant to be deleterious to the protein structure and function but these predictions have not been confirmed by functional studies. Furthermore, missense variants within the consensus splice sites commonly cause abnormal splicing. This variant is not found in population databases. While paternal samples are not available to confirm that the variants are in trans, the patient was given the diagnosis of AMDM based on her clinical presentation. Molecular analysis and clinical description of other patients with AMDM will continue to characterize disease causing variants and natural history of this rare disease.

Abnormal Development of Neural Stem Cell Niche in the Dentate Gyrus of Menkes Disease.

Background and ObjectivesMenkes disease (MNK) is a rare X-linked recessive disease, caused by mutations in the copper transporting ATP7A gene that is required for copper homeostasis. MNK patients experience various clinical symptoms including neurological defects that are closely related to the prognosis of MNK patients. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) produce new neurons throughout life, and defects in DG neurogenesis are often correlated with cognitive and behavioral problems. However, neurodevelopmental defects in the DG during postnatal period in MNK have not been understood yet.Methods and ResultsMottled-brindled (MoBr/y) mice (MNK mice) and littermate controls were used in this study. In vivo microCT imaging and immunohistochemistry results demonstrate that blood vasculatures in hippocampus are abnormally decreased in MNK mice. Furthermore, postnatal establishment of NSC population and their neurogenesis are severely compromised in the DG of MNK mice. In addition, in vitro analyses using hippocampal neurosphere culture followed by immunocytochemistry and immunoblotting suggest that neurogenesis from MNK NSCs is also significantly compromised, corresponding to defective neurogenic gene expression in MNK derived neurons.ConclusionsOur study is the first reports demonstrating that improper expansion of the postnatal NSC population followed by significant reduction of neurogenesis may contribute to neurodevelopmental symptoms in MNK. In conclusion, our results provide new insight into early neurodevelopmental defects in MNK and emphasize the needs for early diagnosis and new therapeutic strategies in the postnatal central nerve system damage of MNK patients.

Early clinical signs and treatment of Menkes disease

Menkes disease (MD) is an X-linked recessive disorder caused by mutations in ATP7A. Patients with MD exhibit severe neurological and connective tissue disorders due to copper deficiency and typically die before 3 years of age. Early treatment with copper injections during the neonatal period, before the occurrence of neurological symptoms, can alleviate neurological disturbances to some degree. We investigated whether early symptoms can help in the early diagnosis of MD. Abnormal hair growth, prolonged jaundice, and feeding difficulties were observed during the neonatal period in 20 of 69, 16 of 67, and 3 of 18 patients, respectively. Only three patients visited a physician during the neonatal period; MD diagnosis was not made at that point. The mean age at diagnosis was 8.7 months. Seven patients, who were diagnosed in the prenatal stage or soon after birth, as they had a family history of MD, received early treatment. No diagnosis was made based on early symptoms, highlighting the difficulty in diagnosing MD based on symptoms observed during the neonatal period. Patients who received early treatment lived longer than their elderly relatives with MD. Three patients could walk and did not have seizures. Therefore, effective newborn screening for MD should be prioritized.

Enhancement of Gene Regulation of ATP7A by Flavanoids from Macrotyloma Uniflorum: Computer-Aided Investigation in Menkes Disease

Enhancement of Gene Regulation of ATP7A by Flavanoids from Macrotyloma Uniflorum: Computer-Aided Investigation in Menkes Disease

The Natural History of Non-operatively Managed Legg\u2013Calv\xe9\u2013Perthes\u2019 Disease

BackgroundThe purpose of this study was to examine the evolution of Legg–Calvé–Perthes’ disease (LCPD) among children from British Columbia (BC), Canada who were treated non-operatively and to compare the results to a previously conducted study in India.MethodsThis was a retrospective review of patients treated non-operatively for LCPD in BC between 1990 and 2006 compared with a cohort from India. Demographic and treatment information were collected from medical records. Radiographs were assigned modified Waldenstrom, Catterall, Salter–Thompson and Herring classifications and intra- and interobserver reliability were assessed. We evaluated epiphyseal extrusion (EE) and metaphyseal width (MW), and assessed radiographs using the Mose and modified Stulberg classifications.Results102 hips (90 patients) had radiographs available for evaluation. 95% of the BC cohort presented as Waldenstrom stages I and II, whereas, 90% of the Indian cohort presented as IIIa. Final EE was similar for both groups (BC 26.8%, India 27.3%) and final MW was 119% in both groups. Modified Waldenstrom and Herring classifications had substantial intra- and interobserver reliability, while Salter–Thompson and Catterall classifications had moderate agreement at best. Most hips were Catterall IV (80%) and Herring C (89%) for the BC cohort compared to only 44% and 43% of Indian hips, respectively. Most hips were irregular according to the Mose classification (BC 43%, India 52%) and aspherical according to the Stulberg classification (BC 78%).ConclusionsWe found similar radiographic progression and final radiographic appearances of LCPD in India and BC though differences in the distribution of the classification systems warrant further study.

Validation of the height-width measurement in Perthes disease among interpreters of different experience levels.

The epiphyseal height and metaphyseal width ratio estimated lateral pillar involvement with limited generalizability among various interpreters. The aim of the study was to evaluate the reliability and the validity of height-width ratio measurement in Perthes disease among interpreters of different experience levels. A cross-sectional study was conducted between 2019 and 2020. We included four groups of interpreters: orthopaedic residents, orthopaedic fellows, radiology residents and radiology fellows who were unaware of radiographic study materials. Each interpreter blindedly evaluated Perthes hip radiographs twice at 1-month intervals using the height-width ratio method. Patients' and interpreters' characteristics, height-width ratio and height-width ratio converted to lateral pillar classification (A, B and C) were collected. Intra- and interobserver reliability validated with the paediatric orthopaedist were estimated. Twenty-four interpreters assessed 18 Perthes radiographs. Intraobserver level of agreement (95% confidence interval) for height-width ratio was 0.022 (-0.017 to 0.062), -0.027 (-0.074 to 0.019), -0.010 (-0.095 to 0.074) and 0.019 (-0.109 to 0.146); and interobserver reliability compared with the paediatric orthopaedist was -0.007 (-0.091 to 0.077), 0.003 (-0.056 to 0.061), -0.021 (-0.077 to 0.035) and -0.002 (-0.090 to 0.086) for orthopaedic residents and fellows, radiology residents and fellows, respectively. Kappa statistics of height-width ratio converting to lateral pillar classification indicated intraobserver agreement of orthopaedic residents and fellows, radiology residents and fellows was 0.83, 0.75, 0.54 and 0.91; and interobserver agreement compared with the paediatric orthopaedist was 0.92, 0.83, 0.42 and 0.83, orderly. Height-width ratio and lateral pillar estimation by orthopaedic and radiology trainees have moderate to excellent reliability. Level of evidence: Level II - diagnostic study.

Evaluation of hair structural abnormalities in children with different neurological diseases

Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice. Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated. In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis. Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.

Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper.

The cuprizone (CPZ) model allows the study of the biochemical processes underlying nonautoimmune-mediated demyelination, remyelination, and chronic white matter disease progression. CPZ is a copper (Cu) chelator that chiefly causes oligodendrocyte apoptosis in the corpus callosum and cerebellum when administered in the mouse diet. While disruption of Cu homeostasis is known to cause neurodegeneration (as is observed in Wilson’s and Menkes disease), no consensus exists to date as to CPZ’s mechanism of action. We sought to determine whether CPZ-induced pathology is due to Cu depletion as is generally believed. Cu supplementation in chow, in stoichiometric excess to the added CPZ, did not reduce CPZ-induced demyelination in C57Bl/6 mice. Moreover, equivalent doses of other known Cu chelators neocuproine and D-penicillamine (D-Pen) failed to induce central nervous system (CNS) demyelination. Since administration of D-Pen in the treatment of Wilson’s disease can induce hypocupremia, we next sought to recreate penicillamine-induced Cu deficiency to compare with purported CPZ-induced Cu deficiency. The resulting clinical phenotype and histopathology were unlike that of CPZ. D-Pen-treated mice exhibited digit paralysis, tail flaccidity, subcutaneous hemorrhaging, and optic and sciatic neuropathy, all of which were prevented with Cu supplementation. No demyelination of the corpus callosum or cerebellum was observed, even with D-Pen doses tenfold higher than CPZ. Intriguingly, addition of D-Pen to the CPZ diet paradoxically prevented demyelination in a dose-dependent manner.Summary StatementThe demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex.

Clinical Characterization and Outcome of Menkes Disease in Saudi Patients

Clinical Characterization and Outcome of Menkes Disease in Saudi Patients

Rickets guidance: part I—diagnostic workup

Rickets is a disease of the growing child arising from alterations in calcium and phosphate homeostasis resulting in impaired apoptosis of hypertrophic chondrocytes in the growth plate. Its symptoms depend on the patients’ age, duration of disease, and underlying disorder. Common features include thickened wrists and ankles due to widened metaphyses, growth failure, bone pain, muscle weakness, waddling gait, and leg bowing. Affected infants often show delayed closure of the fontanelles, frontal bossing, and craniotabes. The diagnosis of rickets is based on the presence of these typical clinical symptoms and radiological findings on X-rays of the wrist or knee, showing metaphyseal fraying and widening of growth plates, in conjunction with elevated serum levels of alkaline phosphatase. Nutritional rickets due to vitamin D deficiency and/or dietary calcium deficiency is the most common cause of rickets. Currently, more than 20 acquired or hereditary causes of rickets are known. The latter are due to mutations in genes involved in vitamin D metabolism or action, renal phosphate reabsorption, or synthesis, or degradation of the phosphaturic hormone fibroblast growth factor 23 (FGF23). There is a substantial overlap in the clinical features between the various entities, requiring a thorough workup using biochemical analyses and, if necessary, genetic tests. Part I of this review focuses on the etiology, pathophysiology and clinical findings of rickets followed by the presentation of a diagnostic approach for correct diagnosis. Part II focuses on the management of rickets, including new therapeutic approaches based on recent clinical practice guidelines.

Acquired Hyperzincaemia Due to Zinc-Laden Denture Adhesives Leading to Hypocupraemia as a Cause of Neutropenia

IntroductionCopper deficiency or hypocupraemia is a rare cause of anaemia and neutropenia.Case descriptionWe hereby present the case of a 34-year-old female with gastric bypass surgery who presented with neutropenic fever, abdominal pain and diarrhoea, later found to have extended-spectrum beta-lactamase resistant Escherichia coli urinary tract infection and small bowel bacterial overgrowth syndrome, with her anaemia and neutropenia being caused by copper deficiency due to hyperzincaemia induced by using zinc denture adhesive cream.DiscussionVarious causes of copper deficiency have been recognized including, but not limited to, malnutrition, gastrectomy, gastric bypass surgery, protein-losing enteropathies (coeliac disease, tropical sprue), Wilson disease and Menkes syndrome. Copper deficiency caused by zinc overuse is not very prevalent. The haematologic abnormalities associated with copper deficiency are neutropenia, sideroblastic anaemia and/or pancytopenia.ConclusionBecause of its low prevalence and nonspecific haematologic and clinical manifestations, the diagnosis of zinc-induced copper deficiency (ZICD) can be missed.LEARNING POINTSZinc toxicity is a rare cause of hypocupraemia.The bone marrow and haematological manifestations of copper deficiency are not pathognomonic but include sideroblastic anaemia, pancytopenia or neutropenia.Early detection of hypocupraemia as a cause for neutropenia will improve morbidity and mortality by avoiding untoward infections due to neutropenia, neurological decline or unnecessary interventions.

Tracking Labile Copper Fluctuation In Vivo/Ex Vivo: Design and Application of a Ratiometric Near-Infrared Fluorophore Derived from 4-Aminostyrene-Conjugated Boron Dipyrromethene.

Specimen differences, tissue-dependent background fluorescence and scattering, and deviated specimen position and sensor concentration make optical imaging for labile copper fluctuation in animals questionable, and a signal comparison between specimens is infeasible. We proposed ratiometric optical imaging as an alternative to overcome these disadvantages, and a near-infrared (NIR) ratiometric sensor, BDPS1, was devised therefore by conjugating boron dipyrromethene (BODIPY) with 4-aminostyrene and modifying the 4-amino group as a Cu+ chelator. BDPS1 possessed an excitation ratiometric copper-sensing ability to show the ratio of NIR emission (710 nm) upon excitation at 600 nm to that at 660 nm, Fex600/Fex660, increasing from 2.8 to 10.7. This sensor displayed still the opposite copper response of its internal charge transfer (ICT; 670 nm) and local (581 nm) emission bands. Ratiometric imaging with this sensor disclosed a higher labile copper region near the nucleus apparatus, and HEK-293T cells were more sensitive to copper incubation than MCF-7 cells. Dual excitation ratiometric imaging with this sensor realized tracking of labile copper fluctuation in mice, and the whole-body imaging found that tail intravenous injection of CUTX-101, a therapeutical agent for Menkes disease, led to a distinct labile copper increase in the upper belly. The ex vivo imaging of the resected viscera of mice revealed that CUTX-101 injection enhanced the labile copper level in the liver, intestine, lung, and gall bladder in sequence, yet the kidney, heart, and spleen showed almost no response. This study indicated that modifying BODIPY as an extended ICT fluorophore, with its electron-donating group being derived as a metal chelator, is an effective design rationale of NIR ratiometric sensors for copper tracking in vivo/ex vivo.

Pili Torti: A Feature of Numerous Congenital and Acquired Conditions.

Pili torti is a rare condition characterized by the presence of the hair shaft, which is flattened at irregular intervals and twisted 180° along its long axis. It is a form of hair shaft disorder with increased fragility. The condition is classified into inherited and acquired. Inherited forms may be either isolated or associated with numerous genetic diseases or syndromes (e.g., Menkes disease, Björnstad syndrome, Netherton syndrome, and Bazex-Dupré-Christol syndrome). Moreover, pili torti may be a feature of various ectodermal dysplasias (such as Rapp-Hodgkin syndrome and Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome). Acquired pili torti was described in numerous forms of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, dissecting cellulitis, folliculitis decalvans, alopecia areata) as well as neoplastic and systemic diseases (such as cutaneous T-cell lymphoma, scalp metastasis of breast cancer, anorexia nervosa, malnutrition, cataracts, and chronic graft-vs.-host disease). The condition may also be induced by several drugs (epidermal growth factor receptor inhibitors, oral retinoids, sodium valproate, and carbamide perhydrate). The diagnosis of pili torti is based on trichoscopic or microscopic examination. As pili torti is a marker of numerous congenital and acquired disorders, in every case, the search for the signs of underlying conditions is recommended.

The molecular and cellular basis of copper dysregulation and its relationship with human pathologies.

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.

Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.

Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. CuGTSM or nCuGTSM (10mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Measuring Proximal Tibial Metaphyseal Width and Lateral Epiphyseal Height Improves Determination of Remaining Growth in Children.

Accurate assessments of skeletal maturity is of critical importance to guide type and timing of orthopaedic surgical interventions. Several quantitative markers of the proximal tibia were recently developed using historical knee radiographs. The purpose of the present study was to determine which marker would be most effective in assessment of full-length radiographs in a modern pediatric patient population. All full-length radiographs at our institutions between 2013 and 2018 were reviewed. Inclusion criteria for our study required that the child reached final height as defined by 2 consecutive unchanged heights, at least 6 months apart, after age 16 for boys and 14 for girls. Patients with metabolic bone disease, prior surgery such as epiphysiodesis, or previous infections around the knee were excluded. Summary statistics for each of the 3 proximal tibial ratios were calculated and multiple linear regression was performed with percent of growth remaining as a dependent variable. A recommended regression model is presented and evaluated. A total of 692 full-length radiographs met inclusion criteria. Proximal tibial ratios were calculated and averaged values for each percent of growth remaining was presented. Multiple linear regression demonstrated that using all 3 variables led to overfitting of the model so tibial metaphyseal width/lateral tibial epiphyseal height was selected as the optimal ratio for use by clinicians. The optimal model for determining growth was found to have R2=0.723 in the developmental set and R2=0.762 in an excluded validation set. This study demonstrates that the proximal tibial metaphyseal width/lateral tibial epiphyseal height is the ideal measurement for clinicians seeking to determine growth remaining in children. It presents average values between 0% and 25% of growth remaining. This study also develops and validates a multivariable regression model for determining percentage of growth remaining in children that will allow for quantitative determination of growth using full-length radiographs. Level III.

Copper Deficiency

BACKGROUND: Acquired copper deficiency in the pediatric population is a rare event but given the hematologic and potentially irreversible neurologic consequences, prompt recognition and treatment is important. Copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. Copper is found in a variety of foods including meats, nuts, legumes, and whole grains while lacking in highly processed foods. Copper requirements in children over the age of 4 is 15 mg/day, which is readily acquired in a typical diet. Copper deficiency is known to occur in patients with the rare X-linked mutation in the ATP7A copper transport protein, known as Menkes Syndrome, and in older individuals with gastrointestinal bypass surgery who lose the ability to absorb copper through the duodenum and proximal jejunum, however, it is rarely reported in other conditions. Pediatric patients with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency thus a high index of suspicion must exist in order to diagnose the disorder.CASE PRESENTATION: A 15 y/o boy with a prior diagnosis of global developmental delay and oral aversion presented with parental concerns for worsening fatigue, weakness and gait instability. Symptoms had been slowly progressive and accompanied by weight loss. His longstanding feeding difficulties had been refractory to intensive feeding programs yet he continued to feed orally (with no prior attempts at enteral/parenteral nutrition). A daily diet consisted only of 50-60 oz of milk and 25-30 individual servings of butterscotch pudding (1680-1880 calories/day, 0.7mg iron/day).Upon presentation he was afebrile with global muscle weakness. Growth parameters were at the 25th and 2nd percentiles for height and weight, respectively. Initial complete blood count demonstrated white blood cell count of 3.3, absolute neutrophil count of 760, hemoglobin of 4.4 with MCV of <50, reticulocyte count of 0.5, platelet count of 392. Review of his peripheral blood smear revealed microcytic, hypochromic red cells without marked fragmentation, anisopoikilocytosis or ringed sideroblasts; there were no morphologic abnormalities of his leukocytes or platelets. Iron studies demonstrated ferritin of 45, total iron binding capacity of 514, and 2% iron saturation. He had no evidence of B12 or folate deficiency. Stool guaiac was negative for occult blood loss. He was hospitalized to receive transfusion of red blood cells and begin IV iron therapy due to his inability to tolerate oral repletion.Over the the next 2 months he demonstrated some improvement in his anemia but had worsening leukopenia, neutropenia and a declining platelet count. He had worsening neurologic function with increasing need for assistance in his activities of daily living. Due to lack response to IV iron and worsening cytopenias, additional evaluation was performed which revealed a serum copper level of 6 (range 60-190), and cerulosplasmin of 2.1 (range 22-58).Once a diagnosis of copper deficiency was made, the patient promptly began a course of parenteral copper repletion. He received IV copper 35mcg/kg/day x 3 days then weekly intravenous infusions. Given his malnutrition, a G-tube was placed to begin oral copper repletion and enteral nutrition. Within 3 weeks his copper level improved as well as his blood counts. Unfortunately, although his blood counts and copper levels normalized, his neurologic status remains below his old baseline although he has made gains in his gross and fine motor abilities.DISCUSSION: Children with limited dietary repertoires are at risk for otherwise rare nutritional deficiencies such as copper deficiency. It is not uncommon that nutritional deficiencies may become more prominent when children reach puberty and have increased dietary requirements not only of calories, but also of micronutrients and trace elements. This patient's clinical course demonstrates the need to have a high index of suspicion of concomitant nutritional deficiencies other than those routinely evaluated such as iron, B12 and folate given his finding of both iron and copper deficiency. Review of his blood smear at presentation was consistent with iron deficiency and did not demonstrate typical hallmarks of copper deficiency such as ringed sideroblasts. DisclosuresMalec:Bioverativ: Consultancy, Other: Research funding; Shire: Consultancy, Other: Research funding.

CONGENITAL CUTIS LAXA: A RARE GENODERMATOSIS

Cutis Laxa (CL) / generalized elastolysis / dermatomegaly is a heterogeneous group of disorders which are related to elastic tissue abnormalities. Depending on extent of abnormal elastic tissue, it may be mild or severe. Severe form presents with loose, inelastic, wrinkled skin resembling ill tted suit. Infant has characteristic facial features like old man appearance, a hooked nose, a short columella, a long upper lip with long philtrum, and everted lower eyelids. CL is categorised as congenital or acquired and the inheritance can be autosomal dominant or recessive, or X linked. Occasionally a few metabolic disorders like Menkes disease, disorders of glycosylation are associated with Congenital CL. Acquired cutis laxa has developed after a febrile illness and various inammatory skin diseases. Here we present a case of a full-term SGA (small for gestational age) female child born with features of CL.

Genetic causes of fractures and subdural hematomas: fact versus fiction.

Genetic disorders are in the differential diagnosis when young children present with unexplained fractures or intracranial hemorrhage. For medical and legal reasons, it is imperative to make the correct diagnosis and provide clear, evidence-based explanations of how alternative diagnoses were ruled out. A genetics consultation in cases of suspected child physical abuse should synthesize the history of present illness, medical history, family history, physical examination, and radiologic and laboratory findings in consultation with other specialists. The medical geneticist highlights how these disorders truly present. When the natural history of a genetic disorder is understood, it becomes clear that genetic disorders are not mysterious or difficult to diagnose. As highlighted in this case-based review, mainstream medical practice allows for differentiation among the intracranial and skeletal manifestations of osteogenesis imperfecta, Menkes disease, glutaric acidemia type 1 and child physical abuse. This review also highlights how a genetic disorder, Ehlers-Danlos syndrome, can be misused in a courtroom. Finally, this review summarizes when genetic testing is appropriate in cases of suspected child physical abuse.