Recurrent Skin Ulcers with Facial Dysmorphism and Sinopulmonary Infections: Thinking Beyond Hyper-IgE Syndrome

Prolidase deficiency (PD) is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. It occurs due to the mutations in the prolidase gene (PEPD) that result in loss of prolidase activity. We reported here a child who had presented with features compatible with hyper-immunoglobulin E syndrome (HIES) like recurrent skin ulcers, recurrent infections, facial dysmorphism, retained primary teeth, and elevated levels of immunoglobulin E levels but with normal flow cytometric assays, which was later diagnosed as PD.

A Neuro-metabolic Syndrome that Needs to Be Discovered: A Child with Late Onset Asparagine Synthetase Deficiency

Asparagine synthetase (ASNS) deficiency is a rare inborn error of metabolism caused by a defect in ASNS—a gene encoding asparagine synthetase. It has mainly been described as a neurological phenotype manifesting as severe developmental delay, congenital microcephaly, spasticity, and refractory seizures; it is not associated with any specific dysmorphisms. ASNS deficiency leads to the inability to synthesize a nonessential amino acid in the brain, this explains why the symptoms are primarily neurological. The accumulation of aspartate/glutamate causes increased neuronal apoptosis leading to brain atrophy and increased neuronal excitability leading to seizures. Asparagine levels in plasma and cerebrospinal fluid are not reliable biomarkers for this disorder, therefore diagnosis is mainly obtained by molecular genetics. This disorder is associated with a poor prognosis and there is no treatment except supportive therapy. Prenatal diagnosis is possible. We report a case of a later onset form, c.146G > A (p.Arg49Gln) variant in the ASNS gene detected by molecular analysis using next-generation sequencing; the patient's clinical presentation included microcephaly, regression of developmental milestones, epilepsy, and hyperthermia.

HEREDITARY OROTIC ACIDURIA WITH UNUSUAL PRESENTATION- A RARE CASE REPORT

Hereditary orotic aciduria (HOA) is an extremely rare inborn error of pyrimidine metabolism. It results from a defect in the uridine-5-monophosphate synthase (UMPS) gene. It can result in megaloblastic anemia, developmental delay and crystalluria. Molecular genetics is the conrm diagnostic modality. Uridine triacetate is the only established treatment. We thus report a case of 13 month male child having developmental delay with regression, dysmorphic facies, nystagmus, skeletal abnormalities and massive hepatosplenomegaly with past history of repeated LRTI. After clinical evaluation, an impression of storage disorder was presumed. Bicytopenia was also obtained in CBC with high MCV. After detailed evaluation with haematological, bone marrow, TMS and GCMS of urine, a diagnosis of hereditary orotic aciduria was established. Although extremely rare, hereditary orotic aciduria should be suspected in any child with megaloblastic bone marrow, immunodeciency or when developmental delay and anemia coexist

Evolution of Our Understanding of XIAP Deficiency

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.

Multiple Sulfatase Deficiency (MSD): Review of the Literature and Case Reports of Two Siblings with Dental Caries and Trauma

Multiple sulfatase deficiency (MSD) (MIM # 272200) is an extraordinarily rare inborn error of metabolism (IEM). The phenotypic spectrum is largely heterogeneous and attributed to the combined effects of deficiencies in the nine sulfatases currently known to be related to human diseases. Systemic sequelae of MSD are vast and multisystemic, primarily encompassing developmental delay and neurological, cardiopulmonary, dermatological, gastroenterological, and skeletal manifestations. The dental phenotype is scarcely described in the literature due to a paucity of cases. Dental treatment under local and general anaesthesia mandates an integrated multidisciplinary approach to safeguard systemic health and optimise outcomes. This paper presents two siblings with multiple sulfatase deficiency who presented to the Paediatric Dental Department at Great Ormond Street Hospital, requiring comprehensive care under general anaesthesia for dental caries and trauma.

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

Citrin deficiency mimicking mitochondrial depletion syndrome

Background Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane. Case presentation We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70–1)_(212 + 1_231–1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months. Conclusions As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.

A Tall and Thin Boy with a Bad Headache: A Case Report of Homocystinuria

Background: Homocystinuria is a rare inborn error of metabolism, resulting in the accumulation of homocysteine and methionine in tissues, which manifests as disorders of the connective tissues and increased risk of thromboembolism. The latter is the primary cause of morbidity and mortality, and can be prevented by the prompt start of the specific therapy aimed at lowering homocysteine plasma levels.Case presentation: A nine-year-old boy was admitted to the Emergency Department for a severe headache associated with torticollis, dysarthria, difficulty in walking and extreme irritability. His past medical history was relevant for bilateral lens ectopia and epilepsy, associated with a “marfanoid habitus”. A brain CT scan was consistent with cerebral venous thrombosis. The association between the marfanoid habitus and the thromboembolic event raised the suspicion of homocystinuria, which was eventually confirmed by the high levels of serum homocysteine, and the genetic testing. Anticoagulation therapy was started, together with pyridoxine and folate, and eventually betaine and dietary protein restriction, with a consequent satisfactory fall in homocysteine levels, along with clinical recovery.Conclusions: This case enhances the importance of dosing serum homocysteine in every child investigated for a marfanoid habitus, given the impact of the early diagnosis and treatment in the prevention of thromboembolic events.

Citrin Deficiency Mimicking Mitochondrial Depletion Syndrome

BackgroundNeonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane.Results We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69+1_70-1)_(212+1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born one year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months.ConclusionAs CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.