A boy, aged 16 months, attended the hospital due to head and facial erythema for 15 months and vulva erythema for 10 months with aggravation for 5 days. The boy developed perioral and periocular erythema in the neonatal period and had erythema and papules with desquamation and erosion in the neck, armpit, and trigone of vulva in infancy. Blood gas analysis showed metabolic acidosis; the analysis of amino acid and acylcarnitine profiles for inherited metabolic diseases and the analysis of organic acid in urine suggested multiple carboxylase deficiency; genetic testing showed a homozygous mutation of c.1522C>T(p.R508W) in the HLCS gene. Finally the boy was diagnosed with holocarboxylase synthetase deficiency and achieved a good clinical outcome after oral biotin treatment. This article analyzes the clinical data of a child with holocarboxylase synthetase deficiency and summarizes the etiology, diagnosis, and treatment of this child, so as to provide ideas for clinicians to diagnose this rare disease.
男性患儿，16月龄，因发现头面部红斑15个月，外阴红斑10个月，加重5 d就诊。患儿新生儿期即出现口周、眼周红斑，婴儿期出现颈部、腋下、外阴三角区等腔口和皱褶部位的红斑、丘疹，可见脱屑和糜烂。血气分析提示代谢性酸中毒，血遗传代谢病氨基酸和酰基肉碱谱分析、尿液有机酸分析结果均提示多种羧化酶缺乏症，基因检测结果提示HLCS基因存在c.1522C>T(p.R508W)纯合突变。最终该患儿诊断为全羧化酶合成酶缺乏症，口服生物素治疗取得良好的临床疗效。该文总结了1例全羧化酶合成酶缺乏症患儿的临床资料，对其病因、诊断、治疗进行归纳总结，为临床医生诊断该类罕见疾病提供思路。.

This study aimed to describe the clinical, biochemical, and molecular characteristics of Chinese patients with holocarboxylase synthetase (HLCS) deficiency, and to investigate the mutation spectrum of HCLS deficiency as well as their potential correlation with phenotype.
A total of 28 patients with HLCS deficiency were enrolled between 2006 and 2021. Clinical and laboratory data were reviewed retrospectively from medical records.
Among the 28 patients, six patients underwent newborn screening, of which only one was missed. Therefore, 23 patients were diagnosed because of disease onset. Among all the patients, 24 showed varying degrees of symptoms such as rash, vomiting, seizures, and drowsiness, while only four cases remained asymptomatic nowadays. The concentration of 3-hydroxyisovalerylcarnitine (C5-OH) in blood and pyruvate, 3-hydroxypropionate, methylcitric acid, 3-hydroxyvaleric acid, 3-methylcrotonylglycine in urine were increased greatly among affected individuals. After prompt supplement of biotin, both the clinical and biochemical symptoms were dramatically resolved and nearly all patients developed normal intelligence and physique on follow-up. DNA sequencing revealed 12 known and 6 novel variants in the HLCS gene of patients. Among them, the variant of c.1522C > T was the most common.
Our findings expanded the spectrum of phenotypes and genotypes for HLCS deficiency in Chinese populations and suggested that with timely biotin therapy, patients with HLCS deficiency showed low mortality and optimistic prognosis. Newborn screening is crucial for early diagnosis, treatment, and long-term outcomes.

Holocarboxylase synthetase deficiency (HSD) is a rare autosomal recessive disorder of biotin metabolism. Typical manifestations include irreversible metabolic disorders and erythroderma-like dermatitis. Most patients respond well to biotin supplementation. Psoriasis-like phenotype associated with this disease has been rarely reported in the literature and experiences with the use of biologics in patients with HSD are still lacking. We reported a rare case of recurrent psoriasis-like skin lesions in a 6-year-old child with HSD. The patient did not respond to initial therapy with high-dose oral biotin. Immunofluorescence staining showed an increased number of interleukin (IL)-17A+ cells in his skin lesions. Based on this finding, the patient was successfully treated with human anti-IL-17A monoclonal antibody (secukinumab). He did not report any side effects and remained healthy during the 2-year follow-up. We provide a comprehensive review of the reported cases of HSD with psoriasis-like dermatitis to date. The psoriasis-like phenotype of HSD is controversial in treatment and IL-17A inhibitor is an alternative therapeutic option.

Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in defects in several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions.
In this paper, we report a Chinese Han pedigree with HLCS deficiency diagnosed by using next-generation sequencing and validated with Sanger sequencing of the HLCS and BTD genes. The Chinese proband carries the common missense mutation c.1522C > T (p.Arg508Trp) in exon 9 of the HLCS gene, which generates an increased Km value for biotin. A novel frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15) in exon 6 of the HLCS gene is predicted to be deleterious through PROVEAN and MutationTaster. A novel heterozygous mutation, c.638_642delAACAC (p.His213Profs*4), in the BTD gene is also identified.
The Chinese proband carries the reported Arg508Trp variant, the novel 2-bp frameshift mutation c.1006_1007delGA (p.Glu336Thrfs*15), which expands the mutational spectrum of the HLCS gene, and the novel heterozygous mutation c.638_642delAACAC (p.His213Profs*4), which expands the mutational spectrum of the BTD gene. Furthermore, reversible hearing damage is rarely reported in patients with HLCS deficiency, which deserves further discussion.

BACKGROUND: Holocarboxylase synthetase (HCLS) deficiency, especially the late-onset type, is a rare disease. Affected patients can present with irreversible metabolic acidosis and may be misdiagnosed with a glucose metabolic disorder. Prompt and correct diagnosis and treatment can reduce mortality to a great extent.
UNASSIGNED: We report 2 Chinese patients who were diagnosed with late-onset HCLS deficiency. The age of onset of the 2 patients was approximately 8 months. The 2 patients had skin lesions, severe profound metabolic acidosis, dyspnea, and hyperglycemia.
UNASSIGNED: The results of urinary and blood organic acid analysis with gas chromatography/mass spectrometry revealed multiple carboxylase deficiency. Maple syrup urine disease and diabetic ketoacidosis could not be excluded. This finding is different from those of hypoglycemic complications reported in previous reports. Human genetic analysis eventually provided a definite diagnosis.
METHODS: Prompt oral treatment with biotin dramatically corrected the metabolic imbalances of the 2 patients, and continued oral biotin therapy was essential to the improvement of their prognoses.
RESULTS: Their metabolic disorders were corrected within 48 hours. During long-term follow-up, the patients achieved developmental milestones.
CONCLUSIONS: Late-onset HCLS deficiency may present with obvious hyperglycemia. Human genetic analysis eventually provided a definite diagnosis. Prompt treatment with biotin is vital to correct metabolic imbalances, and continued therapy is essential to the improving long-term prognoses. Their mutations were p.R508W and c.1088T > A, and these mutations might represent hot-spot genes in Chinese populations with HCLS deficiency. The variants c.1484T > G(p.L495*) and c.835G > T(p.E279x) are likely pathogenic, and more studies are needed to confirm these results.

暂无摘要。

BACKGROUND: Holocarboxylase synthetase deficiency is an inborn error of biotin metabolism leading to multiple carboxylase deficiency which is often biotin responsive. This disease is believed to be relatively common among the Asian population.
METHODS: A 6-year-old Vietnamese boy presented with recurrent episodes of severe metabolic acidosis precipitated by intercurrent illnesses. An extensive skin rash was present since the onset of his illness. Multiple carboxylase deficiency was considered a likely diagnosis based on the history and the characteristic skin rash.
RESULTS: This diagnosis was later confirmed by urine organic acid and molecular genetic studies. Urine organic acid showed characteristic excretion of glycine conjugates. Serum biotinidase activity was normal. Sequencing of the holocarboxylase synthetase gene revealed the patient being homozygous for a common mutation R508W. The patient showed a dramatic response to biotin within days of its administration.
CONCLUSIONS: This case illustrates a potential highly treatable inborn error of metabolism that can be recognized on clinical grounds and its favorable response to biotin treatment.

OBJECTIVE: To report the clinical diagnosis, treatment and follow-up of children with holocarboxylase synthetas(HCS) deficiency and explore the gene mutation spectrum of the disease.
METHODS: Eleven children with HCS deficiency were enrolled. Mass spectrometry analysis and biotinidase activity determination were used for diagnosis of HCS deficiency. HCS gene mutations were analyzed by PCR directed sequencing methods. Ten patients received oral biotin treatment (10-40 mg/d). Clinical effects of biotin treatment were observed.
RESULTS: All 11 cases developed apathetic, lethargy and metabolic acidosis at different degrees, and 10 cases presented with skin lesions. The average blood 3-hydroxyisovaleryl-carnitine concentrations and urinary 3-methylcrontonylglycine and methylcitrate concentrations increased significantly. The biotinidase activity increased, being higher over 30% of the normal reference value. Four mutations in HCS gene were identified, and they were c.1522C>T (R508W), c.1088T>A (V363D), c.126G>T (E42D) and c.1994G>C (R665P) (a new variant) and the frequency was 50%, 29%, 7% and 14% respectively. The symptoms disappeared in 10 cases 1-2 weeks after biotin treatment, and blood and urinary abnormal metabolites were gradually reduced to normal 2-6 months after treatment.
CONCLUSIONS: HCS deficiency is characterized by nervous system damage, skin lesions and metabolic acidosis. Mass spectrometry analysis, biotinidase activity determination and gene mutation analysis may be helpful in the definite diagnosis of this disorder. The effect of early biotin treatment is satisfactory. The mutations R508W and V363D might be hot-spots in Chinese children with HCS deficiency.

OBJECTIVE: To investigate the molecular defects of CYP17A1 gene in a pedigree with two 46,XY patients suffering from 17alpha-hydroxylase deficiency (17-OHD) and explore the steroid biosynthetic difference in carriers of 17-OHD before and after adrenocorticotrophic hormone (ACTH) test.
METHODS: Clinical data and hormone profiles were collected from the members of the pedigree. CYP17A1 genotyping was performed in the patients and family members with PCR-direct sequencing. A short ACTH test was evaluated in some cases.
RESULTS: The CYP17 genes of the patients were proved to hold a homozygous mutation with a base deletion and a base transversion (TAC/AA) in exon 6, which produced a missense mutation of Tyr-->Lys at codon 329 and changed the open reading frame following this codon. The hormone response of the carriers after ACTH stimulation was abnormal between the patients and normal controls.
CONCLUSIONS: 17-OHD in this family was caused by CYP17A1 mutation (TAC329AA); some hormonal response to ACTH stimulation was abnormal in carriers.

Holocarboxylase synthetase (HCS) is an enzyme that catalyzes biotin incorporation into carboxylases, and its deficiency causes biotin-responsive multiple carboxylase deficiency. We report a patient who had his first episode at 32 months of age. The main clinical findings were a characteristic rash, projectile vomiting, progressive consciousness loss, organophosphate order, and hypotension. Laboratory examinations showed metabolic acidosis with ketolactic acidosis, hyperammonemia, and urine organic acid profile suggestive of a biotin utilization abnormality consistent with multiple carboxylase deficiency. Nucleotide sequence analysis of the biotinidase gene of the patient revealed negative finding, however, analysis of HCS gene found a homozygous 1809C->T (R508W) mutation. R508W is a rare mutation in Taiwanese HCS deficiency patients, which is associated with the late-onset phenotype. The patient responded dramatically to biotin, and has remained normal growth and development during more than three years of follow-up. Therefore, a high index of suspicion for timely diagnosis and treatment could prevent severe complications.