A male patient aged 1 year and 8 months with type 2 spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL2) was reported. The clinical characteristics included short stature, flat middle face, hypotonia, limb joint relaxation, hyperextension of metacarpophalangeal articulation, etc. In addition, the patient had a history of congenital laryngeal stridor. Thus, SEMDJL2 was determined according to the above symptoms and medical history. Sanger sequencing showed that the child carried a c.443C>T missense mutation in the KIF22 gene, which resulted in an amino acid variation namely p.Pro148Leu. This phenotype was preliminarily determined as a pathogenic mutation. Therefore, it is suggested that next-generation sequencing genetic testing could be helpful for genetic diagnosis in children with congenital laryngeal stridor, systemic joint relaxation, and excessive joint extension.

Objective:To analyze clinical characteristics and genetic characteristics of children with ATP sensitive potassium passage (K ATP-HI). Methods:Forty-five children with genetically confirmed K ATP-HI and their families admitted to Beijing Children′s Hospital of Capital Medical University between February 2002 and December 2018 were selected as the study subjects. A detailed retrospective analysis of the patient's clinical characteristics, diagnosis and treatment process, disease-causing gene carrying status and later follow-up data was performed. ABCC8/KCNJ11 gene was sequenced by second-generation sequencing technology. Results:Among 45 children with K ATP-HI, 34 cases (75.6%) were neonatal onset, the first symptoms of 21 cases (46.7%) were convulsions. 39 cases had been treated with diazoxide, including 12 cases (30.8%) with good efficacy, 16 cases (41%) with poor efficacy and 11 cases with uncertain efficacy. Octreotide was further applied in 18 patients with uncertain or ineffective efficacy after diazoxide treatment, and 13 cases (72.2%) were effective, 3 cases were ineffective, and 2 cases were uncertain. 10 CHI patients who were ineffective to drug treatment or had clearly focal lesions confirmed by 18F-dopa positron emission by computed tomography ( 18F-DOPA PET) scans had undergone surgical treatment, 8 of which underwent partial pancreatectomy and blood glucose returned to normal after the operation; the other 2 cases underwent subtotal pancreatectomy and both had secondary diabetes after operation. Among 45 children with K ATP-HI, 1 case carried both ABCC8 and KCNJ11 mutations, 10 cases carried ABCC8 compound heterozygous mutations, and the remaining 34 cases carried ABCC8/KCNJ11 single genetic mutation. Among them, 21 cases had paternal inheritance, and 3 cases had maternal inheritance, 6 cases were identified with de novo mutations. Conclusions:Diazoxide treatment was ineffective for most K ATP-HI children, but octreotide had a higher effective rate. Partial pancreatectomy for focal type patients had a higher cure rate, and there was a risk of secondary diabetes after subproximal pancreatectomy, so it was very important to clarify the histological type of children before surgery. ABCC8 gene mutations and KCNJ11 gene mutations were the main pathogenic genes of K ATP-HI. Among patients carrying mutations in single ABCC8 or KCNJ11 gene mutation, K ATP-HI inherited by paternity were the majority. Some K ATP-HI children can relieve the hypoglycemia symptoms by themselves.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease mainly characterized by accele-rated aging, with an incidence rate of 1 in 8 million to 1 in 4 million.It can affect the skin, fat, cardiovascular, bone and other organ systems.Most HGPS children can only live to 6-20 years old, with an average life expectancy of only 14.6 years.HGPS has distinctive clinical features, such as severe growth retardation, special skin manifestations, and craniofacial manifestations.The prognosis of this disease is poor, and no treatment has been proven effective so far.Upon the diagnosis, the progress of the disease should be observed and monitored via long-term and careful follow up, so as to extend the life span of the children as much as possible.In this article, the disease type, clinical manifestations, pathogenesis and clinical examination of HGPS were reviewed.

Objective:To study the clinical and genetic characteristics of Gitelman syndrome in children.Methods:Four children diagnosed with Gitelman syndrome in the Baoding Children′s Hospital from January 2017 to October 2018 were enrolled, and their clinical data and pathogenic gene carrying status were analyzed.Results:There were 2 males and 2 females in the enrolled patients.Two children complained of short stature and 2 children were diagnosed as hypokalemia by accident.All the 4 children showed constipation, short stature, repeated hypokalemia, hyponatremia, hypochloremia, normal urinary calcium/creatinine ratio, elevated renin and angiotensin Ⅱ levels in supine position, and normal aldosterone.Three children had hypomagnesemia and 1 child had a normal blood magnesium level.All of the 4 children had a compound heterozygous mutation of SLC12A3 gene.The mutations of c. 1670-7G>A and c. 1698C>A were not reported in the literature. Conclusions:Constipation and short stature are common clinical manifestations of Gitelman syndrome in children.Typical cases show hypokalemia, hypomagnesemia, hyponatremia and hypochloremia, etc.The blood magnesium level can be normal in few children.Most children with Gitelman syndrome carry SLC12A3 compound heterozygous mutations.

Objective:To analyze the clinical features of a kindred of X-linked adrenoleukodystrophy(X-ALD) with the onset of primary adrenocortical insufficiency, and to detect the mutation of ATP-binding cassette, sub-family D, member l(ABCD1) gene.Methods:A Chinese X-ALD kindred with two affected males from two-generations was studied. The clinical data of the proband′s family members were collected. The sequences of ABCD1 of the proband, his parent and young brother were detected by next-generation sequencing. X-ALD was diagnosed according to clinical manifestations, cranial MRI image, and serum level of very long chain fatty acid(VLCFA).Results:The two cases were all males. The proband was characteristic of primary adrenocortical insufficiency and neurological dysfunction, with extensive cerebral white matter demyelination and high serum VLCFA level. At the age of 2 years and 10 months, the younger brother of the proband presented with primary adrenocortical dysfunction, without neurological symptoms. Gene sequencing results of two patients showed a novel missense substitution(c.1666C>T) in exon 7 of ABCD1 inherited from their mother.Conclusion:The new mutation of ABCDl gene c. 1666C>T may lead to adrenoleukodystrophy. Primary adrenocortical insufficiency and neurological dysfunction are the typical manifestations of X-ALD.

Objective: To summarize the clinical characteristics of 6 children with Hutchinson-Gilford progeria syndrome, and to analyze the pathogenic genes carried by some patients. Methods: The clinical data of 6 patients were summarized. The pathogenic genes of 4 families were analyzed. Genomic DNA was extracted from 3ml of the subject′s blood with EDTA anticoagulation. The first-generation sequencing technology was used to analyze the sequence of Lamin A/C(LMNA) gene and to identify the pathogenic mutation sites by comparing with normal sequencing results. Results: All the children had typical clinical manifestations of the disease which has been previously reported in the literature, such as severe growth retardation, special skin manifestations, and distinctive craniofacial manifestations.Gene sequencing results revealed that 2 patients carried classical heterozygous mutation of LMNA c. 1824C>T(p.G608G). The other two patients carried atypical mutations of LMNA IVS8-4 C>A and c. 1968+ 2T>C, among which the mutation of IVS8-4 C>A has not been reported. Conclusions In Chinese children, both classical and non-classical mutations in LMNA gene lead to the occurrence of premature aging. It is easy to make a diagnosis based on clinical manifestations. Finding of the pathogenic gene may further confirm the diagnosis.

Objective: To analyze the clinical features and genetic characteristics of Chinese children with glutamate dehydrogenase type of congenital hyperinsulinism (GDH-HI). Methods: Pedigrees with 10 GDH-HI children admitted to Beijing Children′s Hospital from February 2008 to December 2018 were selected as subjects. Clinical features, the detection of pathogenic genes and follow-up data were retrospectively analyzed. Polymerase chain reaction DNA (PCR-DNA) direct sequencing method and second generation sequencing technique were used to analyze the GLUD1 genetic sequences of 10 GDH-HI children and their relatives. Results: Of the 10 GDH-HI children, 9 had normal birth weight and 1 was a giant. Nine patients were accompanied by asymptomatic hyperammonemia, and one had normal blood ammonia. 9 had ever been treated with diazoxide, which was all effective. All 10 children carried GLUD1 gene mutations, 5 patients carried c. 965C>T (p.R322H) GLUD1 gene mutation, and the remaining 5 cases carried c. 1388A>T (p.N463I), c. 1495C>A(p.G499C), c. 1493C>T(p. S498L), c. 1519G>A(p.H507Y) and c. 1388A>G(p.N463S), respectively. 9 cases (90%) had de novo mutations, and 1 case had paternal autosomal dominant inheritance. 8 children were followed up in long term. One child had spontaneous remission in 8 years after being diagnosed, and seven patients required long-term oral diazoxide to maintain normal blood glucose levels, two of whom had epilepsy. Conclusions The birth weight of children with GDH-HI in China was usually normal. A small number of GDH-HI children had normal serum ammonia levels. Most of the GLUD1 gene mutations in GDH-HI children in China were de novo mutations, among which the GDH p. R322H mutation was a hot spot mutation in Chinese children with GDH-HI. Most of GDH-HI children were diazoxide-responsive. As the disease progresses, some children may have epilepsy, and a few children have a tendency to relieve by themselves.

Objeetive To analyze the efficacy and safety of diazoxide treatment in patients with congenital hyperinsulinism (CHI).Methods The clinical data of 145 patients diagnosed with CHI hospitalized in Beijing Children's Hospital affiliated to Capital Medical University from February 2002 to January 2016 who received diazoxide treatment were retrospectively analyzed.We conducted a detailed analysis on the efficacy,side effects and prognosis of diazoxide treatment for CHI.Results In 145 patients,there were 89 patients (61.4％) who were responsive to diazoxide and 23 patients (15.9％) unresponsive to diazoxide,and the treatment effect of diazoxide for the other 33 cases (22.8％) was still unclear.In the diazoxide effective group,there were 22 cases (24.7％) of neonatal onset,32 cases (36.0％)of onset from 1-6 months after birth and 35 cases (39.3％) of onset after 6 months of birth,and the birth weight was normal in 67 cases,macrosomia in 16 cases,low in 5 cases and unknown in 1 case.In the diazoxide ineffective group,there were 14 cases (60.8％) of neonatal onset,7 cases (30.4％) of onset from 1-6 months after birth and 2 cases (8.6％)of onset after 6 months of birth,and the birth weight was normal in 9 cases and macrosomia in 14 cases.In the unclear diazoxide effect group,there were 20 cases (60.6％) of neonatal onset,9 cases (27.34％) of onset from 1-6 months after birth and 4 cases (12.1％) of onset after 6 months of birth,and the birth weight was normal in 15 cases and macrosomia in 18 cases.After the application of diazoxide,65 cases (44.8％) had hirsutism,and 43 patients (29.7％) had gastrointestinal side effects.In the diazoxide effective group,the symptom of hypoglycemia was spontaneously alleviated at the age of from 3 months to 7 years old in 20 patients (22.5％),and 33 patients continued to be treated by diazoxide.In the diazoxide ineffective group,the symptom of hypoglycemia was spontaneously alleviated around the age of 1 years old in 4 patients (17.3％),5 patients were treated by octreotide in long term to maintain normal blood sugar level,4 patients received pancreectomy including 3 with normal blood sugar and 1 with occasional hypoglycemia after surgery.In the unclear diazoxide effect group,the symptom of hypoglycemia was spontaneously alleviated at the age of from 10 months to 3 years old in 4 patients (12.1％),2 patients were treated by octreotide in long term to maintain normal blood sugar level,8 patients received pancreatectomy including 5 with controlled blood sugar after surgery.Conclusions Diazoxide is effective in treating CHI children.The efficiency may be higher for the CHI with normal birth weight or whose onset age is after the neonatal period.

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Aging ; genetics ; physiology ; DNA Helicases ; genetics ; Human Embryonic Stem Cells ; metabolism ; physiology ; Humans ; Kinetics ; Lamin Type A ; genetics ; Mesenchymal Stem Cells ; metabolism ; physiology ; Mutation ; Progeria ; genetics ; physiopathology ; Werner Syndrome ; genetics ; physiopathology