Clinical spectrum of steroid sulfatase deficiency: X-linked recessive ichthyosis,birth complications and cryptorchidism

When boys affected with steroid sulfatase deficiency are delivered, the lack of the enzyme in the placenta may cause birth complications. In postnatal life this gene defect gives rise to X-linked recessive ichthyosis. In a series of 25 patients birth complications were reported in 9 cases. Of these boys, 4 displayed bilateral inguinal cryptorchidism and one was affected unilaterally. In a further boy we observed unilateral inguinal cryptorchidism without a history of birth complications. In one patient who had been delivered by forceps, abdominal bilateral cryptorchidism resulted in severe hypogenitalism. A review of the literature revealed 30 cases with X-linked recessive ichthyosis displaying hypogenitalism or cryptorchidism or both. In conclusion, cryptorchidism should be considered as a further clinical manifestation of steroid sulfatase deficiency.     

Hepatic and muscular presentations of carnitine palmitoyl transferase deficiency: two distinct entities

Human carnitine palmitoyl transferase (CTP) deficiency results in two different clinical variants, one with "hepatic" and one with "muscular" symptoms. We studied CPT activity and long-chain fatty acid oxidation in fibroblast cell lines from four patients, two from each group. Overall CPT activity was deficient in patients' fibroblasts with the hepatic presentation, as previously demonstrated in patients' fibroblasts with the muscular presentation. The hepatic patients' fibroblasts displayed a CPT1 deficiency which resulted in impaired long-chain fatty acid oxidation. In contrast, CPT1 activity and palmitate oxidation were normal in muscular patients' fibroblasts. In these latter patients, the mutation presumably involved CPT2 activity. These data suggest that CPT deficiency is due to at least two different mutations, resulting in two distinct patterns of clinical and biochemical abnormalities.     

1个X-连锁鱼鳞病家系的基因突变鉴定与产前诊断

X-连锁鱼鳞病 （XLI）是一种类固醇硫酸酯酶缺乏的代谢性疾病,常于出生时或生后不久发病,编码类固醇硫酸酯酶的基因 （STS）位于X染色体短臂上,STS基因发生缺失或突变时可导致此病的发生。本研究收集一个家系的临床表型资料,其中先证者,男,足月顺产,11岁,全身皮肤干燥、粗糙、呈黑褐色鳞片状,主要累及腹部和肢体伸侧。采集家系中各成员的外周血提取DNA,采用多重连接依赖式探针扩增 （MLPA）技术对家系各成员的X染色体上的STS基因拷贝数进行检测,用全基因组芯片进一步明确X染色体微缺失片段的大小,随后采用MLPA技术对先证者母亲再生育进行产前诊断。结果发现家系中先证者及2个患者均为STS缺失的男性半合子,基因芯片鉴定出Xp22.31存在缺失,缺失大小为1.6Mb （chrX：6,516,735-8,131,442）,另鉴定出2个女性家庭成员为携带者。先证者母亲再生育产前诊断结果证实胎儿为携带者。本研究表明该XLI家系存在STS基因缺失,该缺失引发出XLI特有的皮肤病变,MLPA是XLI分子诊断与产前诊断的便捷可靠技术。     

X-linked icthyosis. A sulphatase deficiency.

In 3 pregnant women oestrogen excretion in the urine was very low. The pregnancies were otherwise uncomplicated and the 3 infants, boys, were normal at birth, but later developed ichthyosis of the X-linked inherited type. Histochemically, the placenta in each case showed deficiency in arylsulphatase-type C activity. In all three children the skin showed the same enzyme deficiency. In the skin of 9 other unrelated (adult) patients with proved X-linked inherited ichthyosis vulgaris, arylsulphatase C activity was deficient. Skin from 5 normal adults and 5 normal children showed arylsulphatase C activity to be present. It is concluded that a sulphatase deficiency is a factor in the causation of ichthyosis of the X-linked inherited type.     

Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure

Growth failure occurs in several of the ichthyoses, a heterogeneous group of inherited disorders characterized by thickened or scaly skin. This suggests that there may be common pathogenic mechanisms causing failure to thrive. Previous studies have proposed that a hypermetabolic state induced by epidermal inflammation and hyperproliferation or enteropathy leading to malabsorption and nutritional deficiencies might account for the growth failure in icthyosis. OBJECTIVE: The purpose of this study was to examine the extent of enteropathy and nutritional deficiency in children with severe ichthyosis and growth failure. METHODS: Ten children with different types of ichthyoses and growth failure were studied. RESULTS: Evaluation of gastrointestinal structure and function revealed few abnormalities other than mild fat malabsorption in two patients. Total caloric intake exceeded established requirements for age, height, and weight in all patients. Deficiencies of fat-soluble vitamins were identified in a few subjects. Mild elevations in total calcium and magnesium blood level, elevated hematocrit levels, and constipation were observed in many patients. CONCLUSIONS: Nutritional deficiencies and gastrointestinal abnormalities are uncommon in children with ichthyosis and failure to thrive. Chronic hypovolemia caused by impaired epidermal permeability barrier may be common in this population.     

Psychologic aspects of childhood reflex neurovascular dystrophy

Psychosocial factors in 21 families with children affected by reflex neurovascular dystrophy were studied. Each family was interviewed and given a battery of standardized psychologic tests. Two distinct types of families were identified. Fifteen families showed high internal cohesion, expressiveness, and organization and low levels of conflict. Six families showed high overt conflict with low levels of family cohesion, expressiveness, and organization. In all families parental enmeshment with the patient was present. Marital discord was present in 12 families. Thirteen patients had significant school problems (ten had learning disabilities). Although most of the children were described as especially bright, only four had above average intelligence test scores. Four had a history of sexual abuse. The patients and their mothers perceived the health problem as significantly worse than did children with arthritis from whom similar scores had been obtained. Possible role models with similar symptoms were reported by ten patients. These data support the concept that childhood reflex neurovascular dystrophy is frequently a stress-related disease; the therapeutic approach to treating these children and their families must take these psychosocial factors into account.     

Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants

Chinese hamster ovary cultured cells were transformed to continuously express wild-type and two mutant ornithine transcarbamylase genes, R141Q and R40H. In addition, these cells were transfected to transiently express the same genes. The R141Q mutation abolishes the enzymatic activity, and the amount of "mature" protein present in transfected cells is equivalent to the wild type. The R40H mutation causes a reduction of enzymatic activity to approximately 26 to 35% of wild type concomitant with a significant reduction in the amount of protein present. Transfection with wild-type and mutant genes together in various proportions did not reveal dominant negative effects of the two mutations studied. This expression system can be used to examine the deleterious effect of private mutations or lack thereof in families with ornithine transcarbamylase deficiency as well as evaluate the potential dominant negative effects of gene delivery for treatment of ornithine transcarbamylase deficiency.     

Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency

Immunoglobulins (Ig) A and G subclass deficiencies are common immune system disorders which cause morbidity especially between 2 and 6 yr of age. Prognosis of these defects and therapeutic approach is unclear. The aim of the present retrospective study was to review the clinical and laboratory records of 87 children with IgA and/or IgG subclass deficiency to determine whether these patients experience changes in serum Ig concentrations during follow-up and to give more clinic and laboratory information to the families about the course of these diseases. Among 87 patients studied, the most frequent defect was partial IgA deficiency combined with IgG3 subclass deficiency (41%). The other groups were as follows; partial IgA deficiency (32%), selective IgA deficiency (8%), partial IgA combined with IgG2-G4 subclass deficiency (6%), and IgG subclass deficiency (13%). The commonest clinical presentations were recurrent upper respiratory tract infections (76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was widely represented in the patients studied (24%). The number of patients who were given prophylactic treatment with benzathine penicilline, prophylactic oral antibiotic, or oral bacterial extract to prevent infections was 68 (78%). Frequency of recurrent infections decreased from 7.9 +/- 4.9 per year to 2.5 +/- 2.3 in 68 patients receiving any prophylactic regimen; however, decrease in frequency of infections did not show any significant difference between different prophylactic groups. None of the patients in the selective IgA deficiency group had reached normal serum levels of IgA. At the age of 58.3 +/- 21.4 months, 52% of patients in partial IgA deficiency group and 51% of patients in partial IgA + IgG subclass deficiency group, serum IgA increased to normal ranges. Serum IgG subclass levels increased to normal range for age in 67% of patients in partial IgA + IgG subclass deficiency group and in 30% of patients in isolated IgG subclass deficiency group. The mean age for reaching age-related normal IgG subclass levels for these patients was 69.0 +/- 14.5 months. In conclusion, findings of this study suggest that IgA and/or IgG subclass deficiency may be either progressive or reversible disorders and emphasize the value of monitoring Ig levels in affected individuals.     

Prevalence of human growth hormone-1 gene deletions among patients with isolated growth hormone deficiency from different populations.

Familial isolated growth hormone deficiency type IA results from homozygosity for either a 6.7-kb or a 7.6-kb hGH-1 gene deletion. Genomic DNA was extracted from circulating lymphocytes of 78 subjects with severe isolated growth hormone deficiency (height less than -4.5 SD score) and studied by polymerase chain amplification and by restriction endonuclease analysis looking for gene deletions within the hGH-gene cluster. The individuals analyzed were broadly grouped into three different populations (North-European, n = 32; Mediterranean, n = 22; and Turkish, n = 24). Ten out of 78 patients studied presented with an hGH-1 gene deletion; eight out of these 10 showed a 6.7-kb gene deletion, the remaining two a 7.6-kb hGH-1 gene deletion. Five of the 10 subjects developed anti-hGH antibodies to hGH replacement followed by a stunted growth response. Family studies of the affected patients were performed, revealing consanguinity in all the families, and the corresponding heterozygosity for the deletion was present in each of the parents. The results of our study revealed a prevalence for an hGH-1 gene deletion in three out of 32 North-European, three out of 22 Mediterranean, and four out of 24 Turkish patients with growth hormone deficiency (height less than 4.5 SD score). These data are important for prenatal diagnosis of at-risk pregnancies and for families at risk for recurrence and underline clearly the fact that the hGH-I gene deletion represents a common cause for growth hormone deficiency associated with severe growth retardation (height less than -4.5 SD score).     

Familial type of hypophyseal nanism. Apropos of 7 families in western Algeria

Eighteen pituitary dwarfs belonging to 7 different West Algerian families were studied. Eleven patients from 4 families presented isolated growth hormone deficiency, 7 patients from 3 families had multiple pituitary hormone deficiencies. Serum GH levels before and after standard pharmacological stimulations were below 2 ng/ml in all cases. Three of 10 hGH treated patients increased significantly their growth rate (8.5 +/- 0.5 cm/year) during the first year of treatment; growth was moderate (5.3 +/- 0.8 cm/year) in 3 patients and poor (4.5 cm/year) in 2 patients. In 2 cases the follow-up is insufficient.     

Carbamyl phosphate synthetase and ornithine transcarbamylase activities in enzyme-deficient human liver measured by radiochromatography and correlated with outcome

Sensitive and specific radiochromatographic methods to measure enzymatic activities of carbamyl phosphate synthetase I (CPS I) and ornithine transcarbamylase (OTC) were developed. The activities of these enzymes were assayed in frozen liver tissue obtained from 23 individuals with hyperammonemia caused by CPS I (five patients) and OTC deficiency (18 patients). In addition, livers of one aborted fetus with OTC deficiency and four normal individuals were studied. The assays use radioactive ornithine as a substrate followed by separation of citrulline formed in the reactions by HPLC and quantitation of the radioactivity in both amino acids by a radioactivity flow monitor or by a scintillation counter. Both CPS I and OTC assays were linear with respect to length of incubation time and concentration of tissue homogenate. The sensitivity of the methods allowed measurements of CPS I and OTC activities as low as 0.1 mumol/g/min on 5 mg of liver tissue and the diagnosis of CPS I or OTC deficiency could be established on as low as 0.5 and 0.05 mg of tissue, respectively. CPS I activity in different sections of four normal livers was 3.01 +/- 0.16 mumol/g/min (mean +/- SEM, n = 19) and OTC activity was 93.4 +/- 6.3 (mean +/- SEM, n = 19). Residual enzymatic activity could be detected and measured in the liver tissues of one of the five subjects with CPS I deficiency and in 14 of 19 subjects with OTC deficiency. OTC/CPS I activity ratio in normal liver tissue was 31.2 +/- 1.3 (mean +/- SEM, n = 19), whereas this ratio ranged from 343 to greater than 5000 in CPS I deficient livers and from less than 0.02 to 1.55 in OTC deficient livers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quality of life in children and families with bleeding disorders

Quality of life (QoL) in children and adolescents with bleeding disorders and their families is a relatively new topic. It is important to understand more about QoL in this patient population to evaluate and if necessary to improve the care patients receive. To achieve this aim, a questionnaire to assess patients' QoL in hemophilia was developed and psychometrically tested. Three hundred twenty hemophiliac children and adolescents from six European countries and their families were asked to fill out a questionnaire regarding different aspects of their well-being and functioning, as well as their views on hemophilia care. Generic QoL questionnaires showed that children with hemophilia have a higher QoL than other patients with chronic disease, such as asthma/atopic dermatitis and obesity. Several determinants affected patients' QoL (e.g., number of bleeds, social support). Parents' and children's assessments differed with regard to social and emotional aspects of QoL. The study showed that variations in QoL can be explained by clinical and psychosocial factors and suggested that QoL can be assessed and enhanced both by medical and non-medical (e.g., psychological) interventions.     

Mutation distribution and CYP21/C4 locus variability in Brazilian families with the classical form of the 21-hydroxylase deficiency

Deficiency of adrenal steroid 21-hydroxylase is the most common form of congenital adrenal hyperplasia and it is considered to be responsible for 90% of the disease. This paper describes for the first time the CYP21B mutation profile in Brazilian patients. We genotyped 41 families with at least one individual affected with the classical form of the 21-hydroxylase deficiency, representing 74 unrelated alleles. In order to characterize different disease-causing alleles, genotyping was performed by Southern blot analysis with three restriction enzymes, allele-specific oligonucleotide hybridization, and allele-specific PCR. Different alleles were distinguished by TaqI C4B RFLP, gene duplications or deletions of either CYP21A + C4B or CYP21B + C4B, large gene conversions and eight mutations that might have been introduced into CYP21B from CYP21A by microconversion events. At least one mutation was detected in 24 different disease-causing alleles, which represents about 85% of the affected alleles in those families. The frequency of the 30 kb deletion of CYP21B was lower than that described for Caucasians. The mutation Sp2 showed the highest frequency (24.65%) and was present mainly in salt-wasting patients, although it was also detected in some patients with the simple virilizing form of the disease. Conversely, I172N showed a frequency of 18.91% and was found mostly in patients affected with the simple virilizing form of the disease. Five other mutations were determined at low frequency, but CL6 was not found in any of the tested alleles.     

Nutritional rickets in ichthyosis and response to calcipotriene

Nutritional rickets has occasionally been described in children with lamellar ichthyosis, but their vitamin D endocrine status has not been described. We report 3 cases of vitamin D-deficiency rickets associated with ichthyosis in African children. A 13-month-old Nigerian boy with lamellar ichthyosis had rib beading, elevated alkaline phosphatase, and rachitic changes on radiographs. His rickets did not resolve with calcium therapy, and his 25-hydroxyvitamin D level was low. His rickets resolved with parenteral vitamin D treatment, but his skin did not improve. Topical 0.005% calcipotriene (an analog of 1,25-dihydroxyvitamin D that has been useful in treating adults with psoriasis) was similarly ineffective in improving the child's skin condition. An 8-year-old Nigerian boy with life-long skin findings consistent with lamellar ichthyosis had windswept deformity of the legs with rib beading and enlargement of the wrists and ankles. Radiographs showed active rickets, and the boy had an elevated alkaline phosphatase level and a decreased calcium level. Before knowing that his 25-hydroxyvitamin D level was low, he was treated with calcium and showed radiologic improvement. The skin did not improve with resolution of the rickets but did improve with unilateral topical application of 0.005% calcipotriene. A 7-year-old South African girl presented with progressive windswept deformities of the legs and a 4-year history of skin disease (and a skin biopsy consistent with X-linked ichthyosis). Radiographs and biochemical data confirmed active rickets. Her rickets improved dramatically with vitamin D treatment. Thus, 3 African children with ichthyosis developed vitamin D-deficiency rickets, probably because of a combination of impaired skin production and sunlight avoidance. This is consistent with previous findings of hypovitaminosis D in adults with ichthyosis and other disorders of keratinization. Measurement of 25-hydroxyvitamin D may be indicated in children with ichthyosis to identify those at risk for vitamin D-deficiency rickets, because it is possible that the cutaneous synthesis of vitamin D in such children is impaired. Although the ichthyosis did not improve with resolution of vitamin D deficiency and rickets, 1 of 2 children treated with topical calcipotriene showed improvement in the treated areas of skin. Calcipotriene does not seem to be effective in reversing systemic vitamin D deficiency but can be effective in improving the severity of skin disease in children with ichthyosis.     

Genetic heterogeneity in patients with X-linked recessive chronic granulomatous disease.

Genetic heterogeneity in 12 patients from 11 different families with X-linked recessive chronic granulomatous disease was studied by Southern blot analysis using cytochrome b heavy-chain cDNA as a probe. We found the abnormal restriction length fragment patterns of the cytochrome b heavy-chain gene in three families, which were not observed in healthy controls. DNA from one patient showed the abnormal patterns after digestion with several restriction enzymes. The DNA of two other patients showed the abnormality only with TaqI and PstI. Analysis of the same family members indicated that these abnormal patterns cosegregated with the disease. The other nine patients from eight families did not have any abnormalities detectable by Southern blot analysis. Although further experimentation should be done to study the molecular genetic heterogeneity in most X-linked chronic granulomatous disease families (eight of 11), we were able to demonstrate at least three different types of mutations in the cytochrome b heavy-chain gene responsible for the disease.     

Alport's syndrome. A report of three Swedish families.

Three families with hereditary nephritis of Alport's type have been studied with particular emphasis on the occurrence of symptoms and signs in different sexes and age groups. Part of the material was tested for impaired hearing or eye anomalies which may be the sole manifestation of Alport's yndrome. The youngest patients were 3-4 years of age, and the proportion of diseases individuals increased with age. In two of the families about half of the investigated males or females were affected whereas in the third family all but one of 16 investigated individuals were affected. In this last family the kidney disease was exceptionally severe, but no differences in the histopathology of the kidney lesions were seen between the families. In all the families renal symptoms progressed more rapidly in males than in females. Affected as well as unaffected sons and daughters were born to healthy as well as to diseased mothers. In contrast, healthy fathers produced only unaffected children. Diseased fathers produced only daughters, two-thirds of whom were affected. It is concluded that Alport's syndrome in these three families most probably is transmitted by autosomal dominant inheritance with variations in expression and penetrance.     

Type 2 Gaucher disease: the collodion baby phenotype revisited

The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.     

肾病综合征合并寻常性鱼鳞病临床特征及相关基因突变研究

目的 研究肾病综合征(nephrotic syndrome,NS)合并寻常性鱼鳞病(ichthyosis vulgaris,IV)患儿的临床特征,探讨FLG基因及NPHS2基因与疾病之间的关系.方法 分析我院3例NS合并IV患儿的临床、病理资料,并采用聚合酶链反应-单链构象多态性、DNA测序法,分析患儿NPHS2基因及患儿和3个家系中的部分IV患者的FLG基因.结果 ①3例NS合并IV患儿(1号女性,2号、3号为男性)对激素及多种免疫抑制剂治疗反应均差,随访观察1.5～4年未缓解.②1号患儿的兄长死于"尿毒症",其他2个家系中无肾脏疾病患者.③初次肾活检,2例为轻度系膜增生性肾小球肾炎,1例为微小病变;其中2例患儿在第1次肾活检的1年半后,重复肾活检,进展为中度系膜增生性肾小球肾炎.④3例患儿及3个家系中部分IV患者均具有FLG基因常见的突变类型R501X 和(或)2282del4,没有发现NPHS2基因突变.结论 3例NS合并IV患儿对激素及免疫抑制剂均耐药,肾脏病理损害进展较快,提示患儿对激素及免疫抑制剂耐药可能与FLG基因相关联.     

Distal arthrogryposis: clinical and genetic findings

Aim: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype‐phenotype correlation. Method: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed. Results: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection. Conclusion: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.