Polydactyly: a study of four generations of a Turkish family including an affected member with bilateral cleft lip and palate.

Polydactyly is one of the most common congenital deformities of the hands. It can occur as an isolated disorder, in association with other malformations of the hands or feet, or as part of a syndrome. It can occur sporadically but it can also be inherited with a mainly autosomal dominant inheritance. We present a Turkish family with affected members in four generations. Bilateral duplication of the second digit in both hands and feet with 24 digits in total was the most common pattern, but one affected member had 26 digits: seven on each hand and six on each foot. In addition, another affected member had complete bilateral cleft lip and complete cleft palate combined with bilateral hand and foot polydactyly without any syndromic association. The pedigree of the affected members of this family suggests an autosomal dominant mode of inheritance, but genetic expression is variable.     

Polydactyly: A Study of Four Generations of a Turkish Family Including An Affected Member with Bilateral Cleft Lip and Palate

Polydactyly is one of the most common congenital deformities of the hands. It can occur as an isolated disorder, in association with other malformations of the hands or feet, or as part of a syndrome. It can occur sporadically but it can also be inherited with a mainly autosomal dominant inheritance. We present a Turkish family with affected members in four generations. Bilateral duplication of the second digit in both hands and feet with 24 digits in total was the most common pattern, but one affected member had 26 digits: seven on each hand and six on each foot. In addition, another affected member had complete bilateral cleft lip and complete cleft palate combined with bilateral hand and foot polydactyly without any syndromic association. The pedigree of the affected members of this family suggests an autosomal dominant mode of inheritance, but genetic expression is variable.     

三个汉族瘢痕疙瘩家系调查

目的：开展汉族瘢痕疙瘩家系的遗传学研究。方法：收集无亲缘关系的汉族瘢痕疙瘩家系的临床资料,绘制家系图谱,抽取部分家系成员的外周静脉血样。结果：三个汉族瘢痕疙瘩家系中四代家系1个,三代家系2个;家系成员共62人,发病13人,可疑发病1人,2个未发病肯定携带者,1个未发病可疑携带者;三代发病家系1个,两代发病家系2个;采集家系成员外周静脉血样37份。结论：这三个汉族瘢痕疙瘩家系的遗传模式符合常染色体显性遗传伴外显不完全,家系调查有助于瘢痕疙瘩的进一步遗传学研究。     

一个多发性骨骺发育不良大家系的临床特点及致病基因分析

目的通过对一个5代疑似多发性骨骺发育不良(multiple epiphyseal dysplasia,MED)的大家系(患者17例)进行临床特征分析和致病基因的筛查,为遗传咨询和产前分子诊断提供实验依据。方法采集家系成员病史,一般体检、关节、髋部X线片资料;收集该家系外周血样,提取样本DNA,靶向基因高通量测序方法对先证者DNA临床全外显子进行测序,使用Next Gene软件对测序序列进行比对分析,并进一步利用Ingenuity软件对存在的突变进行功能注释,寻找先证者致病突变。针对可疑突变,PCR和Sanger测序对家系其他成员DNA样本进行验证。结果该家系共5代,现存家系成员38人,系谱分析符合常染色体显性遗传特征。家系共有患者17例,其临床表现为:幼时出现走路姿势异常,后出现髋关节及膝关节疼痛,X线有典型骨骺发育不良病理改变。高通量测序及数据分析后,筛选出先证者(Ⅳ-3)软骨低聚物基质蛋白(cartilage oligomeric matrix protein,COMP)基因c.1153G>A(p.Asp385Asn)错义杂合突变,该突变导致其编码蛋白的第385位天冬氨酸被天冬酰胺替代。先证者家系其他成员符合基因型与表型共分离。结论COMP基因c.1153G>A错义杂合突变是导致该MED家系患者发病的分子机制,该突变首次在大家系中被报道,进一步明确了COMP基因c.1153G>A突变的致病性,有利于家系患者的进一步的诊治,也为产前诊断提供了实验依据。     

Familial Hirschsprung's disease: report of autosomal dominant and probable recessive X-linked kindreds

Multifactorial sex-modified inheritance has been proposed as the model of transmission in familial Hirschsprung's disease (HD). A review of two separate kindreds suggests that aganglionosis may be inherited as an X-linked recessive or an autosomal dominant trait. Chromosomal anomalies and other syndromes, including G6PD deficiency, may occur with familial HD. Recurrence risk counseling for family members depends on accurate pedigree analysis and a comprehensive understanding of the genetic factors involved.     

Polydactyly, triphalangism of the thumb, and carpal abnormalities in a family

Many authors have documented the anatomic variability of radial-sided polydactyly and triphalangism of the thumb, but the relationship between these two conditions remains confusing. This study was done to determine if all types of radial-sided polydactyly and triphalangism of the thumb are related. Twenty-five members of a family with these abnormalities were evaluated clinically and radiographically by using radiographs of the hands and feet and, where appropriate, the tibia, in order to ascertain whether all variations of radial-sided polydactyly and triphalangism of the thumb could be found in this family. The hand abnormalities comprised eight types based on the number of digits, the number of phalanges, and whether the digits or phalanges were normal, hypoplastic, or rudimentary. Five distinct carpal anomalies were identified. Essentially all described types of radial-sided polydactyly and triphalangism of the thumb occur in this family. The occurrence of these abnormalities is determined by a single autosomal dominant gene. The manner in which the gene is expressed is determined either by its allele or by a combination of genetic and environmental factors. The findings in the parent cannot be used to predict the findings in the offspring.     

Familial expansile osteolysis

Familial expansile osteolysis (FEO) is a unique bone dysplasia, which has, over five generations, affected 42 members of a Northern Ireland family. The disease follows a classic autosomal dominant pattern of inheritance. The condition is distinct enough in its clinical features and natural history to be recognized as a new and unique disease. There are both general and focal skeletal changes, the latter having a predominantly peripheral distribution and an onset from the second decade. Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture. Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities. The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal. The response of the disease to a therapeutic trial using parenteral dichloro-methylene-diphosphonate (dichloro-MDP) produced an initial rapid biochemical response, which was not sustained.     

The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly

Purpose  Greig cephalopolysyndactyly (GCPS) (OMIM 175700), a rare autosomal dominant disorder, is characterized by a distinct combination of craniofacial, hand and foot malformations. The hand and foot malformations often require orthopedic assessment and treatment. The disorder is caused by point mutations or deletions in the GLI3 gene, located on chromosome 7p14.3. Herewith, we review the hand and foot malformations in a cohort of 13 patients referred for genetic testing. Methods  We reviewed the medical files of 13 patients with GCPS seen at the Center for Human Genetics in Leuven between 2003 and 2005. Clinical, molecular and radiological findings, when available, were recorded. Results  We identified six different point mutations in the GLI3 gene, two microdeletions and three larger chromosomal deletions. In the hands, preaxial polydactyly was never observed, but the malformations included postaxial polydactyly, broad thumbs, clinodactyly of the thumbs and various degrees of syndactyly. In the feet the spectrum of malformations included preaxial polydactyly, postaxial polydactyly, different degrees of syndactyly and broad halluces. Syndactyly of the toes and hallux abnormalities were present in all patients. Most frequently, syndactyly was present between toes 1–2–3. The broadening of the hallux was either due to a complete or partial duplication of the first toe or to broadening of the distal phalanx. Mental retardation was found in three cases and was associated with a large chromosomal deletion of the GLI3 region. Conclusion  We found the classic hand and foot malformations associated with GCPS in our cohort of patients. Patients with a large chromosomal deletion had mental retardation, but no structural brain anomalies were found.     

Prophylactic laparoscopic-assisted total gastrectomy for hereditary diffuse gastric cancer.

BACKGROUND: Ten percent of gastric cancer (GC) cases are familial, with one third resulting from a mutation in the tumor suppressor gene CDH1. Loss of this important structure can result in hereditary diffuse gastric cancer (HDGC), which carries a high mortality if early diagnosis is not made. Despite its clear genetic origin, optimal management of HDGC family members is controversial, as the utility and efficacy of current cancer screening programs for mutation carriers are unproven. METHODS: A 53-year-old Caucasian woman was initially seen for genetic screening because multiple family members had mutations of the CDH1 gene. Her pedigree analysis demonstrated 4 generations of gastric cancer, and 2 of the generations carried the CDH1 germline mutation, consistent with HDGC. At endoscopy, the patient's gastric mucosa was normal and random biopsies were also normal. The patient underwent a laparoscopic total gastrectomy. RESULTS: The gross examination of her stomach appeared normal. On histologic examination, however, the stomach was found to have diffuse (signet ring cell) adenocarcinoma in-situ with 11 microscopic foci of invasive adenocarcinoma limited to the lamina propria. CONCLUSION: Our case is the first reported prophylactic total gastrectomy utilizing a laparoscopic approach, and it highlights the importance of taking a thorough family history and obtaining a pedigree analysis. Endoscopic screening in HDGC cannot rule out diffuse GC, because the stomach and biopsies can be normal despite the presence of adenocarcinoma. Therefore, our case supports the recommendation for prophylactic gastrectomy in HDGC.     

中国汉族一瘢痕疙瘩家系易感基因的定位研究

目的定位中国汉族瘢痕疙瘩家系的易感基因。方法采集1个5代发病的中国汉族瘢痕疙瘩大家系32名成员的外周静脉血样,提取基因组DNA;设定Fas基因为导致该家系发病的一个候选基因,选取位于10q23.31上Fas基因周围共约10Mbp范围内与细胞凋亡障碍或肿瘤发生有关的所有已知基因相邻的微卫星标记D10S1687、D10S1765、D10S1735和D10S1562共4个,对这些微卫星位点进行PCR扩增,产物片断基因分型和连锁分析。结果连锁分析发现微卫星标记D10S1765LODZMAX为1.74,D10S1735LODZMAX为1.51,支持连锁;D10S1562LODZMAX为0.59,不排除连锁;在θ=0.0～0.10时,D10S1687标记的所有LOD值都小于-2,排除连锁。结论我们的研究首次发现了该中国汉族瘢痕疙瘩家系的易感基因可能位于10q23.31上D10S1765与D10S1735两位点间约1Mbp区域的遗传学证据。     

Familial torticollis with polydactyly: manifestation in three generations

Familial transmission of congenital muscular torticollis (CMT) has been reported in the literature, and postaxial polydactyly has been frequently reported in familial cases, but, to our knowledge, familial CMT with postaxial polydactyly has not been described. In this article, we report a rare case of CMT with postaxial polydactyly in 3 generations of a family and suggest an autosomal-dominant pattern of inheritance in these cases.     

Orofacial Features of Hypohidrotic Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia (HED) is a type of genodermatosis characterized by the abnormal development of sweat glands, teeth, and hair. The most prevalent form of HED is X-linked hypohidrotic ectodermal dysplasia (XLHED), which is associated with mutations in the EDA gene. The aim of this case report was to describe a family with XLHED with emphasis on differences in orofacial features between members. Family members were systematically evaluated to characterize the pattern of inheritance and clinical features. Dental examination included evaluation of agenesis and abnormal teeth structure. The pedigree of the last seven generations of the family was constructed. Clinical examination and medical history revealed five males affected by HED and nine female as heterozygous carriers. The males exhibited the classic phenotype of XLHED, with dental abnormalities, hypohydrosis, and craniofacial dysmorphologies. The heterozygous carriers of the X-linked gene defect principally exhibited dental agenesis of the lateral maxillary incisors. Careful clinical examination, including dental evaluation, is an important way to detect heterozygous carriers of X-linked HED. Heterozygous parents of patients with HED may also show some features of the disorder. The identification of female carriers results in genetic counseling being offered to affected families, as well as providing adequate treatment as necessary and long-term follow-up of these patients.     

A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene

Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.     

New UMOD gene mutation: a familial study of juvenile hyperuricemia nephropathy

Objective To investigate the etiology, clinicopathological changes and genetic variation characteristics of familial juvenile hyperuricemia nephropathy (FJHN) through pedigree investigation and gene test conducted on a patient with FJHN. Methods Clinical data of the proband family members were collected, routine pathological examination of the proband kidney tissue was conducted, and the expression of the Uromodulin (UMOD) protein in the proband kidney tissue was detected by immunofluorescence staining. Peripheral blood specimens of proband and their relatives were collected, and gene sequencing analysis related to urinary system diseases including UMOD was performed by double-stranded DNA probe gene capture and high-throughput sequencing. Results Seven family members in the family were involved and the inheritance method was consistent with autosomal dominant inheritance. Among the seven affected individuals only a 3-year-old child didn't show any clinical abnormalities. All of the remaining six patients had hyperuricemia accompanied with renal dysfunction and three of them were end-stage renal disease and two of them died of uremia. Proband renal pathological results showed chronic tubulointerstitial lesions and focal glomerular sclerosis with no obvious deposition of immune complexes. Immunofluorescent staining showed that strong positive signals of UMOD protein accumulated in the tubular epithelial cells, which was very specific and could be used to differentiate FJHN from other interstial nephritis. A total of four patients including the proband were tested and all had found heterozygous mutation c.377G>A of UMOD gene, a new missense mutation located on exon 3. Conclusion Involved patients in this family present a typical autosomal dominant inheritance pattern, clinically manifested as hyperuricemia with early renal function impairment, renal pathology manifested as non-immune complex-mediated glomerular sclerosis and renal interstitial fibrosis, and there is abnormal accumulation of UMOD protein in renal tubular epithelial cells. Genetic testing shows a new gene locus mutation c.377G>A, confirming the diagnosis of FJHN. Patients with unexplained hyperuricemia and characteristic pathological changes should undergo renal tissue fluorescent staining of UMOD protein, which may be a simple and feasible method to detect the abnormality of UMOD protein.     

Familial pure proximal renal tubular acidosis--a clinical and genetic study.

BACKGROUND: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease. METHODS: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6. RESULTS: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied. CONCLUSIONS: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.     

Genetic aspects of orthopedic conditions.

Genetic conditions seen by orthopedists may be divided into Mendelian disorders, chromosome abnormalities and multifactorial conditions. Mendelian disorders involve the abnormality of a single gene and obey the rules of Mendelian inheritance. Chromosome abnormalities are caused by the absence or duplication of a sufficient number of genes to allow this abnormality to be detected by chromosome studies. Chromosome studies are used to confirm the diagnosis of well described syndromes of deletion or trisomy. These studies are also necessary to determine whether mongolism has been caused by non-disjunction or translocation, so that proper genetic counseling can be carried out in these conditions. Multifactorial conditions are determined by several genes or more commonly, by a combination of genetic and environmental factors. These conditions recur in families in a greater incidence than one would expect in the general population but do not obey the rules of Mendelian inheritance. Genetic counseling cannot be performed without an absolute diagnosis, an absolute knowledge of the patterns of inheritance and a well documented family pedigree. The basic principles of genetics covered in this article should allow the orthopedist to understand when genetic counseling is indicated for his patients.     

Idiopathic Fanconi syndrome in a family. Part I. Clinical aspects.

Fanconi syndrome is a rare cause of rickets in children. Only six families with Fanconi syndrome following an autosomal dominant pattern of inheritance have been reported. In this report, the results of clinical studies performed in three generations of a family of 39 members with autosomal dominant Fanconi syndrome are presented. Twenty-one members of this family provided blood and urine for biochemical evaluation. Many family members have one or more tubular reabsorptive abnormalities; however, the complete Fanconi syndrome was not present in most members. Three children with the complete syndrome all occur in the last generation. When the characteristic features of this family were compared with those of previously reported families with autosomal dominant Fanconi syndrome, several differences became apparent. Two serious manifestations, diabetes mellitus and renal failure, which occur in previous reports did not occur in this family. This report provides information on apparently the largest number of affected individuals in a single family with Fanconi syndrome. In addition, variable expressivity of tubular reabsorptive defects in a family with Fanconi syndrome has never been reported.     

Preaxial polydactyly

A case of preaxial polydactyly and its surgical correction has been presented. The surgical management and postoperative complications were reviewed from the literature. The genetic basis for this type of polydactyly and its rate of occurrence were discussed. This patient's family exhibited an autosomal dominant gene with incomplete penetrance carried by the female members. The patient's family should be consulted regarding the possible genetic continuation of these anomalies in the female members of the family. The patient has had an unremarkable postoperative course with no reported adverse sequelae. The patient and surgeons were very satisfied with the final result. Figure 8 illustrates the surgical results 1 year postoperatively.     

Hallux Valgus Inheritance: Pedigree Research in 350 Patients With Bunion Deformity

Our objective was to construct 3-generation pedigree charts from 350 patients with hallux valgus. During a 1-year period, all consecutive patients (n = 1174) with a painful bunion deformity evaluated roentgenographically were asked to complete a detailed 3-generation family history questionnaire. We studied 350 probands (22 men, 328 women; male/female ratio, 1:14.9; mean age, 47.8 years). Juvenile hallux valgus was diagnosed in 15 patients. Three or more affected members were observed in pedigrees from 244 probands, 2 affected members in 71, and 1 affected member in 35 (proband) (affected subjects per pedigree ranged from 1 to 16). Ninety percent of probands had at least 1 family member affected. The hallux valgus penetrance according to pedigrees from all probands was 56%. The female sex predominated with regard to the gender of parents with hallux valgus, affected branch of the family, and gender of relatives with bunion deformity. Severity of hallux valgus was not significantly influenced by gender, the affected branch of the family, or gender of the affected relatives. Family history of bunion deformity was present in 90% of probands, with vertical transmission affecting some family members across 3 generations, which is compatible with autosomal dominant inheritance with incomplete penetrance.     

Autosomal dominant polycystic kidney disease associated with familial sensorineural deafness

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by both renal and non-renal disorders. Extrarenal involvement includes noncystic manifestations such as cardiovascular abnormalities, colonic diverticula and intracranial aneurysms. Familial sensorineural hearing loss (SNHL) has been included in the definition of Alport's syndrome. However, other types of nephropathy have been occasionally associated with hereditary deafness. The association of ADPKD with hereditary SNHL has not been previously documented. We report a family with ADPKD associated with bilateral sensorineural deafness in a pedigree of four affected members in four generations.